2022-2023

Cardiovascular
System

CVS-206

Faculty of Medicine, Minia university

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CONTENTS
Anatomy
1- Anatomy of the mediastinum, the pericardium and the heart ……………………………………... 4
2- Development and congenital anomlaies of the heart ………………………………………………... 14
3- Anatomy of the blood supply and nerve supply of the heart ……………………………………….. 20
4- Anatomy and development of great vessels………………………………………………………….. 24

Histology
5- Histology of the Heart …………………………………………………………………….…………….. 33
6- Blood vascular system …………………………………………………………………….…………….. 38
Physiology
7- Electrophysiology of the cardiac muscle & origin of the heart beat …………………………………..
44
8- Cardiac muscle excitation-contraction coupling (i.e. Ecc) ……………………………………… 58
9- Conduction system in the heart ……………………………………………………….……..…… 66
10- Cardiac cycle and heart sounds ……………………………………………………….……..…… 71
11- Radial and jugular pulse curves ………………………………………………………………….. 81
12- Heart rate and cardiovascular reflexes ……………………………………………………..…… 86
13- Cardiac output and cardiac reserve …………………………………………….………….……. 94
14- Heart failure ………………………………………………………………………….……….…… 102
15- Hemodynamics …………………………………………………………………………………….. 108
16- Blood pressure and the flow in arteries and arterioles ………………………………………….. 113
17- Microcirculation (capillary circulation) ………………………………………….…………..….. 125
18- The venus system ……………………………………………………………………………..…… 131
19- Coronary circulation …………………………………………………………….……………..…. 135
Biochemistry
20- Lipoproteins………………………………………………………………………………………… 142
21- Cardiac enzymes and other protein markers ……………………………………………………. 149
Microbiology
22- Rheumatic fever …………………………………………………………………………………… 154
23- Bacterial endocarditis …………………………………………………………………………….. 158
24- Viral myocarditis ………………………………………………………………………………… 161
Pathology
25- Carditis ……………………………………………………………………………….……………. 165
26- Atherosclerosis and aneurysm ……………………………………………………………………. 176
27- Hypertension ……………………………………………………………………………………….. 183
28- Ischemic heart diseases ……………………………………………………………………………. 187

Pharmacology
29- Antiarrhythmic drugs……………………………………………………………………………… 196
30- Drug treatment of heart failure …………………………………………………..……………… 211
31- Antihypertensive drugs …………………………………………………………………………… 219
32- Treatment of hyperlipidemia …………………………………………………...………………… 232
33- Drugs used to treat angina pectoris …………………………………………...………………….. 243
Paracitology
34- Cardiac involvement with parasitic infections …………………………..……………………… 251

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Aanatomy

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(Anatomy)
ANATOMY OF THE MEDIASTINUM,
THE PERICARDIUM AND THE HEART.

MEDIASTINUM
Definition: soft tissue space between the 2 lungs and pleurae.
Boundaries:
- Anterior: sternum& costal cart. - Posterior: the thoracic vertebrae
- Two sides: mediastinal pleurae. - Superior: the thoracic inlet.
- Inferior: the diaphragm
Divisions of the Mediastinum:
A- Superior mediastinum
B- Inferior mediastinum: subdivided into 3 parts;
- Anterior mediastinum.
- Middle mediastinum.
- Posterior mediastinum.
NB: Superior and Inferior mediastina are separated by imaginary line
extend from sternal angle anteriorly to lower border of 4th thoracic
vertebra posteriorly

Superior mediastinum
Boundaries:
- Anterior: Manubrium sterni.
- Posterior: upper 4 thoracic vertebrae
- Two sides: mediastinal pleurae.
- Superior: thoracic inlet.
- Inferior: imaginary line & inferior mediastinum.

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Contents of the superior mediastinum

1- Retrosternal layer: contain thymus or its rudiment;
2- Venous layer:
- right and left brachiocephalic V.
- superior vena cava.
3- Arterial layer:
- Arch of aorta and its 3 branches;
- RT and LT phrenic and vagus n.
4- Tubal layer
- Trachea.
- Esophagus.
- Left recurrent laryngeal nerve
- Thoracic duct.
Anterior mediastinum
Boundaries:
- Anterior: body of the sternum. - Posterior: middle mediastinum.
- Two sides: mediastinal pleurae.
- Superior: imaginary line & superior med. - Inferior: the diaphragm
Contents:
1- Sternopericardial lig.(sup. & inf.)
2- remnants of thymus gland.
3- anterior mediastinal lymph nodes
4- fat.
Middle mediastinum
Boundaries:
- Anterior: anterior mediastinum.
- Posterior: posterior mediastinum.
- Two sides: mediastinal pleurae.
- Superior: imaginary line & superior mediastinum.
- Inferior: the diaphragm

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Contents
1- heart
2- pericardium (fibrous and serous).
3- beginning or termination of great vessels (aorta, pulmonary, SVC and
IVC).
4- phrenic nerves, pericardiacophrenic vessels
5- lymph nodes.
5- fat.

Posterior mediastinum
Boundaries:
- Anterior: middle mediastinum.
- Posterior: lower 8 thoracic vertebrae
- Two sides: mediastinal pleurae. - Inferior: the diaphragm
- Superior: imaginary line & superior mediastinum.
Contents:
① principal bronchi. ② thoracic part of esophagus.
③ descending thoracic aorta. ④ thoracic duct.
⑤ azygos and hemiazygos V. ⑥ vagus nerves.
⑦ sympathetic trunk and lymph nodes.

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PERICARDIUM
- It is a double-walled sac around the heart composed of:
- A superficial fibrous pericardium
- A deep two-layer serous pericardium formed of:
1- Parietal pericardium (outer) lines the internal surface of the fibrous
pericardium
2- Visceral pericardium (inner) or epicardium lines the surface of the
heart
3- Pericardial cavity: fluid-filled cavity between visceral and parietal
layers.

Fibrous pericardium
- Conical in shape with its apex directed upwards and base directed
downwards.
- Its apex fused with the coats of ascending aorta, pulmonary trunk,
pulmonary veins and SVC.
- Its base fused with central tendon of diaphragm.
Relations:
- Anteriory:
= sternopericardial lig. = ant. Chest wall. = lungs and pleurae
- Posteriory: descending aorta and oesophagus.
- On each side: phrenic n., pericardiacophrenic A, lungs and pleurae.

Serous pericardium: formed of 2 layers:

- Parietal (outer layer): lines the internal surface of the fibrous
pericardium.
- Visceral (inner layer): or epicardium lines the surface of the heart
- The 2 layers are separated by the fluid-filled pericardial cavity filled
with pericardial fluid

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Functions of serous pericardium:

- Protects and anchors the heart
- Prevents overfilling of the heart with blood
- Allows for the heart to work in a relatively friction-free environment.
Sinuses of serous pericardium
1- Transverse sinus:
It is a transverse passage inside the pericardial cavity. Its boundaries:
- Anteriory: pulmonary trunk and ascending aorta.
- Posteriory: SVC, RT and LT atria.
- Above: RT pulmonary artery. - Below: the 2 atria.
2- Oblique sinus:
The visceral pericardium ascends on the diaphragmatic surface of the
heart. It is then reflected downwards to form the parietal layer of serous
pericardium. This sinus lies behind the LT atrium and has the following
boundaries:
- Anteriory: back of LT atrium.
- Posteriory: fibrous pericardium
- On LT side: 2 LT pulmonary veins.
- On RT side: 2 RT pulmonary veins.
Blood supply of the pericardium
- Fibrous and parietal serous: by pericardiaco-phrenic and descending
thoracic aorta.
- Visceral: as the heart(coronary vessels).
Nerve supply of the pericardium:
- Fibrous and parietal serous: as thoracic wall (intercostal nerves)
- Visceral: autonomic NS (sympathetic and parasympathetic).

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THE HEART
Site: located directly behind sternum, in the middle mediastinum, with its
⅔ LT and its ⅓ RT to midline.
Axis: downward, forward and to the LT(from base to apex).
Size: approximate size of clenched fist
The heart wall: formed of;
- Epicardium: outer layer
- Myocardium: middle layer
- Endocardium: inner layer
Shape: the heart is cone shaped, has apex, base, 2 surfaces and 4
borders:

Apex -Formed by left ventricle.

-leftmost, lowermost, part of heart.
- Lies at LT 5th intercostal space 9 cm from
midline.
Base - Formed by left atrium mainly.
- related posteriory to posterior mediastinum
contents (descending aorta, esophagus, azygos
vein, thoracic duct).
2 - Anterior - Behind sternum and attached ribs.
surfaces (sterno-costal) - Formed by LT vent (⅓), RT vent (⅔)
- Inferior - Lies on the diaphragm.
(diaphragmatic) - Formed by RT vent(⅓) ,LT vent(⅔)
4 Right border→ Formed by right atrium.
borders Left border. → Formed by left ventricle mainly.
Lower border→ by right ventricle + apex of heart.
Upper border → Formed by both atria
Internal features of the Heart (Chambers of the heart)

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1- Atria of the heart:

Rt atrium Lt atrium
Position: - lies anterior and Rt to Lt atrium - lies behind and to the Lt of Rt
- forms Rt border of the heart. atrium
- share in sternocostal surface of - forms the base of the heart.
the heart.
Its Overlaps the Rt anterior aspect Overlaps the Lt anterior aspect
auricle: of root of pulmonary tract. of root of pulmonary tract.
Its cavity: Divided by crista terminalis into: Its cavity is generally smooth
1- posterior smooth part. except its auricle which show
2- anterior rough part: due to few musculi pectinati.
musculi pectinati.
Interatrial Show fossa ovalis and annulus Showa faint impression
septum: ovalis. corresponding to fossa ovalis
Veins It receive deoxygenated blood It receive oxygenated blood
draining from all the body except lungs returning from lungs through the
into: through: 2 Rt and 2 Lt pulmonary veins
1- SVC. 2- IVC. and also vena cordis minimi
3- Coronary sinus
4- anterior cardiac veins.
5- vena cordis minimi
Exit of Through tricuspid valve which Through mitral valve which has
blood has 3 cusps, and leads to Rt 2 cusps, and leads to Lt
from it: ventricle. ventricle.

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2- Ventricles of the heart:

Rt ventricle Lt ventricle
Position: - lies anterior and Rt to Ltventricle - lies posterior and Lt to Rtventricle
- forms inferior border of theheart. - forms apex and left borderof heart.
- Forms Lt ⅔of sternocostalsurface of - Forms Lt ⅓of sternocostalsurface of
the heart. the heart.
- Forms Lt ⅓ of diaphragmatic - Forms Lt ⅔ of diaphragmatic
surface of heart. surface of heart.

Cross Crescent Circular

section:
Its cavity: Divided into: Divided into:
1- outflow smooth part: called
1- outflow smooth part: called
infundibulum lies below pulmonary
aortic vestibule liesbelow the aortic
orifice.
orifice.
2- inflow rough part: below the
2- inflow rough part: belowopening
opening of tricuspid valve. This
of mitral valve.
roughness due to:
This roughness due to:
A- trabeculi carini: few and coarse
A- trabeculi carini: fine andnumerous
B- papillary muscles(3 , anterior,
B- papillary muscles(2 ,anterior
posterior and septal).
and posterior).
C- the moderator band.
C- no moderator band.
Wall 9 mm 27mm
thickness
Openings: - It receive non oxygenated blood from - It receive oxygenated bloodfrom Lt
Rt atrium throughthe tricuspid valve atrium through the mitral valve(has 2
(has 3cusps, anterior, posterior and
cusps, anterior and posterior)
septal)
- It pump the blood to lung through
pulmonary valve(has3 semilunar cusps,
1 post and 2 ant.)

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Heart Valves
1- Atrioventricular (AV)
Valves
- Right AV valve (tricuspid):
between RA and RV
- Left AV valve (bicuspid or
mitral): between LA and LV
2- Semilunar Valves
- Pulmonary valve: between
RV and pulmonary trunk
- Aortic valve: between LV and aorta.
Surface anatomy of heart
- Point A: on 2nd LT costal cart. 4 cm from
midline.
- Point B: on LT 5th intercostal cart. 9 cm from
midline.
- Point C: on RT 6th costal cart. 3 cm from
midline.
- Point D: on 3rd RT costal cart. 3 cm from midline.
- Upper border of heart: line between points A&B.
- RT border of heart: line between points B&C.
- Lower border of heart: line between points C&D.
- LT border of the: line between points D&A.

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Surface anatomy of cardiac valves

- Pulmonary valve: at 3rd LT sternocostal junction(heared at 2nd LT
space).
- Aortic valve: at 3rd space on LT sternal border (heard at 2nd RT space).
- Mitral valve: at 4th LT sternocostal junction (heard at apex).
- Tricuspid valve: at 4th space behind center of sternum(heard at
xiphisternal junction).
Conducting system of the heart
Definition: it‘s a modified special cardiac muscle fibers.
Function: to start and transmitte of cardiac impulse.
Parts of the conducting system:
1- S.A.N.(sinu-atrial): present in the RT atrium behind the SVC opening
, about 1 Cm, its function is to start the cardiac impulse.
2- A.V.N (atrioventricular node): present in the IA septum above the
opening of coronary sinus.
3- The AV (atrioventricular bundle): arise from AV node, and divides
into 2 bundle branches
- Right bundle branch: to the RT ventricle.
- Left bundle branch: to the LT ventricle.
4- The Purkinje fibres: distribute the impulse to all thickness of the
ventricular wall.

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(Anatomy)
DEVELOPMENT AND CONGENITAL
ANOMLAIES OF THE HEART
Formation of heart tube
- The heart is the first functional organ to develop. It begins to beat at 22
to 23 days.
- Source and Site of heart development: It develops from splanchnic
mesoderm (cardiogenic area)
- The heart primordium begins as collection of angioplastic cells which
soon canalize to form the 2 heart tubes).
- After lateral folding of the embryo, the 2 heart tubes fuse together to
form a single endocardial heart tube
- Bulbus cordis and ventricle grow faster than other regions. So the heart
bends upon itself, forming the U-shaped heart tube, Then the heart tube
turned to Loop shaped Or S-Shaped Heart Tube
Fate of the Heart Tube
The heart tube grows to show 5 alternate dilations separated by 4
constrictions.
These are:
1- Sinus Venosus.
2- Truncus Arteriosus.
3- Bulbus Cordis.
4- Common Ventricle.
5- Common Atrium.
The endocardial heart tube has 2 ends:
1. Venous end; Sinus Venosus.
2. Arterial end; Truncus arteriosus

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NB: the connection between primitive atrium and ventricle is

atrioventricular canal
Sinous venousus
At early stage:
It formed of body and 2 horns, each horn of the sinus venosus receives
3 types of veins:
1. Common cardinal: from the fetal body, it is formed by union of 2 veins
- anterior cardinal: receive blood from upper ½ of the fetal body
- posterior cardinal: receive blood from lower ½ of the fetal body
2.Vitelline: from the yolk sac.
3.Umbilical: from the placenta.
At late stage:
- an anastomotic channel is formed between the 2anterior cardinal veins
→ shift the blood from left to right side→ enlargement of right horn
Fate:
# RT horn→ smooth posterior part of RT atrium.
# LH + Body → coronary sinus.
# Lt common cardinal vein → oblique vein of Lt atrium.
Partitioning of Primordial Heart
Partitioning of:
1- Atrioventricular canal.
2- Common atrium.
3- Common ventricle.
4- Bulbus cordis
5- Truncus arteriosus

Partitioning of the atrioventricular canal

- Two endocardial cushions are formed on the dorsal and ventral walls of
the AV canal.

The AV endocardial cushions approach each other and fuse to form the

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septum intermedium.
- Dividing the AV canal into right & left canals.
- These canals partially separate the primordial atrium from the primordial
ventricle.
Partition of the common atrium (interatrial septum).
1- Septum Primum
- It is sickle- shaped septum that grows from the roof of the common
atrium towards the fusing endocardial cushions (septum intermedium)
- So it divides the common atrium into right & left halves.
- The two ends of the septum primum reach to the growing endocardial
cushions before its central part. So the septum primum bounds a foramen
called ostium primum. It serves as a shunt, enabling the oxygenated blood
to pass from right to left atrium.
- The ostium primum become smaller and disappears as the septum
primum fuses completely with endocardial cushions (septum
intermedium) to form the interatrial septum.
- The upper part of septum primum that is attached to the roof of the
common atrium shows gradual resorption forming an opening called
ostium secondum.
2- septum secundum.
- Another septum descends on the right side of the septum primum.
It forms an incomplete partition between the two atria.
Consequently a valvular oval foramen forms, (foramen ovale)
The upper part of septum primum that is attached to the roof of the
common atrium shows gradual resorption forming an opening called
ostium secondum.
Another septum descends on the right side of the septum primum called
septum secundum.

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It forms an incomplete partition between the two atria.

Consequently a valvular oval foramen forms, (foramen ovale).
Fate of foramen Ovale
- At birth when the lung circulation begins the pressure in the left atrium
increases and exceeds that of the right atrium →So the two septae oppose
each other.
Its site is represented by the Fossa Ovalis. -
- The septum primum forms the floor of the fossa ovalis.
- The septum secondum forms the margin of the fossa ovalis which also
called the limbus (anulus) ovalis.
Sources of the 2 atria
Rt Atrium Lt Atrium

- Smooth posterior part: derived from the - Rough part: derived

right horn of the sinus venosus from the common
- Rough anterior part: derived from the primordial atrium.
primordial common atrium. - The smooth part:
NB: These two parts are demarcated by the derived from the
crista terminalis internally and sulcus absorbed Pulmonary
terminalis externally. Veins.

Partitioning of Primordial Ventricle (interventricular septum).

1- Muscular part of the interventricular septum.
Division of the primordial ventricle is first indicated by a median
muscular ridge, (primordial interventricular septum).
It is a thick crescentic fold which has a concave upper free edge.
This septum bounds a temporary connection between the two ventricles
called interventricular foramen.
2- Membranous part of the IV septum: derived from:
1- A tissue extension from the right side of the endocardial cushion.
2- Aorticopulmonary septum.

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Spiral Aorticopulmonary Septum

A spiral septum develops in the truncus arteriosus dividing it into aorta
and pulmonary trunk.
So, now the pulmonary artery joins the right ventricle while the aorta joins
the left ventricle.
BULBUS CORDIS
The bulbus cordis divides and forms the smooth upper part of the two
ventricles.
- In the right Ventricle: It forms the Conus Arteriosus or (Infundibulum)
which leads to the pulmonary trunk.
- In the left ventricle: It forms the aortic Vestibule which leads to the
aorta.

CONGENITAL HEART DEFECTS (CHD)

1- Anomlies in the position
A- Dextrocardia: Rotation of the heart in opposite direction→heart
chambers reversed in mirror image.
B- Situs inversus: All organs of the body are reversed.
C- Ectopia cordis:- Failure of thoracic wall formation→partial or
Complete exposure of heart.
2- Septal defects
A- Atrial Septal Defects (ASD)
- primum ASD
- secondum ASD (most common), leads to common atrium.
- Sinus Venosus ASD – high in the atrial septum,
- Patent foramen ovale: Excessive resorption of septum primum
B- Ventricular septal defect (VSD)
- Perimembranous (or membranous or Roger‘s disease:): Most
common.

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- Infundibular (subpulmonary or supracristal VSD) – involves the RV

outflow tract.
- Muscular VSD – can be single or multiple.
C- Patent ductus arteriosus (PDA): Persistence of the ductus
arteriosus that joins the Pulmonary artery to the Aorta.
3- Cyanotic defects
A- Fallot’s Tetralogy:
1- VSD.
2- Pulmonary stenosis.
3- Overriding of the aorta
4- Right ventricular hypertrophy.

B- Transposition of great arteries (TGA)

- due to abnormal rotation or malformation of the aorticopulmonary
septum, so the right ventricle joins the aorta, while the left ventricle joins
the pulmonary artery.often associated with ASD or VSD.
C- Persistent Truncus Arteriosus
It is due to failure of the development of the aorticopulmonary
(spiral) septum.
4- Obstructive defects
- Pulmonary stenosis,
- Aortic stenosis
- coarctation of the aorta.

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(Anatomy)

ANATOMY OF THE BLOOD SUPPLY

ANDNERVE SUPPLY OF THE HEART

Arterial supply of the heart

The heart is supplied by coronary arteries:
RT coronary artery
Beginning: Anterior aortic sinus of ascending aorta.
Course: It passes at first anteriorly and slightly to RT
between the rightauricle and pulmonary trunk, it reaches
the AV sulcus and descends to the inferior cardiac
border, curving around it into posterior part of AV
sulcus.
End: by anastomosing with circumflex branch of the LT coronary.

Branches:
1- Marginal artery: it run
along inferior border
towards the apex to supply
the RTventricle.
2- Posterior IV artery: to
both ventriclesand
posterior ⅓ of IV septum.
3- Anastomotic branches with
circumflex branch of LT coronary artery.
4- Small branches to RT atrium, roots of pulmonary trunk and aorta.
5- Nodal branch in 60% to S.A.N.

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LT coronary artery
Beginning: LT posterior aortic sinus of ascending aorta.
Course: larger then RT and supplies large parts of the
heart. This artery lies between the pulmonary trunk and
the left atrial auricle, emerging intothe AV groove, in
which it turns left. Then it divides into two main branches.
End: its circumflex branch end by anastomosing with RT coronary artery.
Branches:
1- Circumflex artery: it turns backwards around LT
border of heart inthe posterior IV sulcus to supply LT
atrium and base of LT ventricle.
2- Anterior IV artery: it descend in ant. IV sulcus then
turn backward in post IV sulcus to end by anastomosing
with post IV artery of RT coronary artery. it supplies both
ventricles and anterior ⅔ of IV septum.
3- Small branches to LT atrium, roots of pulmonary trunk and aorta.
4- Nodal branch in 40% to S.A.N.

Venous drainage of the heart

The veins of the heart fall into three groups:
1. Venae cordis minimae.
2. Anterior cardiac veins.
3. Coronary sinus.

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Coronary sinus
Site: wide venous sinus, 2-3 cm long, lying in the posterior AV
sulcusbetween base and diaphragmatic surface of heart.
Termination: it opens into the right atrium between the opening of
theinferior vena cava and the tricuspid orifice.
Tributaries: are the great, small and middle cardiac veins and
theoblique vein of the left atrium.
1. Great cardiac vein : It begins at the cardiac apex, ascends in
anteriorIV groove passing to the left to enter the coronary sinus at
its origin.
2. Small cardiac vein: It begins near apex
and run upward with the marginal artery
to reach theanterior AV sulcus then turns
in the posterior AV groove and opens
into the coronary sinus near its RT end.
It receives blood from the posterior part
of the right atrium and ventricle.
3. Middle cardiac vein: begins at the cardiac
apex, and runs back in the posterior IV groove to end in the
coronarysinus at its middle.
4. Oblique vein of the left atrium: it descends obliquely on the
back ofthe left atrium to join the coronary sinus near its end.

NB: Veins that don’t open in the coronary sinus;

-Anterior cardiac veins: drain the anterior part of the right
ventricle.Usually 2 or 3. They end in the RT atrium.
- Small cardiac veins(Venae Cordis Minimae): open into all
cardiaccavities.

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 NERVE SUPPLY OF THE HEART
 The heart is supplied by the autonomic nervous system through 2

cardiac plexuses.
 - Origin of the autonomic fibers:
 The sympathetic nerves (6 pairs)--------» 3pairs in the neck + 3pairs in
the thorax.
 The parasympathetic nerves (3 pairs)----» 2 pairs in the neck + 1 pairs
in the thorax
 The 2 cardiac plexuses are.
Superficial cardiac plexus Deep cardiac plexus
 Site  Below the arch of  In front of tracheal
aorta bifurcation

 By all autonomic
 By 2 autonomic branches(8 pairs)
 Formation nerves from the neck except the previous
(1 from vagus, 1 2
from symath)
 Branches 1. to deep cardiac plexus. 1. to Superficial cardiac
2. RT coronary plexus. plexus.
3. LT anterior pulmonary 2. RT coronary plexus.
plexus. 3. LT coronary plexus.
4. LT anterior pulmonary
plexus.
5. RT anterior pulmonary
plexus.

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Lecture(4): ANATOMY AND DEVELOPMENT OF GREAT VESSELS

Ascending aorta
Beginning: from LT ventricle at aortic opening (3rd LT intercostals space).
End: level of second right sternocostal joint to continue as arch of aorta.
Course: Runs upward, forward and to the right,
Branches: right and left coronary arteries.

Arch of Aorta
Beginning: continuation of ascending aorta at RT end of sternal angle.
Course: curves upward, to the left and posteriorly, then downward, arching
over left principal bronchus and pulmonary trunk
End: at lower border of T4, to become descending aorta.
Relations of aortic arch
- Anteriorly and to the left: pleura, lung, phrenic n., pericardiacophrenic
vessels and vagus n.
- Posteriorly and to the right: trachea, esophagus, left recurrent n.,
thoracic duct, deep cardiac plexus
- Superiorly: its three branches, left
brachiocephalic v. and thymus
- Inferiorly: pulmonary a., ligamentum
arteriosum, left recurrent n., left principal
bronchus and superficial cardiac plexus

(structures below concavity)

Branches (from right to left )
1- Brachiocephalic artery: extends to
right sternoclavicular joint, bifurcates into
right subclavian and right common carotid
arteries

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2- Left common carotid artery

3- Left subclavian artery.

Descending thoracic aorta

Beginning: continuation of aortic arch at lower border of T4.
Course:
- Courses downward on LT side then in front of vertebral column
- Passes through aortic hiatus of diaphragm at
level of T12 vertebra to continue in the abdominal
cavity as abdominal aorta.
Relations of thoracic aorta
- Anteriorly: root left lung, pericardium and
esophagus.
- Posterior: vertebral column and hemiazygos v.
- Right: azygos v. and thoracic duct.
- Left: mediastinal pleura.
Branches of thoracic aorta
- 9 pairs of posterior intercostals arteries
- One pair subcostal artery
- Bronchial branches: two for LT lung
- Esophageal branches
- Pericardial branches.
Pulmonary trunk
- Arises from right ventricle at
pulmonary valve.
- Runs up, back ,and to the left
- Bifurcates inferior to aortic arch into
right and left pulmonary arteries, one for each lung

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Pulmonary arteries

- Right pulmonary artery: passes posterior to ascending aorta and superior

vena cava to hilum of right lung
- Left pulmonary artery: passes anterior to descending aorta and left main
bronchus to hilum of left lung
NB: Arterial ligament(ligamentum arteriosum) : remnant of ductus
arteriosus, connects bifurcation of pulmonary trunk to aortic arch

Veins of thorax
- Brachiocephalic veins
- Begin by union of internal jugular and subclavian veins posterior to the
sternoclavicular joint
- Rt and LT brachiocephalic unite to
form SVC.
Superior vena cava
Beginning: by union of right and left
brachiocephalic veins behind the right
1st sternocostal junction.
End: right atrium at lever of lower border of 3rd right sternocostal joint
- it collects blood from veins of upper half of body
Tributaries: azygos vein at level of sternal angle(2nd costal).

Development of Aorta
– Primitive embryonic Aortae:
• Two straight vessels on each side of the midline are present→after
folding, the two arteries are bend to form:
- Dorsal aortae: dorsal to the gut.
- Ventral aortae: ventral to the gut.
- Connecting segment: on each side of the bucco-pharyngeal membrane.

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Aortic sac: dilated arterial channel formed by the union of the 2 ventral
aortae, ventral to the pharynx. It continuous with the truncus arteriosus,
caudally. It has a stem and 2 horns(RT and LT). Its branches are:
– 2 ventral aortae.
– 6 pairs of aortic arches around the pharyngeal arches
• Fate of aortic sac:
– The stem & the left horn: involved into the adult aortic arch.
– Right horn: gives off the proximal part of the brachiocephalic artery.
Aortic arches:
• 6 pairs of arteries between the aortic sac
& 2 dorsal aortae around the
pharyngeal arches.
• Derivatives(fate):
– 1st arch: degenerated, may be involved
in maxillary artery.
– 2nd arch: degenerated, may be involved
in stapedial artery.
– 3rd arch: forms the common carotid arteries.
– 4th arch: on the left side, it is involved in formation of the adult aortic
arch. On the right side, it is involved in the formation of the RT subclavian
artery.
– 5th arch: degenerated.
– 6th arch: forms the right & left pulmonary arteries and ductus
arteriosus.
Dorsal aorta:
• It develops from the fusion of 2 dorsal aortae from 4th thoracic down
to 4th lumbar somite.

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• Fate:
– Cranial to the 3rd aortic arch: it
forms the distal part of internal carotid
artery (ICA).
– Between 3rd & 4th arches:
degenerated.
– Between 4th arch down to 7th
cervical inter-segmental artery:
involved in the right subclavian artery or in the adult aortic arch on the
left side.
– below 7th cervical inter-segmental artery: degenerated on the right side or
involved in descending thoracic aorta on the left side
• the adult aortic arch develops from:
• Proximal part of the arch: from the stem of the aortic sac.
• Middle part: from the left horn of the aortic sac.
• Distal part: from the left 4th arch & left dorsal aorta
down to the origin of 7th cervical inter-segmental artery (LT subclavian
artery).
– The adult descending aorta: from the left dorsal aorta, caudal to the
origin of the 7th cervical intersegmental artery, while the right dorsal aorta
degenerates.
• Aortic anomalies:
1- Coarctation of aorta: the aortic lumen is significantly narrow below
the origin of the left subclavian artery, it affects the blood supply of LL.
2- Abnormal origin of right subclavian artery: The right subclavian arise
from persistent distal part of right dorsal aorta.
3- Double aortic arch: persistent both distal part of right dorsal aorta &
right 4th aortic arch. The second component of the aortic arch passes
behind the esophagus causes difficulty in swallowing and respiration.

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Development of veins
- In a 4th weeks embryo, three paired veins open into the tubular heart:

1- Vitelline veins, returning

deoxygenated blood from the
yolk sac

2- Umbilical veins, bringing

oxygenated blood from the
placenta.

3- Cardinal veins, returning

deoxygenated blood from the
body of the embryo

Vitelline Veins

- Pass through the septum transversum and drain into the sinus venosus

- In relation to the developing liver within the septum transversum, the

vitelline veins are divided into:

♥ Pre-hapatic part: forms anastomosis around the duodenum which later on

gives rise to the portal vein

♥ Hepatic part: interrupted by the liver cords, forms an extensive vascular

network called the hepatic sinusoides

♥ Post-hepatic part: left vein disappears but right vein forms the:

Hepatic veins and hepatic segment of inferior vena cava

Umbilical Veins

- Carry oxygenated blood from the placenta

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- Initially run on each side of developing liver and drain into sinus venosus

- As the liver grows, the umbilical veins loose their connection with heartand open into
the liver.

- The right vein disappears by the end of the embryonic period. The left vein persists.

- A wide channel (ductus venosus), appears through the substance of liverto connect the
left umbilical vein with the inferior vena cava

- After birth:

- The left umbilical vein obliterate to form the ligamentum teres of the liver

- The ductus venosus obliterate to form the ligamentum venosum

Cardinal veins:
• They are longitudinal veins, mesodermal in origin, symmetrical on both side of the
body& drain the body of embryo.
• They developed gradually: anterior, posterior & common cardinal veins developed
earlier than supra-cardinal & sub-cardinal veins
• Anterior cardinal veins: Present cranial to the heart level, drain head &UL buds.
• Posterior cardinal vein: caudal to the heart level, drain trunk & LL buds.
• Common cardinal vein: two short venous channels formed by union ofanterior &
posterior cardinal veins, they drain into the sinus venosus.
• Sub-cardinal vein: Present caudal to the heart level, ventro –medial tothe
mesonephric ridge.
• Supra-cardinal vein: Present caudal to the heart level, dorso-lateral tothe dorsal
aorta.
– Both subcardinal & supracrdinal veins gradually replace the posteriorcardinal.

