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 a LANGE medical book

CURRENT
Diagnosis & Treatment
Cardiology
THIRD EDITION

Edited by
Michael H. Crawford, MD
Professor of Medicine
Lucy Stern Chair in Cardiology
Interim Chief of Cardiology
University of California, San Francisco

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 Contents
Authors xiv 4. Unstable Angina/Non-ST Elevation
Preface xvii Myocardial Infarction 38
Prediman K. Shah, MD & Kuang-Yuh Chyu, MD, PhD
1. Approach to Cardiac Disease Diagnosis 1
General Considerations 38
Michael H. Crawford, MD Background 38
General Considerations 1 Clinical Spectrum 38
Common Symptoms 1 Pathophysiology 38
History 2 Clinical Findings 40
Physical Findings 3 Symptoms and Signs 40
Physical Examination 3 Physical Examination 41
Diagnostic Studies 7 Diagnostic Studies 41
Differential Diagnosis 42
Acute Myocardial Infarction 42
2. Lipid Disorders 14 Acute Aortic Dissection 42
Christian Zellner, MD Acute Pericarditis 42
Acute Pulmonary Embolism 43
General Considerations 14
Gastrointestinal Causes of Pain 43
Lipoproteins and Apolipoproteins 14
Other Causes of Chest Pain 43
Clinical Findings 16 Treatment 43
History 16 Initial Management 43
Physical Examination 16 Definitive Management 49
Laboratory Assessment 17 Prognosis 50
Treatment 17
LDL Goals 17 5. Acute Myocardial Infarction 51
Non-HDL Goals and Hypertriglyceridemia 18
HDL and Lipoprotein(a) 19 Andrew J. Boyle, MBBS, PhD & Allan S. Jaffe, MD
Nonpharmacologic Approaches 20 General Considerations 51
Pharmacologic Therapy 21 Pathophysiology & Etiology 51
When to Refer 24 Clinical Findings 52
Symptoms and Signs 52
3. Chronic Ischemic Heart Disease 25 Physical Examination 53
Diagnostic Studies 53
Michael H. Crawford, MD Treatment 56
General Considerations 25 Pre-hospital Management 56
Pathophysiology & Etiology 25 Emergency Department Therapy 56
Reperfusion Therapy 57
Clinical Findings 26
In-hospital Management 59
Risk Factors 26
Primary PCI versus Fibrinolysis 60
Symptoms 26
Fibrinolytic Agents 60
Physical Examination 27 Adverse Effects of Fibrinolytic Therapy 63
Laboratory Findings 27 Complications of Myocardial Infarction 64
Diagnostic Studies 27 Cardiogenic Shock 64
Choosing a Diagnostic Approach 29 Congestive Heart Failure 64
Treatment 30 Acute Mitral Valve Regurgitation 65
General Approach 30 Acute Ventricular Septal Rupture 65
Pharmacologic Therapy 31 Cardiac Rupture 65
Revascularization 34 Recurrent Ischemia 66
Selection of Therapy 35 Pericarditis 66
Prognosis 37 Conduction Disturbances 66

iii
 iv
 CONTENTS

Other Arrhythmias 67 8. Aortic Regurgitation 95

Mural Thrombi 68
Aneurysm and Pseudo-aneurysms 69 William A. Zoghbi, MD, FASE, FACC &
Right Ventricular Infarction 69 Michael H. Crawford, MD
Prognosis, Risk Stratification, & Management 70 Etiology 95
Risk Predictors 70 Pathophysiology 95
Risk Assessment 70 Chronic Aortic Regurgitation 95
Risk Management 71 Acute Aortic Regurgitation 95
Clinical Findings 96
6. Cardiogenic Shock 73 Symptoms and Signs 96
Laboratory Findings 97
Edward McNulty, MD & Craig Timm, MD Diagnostic Studies 97
General Considerations 73 Treatment 102
Definition 73 Acute Aortic Regurgitation 102
Etiology 73 Chronic Aortic Regurgitation 103
Pathogenesis 74 Prognosis 105
Cardiogenic Shock after Acute MI 74
Mechanical Complications of Acute MI 74 9. Mitral Stenosis 106
Right Ventricular Infarction 75
Arrhythmias 75 Robert J. Bryg, MD
Other Causes of Cardiogenic Shock 76 General Considerations 106
Clinical Findings 76 Clinical Findings 107
History 76 Symptoms and Signs 107
Physical Examination 76 Physical Examination 107
Laboratory Findings 77 Diagnostic Studies 108
Diagnostic Studies 77 Treatment 110
Left Heart (Cardiac) Catheterization 78 Medical Therapy 110
Treatment 78 Percutaneous Mitral Balloon Valvotomy 110
Acute MI 78 Surgical Therapy 111
Mechanical Complications 80 Prognosis 112
Right Ventricular Infarction 80
Arrhythmias 81 10. Mitral Regurgitation 113
Prognosis 81
Michael H. Crawford, MD
7. Aortic Stenosis 82 General Considerations 113
Clinical Findings 114
Blase A. Carabello, MD & Michael H. Crawford, MD Symptoms and Signs 114
General Considerations & Etiology 82 Physical Examination 114
Bicuspid Aortic Valve 82 Diagnostic Studies 116
Tricuspid Aortic Valve Degeneration 82 Differential Diagnosis 118
Congenital Aortic Stenosis 82 Treatment 119
Rheumatic Fever 82 Pharmacologic Therapy 119
Other Causes 83 Surgical Treatment 119
Prognosis 121
Clinical Findings 83
Symptoms and Signs 83
Physical Examination 84
11. Tricuspid & Pulmonic Valve Disease 122
Diagnostic Studies 85 Brian D. Hoit, MD & Subha L. Varahan, MD
Treatment 88 Tricuspid Valve Disease 122
Pharmacologic Therapy 88 General Considerations 122
Aortic Balloon Valvuloplasty 88 Pathophysiology & Etiology 122
Surgical Therapy 89 Tricuspid Regurgitation 122
Prognosis 92 Tricuspid Stenosis 124
Coincident Disease 93 Clinical Findings 124
Follow-up 93 Symptoms and Signs 124
 CONTENTS
 v