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- Fate of cardinal veins:

The cardinal vein Right side Connecting Left side
segment
Anterior cardinal - Rt. Internal jugular - Lt. Internal jugular
Vein vein. vein.
- Rt. Innominate vein. - Lt. innomenate vein.
- Upper half of SVC
posterior cardinal vein Degenerates degenerates
Common cardinal vein - Lower half of SVC - Oblique vein of the
_ right atrium
Sub-cardinal vein - Rt. Suprarenal vein. - Lt. renal -Lt. Suprarenal vein.
- IVC. vein - Lt. Gonadal vein
- Rt. Gonadal vein.
Supra-cardinal vein Azygos vein - Superior & inferior
_ hemi-azygos veins
Adult IVC: it is derived from: (Caudal to cranial):
– Lower most part of right posterior cardinal vein (called sacro-cardinalvein).
– Right subcardinal vein.
– Connecting anastmotic segment with hepato-cardiac channel.
– Hepato-cardiac channel (Right vitelline vein).
Anomalies of SVC:
1- Left SVC: due to persistent anterior cardinal vein on the left sidewhile it is
obliterated on the right side.
2- Double SVC: due to persistent anterior cardinal vein on the bothright & left
sides.
Anomalies of IVC:
1- Double IVC: Due to persistent both right & left sacro-cardinal veins.
2- Absent IVC: Due to absent connecting segment with the hepatocardiac channel. The
right subcardinal vein ends into the supracrdinal (azygos) vein.

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Histology

32
 Basic structure of the heart

Pericardium and Epicardium

Serous pericardium
 ▪Serous pericardium has parietal and visceral
layers of simple squamous epithelium (epithelium
of serous cavities is called mesothelium)
 ▪Between the 2 layers is the pericardial cavity
containing little amount of fluid (15-50 ml).
 ▪Excess fluid in pericardial cavity (egblood [from
injury] or pericardial effusion [from pericarditis]) is
called cardiac tamponade.
 ▪This is life-threatening because the fluid
compresses the heart, preventing its filling with the
blood.
 ▪Relieving the pressure is done by
pericardiocentesis (to drain the fluid from the
pericardial cavity by a needle).
Fibrous pericardium
 Fibrous pericardium is outer to
serous pericardium

Epicardium
 ▪Pericardium is the outer layer of the wall of the heart
(endocardium, myocardium, epicardium)

 ▪It is the visceral layer of serous pericardium, with its

underlying connective tissue rich in fat.

 ▪Nerves and Coronary blood vessels and that supply

the heart lie in the epicardium and are surrounded by
the fat that cushions the heart in the pericardial
cavity

================================================================

33
 Structure of the heart
I. Endocardium (inner layer)
 •Simple squamous epithelium (epithelium lining heart, vessels is called Endothelium)
 •Subendothelial layer of loose connective tissue.
 •The conducting system of the heart (Purkinje fibers) is located here in the endocardium
II. Myocardium (middle, thickest layer).
 •The contractile cardiac muscle fibers are arranged as sheets in a complex and spiral manner
 •Atrial cardiac muscle fibers synthesize atrial natriuretic peptide (ANP), a hormone [Natriuretic =
↑ sodium (Na) in urine] → water follows sodium → ↓ blood volume → ↓ blood pressure]
III. Epicardium (outer layer)
 •Layer of connective tissue (rich in fat) and contains blood vessels, lymphatic and nerve fibers.

 •The visceral layer of pericardium

Cardiac muscle fibers ( Involuntary)

 Fibers branch and join to form a continuous sheet
(network) (to give a squeezing action when they contract)
 Cytoplasm: acidophilic and show striations less marked
than skeletal muscle
 Each cell has a large, pale(=vesicular) single (or
binucleated) and central oval nucleus.
 Numerous mitochondria (active cell), lipofuscin (aging)
pigment granules (non-dividing)
 Sarcoplasmic reticulum ( sER ) is less developed
 T-tubules are found at Z line (not at AI band).
 T-tubule is in contact with only one terminal cistern of
sarcoplasmic reticulum, which form a Diad system.
 Cells are joined end to end by intercalated disc

34
Intercalated disc:
 a step wise junction between cardiac muscle
 It always comes at the Zlines.
 It contains the following junctions:
o Desmosomes, to prevent separation of
muscle cells during contraction.
o Adherent junctions. (fascia adherens)
o Gap junctions, which permit spreading
of impulses over the heart from one cell
to another (area of low electric
resistance). This makes the cardiac
muscles act as one unit.

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Purkinje fibers
 A specialized cardiac muscle fibers (specialized for
conducting)

 ▪Appear lighter and larger than cardiomyocytes, lie

in the subendtheliallayer of endocardium.

 ▪Surrounded by C.T. sheath

 ▪Pale vacuolated acidophilic cytoplasm (glycogen

granules)

 ▪NO transverse striations or intercalated discs.

 ▪Fewer myofibrils

 ▪Eccentric nucleus

Cardiac muscle injury

 Skeletal muscle contains numerous satellite (myogenic) cells
 These are mononucleated quiescent cells.
 When the muscle is damaged, these cells are stimulated to divide. After dividing,
the cells fuse with existing muscle fibres, to regenerate and repair the damaged
fibres.
 The skeletal muscle fibres themselves, cannot divide. However, muscle fibrescan
lay down new protein and enlarge (hypertrophy).

36
 Cardiac muscle can also hypertrophy.
 But, there are no satellite cells. So when cardiac muscle cells die, they are not
replaced.
Heart valves
 Outgrowths from the endocardium which prevent backflow of blood
 Formed of loose fibroelastic CT covered by endothelium on both side

byWith me

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(Histology)

Blood vascular system

Blood vessels are closed system of tubes, through which blood is forced
by the pumping action of the heart.

Types of blood vessels:

Arteries, Veins, and Connections between the arteries and veins
(Capillaries, sinusoids, and Arterio-Venous shunts).

General Structure: contain three major layers with sub-layering:

1. The tunica intima: (the luminal layer):
The lumen is lined by an endothelium of simple squamous epithelium.
A subendothelial layer of loose CT.
An internal elastic lamina marks the boundary between tunica intima and
tunica media.

2. The tunica media (middle layer, the main bulk of the artery):
Concentric layers of helically arranged smooth muscle cells interposed
among the muscle fibers are variable amounts of elastic fibers. The
external elastic lamina (in arteries only) marks the boundary between
tunica media and tunica adventitia.

3. The tunica adventitia (the outermost layer, the main bulk of the
vein):
contains loose to moderately dense CT. Small blood vessels (vasa
vasorum) are present in the tunica adventitia of large arteries and veins. It
also contains a network of nerve fibers.

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ARTERIES

These are blood vessels carrying blood away from the heart. According to
their histological structure, function, and diameter they are classified into
three types:

A. Large (elastic) arteries: Aorta and pulmonary arteries.

They have thick walls and wide regular lumen. They expand greatly to
accommodate blood under high pressure during ventricular systole and
recoil during diastole. So, they minimize fluctuation of blood pressure
during different phases of cardiac cycle.
Structure
1. Tunica Intima
Endothelium is supported by subendothelial C.T.
IEL cannot be distinguished from elastic laminae beneath (of the media).

2. Tunica Media
It represents about 70% of the wall thickness.
It is formed of CT layer with concentrically arranged fenestrated elastic
membranes with circularly arranged smooth muscle fibers.
EEL is also indistinct.

3. Tunica adventitia
It is a layer of loose C.T. with many vasa vasora, lymph vessels and nerve
fibers.

B. Medium-sized (muscular) arteries:

The most common type of arteries as regional and organ arteries. They
control blood flowing to different organs ex: femoral and brachial
arteries.

Structure:
1. Tunica Intima
The wall is thinner than elastic arteries.
Endothelium is supported by subendothelial C.T.
The IEL is clearly detected.

2. Tunica Media
It is formed of C.T. layer with mainly circularly arranged smooth muscle
fibers. Concentrically arranged elastic fibers.

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EEL may be detected but and less clear than IEL.

Tunica adventitia
It is a thin layer of C.T.

C. Small-sized arteries (arterioles):

- The smallest branches of muscular arteries that terminate in capillaries.
- They demonstrate gradual decrease in diameter (≤ 0.5mm)
and wallthickness.
- The tone in their smooth muscles controls the blood
pressure. This tone is regulated by nervous (autonomic) and
hormonal factors.

1. Tunica Intima: Endothelium is supported by very thin subendothelial

C.T. and IEL is less evident till it disappears as arterioles get smaller.

2. Tunica Media: The smooth muscle fibers decrease until completely

disappear and are replaced by pericytes in pre-capillary arterioles.

3. Tunica adventitia: It is a very thin layer of C.T.

Veins
These are blood vessels collecting blood from different body parts
towards the heart. They start as post capillary venules ,muscular then
ending in large veins.

A. Small Veins (Post-capillary venules):

Have very thin walls.
1. Intima: endothelium rests on thin basement membrane and thin sub-
endothelium and absent IEL.
2. Media: includes pericytes and reticular fibers with No EEL then
smooth muscles start to appear as the diameter increases.
3. Adventitia of C.T. relatively thick.

B. Medium-sized veins: Have thin walls and wide lumen.

Collapsed with blood cells inside after death.
Some have valves to prevent back flow of blood.

1. Tunica Intima: Endothelium is supported by subendothelial C.T. and

NO IEL.
2. Tunica Media: It is thin layer with mainly smooth muscle fibers, few
elastic fibers, and NO EEL.
3. Tunica adventitia: It is a thin layer of C.T.

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C. Large veins as (Inferior vena cava): It has thick walls and wide lumen
with valves.
1. Tunica Intima: Endothelium is supported by subendothelial C.T. and
NO IEL.
2. Tunica Media: It is thin layer with mainly smooth muscle fibers, few
elastic fibers, and NO EEL.
3. Tunica adventitia: It is the thickest layer of C.T. with longitudinal
smooth muscle fibers that help in elongation and shortening of the
vessel during respiration.

Specialized arteries
Some arteries have some variations in their structure according to their
location and function:
Cerebral arteries: e.g. basilar artery:
• They have thin walls because they are protected by the skull.
• Tunica intima: has well-developed internal elastic lamina.
• Tunica media: It is thin and consists of smooth muscle cells.
• Tunica adventitia: loose connective tissue.

Coronary arteries:
They have thick wall as they are subjected to high pressure.

Umbilical artery:
• There is no internal elastic lamina.
• The media consists of inner longitudinal and outer circular smooth
muscle cells.
• The adventitia is formed of mucoid connective tissue.

Pulmonary artery
Have thin walls because of a significant reduction in both muscular and
elastic elements.

Capillaries
The smallest blood vessels (diameter 5 – 10 μm), form networks that
allow exchange of metabolites, O2 and CO2 between the blood and
tissues.
Structure: consist only of endothelium but may be partially surrounded by pericytes.
Pericytes dilate and constrict cap helping to regulate blood flow to some organs. share in
repair of injured blood vessels.
Types: EM may distinguish three types of capillaries:

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A. Continuous (type I) capillaries:

The capillary wall is continuous. Cells have relatively thick cytoplasm.
Lateral surfaces of cells are characterized by zonula occludes (tight
junctions), so materials move across cells via pinocytosis or diffusion
(numerous pinocytotic vesicles were observed). These capillaries occur in
most organs. In the brain the blood capillaries have the following

Characters:
The endothelial cells are joined by zonula occludes.
Thick basement membrane.
Few or no pinocytotic vesicles

B. Fenestrated (type II) capillaries:

have extremely thin cytoplasm and the capillary wall is perforated at
intervals by pores or fenestrations. Lateral cell surfaces are characterized
by zonula occludes (tight junctions). The endothelial cells are surrounded
by a continuous basal lamina, which can function as a selective filter.
Materials apparently cross the cells through the fenestrations. Of two
types:
1. Fenestrae have diaphragm as in intestine and endocrine glands.
2. Fenestrae have no diaphragm as found in the renal glomeruli.

C. Sinusoidal capillaries: (Discontinuous capillaries): The

basal lamina is incomplete. They have wide spaces between the lateral
edges of the adjacent endothelial cells. they are found in organs where
exchange of macromolecules and cells occurs between tissues and blood
such in bone marrow, livers, spleen.

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Physiology

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(Physiology)

ELECTROPHYSIOLOGY OF THE CARDIAC

MUSCLE & ORIGIN OF THE HEART BEAT
Introduction:
• The cardiovascular system is a closed system of tubes (i.e.
vessels) inside which blood circulates continuously by the
pumping action of the heart in one direction only by the action
of valves present in the heart and veins.
• It is composed of :
1. The Heart: as a pumping organ of the system.
2. Blood Vessels: as containers, through which the circulation occurs.

Properties of the Cardiac Muscle

• Cardiac muscle is a striated muscle like the skeletal muscle, but it
is different from the skeletal muscle in being involuntary and
syncytial.
• Syncytium means that cardiac muscle cells are able to excite
and contract together as one unit due to the presence of gap
junctions between adjacent cardiac cells.
• Both atria contract together as one unit (upper syncytium) and
both ventricles contract together as one unit (i.e. lower
syncytium), which are completely separated from each other by
the fibrous A-V ring. So, the excitation waves cannot be directly
transmitted from one syncytium to the other.
• Myocardium of the heart is composed of two types of cardiac
muscles:
• A.Contractile Muscle Cells : (form about 98-99% of the cardiac
muscle). Their action potential is called fast AP.

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• B.Non-contractile Muscle Cells: (form about 1-2 % of the cardiac

muscles and are the cells that form excitatory-conductive system of
the heart). Their AP is called slow or pacemaker AP
• Cardiac muscle has four properties, due to which the heart is
able to fulfill its function as a pumping organ. They include:

1. Rhythmicity (Chronotropism). 2. Excitability (Bathmotropism).

3. Contractility (Inotropism). 4. Conductivity (Dromotropism).

1. Rhythmicity (Chronotropism)
• Automaticity: It is the ability of the heart to initiate its own
contraction independent of external stimuli.
• Rhythmicity: It means the heart can beat regularly.
• Spontaneous rhythmicity and automaticity of the cardiac muscle
is due to the existence of a specialized excitatory-conductive
system, which is composed of modified self- exciting, non-
contractile cardiac muscle cells called pacemaker cells.
• Rhythmicity is myogenic in origin (i.e. starts from the muscle
itself independent from autonomic nerve supply that only
controls the heart rate (either ↑ or ↓) but don’t initiate the beat.

Pacemaker(s) of the heart:

Pacemaker means the part of the heart that has the highest rhythmicity
and the whole other parts of the heart follow its rhythm. They include;
1. SA node (1ry Pacemaker):
• It has the highest rhythm (90-110/min).
• So, it is called the normal or 1ry pacemaker of the heart.
• Its rhythm is called sinus rhythm.

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2. AV node (2ry Pacemaker):

• It rate is 45-60 /min.
• It acts only if SA node is damaged or blocked.
• Its rhythm is called nodal rhythm.
3. Purkinje fibres (3ry Pacemaker):
• It rate is 25-40 /min.
• It takes over only if the conduction in AV node is completely
blocked.
• Its rhythm is called idioventricular rhythm.

Ionic Channels in The Heart

1) T type (Transient) Ca+2 channels; present only in pacemaker cells

and after opening → they are rapidly inactivated (i.e. closed) producing
transient Ca+2 influx.
2) L type (Long-lasting) Ca+2 channels; present in both contractile
muscle fibers and pacemaker cells. After opening → they are slowly
inactivated (i.e. closed) producing long-lasting Ca+2 influx.
3) Na+ /Ca++ exchanger: Exchange 3 Na+ for 1 Ca++ . It can operate in
both directions depending on the membrane potential and concentration
gradient of the ions.
4) Na+ /k+ pump which pump 3 Na+ out of the myocyte for each 2 k+
into the myocyte.
5) Funny channels: They are present in pacemaker tissues→ influx of
Na+ and k+ ions → depolarization.
6) Fast Na+ channels: They are present Contractile Muscle Cells →
influx of Na+→ depolarization.

7) K+ channels: Many types but all of them produced outward K+

current→ repolarization.

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Mechanism of Autorhythmicity (Prepotential & Pacemaker AP):

Pacemaker cells can spontaneously and regularly initiate action
potentialand so they are responsible for automaticity and rhythmicity of
the heart.Pacemaker action potential is composed of:
• Phase 4, upstroke (Prepotential):
Resting membrane potential is about -60 mV. At this potential
there is activation of a special type of voltage gated channels called
funny channels → funny current (inward Na+ and k+ ions If). As
the membrane potential reaches about -50 mV, another type of
channels called transient or T-type Ca++ channels opens→ Ca++
enters down its electrochemical gradient → depolarizes the cell to
-40 mV.
• Phase 0:
As the membrane is depolarized to the firing level (about -40 mV)
another type of Ca++ channels opens. These are known long-lasting
or L-type Ca++ channels → entrance of Ca++. Because the
movement of Ca++ through these channels into the cell is not rapid,
the rate of depolarization (slope of phase 0) is much slower than
found in other types of cardiac cells. Therefore AP of pacemaker
cells is called slow response action potential.

• Phase 3, repolarization:
- It occurs due to opening of K+ channels→ outward directed K+
current along concentration and electric gradients. At the same
time, L-type Ca++ channels become inactivated and close →
stop entrance of Ca++.
- Repolarization continues until the membrane potential reaches -60
mV. At this potential the outward K+ current becomes gradually
inactivated, while the inward Na+ current becomes activated again
due to opening of funny current channels and a new phase 4 is
initiated and the whole cycle is spontaneously repeated.

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N.B.:
Phase 1 and 2 are absent

Pacemaker prepotential and action potential.

Ionic basis of Pacemaker action potential.

N.B.
• Although the rhythmicity of the SAN is ~ 110 /min, the resting heart
rate is only 75/min, why?
• This is due the continuous inhibitory discharge from the vagus nerve
on S A node decreasing its inherited rhythm from 110 to 75/min. This
called VAGAL TONE.

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• The vagus nerve supplies the whole cardiac muscle except the
ventricles (i.e. called VAGAL ESCAPE PHENOMENON). This
phenomenon protects the ventricles from abnormally high vagal
stimulation (which can cause cardiac arrest).
Factors affecting the rhythmicity may be also classified into:
A. Nervous Factors:
1. Vagal stimulation via acetylcholine (Ach) → (-ve) chronotropic
effect.
Mechanism:

Ach stimulates M2 cholinergic receptors → decreased level of of cyclic-

AMP → inhibits If → ↓ slope of prepotentials → ↓ rhythmicity. In
addition Ach also stimulates a special type of K+ channels (known as
KAch) → K+ outflux. This K+ efflux opposes the funny current and
decreases the slope of the phase.

2. Sympathetic stimulation via noradrenaline (NA) → (+ve)

chronotropic effect.
Mechanism:
NA stimulates B1 adrenergic receptors → increased formation of cyclic-
AMP→ increase inward Na+ current (If) & ↑ Ca+2 influx → ↑ slope of
prepotentials → ↑ rhythmicity.

3. Vagal Tone & Vagal Escape (see above).

B. Chemical Factors:
1. Adrenaline → ↑ rhythmicity.
2. Acetyl choline (Ach) → ↓ rhythmicity.
3. Thyroxine: ↑ rhythmicity (due to ↑ metabolism of pacemaker tissue).
4. Effect of ions (Na+, K+ & Ca+2):
• Na+ :Na+initiates rhythmicity but cannot maintain it.

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• K+ :
➢ Hypokalemia causes tachycardia due to increase the slope of
phase 4 by decreasing K+ conductance of SA nodal cells.
➢ Hyperkalemia causes bradycardia by decreasing the slope of
phase 4 by increasing K+ conductance of SA nodal cells.
➢ Excess K+ → Cardiac arrest in Diastole.

• Ca+2 :
➢ Ca+2 → help Systole → Excess Ca+2 → Cardiac arrest in Systole
(i.e. calcium rigors).
➢ Ca+2 channel blocking drugs: some types of these drugs causes
bradycardia by inactivation of L-type Ca+2 channels.
N.B.:
Calcium should be injected very slowly because rapid i.v. injection of
calcium leads to death from calcium rigors.

6. Metabolites & Blood gases:

O2 lack (↓O2), ↑ H+ or ↑ Co2 → ↓ rhythmicity.

7. Effect of Drugs:
➢ Sympathomimetic drugs → ↑ rhythmicity.
➢ Parasympathomimitic (i.e. cholinergic drugs) → ↓ rhythmicity.
➢ Digitalis: Although it increases myocardial contractility, it inhibits
SA node activity and decreases HR (i.e. vagal like effect)
8. Effect of toxins:
Certain toxins (e.g. Diphtheria & Typhoid toxins) → ↓ rhythmicity.
C. Physical Factors:
• Moderate warming → ↑ rhythmicity due to increased rate of
discharge of SA node.
• Moderate cooling → ↓ rhythmicity due to decreased rate of
discharge of SA node.

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• Excess or severe warming (≥ 45OC) → Stop rhythmicity (due to

tissue damage).
• Excess or severe cooling (≤ 15OC) → Stop rhythmicity (due to
arrest of metabolism).

2. Excitability (i.e. Irritability, Bathmotropism)

➢ Excitability means the ability of the cardiac muscle to respond to
an adequate stimulus.
➢ The cardiac muscle is self-excited by signals generated in specific
pacemaker cells and conducted via an excitatory conductive
system to generate an action potential called (i.e. Cardiac muscle
or FAST response Action Potential).
➢ The RMP of the cardiac muscle is ~ (-80 to -90 mv).
➢ When the cardiac muscle is stimulated → an Action Potential is
generated which is responsible for initiating cardiac muscle
contraction.
Phases of cardiac muscle (i.e. FAST response) Action Potential:
Phase 0 (i.e. Depolarization phase):
Caused by rapid depolarization (i.e. from -90 to +20 mv) and it is due
to rapid sodium influx (via voltage-gated fast Na+ channels).

Phase 1 (i.e. rapid initial partial repolarization):

A small rapid repolarization, due to inactivation (i.e. closure) of voltage-
gated Na+ channels along with limited K+ efflux.

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Phase 2 (i.e. Plateau):

In which membrane remains repolarization slows down, and
membrane potential is nearly sustained about zero mV. It is caused
by a BALANCE between:
• Ca+2 inflow (i.e. depolarizing Ca+2) due to opening of long lasting
Ca++ channels (L-type Ca+2 Channels). These channels are
voltage gated and they start to open during phase 0 and they
become fully active at membrane potential -40 mV. They remain
open for relatively long time before they become inactivated.

• K+ outflow through K+ channels.

Phase 3 (i.e. Rapid repolarization):

Due to inactivation (i.e. closure) of L-type Ca+2 channels while K+
channels become maximally activated→ repolarization.

Phase 4 (Returning to RMP):

This is the resting membrane potential. It continuous till the cardiac
myocytes become depolarized by electric current from the adjacent active
myocytes. During this phase K+ slowly moves out of the myocyte through
K + channels.

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Cardiac muscle AP (i.e. FAST response).

Cardiac muscle AP Pacemaker AP
(i.e. Fast Response) (i.e. Slow Response)
• The RMP is ~ -90 mv. • The RMP is - 55 to - 60 mv.
• Constant (i.e. stable). • Unstable (i.e. self-excitation or
prepotential).
• The upstroke (i.e. • The upstroke is slow.
ascending limb) is rapid. • It is due to slow Ca2+ influx
• It is due to rapid Na+ and reaches up
influx and reaches up
• to ~ +20 mV. • to ~ +10 mv.

• There is a prominent • There is NO plateau.

plateau.

• Repolarization is • Repolarization is one phaseonly

triphasic.

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Differences between Pacemaker potential (slow response) and Action

potential of the ventricular muscle (Fast response)

Excitability Changes during Cardiac Activity:

I. Absolute Refractory Period (ARP);
➢ The excitability is completely lost (= zero).
➢ It extends from the start of phase 0 → till the middle of Phase 3
of the AP (i.e. phases 0, 1, 2 till the middle of phase 3).
➢ It occupies the whole systole and early part of diastole = long
ARF.
Significance of Long ARP;
1. Prevents the heart from being tetanized.
2. Prevents cardiac fatigue.
3. Allows sufficient time for ventricular filling.
II. Relative Refractory Period (RRP);
➢ The excitability starts to be restored gradually but still less than
normal.
➢ It coincides with the remaining part of phase 3 (i.e. rapid
repolarization).
➢ It occupies the remaining part of diastole.
III. Super normal Phase of Excitability:
➢ The excitability is higher than normal (i.e. can respond to
subthreshold stimuli).
➢ It coincides with phase 4.
➢ It occupies the end of diastole.
Early in this phase, there is the vulnerable period of the heart (i.e. a
dangerous period in which the excitation wave may lead to cardiac
arrhythmia as ventricular fibrillation.

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Clinical Physiology; Extrasystole or Premature beat)

❖ Extrasystole (i.e. ES) is a pathological condition, due to
abnormal impulses, arising from ectopic focus outside the normal
pacemakers of the heart.
❖ It is expressed as an abnormal systole (i.e. premature beat) that
occur during diastole.
❖ Extrasystole is due to a rising of excitability above the normal,
which usually occurs after the end of the relative refractory period
and beginning of supernormal phase of excitability (i.e. the
vulnerable period of the heart).
❖ According the site of the ectopic focus, there THREE types of
ES;
1. Atrial (auricular) ES.
2. A-V Nodal ES.
3. Ventricular ES.
❖ Causes of ES:
1. Normally, e.g. nervous excitement, heavy smokers, emotional
disturbance.
2. Abnormally in heart disease, e.g. coronary heart diseases (i.e. CHD).
Ventricular extrasystole is usually followed by an interval called
compensatory pause (CP) and a stronger contraction called
postextrasystolic potentiation (i.e. Post ES Potentiation).
❖ Explanation:
1. The compensatory pause (i.e. CP); is due to the arrival of the
normal heart beat (i.e. from SAN) during the ARP of the ES so, the
heart will NOT be able to respond (i.e. missed or dropped beat) as
the excitability is zero.

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2. The Post ES Potentiation; is due to release of lager amount of

Ca+2 from SR in addition to increased ventricular filling during
the CP → ↑ EDV → more stronger contraction (i.e. according to
Starling Law).
3. The total duration of ES + CP + the normal beat before ES =
duration of two normal beats.

Ventricular extrasystole.
Excitation-Contraction Relationship:
➢ The mechanical response (i.e. Contraction) of the cardiac muscle
starts just after the beginning of depolarization (i.e. ~ 0.02 sec.)
and takes longer time than the AP (~ 1.5 time) as long as the
duration of AP.
➢ The systole reaches its maximum at the end of the plateau (i.e.
phase 2).
➢ The diastole starts with the rapid phase of repolarization (phase 3),
which is completed at about the mid-diastole.
➢ The second half of diastole coincides with Phase 4 (i.e. RMP is
reached).

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Relation between electric response, mechanical response, and

excitability changes in the heart

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(Physiology)
CARDIAC MUSCLE EXCITATION-
CONTRACTION COUPLING (i.e. ECC)

3. Contractility (i.e. Inotropism)

It means the ability of the cardiac muscle to convert electrical energy of
action potential into mechanical work (i.e. contraction).

Mechanism of Excitation – Contraction coupling (i.e. ECC):

Membrane depolarization initiates the process of excitation
contraction coupling as follows:
• Opening of the L-type Ca+2 channels present in the sarcolemma and
T-tubules→ entry of small amounts of Ca+2 inside the myocyte.
• This Ca+2 is sensed by the Ca+2 release channel in the terminal
cisterns of the sarcoplasmic reticulum → this triggers the release of
large amount of Ca+2 from the sarcoplasmic reticulum. This is
known as calcium induced calcium release.
• Calcium binds to troponin C → allows sliding of actin over
myosin → muscle contraction.
• Muscle relaxation occurs by active reuptake of Ca+2 back to the
SR (by Ca+2 ATPase pump) and by extrusion from the cell by
Na+ /Ca++ exchanger. Na+ is restored by Na+ /K+ ATPase.

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Excitation – Contraction coupling in cardiac muscle

N. B.
• In the cardiac muscle, the Ca+2 required for contraction comes
from TWO sources;
1. Intracellular; from the SR (major source called activator Ca+2).
2. Extracellular, via voltage gated (L-type) Ca+2 channels called
depolarizing Ca+2 (although limited source, but it is very
important as it promotes more Ca+2 release from the SR).
3. Under normal resting conditions Ca+2 releases inside the
myocytes is not maximal. If more Ca+2 is available in the
cytoplasm, cardiac myocyte contracts with greater force i.e. has
higher contractility (known as positive inotropic state).
There are TWO types of Ca+2 channels in the heart;
a) T type (Transient) Ca+2 channels; present only in pacemaker cells
and after opening → they are rapidly inactivated (i.e. closed) producing
transient Ca+2 influx.
b) L type (Long-lasting) Ca+2 channels; present in both contractile
muscle fibers and pacemaker cells. After opening → they are slowly
inactivated (i.e. closed) producing long-lasting Ca+2 influx.

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Physiological Properties of Cardiac Ms. Contraction:

A. All or None rule:
• Due to the syncytial nature of the cardiac muscle (i.e. atrial &
ventricular syncytia), under constant conditions, the cardiac
muscle either;
➢ Contracts maximally if stimulated by threshold or higher
stimuli.
➢ Or does not respond at all on using subthreshold stimuli.
• So, the cardiac muscle is considered an efficient pump.

B. Staircase (Treppe) Phenomenon:

• Increasing the frequency of stimulation of cardiac muscle results in
gradual increase in force of contractions that occur over the first
few contractions. This continues till a new higher steady state is
reached and this higher level of force of contraction is maintained
as long as the high frequency of stimulation is maintained. This is
called staircase phenomenon or treppe.
• Explanation:
Due to improved physiological conditions as rapid repetition of
contractions→ no enough time for complete removal of the
released Ca++→ accumulation of Ca++ → ↑ force of contraction.
The staircase phenomenon doesn’t contradict the all or none rule
because the all or none rule is applied under constant conditions
(which are NOT the case in staircase phenomenon).

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C. Frank- Starling Law of the Heart:

• It describes the relation between the initial length of the muscle
and the force (i.e. tension) generated in that muscle (i.e. Length-
Tension Relationship).
• In the cardiac muscle: Within limits, the force of cardiac muscle
contraction is directly proportional to the initial length of the
muscle (i.e. the greater the initial length of cardiac muscle fiber,
the greater is the force of contraction.
• The initial length of the cardiac muscle is determined by the
degree of diastolic filling or preload (i.e. End Diastolic Volume =
EDV or End Diastolic Filling Length (EDFL) which in turn
depends on the amount of venous return (VR) to the heart.
• The pericardium prevents overstretching of heart, and allows
optimal increase in diastolic volume.
• Thankful to this law, the heart is able to pump any amount of
blood that it receives. So, the heart is considered a SMART pump. But
overstretching of cardiac muscle fibers → marked decrease in
contractility (i.e. heart failure).

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Significance of Frank-Starling’s Law:

1. In normal heart → Allows the heart to pump excess blood returning to
it from veins (i.e. Matches the ventricular output to the changes in
Venous Return). e. g. during muscular exercise (ME).
2. Prevents stagnation of blood in the heart and veins.
3. In failing heart (i.e. HF) → Weak ventricular contraction → ↑ EDV
→ ↑ myocardial contractility of the next beat.
4. In denervated (i.e. transplanted) heart → it is considered the main
mechanism to adjust the pumping capacity of the heart.

Frank - Starling's Law of the heart.

D. The Cardiac muscle CANNOT be tetanized:

• This is due to the long absolute refractory period (i.e. ARP) of the
cardiac muscle that occupies the whole systole and early part of
diastole.
• Tetanic contraction of the cardiac muscle is fatal → as it stops
the pumping action of the heart (i.e. ventricles) → Circulatory
failure → Death.

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N.B.
Loss of the pumping action of atria is NOT fatal (As atria act mainly
as reservoirs) as most of blood (70%) is delivered to the ventricles
DURING VENTRICULAR FILLING by weight of the blood.
Factors affecting Cardiac Muscle Contractility (i.e. inotropism):
A. Nervous Factors:
• Sympathetic Stimulation → ↑ contractility (+ve inotropic effect)
through stimulation of β adrenergic receptors → formation of
cyclic AMP inside the myocytes. C-AMP activates protein
kinase→ phosphorylation of calcium channels →more Ca+2 to
enter in L-type Ca+2 channels and more Ca+2 release from SR.
• Vagal Stimulation (on atria ONLY): → ↓ contractility due to
decrease cyclic AMP (-ve inotropic effect).
B. Chemical Factors:
1. Hormones (e.g. adrenaline, NA, Thyroxine, and glucagon) → ↑
contractility.
2. Acetylcholine, snake venom & bacterial toxins (e.g. Diphtheria &
Typhoid) → ↓ contractility.
3. Drugs: e.g.
• Digitalis → ↑ contractility (+ve inotropic effect).
Mechanism: (via inhibition of Na+- k+ pump →↑ inside Na+
→stimulates Na+- Ca+2 exchanger → ↑ Ca+2 influx and Na+ outflux → ↑
intracellular Ca+2 → (+ve) inotropic effect.

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Mechanism of action of Digitalis

• Xanthines (e.g. Caffeine & Theophylline): These drugs inhibit

breakdown of c- AMP → ↑ contractility.
• Calcium channel blockers: inhibits L-type Ca+2 channels → ↓
Ca+2 inside the myocytes → ↓. Contractility.

4. Hypoxia: Moderate hypoxia (O2) and hypercapnea (CO2 excess)

increase the cardiac contractility through stimulating the peripheral
chemoreceptors. On the other hand, severe hypoxia and hypercapnea
directly depress the cardiac muscle and decrease the contractility.
This is usually due to insufficient blood supply → inhibits ATP
production which is the source of energy of muscle contraction.
6. Effect of ions (Na+, K+ & Ca+2):
• Excess Na+2 (i.e. Hypernatremia) →↓ contractility as it favours
Na+ influx and Ca++ efflux by the antiport Na+- Ca++ exchanger
carrier. On the other hand, hyponatremia exerts a +ve inotropic
effect by an opposite mechanism
• Hyperkalaemia→↓ contractility and may stop the heart in
diastole. On the other hand, hypokalaemia produces +ve inotropic
effect.

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• Excess Ca+2 (i.e. Hypercalcemia) →↑ contractility as a result of

more calcium influx. It prolongs the systole on the expense of
diastole and the heart may stop in systole ( Ca++ rigor).
C. Physical Factors:
• Moderate warming → ↑ contractility.
• Due to increased metabolism and ATP production, decreased
viscosity of myocardial structures and increased Ca+2 influx.
• Moderate cooling → ↓ contractility.
• Excess warming or cooling → Stop contractility.
D. Mechanical Factors:
1. Increased initial length (i.e. EDV) → ↑ contractility (i.e. ↑ force & ↑
velocity of myocardial contraction according to Starling’s Law).
2. Multiple successive stimuli → ↑ contractility (according to Staircase
phenomenon).
3. Increased coronary blood flow (i.e. ↑ CBF) → ↑ Contractility.
Force-Velocity Relationship:
• The velocity of cardiac muscle shortening is directly proportional
to the initial length (i.e. EDV or preload) of the cardiac muscle
fibers (i.e. according to Starling law).
Force-Frequency Relationship:
• The force of myocardial contractility is affected by the frequency
of stimulation. e.g.
• Sudden increase in the frequency of discharge → ↑ force of
contraction (i.e. staircase phenomenon) and vice versa.
• Impulse generated during diastole from ectopic focus outside the
normal pacemaker → a premature beat will be generated called
extrasystole.
******************************************************

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(Physiology)
CONDUCTION SYSTEM IN THE HEART
Conductivity (i.e. Dromotropism):
It means the ability of the cardiac muscle to transmit the excitation wave
from one part of the heart to another through the excitatory conductive
system of the heart.

Parts of Excitatory Conductive System of the Heart

1. Sinoatrial (SA) node (NORMAL pacemaker):
• Here the initial impulses start → then conducted to the atria
through the anterior inter-atrial pathway (to the left atrium) → to
the atrial muscle mass through the gap junction, and to → the
Atrioventricular node (AV node) through anterior, middle, and
posterior inter-nodal pathways.
• The average velocity in the atria → one meter/sec.
2. Atrioventricular (AV) node (SLOWEST conduction):
• The electrical impulses CANNOT be conducted directly from the
atria to the ventricles, because of the fibrous skeleton, which is an
electrical isolator, located between the atria and ventricles.

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• So the only conductive way between atria and ventricles is the AV

node.
• But there is a DELAY in the conduction occurs in the AV node
due to:
1. The smaller size of the nodal fiber.
2. The less negative resting membrane potential.
3. Fewer gap junctions.
• The average velocity of conduction in the AV node → 0.02 - 0.05
m/s.
Significance of AV nodal delay:
a. Allows atria to empty blood in ventricles during the cardiac cycle
before the beginning of ventricular contraction.
b. Protects the ventricles from the pathological high atrial rhythm (to
prevent ventricular fibrillation).
N.B.
• The maximum rate of transmission of impulses through AV
node is ~ 230 impulse/min.
• The conduction from AV node is a one-way conduction. This
prevents the re-entry of cardiac impulses from the ventricles to
the atria.
3. Bundle of Hiss:
• A continuous with the AV node that passes to the ventricles
through the inter-ventricular septum.
• It is subdivided into: Right and left bundle.
• The left bundle is further subdivided into TWO branches: anterior
& posterior branches.

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4. Purkinje`s fibers (FASTEST conduction):

• It is formed of fibers that spread to all parts of ventricular
myocardium
• Large fibers with velocity of conduction → 1.5 - 4 m/s.
• It allows spread of excitation wave to the whole ventricles
simultaneously and thus contraction of the both ventricles as one
unit)
• The high conduction velocity of these fibers is due to:
1. The abundant gap junctions.
2. Their nature as very large fibers.
Factors affecting Conductivity (i.e. Dromotropism):
I. Positive (+ve) dromotropic factors:
1. Sympathetic stimulation: it accelerates conduction and decreases AV delay.
2. Hormones: e.g. Catecholamines & Thyroxine.
3. Mild warming.
4. Mild ischemia.
6. Drugs: e.g. Sympathomimetics.
II. Negative (-ve) dromotropic factors:
1. Parasympathetic stimulation: it decreases conduction and ↑AV delay.
2. Severe warming or cooling.
3. Most of electrolyte disturbances → ↓ conductivity (especially K+)
4. Severe ischemia.
6. Drugs: e.g. cholinergic drugs, Digitalis.
N.B.
Digitalis exerts the following effects on the heart;
1. ↓ Rhythmicity (-ve chronotropic effect).
2. ↓ Conductivity (-ve dromotropic effect).
3. ↑ Contractility (+ve inotropic effect).
So, it is used for treatment of heart failure and arrhythmia.

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Conduction Disturbances
A) Sinoatrial block:
In this case, impulses are produced in the active focus in the S.A.node,
but are not conducted through the nodal tissue to the atrial muscle. It can
be continuous or intermittent. When S.A node block occurs, the A.V.
node takes over as the heart pacemaker.
B) Atrioventricular (i.e. AVN) Heart Block:
-This often results secondary to ischemia of the A-V nodal or infra-nodal
regions.
- According to severity, there are 3 degrees:-
1. First Degree (1st degree HB).
2. Second Degree (2nd degree HB).
3. Third Degree (3rd degree HB).
1. First (i.e. 1st Degree) HB:
• This is the mildest degree.
• All impulses are conducted to the ventricles, but much slower than
normal.
2. Second (i.e. 2nd Degree) HB:
1. In this type, the conduction through the A-V node fails
intermittently.
2. This may occur irregularly leading to dropped ventricular
contractions (partial heart block) or regularly (incomplete heart
block).
3. The latter may be 2:1 or 3:1 block (i.e. a ventricular beat follows
every second or third atrial beat).

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3. Third degree (3rd or Complete) HB:

• This is the most severe degree in which impulse conduction
through the A-V node is completely blocked.
• The atria beat regularly at a rate of about 70 bpm (i.e. sinus
rhythm).
• The ventricles also beat regularly but at a much slower rate (i.e.
idioventricular rhythm = 25-40 bpm).
• Complete heart block is often incompatible with life, and it can be
treated by implanting an electric stimulator in the ventricles.

C) Bundle branch block(BBB):

In this case, impulses cannot be conducted through the left branch
(LBBB) or the right branch (RBBB) of the A.V. bundle. The ventricle
with the normal branch will beat earlier than the ventricle with the
blocked branch.In the latter ventricle, conduction of impulse occurs
directly through the ventricular muscle.
********************************************************

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(Physiology)
CARDIAC CYCLE AND HEART SOUNDS
Definition:
• It means the mechanical events occurring in the heart within one beat
(from the beginning of heart beat to the next one.
• Each cardiac cycle (i.e. CC) consists of atrial systole → followed by
ventricular systole then diastole of the whole heart.
• With the HR 75 bpm → the cardiac cycle duration (i.e. CCD) is ~
0.8 sec.
• ↑ HR → ↓ CCD and vice versa.
• Changes in CCD affects mainly diastole. This is important because
filling of the ventricles & coronaries occur during the diastole.

PHASES OF THE CARDIAC CYCLE

• The following phases occur in the left side of the heart and are nearly
similar to those occurring in the right side.
• The chief difference is the lower pressure in the right ventricle and
pulmonary artery.
• The events of the cardiac occur in the following phases
respectively:
1. Atrial systole phase (i.e. ASP) or late ventricular diastole = 0.1 sec.
2. Isometric (isovolumetric) contraction phase (ICP) = 0.05 sec.
3. Maximum ejection phase (MEP) = 0.15 sec.
4. Reduced ejection phase (REP) = 0.1 sec.
5. Protodiastolic phase (PDP) = 0.04 sec.
6. Isometric (isovolumetric) relaxation phase (IRP) = 0.06 sec.
7. Maximum filling phase (MFP) = 0.1 sec.
8. Reduced filling phase (RFP) or mid ventricular diastole = 0.2 sec

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The Cardiac Cycle.

I. Atrial systole phase (ASP, Late ventricular diastole) = 0.1 second

1. Atrial pressure (AP): ↑ few mmHg due to atrial contraction.

Then returns back to zero by the end of this phase due to

evacuation of atrial blood.
2. Ventricular pressure (VP): ↑ slightly due to entry of blood from

the atrium. Then ↓ due to dilatation of the ventricles.

3. Ventricular volume (VV): ↑ slightly due to entry of blood from

the atrium.
4. Aortic pressure (Ao P): ↓ due to escape of blood from aorta to

arteries.
5. Aortic valve (Ao V): closed.

6. AV valve: opened.

7. Heart sounds (HS): 4th HS.

8. ECG: P wave (which occurs 0.02 sec before the beginning of

atrial systole).

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II. Isometric (isovolumetric) contraction phase (ICP) = 0.05 seconds

During this phase, the ventricles contracts isometrically
(isovolumetrically), i.e. without change in length of muscle fiber.
1. Atrial pressure (AP): slightly increased due to ballooning of AV

cusps towards the cavity of the atrium by the sudden increase in

intraventricular pressure.
2. Ventricular pressure (VP): rapidly increased and becomes higher

than atrial pressure.

3. Ventricular volume (VV): NO change.

4. Aortic pressure (Ao P): decreased due to escape of blood from

aorta to arteries. At the end of this phase, the VP is slightly higher

than Ao P.
5. Aortic valve (Ao V): still closed.

6. AV valve: suddenly closed.

7. Heart sounds (HS): 1st HS (early part).

8. ECG: QRS complex (Q wave starts 0.02 sec before the beginning

of this phase).
III. Maximum Ejection Phase (MEP) = 0.15 seconds.
During this phase, blood is ejected at high rate out of the ventricle to
the aorta.
1. Atrial pressure (AP): sharp decrease due to downward

displacement of the AV ring. Then gradual increase due to venous

return and upward displacement of the AV ring to its normal
position.
2. Ventricular pressure (VP): increased from 80 to 120 mmHg.

3. Ventricular volume (VV): decreased rapidly due to ejection of

most ventricular blood to aorta.

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4. Aortic pressure (Ao P): increased from 80 to 120 mmHg because

the pumped blood by the ventricle is greater than blood escaping

from the aorta to arteries.
5. Aortic valve (Ao V): opened

6. AV valve: closed

7. Heart sounds (HS): 1st HS continues.

8. ECG: origin of T wave is somewhere in this phase.

IV. Reduced Ejection Phase (REP) = 0.1 seconds.

In this phase, blood ejection occurs at a slower rate than MEP.
1. Atrial pressure (AP): gradual increase due to VR.

2. Ventricular pressure (VP): slightly decreased due to decreased

force of pumping blood to aorta.

3. Ventricular volume (VV): still decreasing.

4. Aortic pressure (Ao P): decreased because blood leaving aorta is

more than blood pumped by the ventricle.

5. Aortic valve (Ao V): opened.

6. AV valve: still closed.

7. Heart sounds (HS): NO HS.

8. ECG: top of T wave.

V. Protodiastolic Phase (PDP) = 0.04 seconds.

It denotes the end of systole and the beginning of diastole.
1. Atrial pressure (AP): gradual increase due to VR.

2. Ventricular pressure (VP): rapidly decreased till become lower

than aortic pressure due to relaxation of the ventricle.

3. Ventricular volume (VV): NO change.

4. Aortic pressure (Ao P): the aortic pressure follows that of the

ventricle until the sudden closure of the Ao V which causes sharp

decrease of the aortic pressure called "Incisura" or "Dicrotic Notch".

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5. Aortic valve (Ao V): open.

6. AV valve: still closed.

7. Heart sounds (HS): NO HS.

8. ECG: T wave continues.

VI. Isometric Relaxation Phase (IRP) = 0.06 seconds.

1. Atrial pressure (AP): gradual increase due to VR.

2. Ventricular pressure (VP): rapidly decreased.

3. Ventricular volume (VV): NO change.

4. Aortic pressure (Ao P): shows dicrotic notch due to sudden

closure of aortic valve. This is followed by dicrotic wave due to

elastic recoil of the aorta.
5. Aortic valve (Ao V): suddenly closed.

6. AV valve: still closed.

7. Heart sounds (HS): 2nd HS.

8. ECG: T wave ends during this phase.

VII. Maximum Filling Phase (MFP) = 0.1 seconds.

1. Atrial pressure (AP): is higher than ventricular pressure at the

beginning of this phase, then drops due to rush of blood into the
ventricle.
2. Ventricular pressure (VP): around zero due to progressive

vent. relaxation.
3. Ventricular volume (VV): increases rapidly as blood flows

from the atria into the ventricles.

4. Aortic pressure (Ao P): decreasing

5. Aortic valve (Ao V): closed.

6. AV valve: opened

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7. Heart sounds (HS): A 3rd HS (S3) is usually abnormal and is

due to rapid passive ventricular filling. It occurs in dilated

congestive heart failure, severe hypertension, myocardial
infarction, or mitral incompetence.
8. ECG: NO waves (i.e. isoelectric).

VIII. Reduced Filling Phase (RFP) = 0.2 seconds.

1. Atrial pressure (AP): around zero but higher than the

ventricles.
2. Ventricular pressure (VP): around zero but less than the atria.

3. Ventricular volume (VV): increases.

4. Aortic pressure (Ao P): still decreasing due to escape of blood

to peripheral tissues
5. Aortic valve (Ao V): closed.

6. AV valve: opened.

7. Heart sounds (HS): NO HS.

8. ECG: beginning of p wave of the next cycle.

IMPORTANT REMARKS ON CARDIAC CYCLE:

• Atrial systole = 0.1 second, while atrial diastole = 0.7 second.
• Ventricular systole = 0.3 second, while ventricular diastole = 0.5
second.
• 70% of ventricular filling occurs passively during rapid and reduced
filling phases by blood weight.
• ONLY 30% of blood is actively pumped into ventricle during atrial
systole.
• Aortic valve opens at 80 mmHg pressure in the left ventricle.
• Pulmonary valve opens at 10 mmHg pressure in the right ventricle.
• Highest pressure in the left ventricle is 120 mmHg.

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• Highest pressure in the right ventricle is 30 mmHg.

• Semilunar valves (Aortic & pulmonary) valves are opened
during:
Maximum ejection, reduced filling and protodiastolic phases (i.e. 3, 4,
and 5 phases).
• A-V valves are opened during:
Maximum filling, reduced filling, and atrial systole phases (7,8, and1).
• All valves are closed during:
Isometric contraction & isometric relaxation phases.
• Opening of all valves DOESN’T occur normally.
• Aortic pressure only increase in maximum ejection phase (anacrotic
limb) and the remaining all phases form the catacrotic limb.
• Valves make sound during their closure NOT during their opening.

The Heart Sounds

• Four heart sounds (HS) have been recorded (by phonocardiography)
but ONLY two of them are heard (the first & second heart sounds).
• The third sound is sometimes heard in children.
Method of study:
By The stethoscope.

Auscultatory areas of Normal Heart Sounds:

• To hear the heart sounds, the stethoscope is NOT put on the
anatomical landmarks of the corresponding valves. The heart sounds
are heard on the “Auscultatorty Areas”

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Definition:
Areas of the anterior chest wall where the sound of each cardiac valve is
best heard and it is different from the anatomical site of the valve.

Mitral area: left 5th intercostal space midclavicular line (i.e. Heart apex).
Tricuspid area: at the lower part of the sternum.
Aortic area: 2nd right costo-sternal junction.
Pulmonary area: 2nd left intercostal space parasternal line.

Auscultatory areas of HS.

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Types of Heart Sounds

Item First HS Second HS Third HS Forth HS

Causes Sudden closure of A.V Sudden closure Vibration of Atrial systole
valves ofsemilunar ventricular wall
Vibration of the pulmonary valves during maximum
& aortic arteries. (i.e. Aortic & pulmonary) filling phase.
Phases Isometric contraction phase Isometric relaxation phase Maximum (Rap Atrial systole
& first part max. ejection filling phase phase
phase

Site of best Mitral & tricuspid areas Aortic & pulmonary areas Mitral area Mitral Area
hearing

Duration 0.15 sec 0.10 sec 0.05 sec 0.04 sec.

Characters Audible by the stethoscope Audible by the Audible with the Non audible.
(Heard as lubb) stethoscope (Heard as person leaning Low Soft faint
Low pitched Dup) pitched
Soft High pitched
Sharp

Abnormalities of heart sounds:

1- Splitting of first heart sound: This occurs when closure of the
tricuspid valve is markedly delayed after closure of the mitral valve as in
right bundle branch block
2- Splitting of second heart sound: During inspiration in normal
individuals, the closure of the pulmonary valve is delayed after the
closure of the aortic valve. This leads to physiological split of second HS.
This split disappears during expiration. If the split persists during
expiration, it is usually pathological as in pulmonary stenosis which
prolongs the ejection time of the right ventricle or mitral regurgitation
which leads to early closure of aortic valve.

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3- Gallop rhythm: This is a heart rhythm in which there are more than
two audible heart sounds with each beat. This occurs with accentuation of
S3, S4 or both. The three or four sounds follow each other with each heart
beat in a sequence that resembles the sound of a galloping horse.
4- Heart murmurs: murmurs are abnormal sounds produced by
turbulent flow of blood. Heart murmurs can be classified into two main
categories, systolic and diastolic.
a. Systolic murmurs are murmurs which occur during ventricular systole
(between S1 and S2).

Systolic murmurs could be either physiological due to high cardiac output

or pathological due to stenosis of semilunar valves or regurgitation of AV valves
b. Diastolic murmurs are murmurs which occur during ventricular
diastole (after S2). Diastolic murmurs are pathological murmurs. They
result from either stenosis of AV valves or regurgitation of semilunar
valves.
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(Physiology)
RADIAL AND JUGULAR PULSE CURVES

STUDY OF THE CARDIAC CYCLE

The events of the cardiac cycle can be studied in man indirectly by:
1. Studying the jugular pulse curve (JPC).
2. Studying the arterial pulse curve (APC).
3. Studying the electrocardiogram (ECG).
The Jugular Pulse Curve (JPC)
• It is the record of pressure changes in the internal jugular vein.
• The apparatus used is called the phlebography.

Description of the JPC:

The curve consists of:
• Three positive waves (a, c and v).
• Three negative waves (x, x` and y)
Cause of Positive waves:
1. The (a) wave → due to atrial systole → contraction of the muscle

sleeves around the mouth of SVC → ↑ its pressure → (+ve) a wave.

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2. The (c) wave → due to early ventricular contraction (ICP) → ↑

intraventricular pressure → bulging of AV cusps into the right atrium

→ ↑ pressure in jugular vein → (+ve) c wave.
3. The (v) wave → due to ↑ venous return → ↑ intra-atrial pressure → ↑

pressure in jugular vein → (+ve) v wave.

Cause of Negative waves:
1. The –ve wave (x) → is due to atrial diastole → relaxation of the

muscular sleeves around the mouth of SVC → rush of blood from SVC
to the right atrium → ↓ intraatrial pressure → (-ve) x wave.
2. The –ve wave (x`) → is due to the downward displacement of the

AV ring during the MEP → increased atrial capacity → ↓ pressure in

right atrium and external jugular vein → (-ve) x` wave.
3. The –ve wave (y) → is due to opening of the AV valves during

RFP and rush of blood from the atrium to ventricle → ↓ atrial and
external jugular vein pressure → (-ve) y wave.

The Jugular Pulse Curve (JPC).

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Clinical significance of JPC:

1. a-c interval: from the beginning of (a) to the beginning of (c) =
P-R interval of the ECG (i.e. conductivity in AVB):
• Increased → delayed conductivity e.g. HB.
• Decreased → rapid conductivity e.g. sympathetic stimulation, AV
nodal rhythm.
2. Partial HB: The number of (a) waves is more than the number of

(c + v) waves.
3. Complete HB: The number of (a) waves is independent of the

number of (c + v) waves. The number of (c + v) waves about 25-40

per minute (i.e. idioventricular rhythm).
4. Atrial fibrillation (AF) → Absent (a) waves.

THE RADIAL PULSE CURVE (RPC)

• Powerful pumping of blood by the ventricular systole causes sudden

expansion of the elastic aortic wall.

• This expansion generates a (pulse wave) propagated along the walls of

the arteries causing arterial pulsation.

• The pulse wave spreads rapidly depending upon the rapid velocity of

the pulse wave (~ 6 meters/sec) NOT the velocity of the blood (~

0.5-1.0 meters /sec).
Pressure changes in aorta:
• Systolic pressure (SBP) = 120 mmHg (max. press.)
• Diastolic pressure (DBP) = 80 mmHg (min. press.)
• The Pulse pressure (PP) = the difference between SBP and DBP = 40
mmHg.

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Velocity of the Pulse Wave:

• It is inversely proportionate to the elasticity of arterial wall.
• Normally in adults, the velocity of pulse wave is ~ 6 meters/sec.
• In the newly born, it is ~ 3 m/s.
• In old age, it is about 8-12 m/s.

Radial pulse curve (RPC):

• The apparatus used is called sphygmograph.

• The curve is composed of :

1. Anacrotic limb (i.e. ascending limb):

• It is smooth and rapid.

• The beginning of this limb represents the DBP = 80 mmHg and

its top represents the SBP = 120 mmHg.

2. Catacrotic limb (i.e. descending limb):

• It is slow and wavy.

• TWO components appear in this limb:

- Dicrotic notch (incisura).

- Dicrotic wave.

The Radial Pulse Curve (RPC).

Significance of the RPC:

1. Gives information about HR and its regularity.

2. Recorded together with ECG or apex beat, we can detect pulses

deficit.

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3. Index about the elasticity of arterial wall by measuring the velocity

of the pulse wave.

4. Diagnosis of certain CVD: e.g.

• Water hummer pulse.

• Anacrotic pulse.
• Dicrotic pulse.
• Pulsus alternans.
• Pulsus bigeminus.
The Polygram:
• It is the combined RPC and JPC recorded together.
• It is done when there is difficulty in identifying the waves of the JPC.
• The wave on the JPC which is just before the ascending limb of the
APC is the C wave.

The Polygram and Significance of RPC

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(Physiology)

HEART RATE AND CARDIOVASCULAR

REFLEXES
Innervation of the heart:
• Functions of the heart are controlled by the vasomotor centers which
are bilaterally situated in the reticular formation of medulla oblongata
and the lower part of the pons.
• The heart receives nerve supply from both divisions of Autonomic
nervous system (Parasympathetic and sympathetic).
Vasomotor centers consist of three areas:
i. Vasoconstrictor area (Cardioacceleratory Center or pressor area).
ii. Vasodilator area (Cardioinhibitory Center or depressor area).
iii. Sensory area.
i. Vasoconstrictor Area
Vasoconstrictor area sends impulses to blood vessels through
sympathetic vasoconstrictor fibers. So, the stimulation of this area
causes vasoconstriction and rise in arterial blood pressure. This area is
also concerned with acceleration or increase of heart rate
ii. Vasodilator Area
It suppresses the vasoconstrictor area and causes vasodilatation. It is
also concerned with decrease of heart rate. (It supplies the heart
through the vagus nerve).
iii. Sensory Area
This area receives sensory impulses via glossopharyngeal and vagal
nerves from the periphery, particularly from the baroreceptors.
Sensory area in turn, controls the vasoconstrictor and vasodilator
areas.

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Innervation of the Heart

• The action of vasomotor center depends upon the impulses it
receives from other structures such as baroreceptors, chemoreceptors,
higher centers and respiratory centers.
• Among these structures, baroreceptors and chemoreceptors play a
major role in the short-term regulation of circulation.
1. Baroreceptor Mechanism:
• Baroreceptors are pressoreceptors which give a response to change
in blood pressure.
• Baroreceptors are situated in the carotid sinus and wall of the aortic arch

When blood pressure increases:

• When arterial blood pressure rises rapidly, baroreceptors are
activated and send impulses to inhibit the vasoconstrictor area and
excite the vasodilator area.
• Reduction in vasomotor tone causes vasodilatation, resulting in
decreased peripheral resistance.
• Simultaneous excitation of vasodilator center increases vagal tone
which decreases the rate and force of contraction of heart, leading to
reduction in cardiac output. These two factors, i.e. decreased
peripheral resistance and reduced cardiac output bring the arterial
blood pressure back to normal level.

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When blood pressure decreases:

• The fall in arterial blood pressure causes inactivation of
baroreceptors.
• No inhibition of vasoconstrictor center or excitation of vasodilator
center. Therefore, the blood pressure rises.
2. Chemoreceptor Mechanism:
• Chemoreceptors are the receptors giving response to change in
chemical constituents of blood. Peripheral chemoreceptors influence
the vasomotor center.
• Peripheral chemoreceptors are situated in the carotid and aortic
bodies.
• Peripheral chemoreceptors are sensitive to decreased oxygen
pressure, excess of CO2 and H+ concentration in blood.
• Whenever blood pressure decreases (below 80mmHg), blood flow to
chemoreceptors decreases, resulting in decreased oxygen content and
excess of CO2 and H+. These factors excite the chemoreceptors,
which send impulses to stimulate vasoconstrictor center. Blood
pressure rises and blood flow increases.

Location of baroreceptors and chemoreceptors

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HEART RATE
Definition:
The HR is the number of heart beats per minute. It ranges from 55 to 95
bpm in adult normal persons with an average of 70 bpm.

Methods of study:
1. Counting the radial pulse or apex beat per minute.
2. Counting the cardiac cycle per minute.
3. Recording the ECG.

Physiological Standards of HR:

The average standard of HR is about 70 bpm during rest which is
depending on the vagal tone. Vagal tone is higher in men than women, in
adults than in children, and in athletes than in non-trained persons.
What is vagal tone?
It is a continuous inhibitory effect exerted by the vagi nerves on the heart
rate during rest. It reduces SA node rhythmicity from 120 t0 70 impulses
/min. it occurs by stimulation of arterial baroreceptors in carotid sinus and
aortic arch by the normal ABP.
What is vagal escape?
It is the escape of the ventricles from the inhibitory effect of vagi nerves
i.e the ventricles are not supplied by the vagus nerve.
Factors Affecting HR:
a. Age: HR is 120 bpm in newly born. It gradually decreases till reaches
70 bpm in adult males.
b. Sex: HR is faster in females than in males.
c. Physical Training: HR is about 50 bpm in athletes

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Regulation of HR
Three mechanisms contribute in HR regulation:
A. Nervous
B. Chemical
C. Physical
A. Nervous regulation of heart rate:
I. Afferent Impulses from Circulatory System:
1. The right atrium:

• Bainbridge Reflex: An increase in venous return and pressure in

right atrium produces reflex increase in heart rate (tachycardia). It
helps emptying and prevents stagnation of the blood in the heart.
• Mary's Law: A rise in ABP leads to decrease in HR (due to
stimulation of baroreceptors in the aortic arch and carotid sinus) and
vice versa, provided that other factors affecting heart rate are
constant.
• Carotid Sinus Syndrome (i.e. vasovagal syncope): In some
persons, the carotid sinus is abnormally hypersensitive so that mild
pressure during shaving or by tight collar → leads to bradycardia,
decreased ABP and syncope.
• Stimulation of Chemoreceptors in carotid and aortic bodies by
decreased oxygen content, excess of carbon dioxide and hydrogen
ion → increase heart rate.
• Bezold-Jarish Reflex (i.e. coronary chemoreflex): injection of
certain substances as veratridine and capsaicin into the coronary
arteries leads to vagal reflex that causes bradycardia, VD and
hypotension (through stimulation of ventricular chemoreceptors).

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II. Afferent Impulses from the Respiratory System:

• Respiratory sinus arrhythmia:
The heart rate shows some changes associated with the respiratory
process, i.e. inspiration causes increase in heart rate, while expiration
causes decrease in heart rate.
• Pulmonary chemoreflex (J-receptor reflex):
Injection of certain substances (as serotonin and capsaicin) into the
pulmonary vessels leads to bradycardia, VD and hypotension. It is
due stimulation of pulmonary chemoreceptors and it is similar to
coronary chemoreflex.

III. Afferent Impulses from Higher Centers:

1. Emotions:
• Most types of emotions, e.g. fear, anger, sexual excitement
stimulates the posterior hypothalamic nuclei which control the
sympathetic system leading to stimulation of Cardio-
accelerator center and tachycardia.
• Severe emotions stimulate the anterior nuclei which control the
parasympathetic system leading to stimulation of the Cardio-
inhibitory center and bradycardia.

2. Quite Sleep:
• Impulses from the sleep center present among the parasympathetic
nuclei of the hypothalamus stimulate the CIC leading to
bradycardia.

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IV. Afferent Impulses from Other Parts of the Body:

1.Skeletal muscles (Alam-Smirk reflex):
• Contraction of voluntary muscles produces reflex increase in heart
rate. Even contraction of small muscles like those of a finger
produces acceleration.