Physical Examination 124 Nonpharmacologic Therapy 157

Diagnostic Studies 125 Pharmacologic Therapy 157
Treatment 133 Management of Complicated Hypertension 161
Medical 133 Prognosis 163
Surgical 133
Postoperative Management 134 14. Hypertrophic Cardiomyopathies 164
Prognosis 134
Pulmonic Valve Disease 134 Pravin M. Shah, MD, MACC
General Considerations 134 General Considerations 164
Pathophysiology & Etiology 134 Pathophysiology & Etiology 164
Pulmonic Regurgitation 134 Systolic Function 165
Pulmonic Stenosis 135 Diastolic Function 165
Clinical Findings 135 Clinical Findings 165
Symptoms and Signs 135 Symptoms and Signs 165
Physical Examination 135 Physical Examination 166
Diagnostic Studies 136 Diagnostic Studies 167
Treatment 136 Treatment 169
Prognosis 136 Medical Management 169
Surgical Myectomy 170
12. Infective Endocarditis 137 Chemical Myectomy 170
Pacemaker Implantation 170
Bruce K. Shively, MD* & Michael H. Crawford, MD Cardioverter Defibrillator Implantation 170
General Considerations 137 Prognosis 170
Pathophysiology & Etiology 137 Future Prospects 171
Cardiac Infection—Vegetations 137
Extracardiac Disease 138 15. Restrictive Cardiomyopathies 172
Clinical Syndromes 138
Clinical Findings 142 John D. Carroll, MD & Michael H. Crawford, MD
Diagnostic Criteria 142 General Considerations 172
Symptoms and Signs 143 Definitions and Terminology 172
Physical Examination 143 Pathophysiology 172
Diagnostic Studies 144 Etiology 173
Management 147 Clinical Findings 174
Initial Decisions 147 Symptoms and Signs 174
Antibiotic Therapy 147 Physical Examination 174
Management of Complications 149 Diagnostic Studies 174
Management of High-Risk Endocarditis 150 Differential Diagnosis 176
Surgery 151 Treatment 176
Follow-up after Endocarditis 151 Diastolic Dysfunction 176
Cardiac Complications 178
13. Systemic Hypertension 153 Underlying Disease 178
William F. Graettinger, MD, FACC, FACP, FCCP Prognosis 178
General Considerations 153
16. Myocarditis 179
Pathophysiology & Etiology 153
Natural History 154 John B. O’Connell, MD & Michael H. Crawford, MD
Ethnic and Socioeconomic Factors 154 General Considerations 179
Clinical Findings 154 Pathophysiology 179
Initial Evaluation 155 Clinical Findings 180
Physical Examination 155 Symptoms and Signs 180
Diagnostic Studies 155
Physical Examination 181
Organ Involvement 156
Diagnostic Studies 181
Treatment 157
Treatment 183
Prognosis 184
*Deceased Specific Forms of Myocarditis 184
 vi
 CONTENTS