• Mechanism: Proprioceptors in muscles send impulses that reach

the medulla oblongata to inhibit the Cardio-inhibitory center and
stimulate the Cardio-accelerator center leading to cardiac
acceleration
• Significance: Voluntary muscle contraction reflexly increases
heart rate to supply the active muscles with more O2 and nutrients.
2. Painful stimuli
• Moderate painful stimuli from skin, joints and viscera → causes
tachycardia due to sympathetic stimulation.
• Severe painful stimuli (heavy blow to abdomen, testicles, and
larynx) → cause bradycardia due to parasympathetic stimulation.
It may stop the heart completely.
B) Chemical regulation of heart rate:
1- Oxygen lack:
Hypoxia cause increase heart rate by the following mechanisms
- Direct stimulation of the CAC
- Reflex secretion of adrenaline
- Reflex stimulation of the CAC through the chemoreceptors in
carotid and aortic bodies
2- CO2 excess:
Increase in the CO2 tension leads to stimulation of the chemoreceptors
in the aortic and carotid bodies causing reflex increase in heart rate

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3- Blood hormones:
Adrenaline and thyroxine increase the heart rate due to direct
stimulation of SA node increasing its rhythmicity.

C) Physical regulation of heart rate:

1- Increased blood temperature: Causes increase in the heart rate, a
rise of 1ºC leads to increase in heart rate by 10 beats/min
Mechanism:
- Directing stimulating effect on the SA node and cardiac conductive
system
- Stimulation of the CAC and inhibition of the CIC.
Exception: in typhoid fever and diphtheria the heart rate may decrease
due to effect of bacterial toxins on the cardiac muscle
2- Decreased blood temperature: causes decrease in the heart rate by
the opposite mechanisms described above.
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(Physiology)
CARDIAC OUTPUT AND CARDIAC RESERVE
Cardiac Output (COP)
It is the amount of blood, pumped by each ventricle within one minute
of time. It is also called minute volume.
Cardiac output has two determinants, which are:
1- Stroke volume (SV): The amount of blood, pumped by the heart
within one beat (one cardiac cycle). So the SV equals the difference
between end-diastolic volume (EDV) and end-systolic volume (ESV).
2- Heart rate (HR): The frequency of heart beating within one minute
of time.
So, COP = SV x HR
• The average heart rate in a healthy adult person is about 70 beats per
minute,
• The stroke volume is about 70 ml,
• So we can estimate cardiac output by multiplying these two values:
70 X 70 = 4900 ml (~ 5 L) / minute.
• The venous return (VR), which is the amount of blood returning to the
heart by veins. So cardiac output and venous return express the blood
flow around the circulation, so they are equal in equilibrium.
Factors affecting cardiac output (COP):
As far as cardiac output is determined by stroke volume and heart rate, so
any factor that affect one or both of those determinants would affect the
cardiac output as a whole.
A) Factors affecting Stroke volume (i.e. SV); three factors:
1. Preload (i.e. venous return).
2. Contractility power of the heart.
3. Afterload (i.e. vascular resistance).

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1. Factors affecting venous return (i.e. VR):

a. The pumping action of the heart:
The capacity of the heart to fill has to exceed the capacity of the
vascular system.
b. Pressure gradient:
• Blood to be able to return to heart, the pressure in peripheral veins,
which pushes blood toward the atrium has to be higher than the
intra-atrial pressure.
• The average pressure in venules and veins in a recumbent position is
called mean circulatory pressure (i.e. MCP) and is ~ 7 mm Hg.
• The pressure of right atrium in recumbent position is ~ 2 mm Hg.
• The pressure gradient needed for venous return equals the difference
between the above mentioned pressures.
c. Respiration:
• During inspiration there is a negative intrathoracic pressure and a
positive intra-abdominal pressure, this would lead to sucking of
blood by the thoracic veins and increasing the venous return.
• While, during expiration, the negativity of the intrathoracic pressure
decreases, and then the venous return will decrease too.
d. Gravity:
• Effect of gravity is limited to the erect position.
• Venous return would increase from parts above the heart (head,
neck, and shoulders) while will be decreased from parts below the
heart.
• But, the negative effect of gravity would be counteracted by;
1. The valves in the veins.
2. The contraction of skeletal muscles.
3. The suction power of the -ve intrathoracic pressure.

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e. Skeletal muscle contraction:

• Contraction of skeletal will compress the veins and squeezing the
blood toward the heart.
• During muscle relaxation, there is NO regurgitation of blood under
the influence of gravity, thankful to the valves.
f. Blood vessels:
• Dilation of arterioles will lead to shunting of blood rapidly from
arteries to veins → this will increase the VR.
• This may occur in some physiologic situation such as: digestion,
pregnancy, and in warm weather.
• Dilation of capillaries will cause the blood to accumulate in
capillaries → this will decrease the VR.
• This may occur only in circulatory shock, such as allergic shock,
because in normal situation ONLY, 10% of capillaries are open.
• In allergic shock, ALL capillaries are open due to the vasodilating
effect of Histamine.
• Marked dilation of veins → decreases VR, because it leads to
congestion of blood in distended veins.
g. Blood volume:
• Increasing of blood volume as a result of contraction of blood
reservoir by physical exercise → increases VR.
• While decreasing of blood volume, such as in haemorrhage will
decrease VR.

h. Exercise:
During exercise, the contraction skeletal muscles will squeeze the veins
and increase the VR as a result.

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2. Factors affecting contractility:

• The significant factor that affects the ventricular contractility is
Frank- Starling’ law.
• The force of contraction is increased when the initial length of
cardiac muscle fiber is increased during the diastole.
• This allows the heart to pump any amount of blood, which it
receives.
• In other words: Frank-Starling mechanism could be explained as
follows: When the cardiac muscle fiber is stretched, it will respond
by more forceful contraction. This is due to the increased energy
expenditure in the cardiac muscle fiber when it is stretched. So,
increasing venous return → will increase the EDV and causes
stretching of the cardiac muscle fiber → lead to more forceful
contraction.
• Other factors that affect contractility (positive or negative
inotropic factors) will also affect COP (Revise factors affecting
myocardial contractility).
3. Factors affecting afterload (i.e. Peripheral Resistance; PR):
• When the blood is pumped, it faces resistance. This resistance is due

to the arterial blood pressure (i.e. ABP).

• When the ABP suddenly elevates → the contraction of the ventricles

will NOT be powerful enough to pump the blood that has been filled
during diastole → an additional amount of blood will be added to the
EDV (of the next beat).
• Thus, the next contraction will be more powerful, and so on until the

ventricle restore its power, needed to restore the stroke volume,

previously existed before the elevation of blood pressure.

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B) Factors affecting Heart Rate (i.e. HR)

- With constant VR → physiological or moderate changes in HR
DON‘T affect COP.
- But, excessive increase or decrease in HR → ↓COP(with constant VR)
Regulation of Cardiac Output (i.e. COP)
COP is regulated via TWO main mechanisms extrinsic and intrinsic.
I. Extrinsic regulation of cardiac output: via;
1. Autonomic nervous system (ANS).
2. Humoral (i.e. Chemical) factors.
1. Autonomic Nervous System:
• The autonomic nervous system regulates the cardiac output by:
1. Changing the HR.
2. Changing the power of contraction.
3. Altering the circulatory pressure:
• Increased Sympathetic input, due to excitation, exercise, or others
affect the cardiac output by increasing both HR & SV.
• However, increased heart rate → may decrease the filling time of
the heart and decreases the EDV, but in the same time it will
increase the contraction power of the myocardium (increased
sympathetic input increases the contraction power about 60-70%
above the normal), which will decrease the end systolic volume
(ESV) and so the net effect → increased COP.
• The forceful contraction from its side also leads to rapid relaxation
that acts as suction force which causes more filling even during
short diastole.
• At the same time, the increased sympathetic input causes
vasoconstriction and this will increase the mean circulatory
pressure and the venous return.

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• Increased Parasympathetic input in rest will → decreases HR,

but will NOT affect the contractility of the heart (since NO vagal
supply to ventricles) and so, the net effect will be → decreased
COP.
2. Humoral Factors:
• Such as hormones affecting heart & blood vessels (e.g. Epinephrine,
Norepinephrine, Acetylcholine, thyroid hormones, and others).
• Mechanism:
Please, revise factors affecting properties of cardiac muscle.
II. Intrinsic regulation of cardiac output (i.e. COP):
Intrinsic regulatory factors operate by inherent mechanism of cardiac
tissue. They are subdivided into:

a. Heterometric regulation:
• According to Frank-Starling‘s law → when there is an increase in

initial length of the myocardial fiber, this will cause more forceful
contraction of the fiber.
• So, expansion of the ventricles caused by increased filling of blood

in diastole (i.e. ↑ EDV) → produce more powerful contraction of the

ventricles.
b. Homeometric regulation:
• The term homeometric = NO change in the length of muscle fibers

before contraction.
• It is a steady state mechanism starts after the heterometric

mechanism (~ 5 minutes later) → a gradual return of EDV to its

normal level, with rapid decrease of ESV, so the SV remains
increased.

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• This phenomenon is related to the previous one (i.e. heterometric),

which is caused by increased power of contraction, and better

metabolic state in the ventricles, and decreased peripheral resistance
(due to maximum rate of arterial pressure, which has developed
during the previous phenomenon).

THE CARDIAC RESERVE (i.e. CR)

Definition:
• The cardiac reserve power is the difference between the resting cardiac

power and the maximum cardiac power (e.g. during severe muscular
exercise).
• Significance: The heart uses its reserve power when the work load on

the heart increases.

Mechanisms of cardiac reserve:
1- The heart rate reserve:
• The heart rate can increase from a resting 75 beats/min up to 200
beat/min during severe exercise.
• This may occur through; sympathetic stimulation, stretch of the SA
node, and rise in body temperature.

2- The stroke volume reserve:

The stroke volume can be increased by different mechanisms:
i. dilatation: The EDV increases, then by starling`s law the strength of
contraction increases, thus increasing the stroke volume. It lasts for
only few seconds
ii. Sympathetic stimulation: it occurs to face short term increase in
work load e.g. muscular exercise.

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Sympathetic stimulation increases the force and velocity of myocardial

contraction. This can increase the stroke volume from 75ml up to 125
ml/beat
iii. Hypertrophy: Hypertrophy of the heart occurs when it is exposed
to repeated or prolonged high work load, e.g. repeated muscular
exercise or hypertension.
Limitations of the cardiac reserve mechanisms:
The cardiac reserve mechanisms have their limits, beyond which the
cardiac power decrease rather than increase
(1) The heart rate limits: heart rate lower than 35 beats/min or higher
than 200 beats/min, decreases the pumping capacity (stroke volume) of
the heart.
(2) The dilatation limit: Excessive dilatation of the heart that exceeds
the limits of starling`s law will lead to weakening rather than
strengthening of myocardial contraction.
(3) The hypertrophy limit: Hypertrophy of the heart is NOT
accompanied by parallel increase in the coronary blood flow (blood
supply of cardiac muscle). So ischemia of cardiac muscle will occur
with subsequent fibrosis of myocardial cells leading to weakening of
power contraction.
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(Physiology)
HEART FAILURE

Definition:
It is a clinical syndrome in which the heart can't maintain an adequate
cardiac output for the normal body metabolic needs. This usually occurs
with failure of the compensatory mechanisms.
Cardiac output (COP) = stroke volume (SV) X heart rate (HR)
Becomes insufficient to metabolic body needs
SV determined by preload, afterload and myocardial contractility.

Ejection Fraction:
➢ One of the measurements used by the physicians to assess how
well a patient's heart is functioning.
➢ Ejection referred to the amount of blood that is pumped out of the
hearts mean chamber during each heartbeat.
➢ Fraction referred to the fact that, even in the healthy heart, some
blood always remains in this chamber after each heartbeat.
➢ An ejection fraction is the percentage of blood within the chamber
that is pumped out with every heartbeat.
Normal EF = 55- 75%.

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Grades:
HF may be mild (Signs of HF appear only during activity) or severe
(Signs of HF appear during rest). It may also be acute or chronic.

Classification of heart failure:

I) According to EF:
Systolic heart failure: Decrease contractility. As in myocardial
infarction (left ventricular EF < 40%).
Diastolic heart failure: Impaired ability of the ventricle to relax and fill
→decrease filling→ ↓ SV and COP . EF is normal as there is no much
blood to eject

II) According to clinical presentation:

For practical purposes, HF can also be classified according to the
clinical presentation into:
• Acute heart failure:
- Defined as the rapid onset of symptoms and signs of HF due
to an acute deterioration of cardiac function in the presence
or absence of previous cardiac disease.

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• Chronic heart failure:

- This is a chronic state when patients have stable symptoms .
III) According to predominant side affected:
Heart failure can be classified into Left sided and right sided heart
failure.
Each one of them can be systolic HF, diastolic, or mixed HF.

Left sided heart failure (Left ventricular failure):

• The commonest causes of it are coronary artery disease, chronic
arterial hypertension, and certain valvular diseases e.g. aortic stenosis and
incompetence.
• Its main manifestations are:
1. Left ventricular dilatation.
2. Pulsus alternans.
3. Gallop rhythm.
4. Signs of forward failure: Due to decreased cardiac output.
They include; muscle weakness and rapid fatigue (due to muscle
hypoperfusion), cold extremities, skin pallor and peripheral cyanosis.
5. Signs of backward failure: Due to pulmonary congestion (increase in
pulmonary venous and capillary pressures) and includes:
a) Dyspnea: This first occurs on exertion, but later it become continuous.
It may occur in the recumbent position (orthopnea) or as severe night
attacks (cardiac asthma).
b) Cough (due to irritation of the congested bronchial mucosa).
c) Pulmonary oedema: (may be fatal in acute cases) this occurs due to
rise of the pulmonary capillary hydrostatic pressure.
d) Pulmonary hypertension.

Right sided heart failure (right ventricular failure):

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• It can occur on top of Left sided heart failure (due to loss of left
ventricular aid) or secondary to pulmonary hypertension, pulmonary
valve stenosis, and lung diseases that cause Cor pulmonale (i.e.
congestive heart failure 2ry to a pulmonary disease).
• Its main manifestations are:
a) Right ventricular dilatation.
b) Signs of forward failure: The same as those of left ventricular failure
because the COP is also decreased.
c) Signs of backward failure: These are the results of systemic
congestion and include: -systemic edema - Enlargement of the liver -
congested neck veins.

Edema in lower limbs in right sided heart failure

N.B.:
Can you have right ventricular failure without left ventricular failure?
Yes.
What is this called? Cor pulmonale

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Physiological Compensatory responses to HF:

a) Cardiac responses:
• Increased of EDV due to low COP.
• Increase in cardiac contractility.
• Cardiac hypertrophy.
b) Neuro-hormonal responses:
• Stimulation of sympathetic nervous system: Helps increase in COP
and ABP.
• Renal responses: Through activation of renin-angiotensin system.
• The atrial natriuretic peptide (ANP): It is secreted as a result of
stretch of the atrial wall. It prevents excessive salt and water
retention in the body.

Exhaustion of the compensatory mechanisms:

Without proper treatment, the compensatory mechanisms will be
gradually exhausted as a result of the following:

1. With prolonged sympathetic activity, its +ve inotropic and

chronotropic effects will be gradually decreased and heart will depend
only on the Frank-Starling mechanism.
2. The Frank-Starling mechanism also has a limit beyond which it fails.

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3. Cardiac hypertrophy also has a limit, beyond which the ability of the
hypertrophied muscle to generate force is decreased.
4. The prolonged vasoconstriction produced by sympathetic over
activity and angiotensin II increases the cardiac afterload, and this
decreases the cardiac contractility.
5. When the COP is decreased as a result of exhaustion of cardiac reserve
mechanisms, the excess salt and water retention become a disadvantage,
and its persistence represents an overload to the heart.

Physiological basis of treatment of heart failure:

Management of HF aims at decreasing the cardiac work and improving
the power of cardiac contractility. This can be achieved as follows:
A) Treatment of the underlying cause e.g. valve replacement.
B) Treatment of the precipitating factors e.g. anaemia.
C) General measures:
- Rest until clinical improvement (to decrease cardiac work).
- Low-salt diet (to decrease fluid retention in the body).
D) Use of drugs:
➢ Prevention of myocardial injury and damage due to prolonged
exposure to stretch, adrenergic stimulation, angiotensin II, and
aldosterone. This can be achieved by:
▪ Beta adrenergic receptors blockers.
▪ Angiotensin converting enzyme inhibitors (i.e. ACE inhibitors).
▪ Angiotensin receptor blockers.
▪ Aldosterone antagonists.
➢ Diuretics: ↑ salt and water excretion →↓blood volume→↓cardi
➢ acwork.
➢ Cardiac glycosides: To improve myocardial contractility.

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(Physiology)

HEMODYNAMICS
Definition:
• The study of the physical variables related to the containment and
movement of blood in the cardiovascular system is called
hemodynamics.
• Normal blood flow can be thought of as simple laminar (streamline)
flow in most instances.
• Laminar flow is characterized by a gradient of flow lines representing
different blood velocities at different locations in the tube.

Types of blood flow:

1. Laminar (streamline): this is the normal smooth flow of blood. It is

silent.
2. Turbulent: it produces sounds (= bruit or murmurs) which can be
heard by stethoscope.

Types of blood flow

Causes of laminar (streamline) flow:
1. Wall stress (i.e. shear stress). When a fluid, in this case, blood, flows
through a pipe → friction exists between the fluid and the wall of the

tube → This friction decreases the velocity of the blood closest to the
wall (hence the shorter lines on the diagram closer to the tube wall).

2. Law of Reynolds number.

Reynolds number:
It represents a correlation between the different factors which influence
the production of turbulence inside a vessel as follows:
Re= 2rvp/ Ƞ

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Where Re = Reynolds number; r = radius of the vessel; V = velocity of

blood
P (rho) = density of blood; Ƞ (eta) = viscosity of blood

• At Re number below 400 → there is NO turbulence.

• Turbulence increases gradually with higher numbers until flow is
completely turbulent at Re number 2000 or above.

Compliance
When blood is pumped from the heart, the blood vessels do not act as
complete rigid tubes. They expand and contract with the pressure changes
due to their elastic nature (compliance).
C = ΔV/ΔP
Where, C = the compliance, V = volume, and P = pressure.

Turbulent Flow
• In contrast to streamline flow, turbulent flow occurs when fluid
particles move randomly in all directions in a flow tube or vessel.
• Such flow requires more energy or pressure than streamline flow.
• Turbulent flow occurs when Reynolds‘ number exceeds 2,000.
The Blood Flow:
The blood flow (F) in blood vessels is directly proportionate to the
pressure gradient and indirectly proportionate to the peripheral
resistance:
Pressure gradient Mean systemic BP
F= So, COP =
Peripheral resistance Peripheral resistance
So, Mean systemic BP = COP X peripheral resistance

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Factors affecting the Peripheral Resistance (R):

1. Diameter of blood vessels (especially the arterioles):
• It is inversely proportional to the arteriolar diameter.
• Any factor that may cause vasoconstriction or vasodilation will
affect the blood pressure by increasing or decreasing it respectively.
2. Viscosity of blood:
• It is 5 times more than the viscosity of water.
• It is due to plasma proteins, and the blood cells.
• Viscosity is increased by dehydration and polycythemia, and
decreased by anemia and hypoproteinemia.
3. Length of blood vessels:
It is constant in the human organism, so it would not involve in the
determinants.
Poiseuille-Hagen formula
8LȠ
R = ---------
𝜋r4
R = resistance of the vessel to the flow
L = length of the vessel
Ƞ (eta) = viscosity of the fluid
𝜋(𝑝i) = circle constant (3.14)
r = radius of the vessel
• The resistance to the flow of a fluid through a vessel is directly
proportionate to the length of the vessel and the viscosity of the fluid
but inversely proportionate to the fourth power of the radius of the
vessel.

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VELOCITY OF BLOOD FLOW

• It is calculated by dividing the blood flow rate / cross sectional area.
• In the aorta the blood flow rate (COP) is about 90 ml/sec and its cross
sectional area is 4.5 cm.
• So, VBF = 90/4.5 = 20 cm/sec.
• VBF is slow in capillaries (0.02 cm/sec) as the cross sectional area of
capillaries is wide (4500 cm).

Blood Flow Rate (BFR)

BFR is the volume of blood passing through blood vessels of an organ in
one minute (ml/min).
BFR can be measured by:
1. Using the electromagnetic or ultrasound Doppler flow meter.
2. Applying the Fick's principle
3. Plethysmography.
4. Special method: RBF can be determined using the clearance of PAHA
or Diodrast. PBF can be measured by Fick‘s principle.

The Critical Closing Pressure:

• When the pressure inside a small blood vessel (i.e. intraluminal
pressure) is decreased → the blood flow is proportionally decreased
till it stops.
• The intraluminal pressure at which blood flow stops is called the
critical closing pressure.
The mechanisms of ↑ BFR to an active organ (e.g. during ME) are:
1. Local VD of arterioles in active muscle by:
a) Metabolites.
b) Loven‘s Reflex.
c) ↑ Sympathetic activity.
d) Warming of active muscles.

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2. Increased ABP.
3. Redistribution of blood through:
The same mechanisms mentioned above that cause local VD.
4. Increased COP.
5. Muscle Pump.
6. Contraction of the spleen.
The Circulation Time (CT):
1. Arm to Lung CT.
2. Arm to Tongue CT.
*************************************************************************************************

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(Physiology)
BLOOD PRESSURE AND THE FLOW IN
ARTERIES AND ARTERIOLES
Arteriolar diameter controls:
1. Peripheral resistance
2. Blood flow to tissues.
Arteriolar diameter is controlled by:
I. Local Factors.
II. Central Factors.
I. Local Factors:
1. O2 Supply: O2 demand theory: ↓ O2 → VD of arterioles.

2. Metabolites as adenosine, CO2, H+ and lactic acid → VD of

arterioles.
3. Local Temperature: ↑ temp. → VD of arterioles.

4. Autoregulation: adjust BF nearly constant: *Metabolite Theory.

*Myogenic Theory.
5. Locally Released Paracrine Substances as:
- Serotonin and thromboxane A2.
- PGI2 - EDRF - Endothelin.
II. Central Factors:
1. Hormonal Regulation:
a. Circulating VC: Catecholamines – vasopressin – angiotensin II.
b. Circulating VD: Atrial natriuretic peptide –vasoactive intestinal
peptide- kinins.
2. Neural regulation:
a. VC nerves: Sympathetic.
b. VD nerves: Parasympathetic and sympathetic cholinergic.

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Functions of Vascular Endothelium

• It is smooth to prevent intravascular coagulation (i.e. IVC).
• It secrets:
- EDRF - Endothelin - PGI2
- Thrombomodulin - PDGF - IL (1 & 6)
Active & Reactive Hypermia
(AH & RH)
Active hyperemia (AH) Reactive Hyperemia (RH)
• Increase in LBF that occurs in an • Increase in LBF that occurs after
active tissue temporary occlusion of blood
supply.

Vasomotor Centers
The Vasomotor Centers:
• Present in MO.
• Control the diameter of arterioles.
• They are bilaterally represented.
• Intimately connected and show reciprocal relationship.
• Each VMC is composed of vasoconstrictor center (VCC) and
vasodilator center (VDC).
1. VCC:
• It is more powerful than the VDC.
• It is in a state of continuous activity called VMT.
• It sends continuous impulses to LHCs of all thoracic and upper 2
lumber segments of spinal cord (spinal VMC).
• All VC nerves in the body are sympathetic except those supplying
the coronaries

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2. VDC:
• The VDC is inactive under resting conditions.
• The VDN are of three types:
a. Parasympathetic VDN.
b. Sympathetic VDN.
c. Antidromic fibers.
Factors affecting the VMC:
The VMC is affected by the following factors:
(A) Nervous Factors.
(B) Chemical factors.

ARTERIAL BLOOD PRESSURE (i.e. ABP)

Definitions:
Arterial blood pressure (ABP):
• It is the lateral force exerted by moving column of blood on the wall of
lateral arteries.
• It is necessary to keep the blood flowing, as it also provides enough
hydrostatic pressure inside the capillaries to help the exchange of
nutrients and vital gases as well as to form the interstitial tissue, urine,
etc.
• ABP reaches its maximum during the systole (systolic pressure) and
its minimum during the diastole (diastolic pressure).

Systolic blood pressure (SBP):

• Caused by rapid ejection of blood into the aorta.
• It ranges between 90-140 mmHg.
• Two thirds of the ejected blood during the cardiac cycle distends the
arteries and raise the pressure, while only one third leaves the arteries
in blood flow.

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The diastolic blood pressure (DBP):

• Caused by recoiling of the stretched (during systole) arterial walls this
will keep the blood pressure high enough to drive the blood through the
arterioles.
• It ranges between 60-90mmHg.
Pulse pressure (PP):
• It is the difference between SBP and DBP.
• PP = SBP - DBP = ~ 40 mmHg.
Mean systemic pressure (MSP):
• It is the average pressure in the systemic arteries throughout the cardiac
cycle.
• Mean systemic pressure = diastolic pressure + 1/3 pulse pressure.
• It is ~ 93 mmHg.
Determinants of ABP:
• Blood pressure is directly proportional to COP & total PR.
BP = COP X TPR
• As we know COP is determined by HR and SV, so any factors,
affecting one or both of them, will affect the arterial blood pressure.
• Changes in SV with HR kept constant, affect systolic more than
diastolic BP.
• The peripheral resistance is determined by many factors, including:
1. Diameter of blood vessels (especially the arterioles):
It is inversely proportional to the arteriolar diameter. Any factor that
may cause vasoconstriction or vasodilation will affect the blood
pressure by increasing or decreasing it respectively.

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2. Viscosity of blood:
It is 5 times more than the viscosity of water. It is due to plasma
proteins, and the blood cells. Viscosity is increased by dehydration
and polycythaemia, and decreased by anaemia and
hypoproteinaemia.
3. Length of blood vessels:
It is constant in the human organism, so it would NOT be involve in
the determinants.
Physiologic Variations of Blood Pressure:
1) Age:
ABP varies with age. In the new born it is about 80/40 mmHg. At the age
of 5 years it is about 100/60 mmHg. At the age of 20 years it is about
120/80 mmHg. By aging the ABP increases and at the age of 60 it is
about 150/90 mmHg.
2) Gender:
In female it is slightly lower under the age of 45 years.
3) Race:
The BP of oriental people is lower than that of American and European
due to different climate, stress of life and high cholesterol diet of western
people.
4) Body built:
ABP is higher in obese people.
5) Meals:
After meals, there is a vasodilation in the splanchnic area, which will
increase both the venous return and cardiac output, so it will increase the
ABP especially the systolic.

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6) Gravity:
• Due to gravity when a person stand the blood pressure in any vessel
above the heart is decreased for 0.74 mm Hg for each one cm

distance, while the pressure in any vessel below the level of the heart
is increased for 0.74 mm Hg for each one cm distance.
• This effect of gravity equals the weight of blood column. e.g. The
ABP in a large artery in the foot which is 100 cm below the level of
the heart will be 174 mm Hg .
• This is due to 74 mm Hg increase in arterial blood pressure due to
gravity in addition to 100 mmHg mean arterial blood pressure. 100 +
(100x0.74) = 100 + 74 = 174 mmHg. While the ABP in a large artery
in the head, which is 50 cm above the level of the heart will be: 100 -
(50 X 0.74) = 100 – 37 = 63 mmHg.

7) Site of measurement:
In recumbent position: the pressure in arteries of the lower limb is higher
due to the larger diameter and because they constitute direct continuation
of the aorta. ABP is slightly higher in the right arm in right-handed
people.
8) Emotions:
Due to increased sympathetic activity, strong emotions increase the ABP
especially the systolic.
9) Exercise:
The systolic is increased due to increased cardiac output and
vasoconstriction. The diastolic is firstly decreased due to the vasodilation
of muscular arterioles in the active muscles, and then it may be increased
slightly.

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10) Sleep:
ABP is decreased during sleep. In the stressful dreams it is increased.
11) Respiration:
In the respiratory cycle, the blood pressure is increased during the late
phase of inspiration and the initial phase of expiration. It is decreased
during the late phase of expiration and the initial of inspiration.
Explanation:
• During the beginning of inspiration the intrathoracic P is negative and
this will increase the VR, but the blood returning to the left heart
decreases due to the increasing of the capacity of pulmonary circulation.
• During the late inspiration the respiratory center stimulates the
vasomotor center in medulla oblongata, leading to increase in ABP.
• During the beginning of expiration the pulmonary capacity decreases
due to the positive intrathoracic pressure, and increases blood returning
to the left heart.
• In the late expiration the discharge from vasomotor center decreases
and consequently the blood pressure decreases.

Regulation of Arterial Blood Pressure

I. Short-term regulatory mechanisms.
II. Intermediate-term regulatory mechanisms.
III. Long-term term regulatory mechanisms.
I. Short-term regulatory mechanisms:
• Occurs through different circulatory reflexes within few seconds

after the change in arterial blood pressure and last for few minutes to
hours then decline.
• These reflexes adjust the arterial blood pressure through adjustment

of vasomotor center and cardiac inhibitory centers from the

following receptors:

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1. Baroreceptors:
• They are found in carotid sinus and aortic arch. They are normally

stimulated by normal ABP. These receptors discharge impulses via

carotid sinus nerve (a branch of glossopharyngeal nerve) and aortic
nerve (branch of vagus nerve) to stimulate the cardioinhbitory center in
medulla oblongata to cause vagal tone.
• When the pressure is increased, the response of the stimuli caused by

these receptors is: decrease in heart rate, vasodilation of the arterioles

in skeletal muscles and venodilation (cause decrease in venous return).
The final result of these responses is: decreasing cardiac output and
decreasing of peripheral resistance, and thus decreasing of arterial
pressure.
• When the Blood pressure is decreased, opposite effects occur:

Increased power of contractility, arteriolar vasoconstriction,

venoconstriction, secretion of catecholamines: The final result
increasing both: cardiac output and peripheral resistance, and thus
increasing ABP.
The baroreceptors have the following properties:
• Rapid response (within seconds), respond much more to rapid changes
than to gradually developing changes of BP.
• Negative feedback mechanisms.
• Stimulated at pressure levels of 50 mmHg up to 180 mm Hg.
• Slowly adapting receptors.

2. The peripheral chemoreceptors:

• They are located in the carotid & aortic bodies. They are sensitive to

changes in blood gases especially the decrease pressure of O2.

• When the BP drops below critical levels (below 60 mm Hg) they are

stimulated and send nerve impulses to both respiratory center and

vasomotor center in the medulla oblongata.

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• This will lead to vasoconstriction, increased heart rate, increased

respiratory rate and increased catecholamine concentration.

• The net result: returning of ABP toward its normal level.

3. Atrial baroreceptors (low-pressure receptors):

• They are stretch receptors found in the wall of atria and pulmonary

arteries.
• They are stimulated in response to changes in blood volume. When

there is an increased blood volume in the atria, the atrial baroreceptors

are stimulated and this leads to vasodilation to decrease the ABP.
Vasodilation of afferent arteriole in the kidney causes increase in
glomerular filtration rate, and the loss of fluid by the kidney.
• Atrial baroreceptors also send impulses to the hypothalamus to

decrease the secretion of ADH → thus decrease the reabsorption of

water from the renal tubules and increase water loss by the kidney
more and more. Opposite response occur when the blood volume is
decreased.
4. Ischemic response:
• This response acts only at a very low level of ABP starts at 60 mm Hg

and reaches its highest degree of action at 20 mm Hg.

• Its mechanism of action occurs as follows:

Marked decrease in blood pressure decreases the blood flow and
causes cerebral ischemia. Local ischemia causes strong stimulation of
vasomotor center and leads to vasoconstriction and tachycardia, and
thus leads to increased ABP.
Cushing`s reaction: It is a special type of ischemic response that results
from increased intracranial pressure (as a result of brain tumour or
intracranial haemorrhage) → This will compress the intracranial vessels
and thus causes local ischemia that will causes severe vasoconstriction
and then elevation of ABP.

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II. Intermediate-term regulatory mechanisms:

Start within few minutes and are effective for few hours to days. Most
important are:

1) Capillary fluid shift mechanism:

• Correct the changes of blood pressure by shifting of fluid between
the blood plasma and interstitial fluid.
• When there is an increase in blood volume, there is an increase in
blood pressure which will increase the capillary pressure at the
arterial end (which leads to increase the rate of fluid filtration), in the
same time it will increase the capillary pressure at the venous end
and thus decrease the rate of the fluid reabsorption.
• The net result: decrease the plasma volume and thus decrease the
arterial blood pressure. When the blood volume is decreased, the
opposite effect occurs: Decrease blood volume will lead to a
decrease in blood pressure, and decrease pressure in the capillaries,
and this will decrease rate of filtration at the arterial end, and
increase the rate of reabsorption at the venous end, and thus increase
the blood volume and ABP.

2) Renin -angiotensin -aldosterone system:

• When the blood pressure is decreased, this will decrease the renal
blood flow, and this will stimulate the juxtaglomerular apparatus in
the kidney to release Renin (a proteolytic enzyme).
• Renin in blood acts on a plasma globulin called Angiotensinogen
(inactive protein) and activates it to Angiotensin I.
• Angiotensin I is then activated by Angiotensin Converting Enzyme
(ACE) in the lungs by converting it to Angiotensin II.

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Angiotensin II has the following effects:

a. Vasoconstriction (this will increase the peripheral resistance and thus
increase the arterial blood pressure).
b. Stimulates the release of Aldosterone from the renal cortex.
Aldosterone acts on the distal renal tubule to enhance reabsorption of
sodium .The water will follow sodium as a result of osmosis and thus
the blood volume will be increased and thus the blood pressure.
c. Stimulates the ADH release and thus increase water reabsorption in
kidney. This will lead to increase in blood volume.

Renin -angiotensin -aldosterone system

3) Atrial Natriuretic peptide:
• When arterial blood volume (and respectively blood pressure) is
increased, the blood will stretch the atrial wall. This will release ANP.
ANP acts on the kidney to increase excretion of sodium and water,
which will decrease the blood volume and thus return blood pressure
to normal.
• ANP also promotes vasodilation, and thus decrease the peripheral
resistance and return the blood pressure to normal.

4) Stress- relaxation mechanism:

• When the pressure in blood vessels becomes too high the vessels
become stretched and keeping on stretching more and more for
minutes or hours, as a result the pressure in the vessels falls toward
normal.
• On the other hand, when the pressure falls inside the vessels will
decrease the tension in its wall, the wall then will recoil and
gradually contracts.

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III. Long-term regulatory mechanisms:

Slow mechanisms operate through the kidney. They start within hours
and last fully active as long as required. They regulate ABP by
adjusting body fluid volume, including;
1. Renal- body fluid system:
Increased blood pressure increases the rate at which the kidney excretes
water and salt. This is called pressure diuresis, and pressure natriuresis
.This cause marked loss of extracellular volume and decrease arterial
blood pressure.
2. Accessory mechanisms:
Enhancing water and salt excretion by: decrease secretion of renin,
aldosterone and decreased sympathetic signals to the kidney.

Clinical Physiology:
• Pathologically increased arterial blood pressure is called hypertension,
while pathologically decreased blood pressure is called hypotension.
• Hypertension is the pathologically increased blood pressure: It has
TWO forms:
Primary (Essential) hypertension:
The most common (90%): Without known underlying cause, but
probably due to atherosclerosis.

Secondary hypertension: Due to underlying cause, which could be:

1. A tumour like pheochromocytoma, a benign tumour in the
chromaffin cells in the adrenal medulla that secrete epinephrine and
causes malignant hypertension.
2. Endocrine conditions.
3. Renal disease: such as renal artery stenosis.
4. Drugs and other factors.

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(Physiology)
Microcirculation (capillary circulation)
Capillary Functions:
1. Maintain constant communication between plasma and interstitial fluid.
2. Speeds the distribution of nutrients, hormones, and dissolved gases
throughout tissues.
3. Assist the movement of insoluble lipids and tissue proteins that are
impermeable.
4. Flushes bacterial toxins and other chemical stimuli to lymphoid tissue
and organs that provide immunity.
5. Share in the formation of PR.
6. Capillary tone is important to keep VR.
Measurement of Capillary Pressure:
Direct puncture method:
A very fine glass pipette is connected to sensitive saline manometer and
introduced into the nail-bed capillary of the finger using strong illuminated
microscope. The pressure at the arteriolar end is 30-40 mmHg and at the
venous end is 10-15 mm Hg.
Alteration Phenomenon of Capillaries
(i.e. Vasomotion, Capillary Tone):
• Normally, 10% of capillaries are opened and 90% are closed.
• There is alteration of opening of capillaries every few seconds to few
minutes.
The mechanism of this phenomenon is as follows:
• Hypoxia and metabolites around closed capillaries leads to its opening.
• When metabolites are removed, the capillaries are closed again.
• This occurs in an alternating pattern so that at any time 10% are
opened and 90% are closed.

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Blood capillary circulation.

Factors Affecting Capillary Circulation:
I. Nervous Factors:
The nervous effect is poor as few VC and VD nerve fibers may reach a
certain number of capillaries.
II. Chemical Factors:
1) Vasopressin (ADH) → VC of capillaries.
2) Metabolites → VD of capillaries.
3) Adrenaline and Noradrenaline → VC of capillaries.
4) Acetyl Choline → VD of capillaries.
III. Mechanical Factors:
1) Diameter of arterioles.
2) Venous Pressure.
3) Gentle stroking of skin → white line response.
4) Heavy stroking of skin → tripple response.
5) Gravity.
IV. Physical Factors:
1) Warming → capillary dilatation.
2) Cooling → capillary constriction.
Capillary Fragility (CF):
• Although the capillary are very delicate, they are normally NOT
fragile and do not rupture easily.

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• This is due to the low tension in the capillaries, as the radius is

extremely small (according to Laplace Law).
• The CF is increased in many diseases as scurvy and purpura.
Testing the capillary fragility (Hess Test = Tourniquet Test):
• The sphygmomanometer cuff is wrapped around the arm and the ABP
is measured.
• The cuff is inflated to a pressure midway between SBP and DBP for 8-
10 min.
• The number of petechiae is counted at the cubital fossa in a circular
area of 5 cm in diameter.
• CF is considered high if the number is more than 10.
• The test is +ve in some diseases as scurvy and purpura.
Exchange of Materials across the Capillary Wall:
Transcapillary exchange of materials occurs through:
1. Diffusion.
2. Filtration.
3. Cytopempsis
4. Diapedesis.
1. Diffusion:
• This is the process by which substances move down a concentration
gradient.
• Water and water-soluble substances diffuse only through the pores,
while fat-soluble substances diffuse across the whole capillary wall.
• It is directly proportional to:
a. Concentration gradient.
b. Surface area.
c. Capillary permeability.
d. Water and lipid solubility.
e. Temperature.
• It is inversely proportional to:

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a. Thickness of the capillary wall.

b. Molecular size of the diffused substance.
2. Filtration (transcapillary filtration):
• This is the process by which fluids and the dissolved solutes are
forced through the capillary membrane due to a difference in
hydrostatic pressure.
• So, it is controlled by:
a. The capillary hydrostatic pressure (CHP).
b. Tissue hydrostatic pressure (THP).
c. Osmotic pressure of plasma proteins (OP).
d. Tissue colloid osmotic pressure (TOP).
• So, the net forces of fluid movement through the capillary wall
are:
A. Forces moving fluids out (+ve forces, filtering forces): CHP +
TOP.
B. Forces moving fluid in (-ve forces, absorbing forces): (OP +
THP).
• At the arteriolar end, the net force =
(35 + 3) – (25 + 3) = + 10 mm Hg.
• At the venular end, the net force =
(15 + 3) – (25 + 3) = - 10 mm Hg
3. Cytopempsis (Transcytosis or Vesicular Transport):
• This is the mechanism of transport of large molecules across the
capillary membrane.
• The large molecules are transported by endocytosis at the endothelial
side followed by exocytosis at the interstitial side.
• Normally, small amounts of proteins are transported by this
mechanism.

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4. Diapedsis.
• This is the mechanism by which WBCs (Leucocytes) are transported
across the capillary membrane to areas of inflammation.
Capillary Permeability:
• The endothelial wall of capillaries acts as a semipermeable membrane.
• It allows the passage of substances of small MW.
• Larger molecule cannot pass or pass with difficulty.
• The capillary permeability varies in different organs depending on
their function.
Factors Affecting Capillary Permeability:
1. Plasma Ca2+ Concentration.
2. Blood pH.
3. Capillary dilators.
4. Plasma proteins.
5. Vitamin C.
6. O2 lack.
7. Temperature.
8. Capillary poisons.
9. Glucocorticoids.
Vascular Reactions & Colour of Skin (i.e. Dermographism):
I. Tripple Response.
a. Red Line.
b. Flare.
c. Wheal.
II. White Line response.
III. Reactive Hyperaemia.

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TISSUE FLUID & LYMPH

The factors maintaining lymph flow:
1. Tissue fluid pressure.Respiratory movement.
2. Gravity.
3. Muscle pump.
4. Arterial pulsation.
5. Lymph hearts (in animals).
FACTORS INCREASING LYMPH FORMATION AND FLOW:
1. Capillary permeability.
2. Increased activity.
3. Increased venous pressure.
4. Second class lymphagogues.
FUNCTIONS OF LYMPH:
1. Carriage of proteins, metabolites and colloids from tissue spaces to
blood again.
2. Carriage of bacteria to lymph nodes.
3. Carriage of absorbed fatty acids and fat soluble vitamins
4. Prevention of accumulation of tissue fluids.
5. Defensive function.
EDEMA
Definition:

Abnormal accumulation of fluids in the body which may be intracellular

or extracellular.
Types:
1) Intracellular.
2) Extracellular.
Q: mention the causes and mechanisms of each type?
********************************************************

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(Physiology)
Venous Circulation
Functions of Veins:
1) Carriage of waste products.
2) Carriage of nutritive substances.
3) Carriage of O2 from lungs to heart.
4) Sharing in regulation of ABP and COP

Innervation of veins:
• VC supply from sympathetic fibers to veins of skin and splanchnic
area.
• VD supply is not sure. Dilatation of veins may result from inhibition of
sympathetic VC fibers.

Central Venous Pressure (CVP):

• It is the mean pressure in the right atrium and big veins opening into it.
• It is an important force for cardiac filling.
• The CVP varies from 1-5 mmHg.
• It decreases with hypovolemia and increases with hypervolemia.

MEASUREMENT OF VENOUS PRESSURE:

1) Invasive Method:
By introducing a needle connected to citrated manometer into the vein.
2) Hand to Heart Method:
The hand of the patient is raised in air till the veins of the dorsum of the
hand just collapse. Normally, this occurs when the hand is at the level of
the Manbrusternal junction.

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Hand to Heart Method

3) Measurement of EJV filling:
The patient lies in semi-sitting position (at an angle of 45O) and the degree
of EJV filling is noted.

FACTORS AFFECTING VENOUS PRESSURE:

1) Gravity.
2) Rate of inflow of blood to veins
3) Rate of outflow of blood from veins.
4) Tone of venous wall.
5) Respiratory movements.
6) Muscular exercise.
1. Gravity:
• In the recumbent position → gravity has NO effect on venous
circulation.

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• Standing or sitting → ↑ BP in veins below the heart and ↓ BP in

veins above the heart.
• ↑ Venous Pressure due to gravity leads to:
a. Edema.
b. Varicose veins.
c. ↓ VR, ↓ COP and ↓ ABP.
2. Rate of inflow of blood to veins

3. Rate of outflow of blood from veins

the rate of outflow is more than the rate of inflow → ↓ venous
pressure.
4. Tone of venous wall
Tonic contraction of smooth muscles in venous wall keeps normal
venous pressure.
5. Respiratory movements
• Inspiration → descend of the diaphragm → increased VP in
abdominal veins.
• Forced expiration → increased VP of thoracic veins.
6. Muscular exercise
Contracting muscles press on their veins and increase VP.
Venous Pulsation:
Veins show pulsation in the following conditions:
1. Conduction of pulse pressure from arterioles to corresponding
veins.
2. Transmission of pulsation from right atrium to jugular veins.

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Mean Circulatory Pressure (MCP):

• The MCP determines the degree of filling of vascular system with
blood.
• Its level is ~ 7-8 mm Hg.
• Its level is controlled by the relation between the capacity of CVS and
the volume of the circulating blood.
• So, the increase in the capacity of the venous system and/or the
decrease in circulating blood → ↓ in MCP and vice versa.

Venous Return
Venous return (i.e. VR) is the quantity of blood flowing from large veins
into the right atrium each min.
Factors controlling VR:
• Skeletal muscle pumps → ↑ venous return.
• Pressure drop during inspiration → ↑ venous return
• Forceful expiration (Valsalva maneuver) → ↓ venous return.
• ↑Blood volume → ↑ venous return.
• ↑Pressure gradient → ↑ venous return.
• ↑Venous pressure → ↑ venous return.
• Gravity → ↓ venous return.

*******************************
******************************
**

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(Physiology)
CORONARY CIRCULATION
The heart is supplied by two arteries:
1. Right coronary artery:
It gives marginal artery and posterior descending Branch.
2. Left coronary artery:
• It gives left anterior descending (LAD), marginal artery and
circumflex Artery.
• The two coronary arteries arise from coronary sinus at the base of
the aorta. There are small anastomoses between them.
Coronary venous drainage:
• There are superficial and deep systems.
• The superficial system is formed of the coronary sinus and the
anterior cardiac vein. The coronary sinus drains about 60% of the
cardiac venous blood.
• Deep system: the most important is the besian veins that drain small
amount of the cardiac venous blood in the all chambers of the heart.
Innervation of coronary vessels:
1.Vagal VC nerve supply.
2.Sympathetic VD nerve supply.
CORONARY BLOOD FLOW
• Coronary blood flow in humans at rest is about 225-250 ml/minute,
about 5% of cardiac output.
• At rest, the heart extracts 60-70% of oxygen from each unit of blood
delivered to heart (other tissue extract only 25% of O2).
Why Heart is extracting 60-70% of O2?
• Because heart muscle has more mitochondria.

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• Up to 40% of cell is occupied by mitochondria, which generate energy

for contraction by aerobic metabolism, therefore, the heart needs O2.
• When more oxygen is needed e.g. exercise, O2 can be increased to
heart only by increasing blood flow.

Blood flow to Heart during Systole & Diastole

During systole:
• The cardiac muscle contracts and compresses the coronary arteries,
therefore blood flow is less to the left ventricle during systole and
more during diastole.
• To the sub-endocardial portion of Left ventricle it occurs ONLY
during diastole.
During diastole:
• The cardiac muscle relaxes completely and the blood flows rapidly
into the coronary arteries.
• Coronary blood flow to the right side is NOT much affected during
systole.
Reason → Pressure difference between aorta and right ventricle is
greater during systole than during diastole → therefore more
blood flow to right ventricle occurs during systole.
Variation in CBF during Cardiac Cycle:
1. Coronary inflow occurs mainly during diastole.
2. It ↓ during systole.
3. CBF is modified by variation in aortic pressure.
4. CBF stops during ICP.
5. Then ↑ during MEP due to ↑ aortic pressure then again ↓ during REP
due to ↓ aortic pressure.
6. CBF is markedly ↑ during diastole.

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Effect of pressure gradient of aorta and different chambers of

heart

• As in systole pressure in left ventricular is slightly higher than in

aorta blood flow reduces.
• On the other hand pressure difference in aorta & right ventricle &
aorta & right atrium is more during systole than diastole, coronary
blood flow is NOT appreciably reduce during systole.
Effect of Tachycardia on coronary blood flow:
During increased HR → period of diastole is shorter therefore coronary
blood flow is reduced to heart during tachycardia.
Factors Affecting Coronary Circulation:
1. Mechanical Factors:
2. Chemical Factors.
3. Nervous Factors.
I. Mechanical Factors:
1. Heart Rate:

• Physiological variation of HR no change in CBF

• Excessive in ↑ in HR → ↓ in CBF
• ↓ HR → ↑ in CBF

2. Arterial Blood Pressure:

• CBF is directly proportionate to ABP especially DBP.

• ↓ DBP → ↓ CBF
3. Cardiac Output:
• COP is α with CBF
• Increased CBF by increased COP is helped by vagal tone
and sympathetic activity.

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4. Mechanical Occlusion:

followed by marked increase in CBF (why?)

5. Phases of the Cardiac Cycle (see before)

II. Chemical Factors:

1. Coronary vasodilators (CVD):
a. Increased CO2 and H+
b. O2 lack
c. Histamine
d. Hormones and drugs
- Adrenaline and NA
- Thyroxine
- Acetyl Choline.
2. Coronary vasoconstrictors (CVC):
- Vasopressin (ADH)
- Noradrenaline
- Angiotensin
III. Nervous Factors
1. Vagal Stimulation: ↓ CBF
2. Sympathetic Stimulation: ↑ CBF
3. ↑ VR: ↑ CBF
4. 4) Distension of the stomach: ↓ CBF (gastro-coronary reflex).
NOTE – Adenosine, which is formed from ATP during cardiac
metabolic activity, causes coronary vasodilatation.

Effect of sympathetic stimulation in intact body:

• Epinephrine and Norepinephrine causes VASODILATATION. HOW?
• But the Direct effect of sympathetic on Coronary arteries is
VASOCOSTRICTION. WHY?

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• Indirect effect:
Stimulation of sympathetic nerves → release of noradrenaline →
increase of HR &force of contraction → Release of vasodilator
metabolites → vasodilatation.
• Direct effect:
When the inotropic & chronotropic effect of noradrenergic discharge
are blocked by Beta adrenergic receptor blocking drugs → injection of
noradrenaline or stimulation of noradrenergic nerves in anaesthetized
animal elicits coronary vasoconstriction.
Thus, the direct effect of noradrenergic stimulation is V.C
Beneficial effect of indirect effect of noradrenergic discharge:
When systemic B.P decreases very low → reflex increase of
noradrenergic discharge → Increase CBF secondary to metabolic
changes in myocardium → In this way circulation of the brain is
preserved while flow to other organs compromised.

Coronary artery heart disease (i.e. CHD)

➢ Ischemic heart disease (IHD) (angina pectoris)
➢ Myocardial infarction
➢ Angina pectoris:
Mechanism: There is reduced coronary artery blood flow due to
atherosclerosis (cholesterol deposition subendocardially → plaque).
Risk factors of IHD:
a. Cigarette smoking
b. Hypertension
c. Diabetes mellitus
d. Increased lipids (cholesterol)
e. Other factors: lack of exercise, anxiety etc.

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IHD:
• IHD is used to describe discomfort in the chest due to decreased
coronary blood flow (transient myocardial ischemia).
• Patient complains of tightness or pain in the middle of chest
(retrosternal) for few minutes. Pain often radiates to inner side of left
arm.
• Pain is precipitated by effort and relieved by rest.
Myocardial infarction (MI):
• It is due to obstruction to the coronary blood flow, at least 75 % of
lumen of coronary artery is blocked by thrombus.
• MI is the common cause of death.
Investigations:
• ECG
• CARDIAC ENZYMES e.g. CK, LDH, TROPONIN etc.
• ECHOCARDIOGRAPHY
• TREADMILL EXERCISE TEST
• THALLIUM STRESS TEST
• CORONARY ANGIOGRAPHY
NOTE:
• ECG CHANGES IN IHD:
ST depression occurs in ECG in respective leads.
• ECG CHANGES IN MI:
ST elevation occurs in ECG in respective leads.
TREATMENT:
• CORONARY DILATORS e.g. NITRATES
• BETA-BLOCKERS
• ANGIOPLASTY (DILATE AREA OF CONSTRICTION)
• STENT
• BYPASS.

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Biochemistry

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(Biochemistry)
LIPOPROTEINS
Definition &functions:
Clusters of lipids associated with proteins that serve as transport vehicles
for lipids in the lymph and blood.

Structure & Classification

• Core of TG and CE
• Surface of phospholipids and some cholesterol
• Apolipoproteins (regulators of LP metabolism)

Outer coat: Apoproteins, Phospholipids, Cholesterol

Inner core: TG, Cholesterol ester
Distinguished by size and density :

• Each contains different kinds and amounts of lipids and proteins

• The more lipid, the lower the density
• The more protein, the higher the density.

General Function
Keep lipids soluble as they transport them in plasma.
1- Provide an efficient mechanism for delivering their lipid content to
tissues
Apo proteins
-are only weakly associated with a particular lipoprotein and are easily
transferred to another lipoprotein of a different class.
-Are either peripheral (can be transferred) or integral (cannot be
transferred).

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-Apo proteins have various functions including:

• They act as activator for the enzymes that act on lipoproteins

• Structural role.
• They are important for receptor recognition to uptake the
lipoproteins by certain tissues.

Plasma lipoprotines:For triacylglycerol transport (TG-rich):

- Chylomicrons:TG of dietary origin .
-VLDL: TG of endogenous (hepatic) synthesis
For cholesterol transport (cholesterol-rich):
-LDL: Mainly free cholesterol
-HDL: Mainly esterified cholesterol

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Types of lipoproteins:
Class Source and Clinical Origin
function significance
chylomicron transport dietary Increase in Intestine
TAG (mainly), deficiency of
cholesterol & lipoprotine lipase
cholesterol
esters from the
intestine to the
peripheral
tissues
VLDL Transport Defect in their Liver
endogenous synthesis lead to
TAG from the fatty liver
liver to the
peripheral
tissues
(Mobilize fat
from liver
LDL Transport Their increase Breakdown of
cholesterol from lead to VLDL via IDL
the liver to the atherosclerosis
peripheral
tissues
HDL Remove free Their decrease Liver
cholesterol from lead to
peripheral atherosclerosis
tissues &
esterifies it
•Transport
cholestrol esters
to the liver to be
eliminated.
•Transfer
cholestrol esters
to VLDL and
LDL

Lipid metabolism occurs in three major areas:

-Intestine.
-Liver.
-Extrahepatic tissues (Muscle and adipose tissue).

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Apo lipoprotein Function of apolipoprotein

AI Activates LCAT
B100 TG and cholesterol transport and
binds LDL receptor

B48 TG transport
CII Activate LPL
E Bind to LDL receptors

Chylomicron assembly

• Assembled in enterocyte Golgi/ER Apolipoprotein (Apo) B48

organizes assembly Picks up apo A,C and E in plasma
• Carry dietary lipids to peripheral tissues
• Responsible for physiological milky appearance of plasma (up to 2
hours after meal)
• Chylomicrons are released from the intestine into the lymphatic,
bypassing the liver.

VLDL assembly
-VLDL is transported in the bloodstream,
-LP Lipase catalyzes TG removal by hydrolysis.
-With removal of TG and some proteins, the % weight that is cholesterol
esters increases.

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-Carry lipids from liver to peripheral tissues.

-mature VLDL contains: Apo B- 100 + Apo C-II and Apo E (from HDL)
-VLDL is converted to IDL, and eventually to LDL.
VLDL → IDL → LDL
-Cells take up LDL by receptor-mediated endocytosis.

LDL and HDL assembly

The LDL returns apoprotein CII and E to HDL and are taken up by
receptor mediated endocytosis by the extra hepatic tissues (with some
being taken back up by the liver).
•HDL Removes free cholesterol from peripheral tissues & esterifies it
•Transports cholestrol esters to the liver to be eliminated.
•Transfers cholestrol esters to VLDL and LDL.

Derived lipid (cholesterol)

- Cholesterol is white waxy compound
-Widely distributed in almost all the tissues of the body especially in
brain, other nervous tissues, adrenals and liver.
-Steroids are derived lipids in which the basic or principal structure is
Cyclopentano Perhydro Phenanthrne Nucleus (CPPP Nucleus) (Steroid
Nucleus) with an OH gp at 3rd C which is important for cholesterol
metabolism • Examples: Steroid hormones, Vitamin D etc.

Important biological functions Of Cholesterol:

-One of the important members of membrane lipids.
-Precursor of Steroids & Vitamin D.
- Forms Adrenal hormones.
- Forms Bile acids and salts

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Lipoproteins and cardiovascular disease (CVD) risk:

-LDL is positively associated with CVD.
- LDL is negatively associated with CVD.
Recommended blood lipids
-Total cholesterol Less than 200 mg/dL (WHO-<150)
-LDL cholesterol ("bad" cholesterol) Less than 100 mg/dL
-HDL cholesterol ("good" cholesterol) 40 mg/DL or higher
-Triglycerides Less than 150 mg/Dl.
VLDLs Related diseases
Hypolipoproteinemia Abetalipoproteinemia
Defect in TG-transfer protein Apo B-100 cannot be loaded with lipid
Accumulation of TG in liver

Fatty Liver (hepatic steatosis)

Imbalance between hepatic synthesis of TG and secretion of VLDLs.
Accumulation of TG in liver
Hyperlipidemia:
Major CV risk factor - 25% of population
LDL, Total Choles., Total Choles./HDL, and HDL all predict CVD
Hyperlipoproteinemia
Type I Hyperlipoproteinemia
Familial Lipoprotein lipase deficiency or Apo C-II deficiency
Usually associated with acute abdomen due to acute pancreatitis
Type III Hyperlipoproteinemia
Familial dysbetalipoproteinemia
Apo E deficiency
Hypercholesterolemia and atherosclerosis
Some genetic causes of dyslipidemia:

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Common causes of secondary hyperlipidemia

Disease Dominant lipid abnormality
Diabetes mellitus Increased triglyceride

Chronic renal failure Increased triglyceride

Increased triglyceride
Alcohol excess increased triglyceride

Drug, e.g. thiazide diuretics Increased triglyceride

Hypothyroidism Increased cholesterol

Nephrotic syndrome Increased cholesterol

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(Biochemistry)
CARDIAC ENZYMES AND OTHER PROTEIN
MARKERS
Diagnosis of acute myocardial Infarction
Based on 2 out of three (WHO criteria)
1- Prolonged chest pain silent (painless) infarction.
2- ECG changes lacks sensitivity.
3- Serum enzyme concentrations.
CKMB lack sensitivity in diagnosis of perioperative
infarction.
Protein makers as troponins and myoglobin are now
emerging.
Ideal markers to detect AMI
-Rapid release into blood following myocardial infarction
-high concentration in myocardium
-absent in non myocardial tissue
-high sensitivity and specificity
-remain in blood for several days to allow detection
-blood level correlate with extent of myocardial injury and prognosis
-monitor the success of reperfusion after thrombolytic injury.
Biochemical Markers In Clinical Cardiology
1) Aspartate aminotransferase.
2) Lactate dehydrogenase and its isoenzyme LD1
3) Creatine kinase and its isoenzyme MB
4) Myoglobin
5) Cardiac Troponins.
7) Cardiac Natriuretic Peptides
6) C-reactive protein (Inflammation marker)

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Cardiac Enzymes
-First reported that serum glutamate oxaloacetate transaminase was
increased in patients with AMI.
-Assays for serum lactate dehydrogenase (LDH) and serum CK were then
developed and utilized as cardiac markers, in the early 1960s, with CK
gradually becoming the marker of choice as a result of its early increase
after injury.
-It is now generally accepted that activity measurement of enzyme
markers such as aspartate aminotransferase (AST) and LDH is of little
value in the assessment of myocardial injury, because of the lack of tissue
specificity.

Creatine Kinase and CK-MB Isoenzyme

-CK is a dimer, composed of M and/or B subunits, which associate
forming CK-MM, CK-MB and CK-BB isoenzymes. Creatine kinase acts
as a regulator of high-energy phosphate production and utilization within
contractile tissues.
-The pattern of isoenzymes found in the plasma may, therefore, serve as a
means of identifying the site of tissue damage.
-Following an acute MI, CK2 appears approximately 4–8 hours following
onset of chest pain, reaches a peak of activity at approximately 24 hours,
and returns to baseline after 48–72 hours.

CK-MM is the main isoenzyme found in striated muscle (approximately

97% of the total CK). CK-MB is found mainly in cardiac muscle, where
it comprises 15±40% of the total CK activity, with the remainder being
CK-MM. CK-BB is the predominant isoenzyme found in brain, colon,
ileum, stomach and urinary tract.

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Serum CK-MB is considerably more specific for myocardial damage than

is serum total CK, which may be elevated in many conditions where
skeletal muscle is damaged. Consequently, CK should not be used for the
diagnosis of myocardial injury unless used in combination with other
more specific cardiac markers

Currently Used Biomarkers

Myoglobin was the first non-enzymatic protein used for diagnosis of
AMI, dating back to the 1970s. As a small molecule (17.8 kDa), its quick
release into circulation as early as 1 hr upon symptom onset with high
sensitivity makes myoglobin a valuable early screening test for AMI
However, the clinical specificity of myoglobin is poor due to its abundant
presence not only in myocardial but also in skeletal muscle cells.

Troponins
Regulatory proteins in striated muscle Responsible for calcium-
modulated interaction exist in a number of isoforms

Cardiac specific forms immunologically separable:

Troponin T (TpnT
Troponin I (TpnI)

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Since the first report on the measurement of cTnT in 1989, followed by

the subsequent description of the measurement of cTnI in 1992, there has
been a revolution in the cardiac marker measurements.
Due to their great sensitivity and specificity for myocardial cell damage,
cardiac troponins (cTnI, cTnT) have been considered as the ―gold
standard‖ for AMI diagnosis.
Troponin T and troponin I are regulatory proteins involved in myocardial
contractility. They are released into the plasma in response to cardiac
damage. Cardiac troponin I (cTnI) is highly sensitive and specific for
damage to cardiac tissue.
cTnI appears in plasma within 4–6 hours after an MI, peaks in 8–28
hours, and remains elevated for 3–10 days. Elevated cTns, in combination
with the clinical presentation and characteristic changes in the
electrocardiogram, are currently considered the ―gold standard‖ in the
diagnosis of a MI.
Troponin is the biomarker of choice for the detection of cardiac injury,
the fact that elevated troponin levels are highly specific for cardiac injury.
They remain abnormal for 4-10 days after the onset of AMI, with the
peak concentration closely correlated with the infarct size.

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Microbiology

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(Microbiology)
RHEUMATIC FEVER
Streptococcus pyogenes
The pathogen has a unique tendency to initiate autoimmunity after acute
in- fection, resulting in the non-suppurative sequelae acute rheumatic
fever (ARF) and post-streptococcal acute glomerulonephritis (AGN).
Over 100 different M proteins have been identified in the group A
streptococci, but there are specific M types that are identified most often
with ARF, pharyngitis- associated , and pyoderma-associated AGN M
types.
Rheumatic Fever:
• It is a multisystem inflammatory disease that may occur following
pha- ryngeal infection with group A β-hemolytic streptococci
(Streptococcus pyogenes)
• It usually affects children aged 5–10 years.
• Mechanism: streptococcal antigens elicit production of antibodies
that cross-react with cardiac antigens (Antigenic Mimicry).
• Classically, patients complain of a past history pharyngeal infection
1–4 weeks earlier
• Patients with more severe streptococcal sore throats have a greater
chance of developing rheumatic fever.
• It has classic symptoms (collectively referred to as the Jones
criteria)

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Jones Criteria:

Sydenham’s Chorea: Involuntary, purposeless

contractions of trunk muscles and extremities

• Erythema marginatum : evanescent rash with ring

margin
• The carditis characteristically leads to thickened and deformed valves
(affects heart valves—mitral > aortic >> tricuspid (high-pressure
valves affected most) and to small perivascular granulomas in the
myocardium (Aschoff bodies) that are finally replaced by scar tissue.
• Rheumatic fever has a marked tendency to be reactivated by recurrent
streptococcal infections.
• The first attack of rheumatic fever usually produces only slight cardiac
damage, which, however, increases with each subsequent attack. It is
therefore important to protect such patients from recurrent S pyogenes
infections by prophylactic penicillin administration.