Chagas Disease, or American Trypanosomiasis 184 Clinical Findings 206

HIV 184 Symptoms and Signs 206
Toxoplasmosis 185 Physical Examination 207
Cytomegalovirus 185 Laboratory Findings 208
Lyme Myocarditis 185 Diagnostic Studies 209
Giant Cell Myocarditis 185 Differential Diagnosis 209
Sarcoidosis 185 Treatment 210
General Measures 210
17. Pericardial Diseases 187 Pharmacologic Treatment 210
Nonpharmacologic Treatment 218
Martin M. LeWinter, MD
Prognosis 220
General Considerations 187
Normal Pericardial Anatomy and Physiology 187 19. Heart Failure with Preserved
Pericardial Pressure and Normal Function 187 Ejection Fraction 221
Pathogenesis 187
Infectious Pathogens 187 Sanjiv J. Shah, MD
Iatrogenic Causes 189 General Considerations 221
Connective Tissue Disorders 190 Pathophysiology 222
Other Causes 190 Diastolic Dysfunction 222
Acute Pericarditis 192 Left Ventricular Enlargement and
General Considerations 192 Increased Intravascular Volume 222
Clinical Findings 192 Abnormal Ventricular-Arterial Coupling 223
Symptoms and Signs 192 Left Ventricular Hypertrophy 223
Physical Examination 192 Coronary Artery Disease 223
Diagnostic Studies 192 Clinical Findings 223
Treatment 194 Risk Factors 223
Pericardial Effusion 194 Symptoms and Signs 224
General Considerations 194 Diagnostic Studies 224
Clinical Findings 194 Differential Diagnosis 228
Symptoms and Signs 194 Prevention 229
Physical Examination 194 Treatment 229
Diagnostic Studies 195 Nonpharmacologic Therapy 229
Treatment 195 Pharmacologic Therapy 229
Cardiac Tamponade 195 Prognosis 232
General Considerations 195
Clinical Findings 195 20. Supraventricular Tachycardias 233
Symptoms and Signs 195
Byron K. Lee, MD & Peter R. Kowey, MD
Diagnostic Studies 196
Treatment 197 General Considerations 233
Constrictive Pericarditis 197 Pathophysiology & Etiology 233
General Considerations 197 General Diagnostic Approach 236
Clinical Findings 198 Sinus Tachycardia & Sinus Node Reentry 236
Symptoms and Signs 198 Sinus Tachycardia 236
Physical Examination 198 General Considerations 236
Diagnostic Studies 198 Treatment 237
Differential Diagnosis 200 Sinus Node Reentry 237
Treatment 201 General Considerations 237
Effusive-Constrictive Pericarditis 201 Treatment 238
Atrial Flutter 238
18. Congestive Heart Failure 203 General Considerations 238
Pathophysiology 238
Prakash C. Deedwania, MD & Enrique V. Carbajal, MD Clinical Findings 238
General Considerations 203 Prevention 238
Pathophysiology & Etiology 203 Treatment 239
Types of Heart Failure 204 Conversion 239
Causes 206 Rate Control 239
 CONTENTS
 vii

Catheter Ablation and Other Modalities 239 Rate Control 260

Stroke Prophylaxis 240 Long-Term Antiarrhythmic Therapy
Multifocal Atrial Tachycardia 240 and Elective Cardioversion 260
General Considerations 240 Antiarrhythmic Drug Therapy for
Treatment 240 Atrial Fibrillation 261
Prognosis 240 Nonpharmacologic Treatment of
Atrial Tachycardia 241 Atrial Fibrillation 265
General Considerations 241
Treatment 242 22. Conduction Disorders & Cardiac Pacing 267
Pharmacologic Therapy 242
Ablation 242 Richard H. Hongo, MD & Nora Goldschlager, MD
General Considerations 242 General Considerations 267
Pathophysiology 242 Pathophysiology & Etiology 267
Prevention 243 Sinus Node Dysfunction 267
Treatment 243 Atrioventricular Nodal-His Block 268
Vagal Maneuvers 243 Clinical Findings 268
Pharmacologic Therapy 243 Symptoms and Signs 268
Radiofrequency Modification in Physical Examination 270
Slow–Fast AVNRT 243 Diagnostic Studies 273
Junctional Tachycardia (Accelerated Treatment 278
AV Junctional Rhythm) 246 Cardiac Pacing 283
General Considerations 246 Pacing System Malfunctions 293
Clinical Findings 246 Assessment of Pacing System Function 296
Treatment 247
Bypass Tracts & the 23. Ventricular Tachycardia 299
Wolff-Parkinson-White Syndrome 247
General Considerations 247 Nitish Badhwar, MD
Epidemiology 247 Diagnostic Issues 299
Pathophysiology 247 Underdiagnosis 299
Anatomy 247 Misdiagnosis 299
Cardiac Electrical Conduction 248 Diagnostic Approach to the Patient
Mechanism 249 with Wide QRS Complex Tachycardia 300
Treatment 251 Atrioventricular Relationship 301
Vagal Maneuvers 251 QRS Complex Duration 301
Pharmacologic Therapy 251 Specific QRS Morphology 301
Radiofrequency Catheter Ablation Therapy 254 QRS Complex Axis 303
Surgical Ablation Therapy 255 History, Physical Examination and 12-Lead ECG 303
Other Bypass Tracts 255 Monomorphic VT in Association
Sinus Node Arrhythmia 256 with Idiopathic Dilated Cardiomyopathy 304
Other Supraventricular Arrhythmias 256 Monomorphic VT in Arrhythmogenic
General Considerations 256 Right Ventricular Cardiomyopathy 305
Treatment 256 Monomorphic VT in Patients
Wandering Atrial Pacemaker 257 with Congenital Heart Disease 306
General Considerations 257 Monomorphic VT in Other Forms
Treatment 257 of Structural Heart Disease 306
Idiopathic Left Ventricular Tachycardia
21. Atrial Fibrillation 259 or Fascicular VT 307
Outflow Tract Ventricular Tachycardia 307
Melvin M. Scheinman, MD Annular Ventricular Tachycardia 308
General Considerations 259 Diagnostic Studies 308
Epidemiology 259 Immediate Termination 310
Clinical Findings 259 Prevention 310
Symptoms and Signs 259 Pharmacologic Therapy 310
Physical Examination 259 Nonpharmacologic Therapy 311
Treatment 260 Polymorphic Ventricular Tachycardia 311
 viii
 CONTENTS