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• Evidence of Streptococcal Infections:

A- Anti-streptolysin O (ASO) titers.
• Antibody to streptolysin O develops after infection
• it blocks hemolysis by streptolysin O but does not indicate
immunity.
High titers (>250 units) or rising titre indicate recent or repeated
infections and are found more often in rheumatic individuals than
in those with uncomplicated streptococcal infections.
B- Positive throat culture for Streptococcus pyogenes:
1- Specimens suspected of containing streptococci are cultured on
blood agar plates : beta hemolysis.
2- Several commercial kits are available for rapid detection of group A
streptococcal antigen from throat swabs. These kits use enzymatic or
chemical methods to extract the anti-gen from the swab, then use
enzyme immunoassay (EIA) or agglutination tests to demonstrate the
presence of the antigen.
Diagnosis:
• usually made through clinical suspicion and fulfillment of the
Jones criteria including evidence of prior streptococcal infection.
• Echocardiography can aid in diagnosing cardiac complications.
Treatment:
-Antibiotics against Streptococcus pyogenes: high- dose penicillin (long-
acting penicillin)
-Symptomatic treatment:
Steroids and salicylates aid in reducing pain and inflammation, whereas
digitalis may reduce symptoms of heart failure. Haloperidol is the
treatment of choice for Sydenham chorea

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Prophylaxis (Prevention):

1- Detection and early antimicrobial therapy of throat infection. Prompt

eradication of streptococci from early infections (before day 8) can
effectively prevent the development of ARF. This requires maintenance
of adequate penicillin levels in tissues for 10 days (eg, benzathine penicil-
lin G given once intramuscularly). Erythromycin is an alternative drug,
although many S pyogenes are now resistant.
2- Anti-streptococcal chemoprophylaxis in persons who have suffered an
attack of rheumatic fever:
One injection of benzathine penicillin G intra- muscularly every 3–4
weeks or daily oral penicillin or oral sulfonamide.

N.B: The first attack of rheumatic fever infrequently causes major heart
damage; however, such persons are particularly susceptible to
reinfections with streptococci that precipitate relapses of rheumatic
activity and give rise to cardiac damage. Chemoprophylaxis in such
individuals, especially children, must be continued for years.

Reference:
1. First Aid for the Basic Sciences (pages 75-76)
2. First Aid for the USMLE (308).

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(Microbiology)
BACTERIAL ENDOCARDITIS
Definition: Endocarditis is an inflammation of the lining of heart and
heart valves.
✓ Heart valves are avascular, thus leukocytes cannot recruited if bacteria
adhere to valves.
✓ The causative organisms: Staphylococcus aureus, Streptococcus
viridans. Enterococcus, fungus and Pseudomonas aertginosa
✓ Types: Bacterial Endocarditis may be acute bacterial endocarditis
(signs and symptoms present for days up to six weeks) or subacute
bacterial endocarditis (signs and symptoms persist more than 6
weeks).

Acute bacterial endocarditis

• It tends to affect normal heart valves .It is often associated with
staphylococcus aureus (gram positive cocci arrange in clusters )
which is extremely virulent organism. staphylococcus aureus is the
most common cause of endocarditis.
• IV drug user is particularly at risk. It is a serious disease, with
mortality rate 50%.
Sub-acute bacterial endocarditis (SBE)
• The causative organism is Streptococcus viridans. (gram positive
cocci arrange in chains )
• Streptococcus viridans usually colonizes or settles on abnormal heart
valves or previously damaged heart valves or prosthetic valves.
• Organism may reach the blood stream as a result of trauma or after
tooth extraction or tonsillectomy

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✓ Clinical Presentation
1. Fever
2. Chills
3. Weight loss
4. Systemic emboli
5. Pleuritic chest pain if pulmonary embolism occurs
6. Janway lesions: small painless erythematous lesions on palms and
soles
7. Osler nodes: painful raised lesions in fingers and toe pads
8. Splinter hemorrhage: linear streak under fingernails and toenails
9. Roth spots : round white spot on the retina surrounded by
hemorrhage
10.Valvular involvement : mitral , aortic or tricuspid
✓ Diagnosis
1. Blood culture technique: (5-10 ml of blood sample inoculated in
50 ml broth and incubated at 37°C), then repeated subculture on
blood agar. On blood agar, Streptococcus viridans, produces a
zone of greenish discoloration (alpha hemolysis). But
Staphylococus aureus produces complete clear zone (Beta
hemolysis) on blood agar.
2. Fever
3. Valvular lesion detected by Echocardiography
4. Vascular lesions
✓ Prevention
Congenital heart disease and prosthetic heart valves patients take oral
amoxicillin or intramuscular ampicillin one hour before any procedure

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✓ Treatment:
1- Intravenous antibiotic targeted against specific organism
2-For acute endocarditis: start treatment rapidly by gentamicin and
nafcillin
3-For subacute endocarditis: obtain blood culture before treatment.
a) Ampicillin + gentamicin in native valves
b) Gentamicin +vancomycin + rifampin for prosthetic valves

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(Microbiology)
VIRAL MYOCARDITIS
✓ Definition: Inflammation of cardiac muscle due to viral infection
✓ Most common causative viruses
A. Enteroviruses:
• Types:
1. Coxsackie A and, Coxsackie B, types 1-6
2. Echoviruses, types 1-34
• Diseases: In addition to pericarditis and myocarditis; they can cause
pharyngitis, herbangina, hand, foot and mouth disease.
• Transmission: Virus is transmitted by fecal oral route
• Properties of enteroviruses:
1. RNA viruses20-30nm in diameter ,positive sense, non-enveloped,
Capsid symmetry is of icosahedral
2. Optimal growth at37Ĉ
3. They are acid stable

COXSACKIEVIRUSES
The coxsackieviruses comprise a large subgroup of the enteroviruses.
They produce aseptic meningitis, hand, foot, and mouth disease,
myocarditis and pericarditis. It may leads to what is called devil's grip
with sharp chest and side pains.
ECHOVIRUSES
The echoviruses (enteric cytopathogenic human orphan viruses) are
grouped together because they infect the human enteric tract and they can
be recovered from humans only by inoculation of certain tissue cultures.
Aseptic meningitis, febrile illnesses with or without rash, common colds,
and acute hemorrhagic conjunctivitis are among the diseases caused by
echoviruses. General Properties: Echoviruses are typical enteroviruses
measuring 24-30 nm. Not produce diseases in sucking mice.

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B. Adenoviruses
• General properties: The virus is 70-90 nm. It is a non –enveloped
double stranded DNA virus with an icosahedral nucleuocapsid.
Adenoviruses are the only viruses with fibers protruding from the
capsid The fiber is the organ of attachment
• Transmission: It is transmitted by fecal oral route

C. Other viruses can cause viral myocarditis:

1. HHV6 (Human herpes virus 6)
2. Cytomegalovirus
3. HIV (Human Immunodeficiency virus)
4. COVID-19
✓ Clinical presentation:
1. Patient may present with manifestations of congestive heart
failure(CHF) including chest pain, peripheral edema and dyspnea
2. Palpitations from arrhythmias
3. General manifestations of viral infections, fever ,fatigue and
diarrhea
4. On physical examination muffled S1 anS3 mitral regurgitation
murmur (MR)
5. Tachycardia due to persistent fever

✓ Complications:
1. Sudden death
2. Heart block
3. Dilated cardiomyopathy
4. Heart failure

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✓ Diagnosis:
1. ECG shows diffuse T wave inversions and ST segment elevations
resembling myocardial infarction or pericarditis
2. Cardiac biopsy is the gold standard for diagnoses showing massive
lymphocytic infiltration
3. Elevated Creatine kinase myocardial bound fraction(CK-MB) and
troponin
✓ Treatment:
1. Supportive therapy for acute heart failure with diuretics
2. Nitrates are indicated
3. Viral myocarditis requires strong anti-inflammatory e.g.
Nonsteroidal Anti-inflammatory Drugs (NSAID).

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Pathology

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(Pathology)

CARDITIS

Rheumatic Heart Disease

• Definition: Rheumatic fever (RF) is a systemic, post-streptococcal,

non-suppurative inflammatory disease.
• Mainly affects the heart, joints, central nervous system, skin and
subcutaneous tissues.
• The chronic stage of RF involves all the layers of the heart
(pancarditis) causing rheumatic heart disease (RHD).
• Rheumatic heart disease remains an important cause of morbidity
and mortality in the developing world.
• Rheumatic heart disease is caused by an abnormal host immune
response (usually occurring in adolescents) to an infection with β -
haemolytic group A streptococci.
• The attack rate of myocarditis following infection is 1% to 3% and
is dependent on HLA type, with strong HLA-DR2 and -DR4 linkage
in the United States.
• Heart disease develops long after the infection has cleared (lesions
are microbiologically sterile).
• The pathophysiology of rheumatic heart disease remains
controversial.
• It is probably best understood as a transient autoimmune state.
• There is cross-reactivity between some myocardial connective tissue
proteins and bacterial antigenic determinants, but
immunocomplexes do not appear to play a pivotal role in rheumatic
heart disease (in contrast to poststreptococcal glomerulonephritis,
which is caused by different bacterial serotypes with deposition of
immunocomplexes in the glomeruli).

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• The cellular infiltrate in rheumatic myocarditis is composed almost

exclusively of helper T cells (V-8 subclass), and the identification of
streptococcal M protein as a superantigen supports a cell- mediated
autoimmune mechanism.
• Rheumatic myocarditis develops 4 weeks after bacterial infection
and begins with fibrinoid necrosis of collagen associated with a T-
cell inflammatory infiltrate.
• The morphologically diagnostic lesion of rheumatic heart disease is
called an Aschoff body, which is composed of multinucleated
histiocytes with unique nuclear features (dense striated chromatin
bar surrounded by a zone of nuclear clearing).
• These myocardial lesions heal as small scars. In contrast,
inflammation of the cardiac valves with verrucae composed of
degenerating connective tissue and inflammatory cells has severe
sequelae.
• Verrucae form along the lines of valve closure and result in
neovascularization and scarring of the valve, often with fusion of the
valve leaflets and severe stenosis.
• The mitral valve is most commonly affected, with only rare
involvement of the right heart valves.
• Recurrent attacks of rheumatic fever tend to be more severe and
cause progressive valvular disease.
Complications

1. Cardiac failure is the most common cause of death from RHD due to
valvular deformities.

2. Bacterial endocarditis of both acute and subacute types is due to

inadequate use of antibiotics.

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3. Embolism originates most commonly from mural thrombi in the left

atrium, in association with mitral stenosis.

4. Sudden death may occur in RHD as a result of ball thrombus in the left
atrium or due to acute coronary insufficiency in association with aortic
stenosis.

II. Extra-Cardiac Lesions:

1. Polyarthritis: Acute painful inflammation of some of the large joints is

seen in about 90% of cases. The characteristic 'migratory polyarthritis'
involving two or more joints at a time (called also fleeting arthritis) is
diagnostic.

2. Subcutaneous nodules: Small (0.5-2 cm), spherical painless nodules.

Characteristic locations are extensor surfaces of the limbs.

3. Erythema marginatum: occur mainly on the trunk and proximal parts of

the extremities showing central clearing and elevated margins.

4. Rheumatic arteritis: Detected in the coronaries, aorta, renal, mesenteric

and cerebral arteries.

5. Chorea minor (Sydenham's chorea): Results of involvement of the CNS

which occurs more in younger girls. The condition is characterized by
involuntary jerky movements of the trunk and the extremities accompanied
by emotional instability.

6. Rheumatic pneumonitis and pleurisy: rare.

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Pericarditis

Definition:

• Pericarditis is the inflammation of the pericardial layers and is

generally secondary to diseases in the heart or caused by systemic diseases.
Primary or idiopathic pericarditis is quite rare.
• The pericardium composed of connective tissue lined by a single
layer of mesothelial cells that encases the heart. It secretes lubricant
allowing the heart to expand and contract easily.
• Pericarditis → disturbance of normal motion of the heart. Fibrin
deposition to the pericardial surface is painful and give a characteristic
diagnostic friction rub.
• More severe inflammation and fibrosis due to metastatic cancer or
bacterial infection usually results in life threatening impairment of diastolic
filling (constrictive pericarditis).
Classification of Pericarditis:

A. Acute Pericarditis:

1. Serous pericarditis. Causes are: viral infection, Rheumatoid

arthritis, Malignant tumours as carcinoma, Tuberculous pericarditis
2. Fibrinous or serofibrinous pericarditis. Causes are: Uraemia,
Myocardial infarction, Rheumatic fever, Trauma, Acute bacterial
Infections.
3. Purulent or fibrinopurulent pericarditis. Caused by pyogenic bacteria

4. Haemorrhagic pericarditis. Causes: Neoplastic involvement of the

pericardium, Haemorrhagic diathesis with effusion, Tuberculosis, Severe
acute infections.

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B. Chronic Pericarditis:
1. Tuberculous pericarditis.
2. Chronic adhesive pericarditis.

3. Chronic constrictive pericarditis.

C. Pericardial plaques (milk spots, soldiers' spots).
• Fluid accumulations in the pericardium → impaired diastolic filling
of the ventricles.
• Slow accumulation is accommodated, whereas rapid accumulation
results in fatal acute heart failure (tamponade).

Endocarditis
Definition:
Inflammatory involvement of the endocardial layer of the heart is called
endocarditis.

Classification of Endocarditis:
A. Non-Infective:
1. Rheumatic endocarditis.
2. Atypical verrucous (Libman-Sacks) endocarditis.
3. Non-bacterial thrombotic (cachectic) endocarditis.
B. Infective:
1. Bacterial endocarditis.
2. Other infective types (tuberculous, syphilitic, fungal, viral, rickettsia).
Most types of endocarditis are characterized by the presence of
'vegetations' or 'verrucae' which have distinct features.

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Bacterial Endocarditis
• Bacterial endocarditis acute (ABE) or subacute (SABE) depending
on the organism involved.
• Staphylococcus aureus is the prototypical agent of acute
endocarditis, resulting in rapid destruction of the valve substance and
severe valvular insufficiency.
• Streptococcus viridans is the prototypical organism of subacute
bacterial endocarditis.
• The characteristic pathologic feature in both ABE and SABE is the
presence of typical vegetations on the valve cusps and less often, on
mural endocardium.
• In immunocompromised patients, fungal organisms may be a
significant cause of endocarditis.

Vegetations

• Congenitally abnormal valves and valves previously scarred by

rheumatic endocarditis are at increased risk for the development of SABE,
whereas the vegetations of ABE are seen on normal valves.
• The left-sided valves are more commonly involved than the right
except in intravenous drug abusers, in whom direct seeding of the right-
sided heart valves may occur.
• The vegetations of SABE are large, irregular, single or multipleand
typically friable on the valve surface (composed of fibrin, inflammatory
cells, and bacteria) with slower destruction of the valve.
• The vegetations in ABE tend to be bulkier and globular than those
of SABE and may cause ulceration or perforation of valve leaflet.
Septic emboli from these vegetations and autoimmune phenomena related
to antigen-antibody complexes tend to dominate the clinical picture of
subacute endocarditis, with valvular insufficiency occurring late.

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Myocarditis

• Many viral infections produce a transient myocarditis that is

usually subclinical.
• Myocarditis may be prolonged or associated with an unusually
strong host immune response that causes symptomatic myocarditis.
• Occasionally, the inflammatory process, may be sustained or
progressive.
• Viral myocarditis is probably a significant cause of dilated
cardiomyopathy.
• Other forms of acute infectious myocarditis caused by protozoal
disease and in some idiopathic conditions such as sarcoidosis.
• These forms of myocarditis may interfere with the conduction
system as well as directly damage cardiac myocytes.

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Cardiac Transplantation

• Rejection of transplanted hearts is due to an immune responsesimilar

to that of viral myocarditis but directed against transplantation antigens. In
severe acute rejection, myocardial necrosis and heart failure may result.
• Acute rejection is well controlled by immunosuppressive therapy.
• In contrast, chronic rejection corresponds to diffuse intimal
hyperplasia of the graft coronary arteries and results in significant luminal
narrowing over the course of years and is not currently amenable to
therapy. Chronic rejection is a major cause of long-term graft failure.

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Cardiomyopathy

• Cardiomyopathy is a rare condition that is typically defined as a

primary disease of heart muscle.
• In practice, it may be difficult to distinguish cardiomyopathy (rare)
from ischemic heart disease (very common) during life.
• Cardiomyopathy is typically classified by three functional
categories: hypertrophic, restrictive, and dilated.
Hypertrophic Cardiomyopathy

 Results in thickening of the myocardial wall and is almost always

inherited as an autosomal dominant trait caused by point mutations in
structural proteins within the contractile apparatus of cardiac myocytes.
 The most common gene involved is the cardiac β-myosin heavy
chain gene, which accounts for nearly 50% of cases, resulting in defective
contraction with compensatory hypertrophy of cardiac myocytes, myofiber
disarray, and associated interstitial fibrosis.
 Mutations in other sarcomeric proteins account for most the other
cases of hypertrophic cardiomyopathy.
 Patients typically are young or middle-aged adults with enlarged
hearts and evidence of congestive heart failure without significant coronary
artery disease.
 The age and severity of presentation can be modified by
environmental factors
 Left ventricular hypertrophy is associated with an sudden death and
hypertrophic cardiomyopathy is common in young athletes with sudden
death due to defective diastolic filling

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Dilated Cardiomyopathy
• Results from primary systolic dysfunction with massive left
ventricle dilatation and diminished ejection fraction. It is an important
cause of death.
• There are multiple genetic causes including some storage diseases
(glycogen and lysosomal) as well as Duchenne‘s muscular dystrophy, but
inheritance patterns are heterogeneous and only a few single gene defects
have been implicated to date.
• Genetic lesions are responsible for a relatively small percentage of
patients with dilated cardiomyopathy.
• The inciting virus may no longer be present when heart failure
supervenes so that definitive diagnosis may not be possible.
• Abnormalities in other organ systems (e.g., musculoskeletal) tend
to dominate the clinical course.
• Toxin exposure including heavy ethanol exposure and excess
catecholamines also can produce dilated cardiomyopathy.
• A significant proportion of patients with a dilated cardiomyopathy
actually have chronic ischemic heart disease, which is much more
prevalent than cardiomyopathy.

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Restrictive Cardiomyopathy

• Amyloidosis is a typical cause of restrictive cardiomyopathy in

which there is deposition of abnormal protein with a β-pleated sheet
conformation in the interstitium of the myocardium.
• This material increases the stiffness of the wall and impaired
diastolic filling.
• Patients tend to have signs of right heart disease because of the
backup of pressure into the pulmonary circulation.
Systolic dysfunction increases as more and more amyloid is deposited in
the interstitium.

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(Pathology)
ATHEROSCLEROSIS AND ANEURYSM
Definition:

▪ Atherosclerosis is a specific form of arteriosclerosis affecting

primarily the intima of large and medium sized muscular arteries and is
characterised by formation of fibrofatty plaques or atheroma.
▪ The most commonly affected arteries are the aorta, the coronary
and the cerebral arterial systems.
Aetiology:

- A number of risk factors are associated with increased risk of

developing clinical atherosclerosis.

- These risk factors are divided into two groups:

I. Major risk factors.

II. Minor risk factors.

Risk Factors of Atherosclerosis:

I. Major risk factors:

A. Non modifiable:

1. Age (frequency increases with age): Atherosclerosis is an age-

related disease. Usually appear in the 4th decade and beyond.
2. Sex: The incidence and severity of atherosclerosis are more in men
than in women. The lower incidence of IHD in women, especially in
premenopausal age, is probably due to high levels of oestrogen and high-
density lipoproteins, both of which have anti-atherogenic influence.

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3. Genetic factors.

4. Familial and racial factors.

B. Modifiable:

1. Hyperlipidaemia:

- Hyperlipidaemia may be due to various causes such as metabolic

(diabetes mellitus), familial or dietary hyperlipidaemia, have increased
risk of developing atherosclerosis.

- High concentration of low-density lipoprotein (LDL) is associated with

increased risk of atherosclerosis

2. Hypertension: It acts probably by mechanical injury to the arterial wall

due to increased blood pressure.

3. Diabetes mellitus: The causes of increased severity of atherosclerosis

are numerous which include increased aggregation of platelets, increased
LDL and decreased HDL.

4. Smoking: The increased risk and severity of atherosclerosis in

smokers is due to:
a. Reduced level of HDL
b. Accumulation of carbon monoxide in the blood that produces carboxy-
haemoglobin and hypoxia in the arterial wall favouring atherosclerosis.

II. Minor risk factors:

1. Physical inactivity.
2. Obesity.
3. Oral contraceptives.
4. Lack of exercise.
5. Stress.

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6. Consumption of alcohol.
7. High carbohydrate intake.
8. Postmenopausal oestrogen deficiency.

Pathogenesis:

i. Endothelial injury: is the initial triggering event in the development of

lesions of atherosclerosis. Risk factors such as hypertension, cigarette
smoking and chronic hyperlipidaemia can cause endothelial damage.

ii. Role of blood monocytes: Plasma LDL on entry into the injured intima
undergoes oxidation. The 'oxidized LDL' performs the following
functions on monocytes and endothelium;

• For monocytes, oxidized LDL acts to attract, proliferate, immobilise and

activate them to transform it to a lipid-laden foam cell after LDL
engulfment. Death of foam cell by apoptosis releases lipid to form lipid
core of plaque.

• For endothelium, oxidized LDL is cytotoxic.

iii. Smooth muscle cell proliferation: Endothelial injury causes adherence,

aggregation and platelet release reaction at the site of exposed
subendothelial connective tissue. Migration of smooth muscles from
media to intima occurs first, followed by proliferation of smooth muscle
cells which is stimulated by various mitogens, the most important of
which is platelet-derived growth factor (PDGF).

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Pathological changes:

1. Fatty streaks and dots:

I. Gross picture: the lesions may appear as flat or slightly elevated and
yellow. They may be either in the form of small, multiple dots, about 1
mm in size, or in the form of elongated, beaded streaks.

II. Microscopic picture: fatty streaks lying under the endothelium are
composed of Deposition of lipids in the subendothelial part of intima with
several foam cells (macrophages engulfing lipids).

- On paraffin section the dissolved cholesterol crystals appear in the form

of needle shaped clear clefts

2. Atheromatous plaques:

I. Gross picture:

Atheromatous plaques are firm raised yellowish white plaques and

nodules, 1-2cm in diameter. They may become hard due to dystrophic
calcification

II. Microscopic picture:

The appearance of plaque varies depending on the age of the lesion.

However, the following features are invariably present:

I. The superficial luminal part of fibrous cap is covered by endothelium,

and is composed of smooth muscle cells, dense connective tissue and
extracellular matrix containing proteoglycans and collagen.

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• The cellular area under the fibrous cap is formed of a mixture of

macrophages, foam cells, lymphocytes and a few smooth muscle cells
which may contain lipid.

• The deeper central soft core consists of extracellular lipid material

cholesterol clefts, fibrin, necrotic debris and lipid-laden foam cells.

• In older and more advanced lesions, the collagen in the fibrous cap may
be dense and hyalinised, smooth muscle cells may be atrophic and foam
cells are fewer.

Complications of atherosclerosis:

These account for the most serious harmful effects of atherosclerosis and
even death. It is not uncommon to see more than one form of
complication in a plaque. These changes include:

1. Luminal narrowing: causing ischemia or infarction if complete

vessel occlusion occurs.
2. Calcification.
3. Ulceration: The layers covering the soft material of an atheroma
may ulcerate. This results in discharge of emboli composed of lipid
material and debris into the blood stream leaving a shallow ulcer with
yellow lipid debris in the base of the ulcer.
4. Thrombosis: The ulcerated plaque and the area of endothelial
damage are vulnerable sites for formation of superimposed thrombi.
5. Haemorrhage: occurs either from the blood in the vascular lumen
through an ulcerated plaque or from rupture of thin-walled capillaries that
vascularise the atheroma.

6. Aneurysm formation: due to atrophy, thinning and fragmentation

of the internal elastic lamina.

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Aneurysms

Definition:

An aneurysm is defined as a permanent abnormal dilatation of a blood

vessel occurring due to congenital or acquired weakening or destruction
of the vessel wall.

Classification:

Aneurysms can be classified on the basis of various features:

A. Depending upon the composition of the wall:

1. True aneurysm: composed of all layers of a normal vessel wall.

2. False aneurysm: having fibrous wall and occurring often from trauma
to the vessel.

B. Depending upon the shape:

1. Saccular having large spherical out pouching.

2. Fusiform having slow spindle-shaped dilatation.

3. Cylindrical with a continuous parallel dilatation.

4. Serpentine or varicose which has tortuous dilatation of the vessel.

5. Berry aneurysms which are small dilatations especially affecting the

circle of Willis in the base of the brain.

C. Based on pathogenic mechanisms:

1. Atherosclerotic (arteriosclerotic) aneurysms are the most common

type.

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2. Syphilitic aneurysms found in the tertiary stage of the syphilis.

3. Dissecting aneurysms (Dissecting Hematoma) in which the blood

enters the separated or dissected wall of the vessel.

4. Mycotic aneurysms which result from weakening of the arterial wall by

microbial infection.

Complications of true aneurysm

1-Pressure on the surroundings

2- Thrombosis and embolism

3- Rupture and haemorrhage

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(Pathology)
HYPERTENSION

Hypertension

Hypertension is the chronic elevation of blood pressure that in long term

causes end organ damage and results in increased morbidity and
mortality.

Defined as a blood pressure above 140/90 mmHg, in two separate

occasions occurs in ∼25% of the population, and in more than half of
people who are middle aged or older

Predisposing factors

• Advancing Age
• Sex (men and postmenopausal women)
• Family history of cardiovascular disease
• Sedentary lifestyle & psycho-social stress
• Smoking, High cholesterol diet, Low fruit consumption
• Obesity Co-existing disorders such as diabetes, and
hyperlipidaemia
• High intake of alcohol
Types

• Hypertension may be primary or secondary.

• Primary (essential) hypertension is much more common (95% of
cases) than secondary and is associated with:
• Genetic factors→ un-controllable.
• Environmental factors→ controllable and include:
• Stress.

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• Obesity.
• Smoking and alcohol.
• Low physical activity.
• Excess salt intake.

• Causes of secondary hypertension

A. Renal (80%) AGN (acute glomerulonephritis Renal Artery stenosis

CGN, (chronic
glomerulonephritis)

Polycystic. kidney disease

B. Endocrine Adrenal Primary aldosteronism

Cushing‘s syndrome

Pheochromocytoma

Acromegaly

Exogenous hormone Oral contraceptive

Glucocorticoids

Others causes

 Coarctation of the aorta

 Pregnancy Induced HTN (Pre-eclampsia)
 Sleep Apnoea Syndrome.
 Oral contraceptives

 Malignant or accelerated hypertension is an uncommon condition

 that develops quickly, involves large elevations in pressure,
 often secondary to other conditions,
 rapidly damages the kidneys, retina, brain and heart, and if
untreated causes death within 1–2 years.

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Complication and Effects of chronic hypertension

• changes in the vessel wall leading to vessel trauma and

arteriosclerosis throughout the vasculature
• Complication arises due to the target organ dysfunction and failure
• Target organ
• Heart and blood vessels, kidneys, NS, and the eyes
A-On the blood vessels it causes
1- endothelial damage and arteriosclerosis which may be hyaline
arteriolosclerosis (deposition of hyaline material, hyperplastic
arteriolosclerosis (thickening of the intima and necrotizing arteriolitis
(there is fibrinoid necrosis).

2- Accelerates atherosclerosis

B- on the Heart it causes

• Left ventricular hypertrophy due to higher cardiac workload caused

by the increased arterial pressure followed by dysfunction, and
failure
• Arrhythmias
• Coronary heart diseases, myocardial infarction (MI) and sudden
death.
• Arterial aneurysm, dissection, and rupture

C- on the kidney it causes

1. Glomerular sclerosis which impairs kidney function and cause end
stage kidney
2. Ischemic kidney disease specially if cause renal artery stenosis
D- on nervous system
1. Stroke
2. Intracerebral and subaracnoid haemorrhage
3. Cerebral atrophy

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E-On the eye it causes

1- Retinopahy, retinal haemorrhages and impaired vision

2- vitreous haemorrhage, retinal detachment

Clinical manifestation

• No specific complains or manifestations other than elevated

systolic and/or diastolic BP (Silent Killer most of patients
discovered accidentally
• Morning occipital headache
• Dizziness
• Fatigue
• In severe hypertension, epistaxis or blurred vision

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(Pathology)
ISCHEMIC HEART DISEASES

Definition: Ischaemic heart disease is a group of disorders in which

myocardial ischemia is the common pathophysiologic mechanism.

Myocardial ischemia occurs when blood flow to your heart is reduced,

preventing the heart muscle from receiving enough oxygen. The reduced
blood flow is usually the result of a partial or complete blockage of heart's
arteries (coronary arteries).

Myocardial ischaemia, also called cardiac ischemia, reduces the heart

muscle's ability to pump blood.

Risk factors

In the vast majority of cases, this ischemia results from obstruction of

coronary artery blood flow by atherosclerosis

Causes of myocardial ischemia

🠶 Atheroma. Plaques can progressively occlude flow (severe, fixed

coronary obstruction), resulting in a slow diminution of blood flow
🠶 Acute plaque change (haemorrhage, rupture, erosion) can result in
catastrophic occlusion of blood flow or embolisation to the distal coronary
vasculature with microinfarction.

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Ischemic heart disease can be presented by one of the following four

clinical syndromes:

1) Angina pectoris
2) Myocardial infarction
3) Chronic ischemic heart disease
4) Sudden cardiac death.

Angina Pectoris
Angina pectoris is a symptom complex characterized by recurrent attacks
of crushing substernal chest pain, which often radiates to the left arm and
jaw.

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Types of angina

• Stable
• Variant
• Unstable

• Unstable angina: coronary occlusion of insufficient duration and/or

extent to cause cardiac necrosis (No necrosis in cardiac muscle occurs)
• Unstable angina is dangerous and requires emergency treatment.

Myocardial infarction

Definition: Myocardial infarction is a discrete focus of ischemic necrosis

(coagulation necrosis) in the heart that occurs when myocardial ischemia
is prolonged for more than 20 or 30 minutes.

Types: Transmural (full wall thickness) and subendocardial (limited to the

subendocardial).

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1) Transmural Infarction
Ninety percent of transmural infarcts are caused by an occlusive
intracoronary thrombus, usually associated with an ulcerated atheromatous
plaque.

Pathological features
Over the course of 20 to 30 minutes, ischaemia produces irreversible cell
injury, with membrane disruption and coagulative necrosis.

Gross pathological changes in an acute transmural myocardial infarct

become visible after approximately 4 hours as a discrete, dark, mottled area
in the myocardium. Over the next 3 days, the infarct becomes more clearly
defined with an increasingly pale centre

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• Next week, the infarct is sharply outlined with a central pale

yellowish centre (coagulation necrosis and neutrophilic infiltrate figure
below) bordered by a hyperaemic zone composed of granulation tissue.

Over the course of months, the infarcted region progresses to an

organized gray-white scar, and necrotic tissue is removed by histiocytes
and replaced with collagen from proliferating fibroblasts.

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🠶 Clinical Findings in Transmural Infarcts

The clinical diagnosis of transmural myocardial infarction is critically
dependent on electrophysiologic changes as well as serum biomarkers

Elevation of these cardiac biomarkers results from release of cytoplasmic

proteins into the bloodstream by necrotic myocytes.

LDH =Lactic dehydrogenase

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2) Subendocardial Myocardial Infarcts

🠶 Subendocardial myocardial infarcts are usually not caused by acute

coronary thrombosis. The subendocardial region is more susceptible to
ischemic damage, since it is far from its vascular supply (i.e., the coronary
arteries). Most patients with subendocardial infarcts have diffuse stenosis
of all coronary arteries without evidence of plaque rupture or thrombosis.

🠶 Subendocardial ischemia/infarction results from diminished blood flow

secondary to systemic hypotension and/or hypoxia (diminished pulmonary
function, anaemia, and carbon monoxide from smoking).
🠶 Clinical findings:
🠶 Non-ST elevation MI, is an unstable coronary syndrome which is
differentiated from unstable angina by a subsequent rise in cardiac
enzymes.

Complications of myocardial infarction

1- Cardiogenic shock (CS): Cardiogenic shock is a medical emergency. It
is a condition in which your heart suddenly can't pump enough blood to
meet your body's needs due to the dysfunction of the ventricles of the

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heart. the risk is dependent on baseline myocardial function and volume

of infarct.

2-Arrhythmia is a problem with the rate or rhythm of your heartbeat. It

means that your heart beats too quickly, too slowly, or with an irregular

3- Mural thrombus formation: Anytime

4- Papillary muscle rupture resulting in mitral valve incompetence: 3–6

days postinfarct

5- Cardiac tamponade, also known as pericardial tamponade, is when fluid

in the pericardium (the sac around the heart) builds up, resulting in
compression of the heart pattern. Myocardial rupture with cardiac
tamponade: 3–6 days postinfarct

6- Ventricular aneurysm is a blood-filled bulge that occurs as a result of an

area of weakened tissue in the heart wall. In most cases, ventricular
aneurysms form as a result of damage from a previous MI. Weeks to
months postinfarct

7- Chronic ischemic heart disease: Months to years postinfarct

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Pharmacology

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(Pharmacology)

ANTI-ARRHYTHMIC DRUGS

Objectives: By the end of this lecture, you should be able to:

1. List the different groups of antiarrhythmic drugs.

2. Name the main drugs in each group.

3. Describe the mechanism of action of each group.

4. Name the first line drugs used in treatment of commonly

encountered arrhythmias.

5. List the clinical indications and side effects of each group.

Background

What is arrhythmia? : Arrhythmia (or dysrhythmia) means abnormal

rhythm of the heart.

It is the most common cause of death in patients with myocardial

infarction and end-stage heart failure.

Normal Rate:

1. HR: 60-100 (with Exceptions in some cases as athelets,…)

2. Regular

3. Origin: SA node

4. Pathway of normal conduction

(see the figure)

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Mechanisms and causes of arrhythmia:

1) Abnormal generation of impulse (i.e. outside SA Node)

2) Abnormal conduction of the impulse (e.g re-entery or complete block)

Causes of arrhythmias:

1) Cardiac diseases (ischemia, HF, hypertension.

2) Non cardiac Diseases: Thyrotoxicosis,

3) Drugs (e.g. antiarrhythmic drugs, digitalis; some anibacterials

(Macrolids, quinolones,)

Physiology of cardiac action potential:

Phases of action potentials: four phases.

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1. Before excitation, an electrical gradient exists in which the inside

of the myocytes are - 80 to -90 mV more negative with respect to
the outside of the cell.

2. Phase 4 is unique to pacemaker cells. During phase 4, there is a

slow leak of Na+ ions into the cell and a slow K+ efflux. Over
time, K+ efflux diminishes but Na+ influx continues.

3. Phase 0 (or depolarization: voltage-gated Na+ channels open and

Na ions rapidly rush into the cell.

4. phase 1, there is passive chloride ion

influx and potassium efflux.

5. Phase 2: The hallmark features of

phase 2, or the plateau phase, are
Ca++ influx and K+ efflux.

6. Phase 3, the cell repolarizes as

potassium efflux (outward)
continues.

Note: the Na+;K+-ATPase pump is

constantly working to reestablish Na+ and
K+ homeostasis

Types of arrhythmias

A) Tachyarrhythmia (↑HR)

i) Tachycardia in Atria

1. Atrial fibrillation
2. Atrial flutter
3. Supraventricular tachycardia
4. WPW syndrome.

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ii) Tachycardia in ventricles

1. Ventricular tachycardia

2. Ventricular fibrillation

3. Long Q-T syndrome (Torasades de pointes)

B) Brady-arrhythmias (↓HR)

1. Conduction block B) Sick sinus syndrome

Treatment of arrhythmias

A) Non pharmacological treatment: For examples:

a) Vagal maneuvers. You may be able to stop supraventricular

tachycardia by using particular maneuvers that include:

1. 1) holding your breath and straining.

2. 2) dunking your face in ice water, or

3. 3) coughing.

These maneuvers affect the nervous system that

controls your heartbeat (vagus nerves), often causing
your heart rate to slow. However, vagal maneuvers
don't work for all types of arrhythmias

b) Pacing

c) Defirilator

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d) Cardioversion

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B) Antiarrhythmic drugs:

1. Class I (sodium channel blockers)

Class Drugs Action

Class I (Na channel Sodium channel

Blockers) blockade

IA Quinidine, Prolong duration of

procainamide, action potential

disopyramide.

IB Lidocaine, mexiletine, Shorten duration of

action potential
Tocainide

IC Propafenone Little effect on duration

of action potential

Class II (Beta- Metoprolol, Propranolol Beta-adrenergic

blockers) blockade

Class III (K channel Amiodarone, sotalol, Prolong action potential

Blockers) duration (potassium
, dofetilide, bretylium
channel blockade;
others)

Class IV (CC Verapamil and diltiazem Calcium channel

Blockers) blockade

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Miscellaneous Adenosine, digitalis Miscellaneous actions

2. Class II (Beta blockers)

3. Class III (K channel blockers)

4. Class IV (CCB)

Clinically useful antiarrhythmic drugs

Arrhythmia Commonly used Alternative drugs

drugs

Atrial Fibrillation Metoprolol or Digoxin or

Diltiazem or propafenone or
Amiodarone dofetilide

Atrial flutter Metoprolol or Digoxin

Verapamil

Acute supraventricular Adenosine Diltiazem

tachycardia

supraventricular Metoprolol or Digoxin

tachycardia (reentry) Verapamil

Acute ventricular Amiodarone (or

Tachycardia Lidocaine )

Ventricular Amiodarone Lidocaine

fibrillation (not
responding to

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electrical
defibrillation)

NB. Addition of oral anticoagulant (warfarin) is mandatory as first

line therapy in treatment of AF)

Clinical Pharmacology of the most commonly used antiarrhythmic

drugs

Therapeutically useful drugs bind readily to activated channel ( i.e. during

phase 0) and Inactivated channel (i.e. during phase 3) and bind poorly or
not at all to rested channel (i.e. this is called use dependent).

Class 1: Sodium channel blockers

- Class I A (Quinidine and procainamide)

1. They are rarely used because of adverse effects and

drug interactions
2. Quinidine in large doses may cause cinchonism
((headache, dizziness and tinnitus, vomiting, visual Cinchon
and hearing disturbances). It increase serum
level of digoxine.
3. Procainamide may cause Lupus like syndrome

Class-1B (Lidocaine (i.v) and Mexiletine (oral)

They are used in ventricular arrhythmia, usually in

Lupus-like syndrome
combination with amiodarone.

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Lidocaine is not used orally because of extensive first pass metabolism. It

is also used as local anaethetics.

Mexiletine is used orally, metabolized in the liver and eliminated by

biliary route. It has a narrow therapeutic index. GIT troubles are the
most common adverse effects of mexiletine (to minimize gastric
irritation, it should be taken with food).

It is used in resistant cases of ventricular arrhythmia.

Class-1C (Flecainide and propafenone)

They are used orally, metabolized in the liver and eliminated in the
urine (? Drug interaction)

Indications: Treatment of paroxysmal atrial fibrillation/flutter &

PSVT in patients WITHOUT structural heart disease.(i.e. Contraindicated
in patients with coronary diseases)

NB: Concurrent propafenone administration reduces the clearance of

warfarin, resulting in plasma warfarin concentration.

Main adverse effects are strange (metallic taste),GIT troubles.

The most serious adverse effects are arrhythmias.

Class II: Beta blockers (e.g. Metoprolol, bisoprolol)

Mechanism of Action:

These drugs diminish phase 4 depolarization, and thus depress

automaticity, prolong AV conduction, and decrease heart rate and
contractility.

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The most commonly used is

metoprolol (selective-beta-1
blocker with good lipid solubility,
metabolized in the liver, and
eliminated in the urine).

Esmolol is a very short and rapidly acting beta-blocker (t-

half: 9 min) used for intravenously in acute arrhythmias
that occur during surgery or emergency situations.

It is metabolized by RBCs esterases.

Remind the differences between selective and non selective

beta-blockers

Indications

1. Supraventicular arrhytmias

2. Tachycardia caused by pheochromocytmoa, hyperthyrodism,

digoxin, halothane,..

3. Prophylactic after MI

Contraindications

1. Sinus bradycardia
2. Heart block greater than first degree
3. Cardiogenic shock
4. Overt (sever) cardiac failure
5. Sinus bradycardia

6. Heart block greater than first degree

7. Cardiogenic shock

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8. overt cardiac failure

NB: Avoid sudden withdrawal of beta-blockers.

Class III: (K+ channel blockers) (e.g. Amiodarone, and Sotalol)

They diminish the outward K current during during repolarization of

cardiac cells and prolong the duration of action potential.

Amiodarone:

Mechanism of action:

Amiodarone contains iodine and related structurally to thyroxine. It has

complex effects, showing class I, II, III, and IV actions, as well as alpha-1
blocking effects. The predominant action is prolongation of action
potential duration and the effective refractory period by blocking
potassium channels.

Uses:

It is effective in supraventricular and ventricular tachyarrhythmias.

Adverse effects:

Pulmonary fibrosis, neuropathy, hepatotoxicity, corneal deposits,

blue-gray skin (in sun-exposed area), thyroid dysfunction (hypo
or hyperthrodism), and arrhythmias.

Drug interaction Corneal deposits

1. All other medications being taken should be reviewed prior

to initiating amiodarone therapy.

2. Amiodarone is a substrate for P-450 CYP3A4.

3. Drugs that inhibit CYP3A4 (e.g. cimetidine) or induce it

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(e.g. rifampin) will alter amiodarone plasma levels.

4. Amiodarone inhibits most other cytochrome enzymes & may

result in elevated levels of drugs that are substrates for these
enzymes (e.g. warfarin).

5. Amiodarone coadministration can predictably double

digoxin plasma levels due to inhibition of the P-
glycoprotein mechanism by which digoxin is secreted by
renal tubules.

6. It has a dangerous interaction (bradyarrhythmia) with Anti

HCV drugs.

Sotalol

1. Mechanism of action: It has Class III and II effects

2. Indications:

1. ventricular arrhythmias

2. maintenance of sinus rhythm in patients with Atrial

Fibrillation/Flutter (or delay in time to recurrence).

3. Contraindications:

1. sinus bradycardia, 2nd or 3rd degree AV block, long QT

syndrome, heart failure, cardiogenic shock

2. drug hypersensitivity

3. asthma (beta blocker contraindication)

Adverse effects: Like beta blockers

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Class IV: Calcium channel blockers (verapamil and ditiazem)

They block calcium channels in cardiac muscles more than in other

tissues; so they called cardioselective calcium channel blockers
(verapamil more than diltiazem). They prevent inward calcium currents in
calcium dependent tissues; for examples SA node (decrease phase 4
spontaneous depolarization). They decrease automaticity and AV
conduction

Uses:

Atrial tachycardia

Adverse effects: Hypotension, bradycardia, peripheral edema, and

constipation (verapamil).

Contraindications

1. Severe hypotension

2. 2nd or 3rd degree AV block

3. Cardiogenic shock

4. Severe CHF

5. In patients under beta blockers

Caution is required when using verapamil with digoxin…Why?

Verapamil significantly increases serum digoxin concentration by

reducing digoxin clearance and, possibly, by reducing its volume of
distribution.

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Other antiarrhythmis drugs (adenosine, digoxine, magnesium sulfate,

ra)

1) Adenosine

4. Mechanism of Action:

1. Binds to adenosine receptors in the heart & produces effects

on the AV node & atria similar to acetylcholine (for which it
shares the same signal transduction pathway)

2. Slows conduction time through the A-V node

5. Pharmacokinetics:

1. Adenosine is a sterile solution for rapid bolus intravenous

injection

6. Intravenously administered adenosine is rapidly cleared from the

circulation (half life of less than 10 seconds) via cellular uptake,
primarily by erythrocytes and vascular endothelial cells.

Uses:

1. Acute conversion to sinus rhythm of paroxysmal

supraventricular tachycardia (PSVT)

Adverse effects:

When larger doses are given by infusion, adenosine decreases blood

pressure by decreasing peripheral resistance.

Facial flushing is also common.

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2) Digoxin

It inhibits Na/K-ATPase enzyme pump, and delay conduction in AV

node.

Used in atrial flutter and atrial fibrillation to prevent rapid ventricular

response.

Adverse effects:

GIT disorders and arrhythmias.

3) Intravenous Magnesium sulfate: is the drug of choice for treating the

potentially fatal arrhythmia torsade de pointes and digoxin-induced
arrhythmias.

4) Ranolazine

It is antianginal drug and used in treatment of refractory cases of atrial

and ventricular tachycardia in combination with other antiarrhythmic
drugs. Its main adverse effects are dizziness and constipation.

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(Pharmacology)
DRUG TREATMENT OF HEART FAILURE
What is the heart failure?
HF occurs when myocardial dysfunction is so severe that COP is
inadequate to provide O2.
Main common problems associated with heart failure
1- Increased Preload
2- Increased afterload
3- Increased blood volume
4- Increased sympathetic activity
5- Increased aldosterone level
6- Increased remodeling
7- Decreased contractility

Symptoms and signs

⚫ Dyspnea on exertion, orthopnea, and paroxysmal nocturnal
dyspnea,
⚫ Fatigue, weak pulse, oliguria,
⚫ GIT congestion and peripheral edema.
Goals of pharmacologic treatment

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1- Alleviate symptoms 2- Slow disease progression 3- Improve

survival.
Drugs used to treat heart failure:
1- Vasodilators. 2- Aldosterone antagonist
3- Beta-blockers. 4- Diuretics.
5- Positive inotropic drugs
6- Recently approved drugs
1- Vasodilators
A- Angiotensin-converting enzyme inhibitors (ACEIs)
Mechanism of action
1- Reduce salt and water retention by reducing aldosterone secretion →
reduce preload.
2- Reduce peripheral resistance → reduce afterload.
3- Reduce sympathetic activity.
4- Reduce long-term remodeling of the heart and vessels → reduce
mortality and morbidity.
5- Improve exercise tolerance quality of life.

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Indications
All patients with asymptomatic and symptomatic HF alone or in
combination with other drugs
Examples: Captopril, enalapril,……
• Side effects: Cough, angioedema, postural
hypotension, teretogenicity, altered Tast,
↑potassium level, renal failure.
b- Angiotensin receptor blocker (ARBs)
Substitute for ACEIs in patients who cannot tolerate
ACEI
Examples: Losartan, valsartan,……..
Side effects: The same side effects of ACEIs with no
cough or angioedema

2- Aldosterone antagonists
Example. Spironolactone
⚫ Direct aldosterone antagonist
⚫ ↓ Salt retention,
⚫ ↓ Myocardial hypertrophy and remodeling
⚫ ↓ Cardiac fibrosis
⚫ ↓ Hypokalemia.
Used in severe stages of HF or HF+ recent myocardial infarction.

3- Beta-adrenoceptors blockers
Example. 1- Carvedilol (Non-selective beta-blocker with alpha-blocking
effects)
2- Metoprolol and Bisoprolol (selective beta-1 blockers)
Mechanism of beneficial effect:

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- Attenuation of the adverse effects of high concentrations of

catecholamines.
- Reduced remodeling.
- Reduction in arrhythmias.
-Reduction of morbidity and mortality
Indication
Beta blockers are recommended in all cases of heart failure except two
cases:
1- Acute heart failure.
2- Non symptomatizing high risk cases.
N.B. Start at low doses and gradually titrate to target doses based on
patient tolerance and vital signs
4- Diuretics
Mechanism of action in heart failure:
- Reduce salt and water retention→ reduce ventricular preload.
- The reduction in venous pressure has two useful effects: reduction of
edema and its symptoms and reduction of cardiac size which leads to
improved efficiency of pump function.
- Don‘t improve survival in HF
1) Loop diuretics (e.g. furosemide) are the most commonly used diuretics
in HF.
2) Thiazide diuretics (e.g. Hydrochlorothiazide,..).
3) Potassium sparing diuretics (e.g eplerenon,..)
4) Sodium- glucose co-transporter inhibitors (dapaglifozin) which prevent
glucose re-absorption, increase its excretion associated with water. It has
Cardioprotective, renoprotective and diuretic effect.

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5-Positive Inotropes
(digoxin, milrinone, dopamine doputamine, nesiritide)
• +ve inotropic agents→ ↑cytoplasmic calcium → ↑cardiac
contractility →↑COP.
A. Digoxin (Cardiac glycosides), oral and i.v.
Mechanism of action: Glycosides inhibit the cardiac Na+/K+ pump → ↑

intracellular Ca++ → ↑ cardiac contraction.

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Cardiac Actions
1. ↑Calcium ion→ ↑ cardiac contraction → ↑COP
2. ↑ Vagal tone → ↓ HR → ↓ O2 requirements
3. Digoxin slows conduction velocity through the
AV node, making it useful for atrial fibrillation
Therapeutic uses:
1- In patients with severe systolic, left sided HF after
Initiation of ACE inhibitor, β-blocker, and diuretic therapy.
1- HF with AF to protect the ventricle by ↓ AV conduction
Pharmacokinetics
➢ Digoxin is oral and injectable formulations.
➢ It has a large Vd (tissue binder).
➢ In acute situations such as symptomatic AF, a loading dose
regimen is used.
➢ Has a long t1/2 of 30 to 40 h.
➢ Renal elimination requiring dose adjustment in renal dysfunction.
Side effects
• Digoxin toxicity is one of the most common adverse drug reactions
(narrow safety margin).
• Keep plasma level 0.5-1.5 ng/ml
• Anorexia, nausea, and vomiting (early).
• Blurred vision, yellowish vision.
• Cardiac arrhythmias.
• Severe toxicity resulting in ventricular tachycardia
Predisposing factors of toxicity
1- Hypokalemia (K+ and digoxin compete on the same binding site)
2- Concomitant treatment with other CV drugs as (Verapamil,
amiodarone, β-blockers)

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Management of toxicity
⚫ Discontinuing digoxin
⚫ Correction of hypokalemia.
⚫ Antiarrhythmic drugs.
⚫ Use of antibodies to digoxin (digoxin immune Fab)

B. β-Adrenergic agonists (dobutamine & dopamine)

⚫ Improve cardiac performance by causing +ve inotropic effects and
vasodilation (inodilators).
⚫ Both drugs must be given by i.v. in the short-term treatment of
acute HF in the hospital setting.
⚫ ↑ in intracellular cAMP which results in the activation of protein
kinase (PK) → phosphorylation of slow calcium channels
⚫ ↑ entry of calcium ions into the myocardial cells → ↑ contraction
C. Milrinone
- Inhibits phosphodiesterase enzyme (found in cardiac and smooth
muscle) → cAMP → increase cardiac contractility and vasodilatation
- Increases cardiac output and reduce peripheral vascular resistance.
- Is used only intravenous infusion and only for acute heart failure as
prolonged use leads to arrhythmia and increased mortality.
D. Nesiritide (B-type natriuretic peptide): has vasodilator and anti-
remodeling activity.

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❖ New strategies in treatment of heart failure:

1- Sacubitril/Valsartan: is a first-in-class angiotensin receptor neprilysin

inhibitor (NEPi; ARNi) has 2 components—an angiotensin receptor

blocker (ARB) and a NEP inhibitor (NEPi)—which block RAAS

activation while enhancing the adaptive actions of atrial natriuretic peptide
(ANP) resulting in a potent natriuretic and vasodilatory effect. In addition,
to the inhibiton of the renin–angiotensin–aldosterone system,it reduce
sympathetic drive, and have antiproliferative and antihypertrophic effects
as well.

2- Glucagon-Like Peptide-1 Receptor Agonists

❖ Currently used for diabetes mellitus, has also been repurposed for
HF.

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(Pharmacology)
ANTIHYPERTENSIVE DRUGS
Objectives
By the end of this lecture you should be able to:
1. List the different groups of antihypertensive drugs and give examples
for each group.
2. Describe the mechanism of action of each group.
3. Describe the clinical pharmacokinetics of some antihypertensive
drugs.
4. List the major side effects associated with the different
antihypertensive drugs.
5. List the drugs used in the treatment of hypertensive emergencies.

Hypertension is defined as either a sustained systolic blood pressure of

greater than 140 mm Hg or a sustained diastolic blood pressure of greater
than 90 mm Hg.

Types:More than 90% of patients have essential hypertension

(hypertension with no identifiable cause.

Risk factors: Persons with diabetes, obesity, or disability status are all
more likely to have hypertension than those without. In addition,
environmental factors, such as a stressful lifestyle, high dietary intake
of sodium, and smoking, may further

predispose an individual to hypertension.

Physiological control of blood pressure:Arterial blood pressure is directly

proportional to cardiac output and peripheral vascular resistance.
Cardiac output and peripheral resistance, in turn, are controlled mainly by
two overlapping control mechanisms: the baroreflex and the renin–
angiotensin–aldosterone system.

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A. Baroreceptors and the sympathetic nervous system:

A fall in blood pressure causes pressure-sensitive neurons (baroreceptors
in the aortic arch and carotid sinuses) to send fewer impulses to
cardiovascular centers in the spinal cord. This prompts a reflex response of
increased sympathetic and decreased parasympathetic output to the heart
and vasculature, resulting in vasoconstriction andincreased cardiac output.

These changes result in a compensatory rise in blood pressure

B. Renin–angiotensin–aldosterone system.

Renin release stimulted by: vasodilator as hydralazine, beta- agonist as

isoprenaline, alpha antagonist, phosphodiestrase inhibitors, most diuretics
and anesthetics.

RAS inhibited by: inhibition of renin secretion (clonidine-Methyle dopa-

β blockers), renin antagonist (Aliskiren), ACEIs and ARBs

RAS controls BP by controlling:

1- Blood volume (BV and salt and water)

2- vessels condition.

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Classification of antihypertensive drugs by their primary site or

mechanism of action
1- Diuretics:
2. Thiazide and related agents (e.g.
hydrochlorothiazide, chlorthalidone).
3. Loop diuretics (e.g. furosemide, ethacrynic acid).
4. K+ sparing diuretics (e.g. amiloride, triamterene, spironolactone)
2- Sympatholytic drugs:
1. Beta-adrenergic antagonists (e.g. propranolol, metoprolol, atenolol).
2. Alpha-adrenergic antagonists (e.g. prazosin, doxazosin, terazosin).
3. Mixed adrenergic antagonists (e.g. labetolol, carvedilol).
4. Centrally acting agents (e.g. methyldopa, clonidine).
5. Adrenergic neuron blocking agents (e.g. reserpine, guanethidine).

3- Vasodilators:
1. Arterial (hydralazine, minoxidil, diazoxide, fenoldopam).
2. Arterial and venous (nitroprusside).

4- Calcium channel blockers

(e.g. verapamil, diltiazem, nifedipine).

5- Angiotensin-converting enzyme inhibitors

(e.g. captopril, enalapril, lisinopril, ramipril, perindopril).

6- Angiotensin II receptor antagonists

(e.g. losartan, candesartan, valsartan).

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1- Diuretics (see Diuretics Chapter)

Mechanism of action in Hypertension:
5. Diuretics lower blood pressure primarily by depleting body sodium
stores.
6. Initially, diuretics ↓ blood pressure by ↓ blood volume and cardiac
output.
7. After 6 – 8 weeks, cardiac output is normal while peripheral
vascular resistance declines.
Selection of diuretics:
- Thiazide diuretics (e.g. hydrochlorothiazide) are appropriate for most
patients with mild or moderate hypertension and normal renal and
cardiac function.
- Loop diuretics (e.g. furosemide) are appropriate for severe
hypertension, in renal insufficiency and in cardiac failure.
- Potassium-sparing diuretics (e.g. spironolactone) are useful both
to avoid excessive potassium depletion and to enhance the natriuretic
effects of other diuretics.
- Carbonic anhydrase inhibitors (CAI) (Acetazolamide) is a valuable
mainly in treatment of glucoma and idiopathic intracranial
hypertension
Side Effects: (see Diuretics Chapter)

]]]]]]

2- Sympatholytic drugs

a- Centrally acting sympathoplegic drugs (Selective alpha-2

adrenoceptor agonists)

Clonidine
Mechanism of action:
- Stimulates central alpha-2 adrenoceptors → reduce sympathetic
outflow from the CNS.

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- ↓ blood pressure results from reduction of cardiac output due to

decreased heart rate and relaxation of capacitance vessels with a
reduction in peripheral vascular resistance.

- Abrupt cessation of the therapy precipitate a hypertensive crisis.

Side effects: Dry mouth, Sedation.

Methyldopa
Mechanism of action:
- Methyldopa is converted to α-methyldopamine and α-
methylnorepinephrine.
- α-methylnorepinephrine stimulates central alpha-2 adrenoceptors →
reduce sympathetic outflow from the CNS leading to reduced total
peripheral resistance and a decreased blood pressure.
- Cardiac output is not decreased and blood flow to vital organs is not
diminished.
- Because blood flow to the kidney is not diminished by its use, α-
methyldopa is especially valuable in treating HT patients with renal
insufficiency and in pregnancy.
• Side effects : sedation and drowsiness.

b- Beta-adrenoceptor blocking agents (beta-blockers)

e.g. propranolol (non-selective β blocker) & atenolol (selective β1
blocker)
Mechanism of the antihypertensive effect:
- ↓ myocardial contractility and cardiac output.
- ↓ secretion of renin → ↓ levels of angiotensin II.
- Act on presynaptic β adrenoceptors to reduce sympathetic
vasoconstrictor nerve activity.
- Central actions of beta-blockers.

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- Labetolol can also block α1-adrenoceptors → ↓ peripheral resistance.

Advantages:
No postural hypotension

No salt and water retention

Low incidence of side effects

Low cost

Once a day regime

Preferred in young non-obese patients, prevention of sudden cardiac

death in post infarction patients and progression of CHF

Drawbacks (side effects):

Fatigue, lethargy (low COP) – decreased work capacity

Loss of libido – impotence

Cognitive defects – forgetfulness

Difficult to stop suddenly

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Therefore cardio-selective drugs are preferred in asthma,

in diabetes mellitus, and in peripheral vascular disease.

Contraindications:

1- Obstructive lung disease.

2- Congestive heart failure
3- Severe symptomatic occlusive peripheral vascular disease)

c- Alpha-1 blockers
Prazosin, Doxazosin, Terazosin
Mechanism of action:
- Reduce blood pressure by dilating both resistance and capacitance
vessels.
- Produce less reflex tachycardia than nonselective α-adrenoceptor
antagonists.
- Fluid retention in monotherapy and Headache.

- Not used as first line agent, used in addition with other conventional
drugs as diuretic or beta blocker

- First-dose syncope are almost universal adverse effects.

3. Vasodilators
a- Hydralazine
They dilate arterioles but not veins → ↓ systemic vascular resistance
→↓blood pressure.
Pharmacokinetics:
- This group is metabolized in part by acetylation. Rapid
acetylators have greater first pass metabolism, lower

bioavailability and less antihypertensive benefit from a given

dose than do slow acetylators.

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Side effects:
- Palpitations, sweating, flushing and reflex tachycardia (using with β
blocker is preferred .
- Lupus erythematous like syndrome (arthralgia, myalgia, skin rashes
and fever).
- Peripheral neuropathy.
b- Diazoxide
Mechanism of action:
- It prevents vascular smooth muscle contraction by opening potassium
channels and stabilizing the membrane potential at the resting level.
- It is a relatively long-acting parenterally administered arteriolar
dilator that is used to treat hypertensive emergencies.
Side effects:
- Hypotension → stroke and myocardial infarction.
- Reflex tachycardia → angina in patients with IHD.
- Hyperglycemia.
- Salt and water retention.
c- Minoxidil
Mechanism of action:
- It is a very efficacious orally active vasodilator,
- Open potassium channels in vascular smooth membrane → stabilizes
the membrane at its resting potential and makes contraction less likely
- Dilates arterioles but not veins.
Side effects:
- Reflex tachycardia (use with a beta-blocker) and palpitations.
- Edema (use with diuretics).
- Headache and hypertrichosis.

d- Sodium Nitroprusside

It Dilates both arteries and veins

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Uses: Hypertensive Emergencies

Side effects:: accumulation of cyanide leads to cyanide toxicity , treated

by thiosulphate.

4- Calcium Channel blockers (CCBs)

(See Angina)

CCBs block L-Type channel:

Smooth Muscle relaxation

CCBs have an intrinsic natriuretic effect and, therefore, do not usually

require the addition of a diuretic.

Negative chronotropic, ionotropic effects in heart.

These agents are useful in the treatment of hypertensive patients who also
have asthma, diabetes, angina, and/or peripheral vascular disease.

Examples: Verapamil, Diltiazem, nifedipine

Nifedipine has highest smooth muscle relaxation and vasodilator action

followed by verapamil and diltiazem

CCBs are effective in low Renin hypertension

They are next to ACE inhibitors in inhibition of diabetic nephropathy

Contraindications:

Heart failure, hypotension, post infarct cases and severe aortic stenosis

Side effects: Constipation, , AV-Block, Edema (verapamil) -Hypotension

and Tachycardia (nifedipine)

5- Angiotensin converting enzyme inhibitors (ACEI)

- Examples: captopril, enalapril, lisinopril., fosinopril.
ACEI differ in their potency, bioavailability, distribution, plasma half-

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life and their route of elimination.

- Some of them are administered as prodrugs: enalapril is a prodrug
that is by de-esterification to enalaprilat. Fosinopril :is the only ACE
inhibitor that is not eliminated primarily by the kidneys and does not
require dose adjustment in patients with renal impairment.

Mechanism of action:

- Inhibit the converting enzyme that hydrolyses angiotensin I to

angiotensin II and inactivates bradykinin.

- They lower blood pressure by decreasing peripheral vascular

resistance.
- Cardiac output and heart rate are not significantly changed.
- Unlike direct vasodilators, these agents do not result in reflex
sympathetic activation (can be used safely in persons with IHD).
- The absence of reflex tachycardia may be due to downward resetting
of the baroreceptors or to enhanced parasympathetic activity.

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Side effects and contraindications:

- Severe hypotension after initial doses of any ACE inhibitor in
hypovolemic patients (e.g. due to diuretics).
- Acute renal failure in patients with bilateral renal artery stenosis.
- Hyperkalemia.
- Cough and angioedema.
- ACE inhibitors are contraindicated in the second and third trimester
of pregnancy (risk of malformations).
- Allergic skin rashes.
- High doses of captopril when given to patients with renal
insufficiency → neutropenia or proteinuria.
Drug interactions:
- With potassium supplements or potassium sparing diuretics →
hyperkalemia.
- NSAIDS may impair the hypotensive effects of ACE inhibitors by
blocking bradykinin- mediated vasodilation, which is at least in part,
PG mediated.
Therapeutic uses:

▪ Hypertension

▪ Congestive Heart Failure

▪ Myocardial Infarction

▪ Prophylaxis of high CVS risk subjects

▪ Diabetic Nephropathy

Contraindications: Pregnancy, bilateral renal artery stenosis,

hypersensitivity and hyperkalaemia

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6- Angiotensin receptor blocking agents

- Examples: losartan and valsartan
•They have no effect on bradykinin metabolism and are therefore more
selective inhibitors of angiotensin II effects than ACE inhibitors.
• They also have the potential for more complete inhibitionof
angiotensin action compared with ACE inhibitors because there
are enzymes other than ACE that are capable of generating
angiotensin II.
•The adverse effects are similar to those described for ACE
inhibitors, including the hazard of use during pregnancy, but cough
and angioedema are less common with angiotensin receptor
blockers than with ACE inhibitorsas there is no effect on
Bradykinin.

Combination Therapy of Hypertension

In clinical practice a large number of patients require combination therapy

– the combination should be rational and from different patterns of
haemodynamic effects:

1- Sympathetic inhibitors (not beta-blockers) and vasodilators + diuretics

2- Diuretics, CCBs, ACE inhibitors and vasodilators + beta blockers
(blocks renin release)

3- Hydralazine and CCBs + beta-blockers (tachycardia countered)

4- ACE inhibitors + diuretics

Three Drug combinations: CCB+ACE/ARB+diuretic; CCB+Beta

blocker+ diuretic; ACEI/ARB+ beta blocker+diuretic

Selection of antihypertensive drugs

- Select from the first line drugs (Thiazide diuretic, CCC, ACEIs (orARBs))

In presence of associated conditions, select according to the following table:

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Treatment of hypertensive emergencies: high BP with:

1. Cerebrovascular accident or head injury
2. Left ventricular failure with pulmonary edema

3. Hypertensive encephalopathy

4. Angina or MI
5. Acute renal failure

6. Eclampsia

7. Pheochromocytoma, cheese reaction and clonidine withdrawal.

Drugs:
Hydralazine, Fenoldopam
Sodium Nitroprusside

Glyceryl trinitrate (GTN)

Esmolol ; Labetolol: useful in reducing cardiac work

Phentolamine – pheochromocytoma, cheese reaction and clonidine

withdrawal

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(Pharmacology)
TREATMENT OF HYPERLIPIDEMIA
• Hyperlipidemia is defined as elevated total cholesterol, LDL
cholesterol, or triglycerides; a low HDL cholesterol; or a
combination of these abnormalities.
• Hyperlipoproteinemia describes an increased concentration of the
lipoprotein macromolecules that transport lipids in the plasma.
• Abnormalities of plasma lipids can result in a predisposition to coronary,
cerebrovascular, and peripheral vascular arterial disease.

Triglycerides and cholesterol are the two most common lipids

Triglycerides:

• Used for fat storage and as an energy source.

• Are the major fat in human

Cholesterol:
• Cholesterol is very insoluble in water so is transported as acomponent
of blood lipoproteins
• Serves as a stabilizing component of cell membranes. Serves as a
precursor to bile salts. Serves as a precursor for all steroid hormones
• High levels of LDL (Low-Density Lipoproteins) cholesterol are atherogenic
• High levels of HDL (High-Density Lipoproteins) cholesterol are
protective because the HDL removes cholesterol from tissues and
returns it to the liver.

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Cholesterol Metabolism

• Obtained from the diet or synthesized in liver, intestine, and

endocrine glands.

• HMG-CoA reductase is the major rate-limiting enzyme in

cholesterol synthesis which is controlled in most tissues by
negative feedback to HMG-CoA reductase.

Management of hyperlipidemia

• Lifestyle Modifications: regular exercise, quitting smoking, weight

loss and eating antioxidant-rich foods with low saturatedfats.
• Drug Therapy of hyperlipidemia: lipid-lowering therapy. Beforedrug
therapy is initiated, secondary causes of hyperlipidemia should be
excluded. Most secondary causes can be excluded by ascertaining the
patient's medication history and by measuring serum creatinine, liver
function tests, fasting glucose, and thyroid-stimulating hormone levels.

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• Classification of antihyperlipidemics (lipid-lowering agents)

o HMG-CoA reductase inhibitors (statins)
o Niacin (nicotinic acid)
o Fibric acid derivatives (Fibrates)
o Bile acid sequestrants
o Cholesterol Absorption Inhibitor (Ezetimibe)
o Omega-3 fatty acids
o Comnabition drug therapy

42. HMG CoA reductase inhibitors (statins)

They are first-line treatment for patients with

elevated risk of atherosclerotic cardiovascular
disease (ASCVD) (e.g., atorvastatin, simvastatin,
and rosuvastatin).
Mechanism of Action
• Statins exert their major effect; reduction of LDL levels; through a mevalonic
acid–like moiety that competitively inhibits HMG-CoA reductase. By
reducing the conversion of HMG-CoA to mevalonate, statins inhibit an
early and rate-limiting step in cholesterol biosynthesis.
• Statins affect blood cholesterol levels by inhibiting hepatic cholesterol
synthesis which results in increased expression of the LDL receptor gene. In
response to the reduced free cholesterol content within hepatocytes. The
greater number of LDL receptors on the surface of hepatocytes results in
increased removal of LDL from the blood, thereby lowering LDL-C levels.

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Potential cardioprotective effects other than lipid lowering

• Atherosclerotic plaque
stabilization.

• Improvement of coronary
endothelial function.

• Inhibition of platelet
thrombus formation.

• Vascular anti-inflammatory
activity.

• For these, they are used in

Covid-19.

Statins kinetics
• Oral absorption of the statins is variable (30% to 85%)
• All statins are metabolized by hepatic CYP450, except pravastatin.
• Hepatic cholesterol synthesis is maximal between midnight and 2:00
A.M. Thus, statins with t1/2 ≤ 4 hours (all but atorvastatin and rosuvastatin)
should be taken in the evening.
• These drugs are contraindicated during pregnancy and lactation.

Side effects are rare (well tolerated):

• Hepatotoxicity

• Myopathy or rhabdomyolysis (can progress to myoglobinuria

and renal failure), espcially when statins are administerated with
P450 inhibitors, gemfibrozil or niacin
• Abdominal cramps, constipation, diarrhea,and heartburn
• Headache,rash,and itching

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43. Niacin (nicotinic acid)

▪ Niacin can reduce LDL-C by 10% to 20% and is the most
effective agent for increasing HDL-C.
▪ It also lowers triglycerides by 20% to 35% at typical doses of
1.5 to 3 grams/day.
▪ Niacin can be used in combination with statins, and a
fixed-dose combination of lovastatin and long- acting
niacin is available.
Mechanism of action:

Niacin strongly inhibits lipolysis in adipose tissue,

thereby reducing production of free fatty acids. The
liver normally uses circulating free fatty acids as a
major precursor for triglyceride synthesis. Reduced
liver triglyceride levels decrease hepatic VLDL production, which in turn
reduces LDL-C plasma concentrations.

Pharmacokinetics:

▪ Niacin is administered orally.

▪ It is converted in the body to nicotinamide, which is incorporatedinto the
cofactor NAD+.
▪ Niacin, its nicotinamide derivative, and other metabolites are excreted in
the urine. [Note: Nicotinamide alone does not decreaseplasma lipid Levels.]

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Therapeutic uses:

• Since niacin lowers plasma levels of both cholesterol and triglycerides, it

is useful in the treatment of familial hyperlipidemias.

• It is also used to treat other severe hypercholesterolemias, often in

combination with other agents.

Adverse effects:

▪ The most common side effects of niacin are an intense cutaneous flush
(accompanied by an uncomfortable feeling of warmth) and pruritus.
Administration of aspirin prior to taking niacin decreasesthe flush, which
is prostaglandin mediated.
▪ Some patients also experience nausea and abdominal pain.
▪ Slow titration of the dosage or usage of the sustained-release
formulation of niacin reduces some initial adverse effects.

▪ Niacin inhibits tubular secretion of uric acid and, thus, predisposes to

hyperuricemia and gout.

▪ Impaired glucose tolerance (hyperglycemia) and hepatotoxicity have

also been reported. The drug should be avoided in diabetes mellitus and
hepatic disease.

44. 3-Fibric acid derivatives (Fibrates)

▪ Fenofibrate,clofibrate,ciprofibrate,benzafibrate and gemfibrozil

▪ Peroxisome proliferator activated receptors (PPARs) agonists
▪ They are derivatives of fibric acid that lower serum triglycerides and
increase HDL levels

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Mechanism of action
•Stimulate PPARs 🢡 regulate lipid metabolism
• ⮇TG (40%) (⮅ Lipoprotein lipase expression🢡
VLDL+chylomicron hydrolysis 🢡⮇TG)
• ⮅ HDL-C (5%) (⮅ apo AI and apo AII expression).

• ⮅ LDL-C clearance by liver

• Fenofibrate more effective than gemfibrozil in ⮇TG.

Pharmacokinetics:

Gemfbrozil and fenofbrate are completely absorbed after oral

administration and distribute widely, bound to albumin. Fenofbrate is a
prodrug, which is converted to the active moiety fenofibric acid.

Both drugs undergo extensive biotransformation and are excreted in the

urine as glucuronide conjugates.

Therapeutic uses: The fibrates are used in the treatment of

hypertriglyceridemias.

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Adverse effects:

▪ The most common adverse effects are mild GI disturbances.

▪ Because these drugs increase biliary cholesterol excretion, there isa
predisposition to form gallstones (most common).
▪ Myositis (inflammation of a voluntary muscle) can occur, and muscle
weakness or tenderness should be evaluated. Patients with renal
insuffciency may be at risk.

▪ Myopathy and rhabdomyolysis have been reported in patients taking

gemfbrozil and statins together. The use of gemfbrozil is
contraindicated with simvastatin.
▪ Both fibrates may increase the effects of warfarin. INR should,
therefore, be monitored more frequently when a patient is taking both
drugs.
▪ Fibrates should not be used in patients with severe hepatic or renal
dysfunction or in patients with preexisting gallbladder disease.

4- Bile acid sequestrants (resins)

(cholestyramine, colesevelam and colestipol)

Mechanism of action

Bind bile acids and bile salts in the small intestine (++/--) 🢡 form
resin/bile acid complex 🢡 excreted in feces 🢡⮇ bile acid
concentration 🢡 This causes hepatocytes to increase
conversion of cholesterol to bile acids 🢡⮇ intracellular
cholesterol 🢡⮅ hepatic uptake of LDL-C🢡 ⮇ plasma
LDL-C.

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Pharmacokinetics
• Insoluble in water and have high MW.
•After oral administration, they are neither absorbed nor
metabolically altered by the intestine, totally excreted in feces.

Therapeutic uses
•Treatment of hyperlipidemias
•Colesevelam is indicated for type 2 diabetes
Adverse effects
(Bind with all –ve charged..acidic drug)
• GI disturbances (COMMENEST) (Colesevelam has fewer GI side
effects than other bile acid sequestrants).

• Impair the absorption of fat soluble vitamins.

• Interfere with the absorption of many drugs (Digoxin, warfarin, and

thyroid hormone) (Drugs taken at least 1 to 2 h before, or 4 to 6 hours
after).

•⮅ TG 15% (C/I significant hypertriglyceridemia ≥400 mg/dL).

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5-Cholesterol absorption inhibitor (Ezetimibe)

Mechanism of action
•Selectively inhibits intestinnal absorption of dietary and biliary
cholesterol 🢡⮇ delivery of cholesterol to the liver 🢡⮇ hepatic
cholesterol stores 🢡⮅clearance of cholesterol from the blood 🢡⮇
LDL-C (18% - 20%) + ⮇ TG (10%)

Pharmacokinetics
•Metabolized in the small intestine and liver via glucuronide conjugation
🢡biliary and renal excretion.

•NOT used in moderate to severe hepatic insufficiency

Adverse effects (well tolerated)

• Allergy, back pain,GIT upsets

6- Omega-3 Fatty Acids (fish oil)

Omega-3 polyunsaturated fatty
acids (PUFAs) are essential fatty
acids

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Mechanism of action
•⮇ Hepatic VLDL and TG
•Small increases in LDL-C!!! And HDL-C.
•Icosapent ethyl; Does not significantly raise LDL-C.
•Used as adjunct to other lipid-lowering therapies
Adverse effects
•Abdominal pain,nausea, diarrhea and a fishy after taste.
•Bleeding risk (the risk increased when combined with anticoagulants
or antiplatelet agents).
7- Combination drug therapy

▪ It is often necessary to use two antihyperlipidemic drugs to achieve

treatment goals.
▪ The combination of statins with a bile acid–binding agent has beenshown
to be very useful in lowering LDL-C levels.
▪ Simvastatin and ezetimibe, as well as simvastatin and niacin, are
currently available combined in one pill to treat elevated LDL
cholesterol.
▪ Many experts recommend maximizing statin dosages and adding niacin
or fbrates only in those with persistently elevated triglycerides (greater
than 500 mg/dL) or those with low HDL cholesterol levels (less than
40 mg/dL).
▪ Combination drug therapy is not without risks. Liver and muscletoxicity
occurs more frequently with lipid-lowering drug combinations.

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(Pharmacology)
DRUGS USED TO TREAT ANGINA PECTORIS

Angina pectoris, the primary symptom of ischemic heart disease, is

caused by transient episodes of myocardial ischemia that are due to an
imbalance in the myocardial oxygen supply-demand relationship.

Typical angina is experienced as a heavy, pressing substernal discomfort,

often radiating to the left shoulder, flexor aspect of the left arm, jaw, or
epigastrium.

Types of angina pectoris:

Typical angina: coronary atherosclerosis can impair coronary blood flow
and lead to symptoms of angina when myocardial O2 demand increases,
as with exertion
Unstable angina or ACS: increasing in frequency or severity and even
occurring at rest due to coronary thrombosis.
Variant or Prinzmetal angina: Occurs at rest as a consequence of an
abrupt reduction in blood flow due to localized vasospasm
Silent angina: ECG changes with absence of symptoms
Principles of therapy of angina :

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1.Antianginal drugs:
1. Nitrates.
2. calcium channels blockers (CCBs).
3. beta blockers (BB).
4. other drugs: Nicorndil , Trimetazidine , Ranolazine .
Adjuvant drugs:
1. Antiplatelet
2. Drug treatment of Risk and precipitating factors: Antihyperlipidemic
Organic Nitrates
Mechanism of action
They are prodrugs that are sources of NO. NO activates the guanylyl
cyclase, thereby increasing intracellular levels of cGMP. cGMP promotes
the dephosphorylation of the myosin light chain and the reduction of
cytosolic Ca2+ and leads to the relaxation of smooth muscle cells in a
broad range of tissues.
Actions
NO-dependent vasodilation; At low-to-medium doses, preferential
venodilation decreases venous return, leading to a fall in left and right
ventricular chamber size and end-diastolic pressures, and thereby reduced
cardiac O2 demand. Systemic vascular resistance and arterial pressure are
not or only mildly decreased, leaving coronary perfusion pressure
unaffected. Heart rate remains unchanged or may increase slightly in
response to a decrease in blood pressure.
inhibition platelet aggregation
relaxes smooth muscle in the bronchi and GI tract.
Pharmacokinetics &therapeutic uses
For stable angina
Nitroglycerin has a t1/2 of 1–3 min sublingual for acute attack
Isosorbide Dinitrate sublingual for acute attack and oral for chronic
prohylaxis

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Isosorbide-5-Mononitrate in tablet form does not undergo significant

first-pass metabolism
Patients should be instructed to seek medical attention immediately if 3
nitroglycerine tablets taken over a 15-min period do not relieve a
sustained attack because this indicative of MI.
Side effects
Tolerance marked attenuation in the magnitude of most of their
pharmacological effects.
Headache is common and can be severe, usually decreasing over a few
days
Transient episodes postural hypotension may develop in severe nitrate
syncope, positioning and other measures that facilitate venous return are
the only therapeutic measures required.
Drug interaction
Sildenafil potentiates the action of the nitrates and can cause extreme
hypotension. The accumulation of cGMP is enhanced by inhibition of the
cGMP-specific PDE5 family. Sildenafil and congeners inhibit PDE5 to
improve sexual dysfunction

Ca2+ Channel Blockers

Mechanism of action
They block Voltage-gated Ca2+ channels (L-type) mediate the entry of
extracellular Ca2+ into smooth muscle and cardiac myocytes and SA and
AV nodal cells in response to electrical depolarization. Ca2+ is a trigger
for contraction,
Actions
➢ Vascular Tissue. The dihydropyridines (nifedipine, amlodipine,
clevidipine, isradipine, nicardipine, , nimodipine) decrease
arterialresistance, blood pressure, and cardiac afterload

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• Cardiac Cells.Verapamil and diltiazem depress the rate of the sinus node
pacemaker and slow AV conduction lead to a reduction in myocardial O2
demand.
Pharmacokinetics &therapeutic uses
Variant angina results from reduced blood flow (a consequence of
transient localized vasoconstriction). CCBs are considered first-line
treatment
CCBs also are effective in the treatment of exertional, or exercise-
induced, angina.
Concurrent therapy of a dihydropyridine with a β blocker has proven
more effective than either agent given alone in exertional angina, why?
In patients with hepatic cirrhosis, old age, the bioavailabilities and half-
lives may be increased, and dosage should be decreased accordingly.
Side effects
nifedipine often cause headache, flushing, dizziness with immediate
release preparations
Peripheral edema
CCBs can cause or aggravate gastroesophageal reflux.
Constipation is a common side effect of verapamil
bradycardia, transient asystole, and exacerbation of heart failure may
occur with IV verapamil
Drug interaction
the concurrent administration of verapamil or diltiazem with a β blocker
is contraindicated.
The bioavailability of all CCBs is reduced, markedly, by first-pass
metabolism
verapamil is a relatively efficient inhibitor of the intestinal and renal Pgp
and can thereby increase plasma levels of digoxin, cyclosporine, and
loperamide and other agents

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Beta Blockers

Mechanism of action
Blocking beta receptors in the cardiac tissue leads to negative
chronotropic effect (particularly during exercise) and a negative inotropic
effect
Actions
fall in myocardial O2 consumption at rest and during exertion.
reduction in arterial blood pressure (particularly systolic pressure) during
exercise.
A decrease in heart rate prolongs the time of myocardial perfusion during
diastole.
β blockers can increase blood flow toward ischemic regions―reverse steal
phenomenon‖
Pharmacokinetics &therapeutic uses
β1-selective and without ISA (e.g., atenolol, bisoprolol, or metoprolol)
B blockers are the only drug class that is effective in reducing the severity
and frequency of attacks of exertional angina and in improving survival
in patients who have had an MI.
They are therefore recommended as first line treatment of patients with
stable CAD and unstable angina/ACS.
β Blockers are not useful for vasospastic angina
Side effects
Bradycardia,
patients with limited cardiac reserve who are critically dependent on
adrenergic stimulation, β blockade can result in profound decreases in left
ventricular function.

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Other antianginal drugs

Nicorandil
• Nicorandil has nitrate-like (cGMP-dependent) properties and acts as an
agonist at ATPsensitive potassium (KATP) channels.

• Nicorandil dilates both arterial and venous vascular beds, leading to

decreases in afterload and preload of the heart
Trimetazidine:
• Inhibit FFA β-oxidation pathway. This leads to a partial shift from FFA to
glucose oxidation in the heart, which provides less ATP but requires less
O2 and may therefore be beneficial in ischemia
• Trimetazidine can cause GI upset, nausea, and vomiting, and, rarely, it
has been associated with thrombocytopenia, agranulocytosis, and liver
dysfunction. More important, trimetazidine may increase the risk of
movement disorders such as Parkinson disease, particularly in older
Ranolazine:
▪ Ranolazine inhibits several cardiac ion fluxes, including IKr and Ina.
▪ Its anti-ischemic and antianginal effects occur independently of
reductions in heart rate and arterial blood pressure or changes in coronary
blood flow.
▪ approved as a second-line agent for the treatment of chronic angina.

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Treatment of different types of angina

Stable angina
1. To prevent myocardial infarction and death:
- Lipid lowering agents (e.g. statins).
- Antiplatelet agents (e.g. aspirin).
- ACEI: reduce CV deaths, MI and strokes.
2. To reduce symptoms of angina and occurrence of ischemia:
- Sublingual nitroglycerin is used to relieve pain in an acute attack.
- The frequency of anginal attacks can be reduced by regular use of
long acting nitrates, calcium channel blockers or beta-blockers.

variant angina :
Nitrates and calcium channel blockers are effective drugs for
relieving and preventing ischemic episodes in patients with variant
angina.

unstable angina :
- Bed rest, oxygen, pain relief (morphine).
- Aspirin. - Heparin.
- Nitrates, beta-blockers or calcium channel blockers

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Parasitology

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(Parasitology)

CARDIAC INVOLVEMENT WITH PARASITIC

INFECTIONS
Pericarditis is inflammation of the pericardium (the fibrous sac
surrounding the heart). Symptoms are sudden onset of sharp chest pain.
Myocarditis: It is an inflammation of the heart muscle (myocardium)
accompanied by myocellular necrosis. Myocarditis can affect the heart
muscle and the heart's electrical system, reducing heart's ability to pump
and causing rapid or abnormal heart rhythms (arrhythmias
Endocarditis: Inflammation of inner layer of heart very rare
Pancarditis: is the inflammation of the entire heart: the epicardium, the
myocardium, and the endocardium.
Cardiomyopathy: refers to diseases of the heart muscle. In most cases,
cardiomyopathy causes the heart muscle to become enlarged, thick or rigid.
As cardiomyopathy worsens, the heart becomes weaker.

Trypanosoma Cruzi
(American trypanosomiasis, MonomorphicTrypanosoma, Chagas
disease)
Protozoan hemoflagellates
Infective stage: Metacyclic trypanosomes In Triatomine bug feces
Diagnostic Stages: Trypomastigote in blood and Amastigotes inside cells

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Mode of transmission:
Contamination of bite wound by feces of kissing bug, less frequently
blood transfusion, organ transplantation and congenital infection
Life cycle

Clinical presentation
Acute phase
Parasites found in blood , Most adults asymptomatic
Chagoma (local at site of bite)
Localized painless induration
Romaña‘s sign (unilateral edema of eyes and conjunctivitis)
Hepatosplenomegaly,fever
Indeterminate phase
Asymptomatic phase of varying length
Parasites disappear from blood
Most patients enter chronic phase within 5 to 15 years
Chronic stage
Dilated cardiomyopathy or/and megacolon or mega esophagus
Cardiac muscle Dysfunction with dysrhythmias, including atrial
bradyarrhythmia and fibrillation and bundle branch blocks.
Fibrosis and cardiomyopathy show cardiac myocyte hypertrophy,
chronic inflammation, and fibrosis

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Diagnosis
1-Microscopic examination is useful in acute stage of thin blood film
2-In chronic phase serology (ELISA)
3- PCR
4- Xenodiagnosis: clean non infected laboratory bred winged bug starved
for 2 weeks then are allowed to feed on suspected person‘s blood. 30 days
latter winged bug feces and gut examined for Trypanosoma
5- Imaging as chest Xray,
Barium swallow and electrocardiogram
Human African Trypanosoma
Polymorphic Trypanosome (HAT)
There are two forms of African trypanosomiasis: the West African form
caused by T.brucei gambiense (T. b. gambiense) and the East African
form caused by T. brucei rhodesiense(T. b. rhodesiense).
Diagnostic stage: Trypomastigote (Trypanosoma form) in blood
Infective stage: Metacyclic trypanosome in Glossina (TseTse) fly
Mode of transmission
Bite of infected Glossina spp. inoculating the metacyclic trypomastigotes
with saliva while taking their blood meals. Rarely by blood transfusion or
congenital transmission.

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Life cycle

Clinical presentation
Early stage
Parasite found in peripheral circulation Within 1-2 weeks of bite
Fever, muscle/ joint pain, headache, itching, enlarged lymph nodes and
Weight loss
Chronic stage
Cross blood brain barrier infects CNS After few weeks of infection
Neurological symptoms
Night-time sleep disturbance Sleepy during daytime
‗‘sleeping sickness‖ Progressive confusion
Trypanosomal pancarditis is accompanied by a diffuse interstitial
lymphocytic infiltrate and edema in the pericardium, myocardium, and
endocardium. Pancarditis (within months or years after infection) in
case of T gambiense. Pancarditis (within weeks after infection) in
case of T rhodesiense. Resulting in Conduction abnormalities,
pericardial effusion, and heart failure

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Toxoplasmosis
Toxoplasma gondii is an obligate intracellular parasite. It is one of
important opportunistic parasites.
Habitat:
1- Enterocytes of cat where sexual cycle takes place in cats.
2- The asexual stages of the parasite develop within reticulo-endothelial
cells and other nucleated cells (e.g. muscle and intestinal epithelium) of
the intermediate host (all mammals).
Infective stage or stages: Oocyst, tissue cyst and trophozoites
Diagnostic stage: Tissue cyst
Clinical presentation: In immunosuppressed
(immunocompromised) patient causes 1-Encephalitis
2- Myocarditis with Multiple bradyzoites (true cysts) and tachyzoites
(pseudocysts) of Toxoplasma gondii were seen within the myocardial
fibres. Inflammatory cells of neutrophils, lymphocyte, eosinophils,
and plasma cells infiltrate myocardium and may extend to
endocardium and pericardium
3- Chorioretinitis
Life cycle of Toxoplasma gondii

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Diagnosis
Direct detection Less frequently used: parasites in stained tissue
sections and cerebrospinal fluid
Most common is serologic testing to detect antibodies
IgM in acute infection
IgG in chronic infection
Prevention and control
1- Wash your hands with soap and water after any exposure to soil, sand,
raw meat, or unwashed vegetables.
Cooking meat completely
2- Freeze meat for several days before cooking to greatly reduce the
chance of infection.
3- Wash all cutting boards and knives thoroughly with hot soapy water
after each use. •
4- Wash and/or peel all fruits and vegetables before eating them.
5- Wear gloves when gardening or handling sand from a sandbox. Wash
hands well afterward.
6- Avoid drinking untreated water.

Trichinella spiralis (Small thread like nematodes )

Disease: Trichinelliasis, trichiniasis or trichinosis.
Habitat: Small intestine in the adult stage partially embedded in the mucosa
larval stages are encysted in striated muscles.
Mode of transmission
Trichinosis is a food-borne disease that is caused by eating raw or
undercooked meats, particularly pork products infested with the larvae of
trichinella spiralis

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Life cycle:

Pathology and Clinical presentation

1- Intestinal invasion: nausea, vomiting, diarrhea, and colic
2- Migration and encystation stage: allergic symptoms include fever, edema of
the face mainly orbital, headache and eosinophilia. Myocardial involvement
leading to myocarditis
3- Stage of encapsulation: Occurs in striated muscles
Cardiac manifestation: Eosinophilic myocarditis and maybe pericardial
effusion
Diagnosis

Clinical Diagnosis Laboratory diagnosis Serology

History of eating 1- Stool examination foradults ELISA and

IFAT
pork2 weeks 2- Blood examination:Eosinophilia
earlier Recent 3- Xenodoagnosis4-Muscle
gastroenteritis biopsy
5-Intradermal test of Bachman

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Cysticercosis
Invasion of human tissue by larval stage of Taenia solium.

Infective stage: Eggs of pork tapeworm Taenia solium

Diagnostic stage: Cysticercus cellulosae
Mode of transmission:
Heteroinfection: Ingestion of food or water contaminated with eggs of T.
solium.
External autoinfection: Hand to mouth infection in a patient having
adult worms in his intestine.
Internal autoinfection: Regurgitation of detached gravid segments
occurs by antiperistalsis movement to the stomach, the released eggs
descent again to the intestine where they hatch. The oncosphere from the
egg penetrates intestinal mucosa to the circulation.
Life cycle

Clinical presentation: According to site of cyst

1- Heart
Single or multiple cystic lesions producing inflammatory response varies
from minimal myocardial damage to granuloma formation. Thus, patient
maybe asymptomatic or has conduction abnormalities and arrhythmias
2- Brain (neurocysticercosis) cause Convulsions and may be death
3- Eye: vision defect.

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Diagnosis
Most common used:
1- Stool examination shows gravid segments if Taenia solium infected
persons
2- Serology: ELISA
3- Imaging
4- Biopsy after surgery

Entamoeba histolytica
Amoebiasis.
Habitat: caecum and sigmoido-rectal region of man.
Infective stage: Quadrinucleate cyst.
Diagnostic stages: Trophozoite, uninucleate cyst ,binucleate cyst,
quadrinucleate cyst
Mode of infection:
Eating raw vegetables (salad)
Drinking water
Flies and food handlers (cyst passer)
Feco-oral
Life cycle

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Clinical presentation
Intestinal
Asymptomatic infection
Symptomatic infections
1- Acute amoebic dysentery
2-chronic amoebic dysentery
Maybe complicated by
Intestinal perforation of ulcer and peritonitis, amoeboma, ulcerative
colitis or extra-intestinal spread
Of the trophozoites
Spread of the trophozoites by blood to liver or other sites as lung, brain,
spleen, kidney, and skin producing amoebic abscess

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Extra-intestinal amoebiasis: Spread of the trophozoites by blood to liver

or other sites as lung, brain, spleen, kidney, and skin producing amoebic
abscess
Amoebic pericarditis
Amebic pericarditis may present associated with an abscess of the left
lobe of liver or purulent pericarditis from the perforation of the abscess
into the pericardium
The presenting clinical syndrome is usually one of two forms:
(i) sudden onset as cardiac tamponade with chest pain, shortness of
breath, and shock or
(ii) progressive effusion with a slower course to develop fever,
dyspnea, and pain. Amebic pericarditis has been more frequently
described for pediatric populations in which the association of
concomitant intestinal amebiasis may be as high as 20%
Diagnosis of Extra-intestinal amoebiasis
1-Echocardiography and Aspiration of abscess or pericardial
effusion
(Anchovy sauce like fluid)
2-Serology: ELISA
Prevention and control

1. Treatment of patients and periodic examination of

asymptomatic cysts passers as food handlers
2. Wash of fresh eaten vegetables and fruits
3. Safe water supply and sewage disposal
4. Human excreta should not be used as a fertilizers
5. Control of house fly

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Hydatid disease
Invasion of human tissue by larval stage (Hydatid cyst) of dog
tapeworm Echinococcus granulosis.
Infective stage: E granulosis eggs
Diagnostic stage: Hydatid cyst
Mode of infection
Man becomes accidentally infected by ingesting eggs of Echinococcus
contaminating hands, food, or drinks.
Life cycle

Clinical presentation:
Asymptomatic for years before the cysts grow large enough to cause
symptoms in the affected organs. Symptoms depends on the location
of the cyst. Liver followed by lung are the most common sites then
brain.
Cardiac hydatid cysts: have been described for 0.5 to 3% of
echinococcosis cases. Clinical presentations of cardiac echinococcosis
include myocardial infarction, cardiac tamponade, purulent
pericarditis, and sudden cardiac death. Most cases of pericardial
echinococcosis may be due to spread from an initial location at the
liver dome

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Diagnosis
1- Serology: IgG ELISA test
2- Imaging: CT, Echocardiography and MRI

Control and prevention

1-Regular treatment of infected pit dogs to reduce worm load.
2-Elimination of stray and infected dogs.
3- Prevention of dogs from eating infected offal‘s of domestic animals
(cattle, sheep, ect.) in the slaughterhouses.
4- Strict personal hygiene (e.g. such as washing hands after playing with
or feeding the dogs).
5- Avoidance of unnecessary contact with infected dogs

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