Polymorphic VT in the Setting of Surgical or Catheter Ablation 334

Prolonged QT Interval 311 Implantable Cardioverter Defibrillators 334
Clinical Findings 311 Identification of Patients at Risk 335
Management 312 Risk-Assessment Studies 335
Polymorphic VT with a Normal QT Interval 313 Primary Prevention of Sudden Death 336
Prognosis 313
26. Pulmonary Embolic Disease 337
24. Syncope 315
Rajni K. Rao, MD
Michael H. Crawford, MD General Considerations 337
General Considerations 315 Etiology 337
Pathophysiology & Etiology 315 Thrombophilia 337
Cardiac Causes 315 Women’s Health 338
Neurocardiogenic Causes 316 Clinical Findings 338
Orthostatic Hypotension 317 Symptoms and Signs 338
Psychiatric Disorders 318 Diagnostic Studies 339
Neuralgia 318 Prevention 345
Syncope of Unknown Cause 318 Risk Stratification 346
Clinical Findings 318 Treatment 346
History and Physical Examination 318 Heparin 346
Noninvasive Diagnostic Studies 320 Low-Molecular-Weight Heparin 347
Invasive Electrophysiology Studies 322 Thrombolysis 347
Differential Diagnosis 323 Embolectomy 348
Seizure 323 Inferior Vena Caval Filters 349
Metabolic Disorders and Hypoxia 323 Warfarin 349
Cerebral Vascular Insufficiency Adjunctive Measures 350
and Extracranial Vascular Disease 323 Venous Thromboembolism in Pregnancy 350
Psychiatric Disorders with Counseling 350
Hyperventilation and Pseudoseizure 324
Treatment 324 27. Pulmonary Hypertension 352
Pharmacologic and Nonpharmacologic 324
Electrophysiologic Therapies 325 David D. McManus, MD & Teresa De Marco, MD
Prognosis 325 General Considerations 352
Classification & Pathogenesis 352
25. Sudden Cardiac Death 327 Pulmonary Arterial Hypertension 352
Pulmonary Hypertension with
John P. DiMarco, MD, PhD Left-Sided Heart Disease 355
General Considerations 327 Pulmonary Hypertension Associated
Pathophysiology & Etiology 327 with Lung Diseases and Hypoxemia 355
Coronary Artery Disease 327 Pulmonary Hypertension due to
Hypertrophic Cardiomyopathy 328 Chronic Thrombotic or Embolic Diseases 356
Nonischemic Dilated Cardiomyopathy 329 Miscellaneous 356
Other Cardiac Diseases 329 Pathophysiologic Consequences of
Inherited Arrhythmia Syndromes 329 Pulmonary Hypertension 357
Drug-Induced Arrhythmias 330 Clinical Findings 358
Other Arrhythmias 330 Symptoms and Signs 358
Management of Cardiac Arrest: Physical Examination 359
Initial Resuscitation 330 Diagnostic Studies 359
Management of Cardiac Arrest Survivors: Differential Diagnosis 363
In-Hospital Phase 331 Treatment 365
Complications of Resuscitation 331 Pulmonary Arterial Hypertension 365
Diagnostic Studies 332 Pulmonary Hypertension with
Treatment of Cardiac Arrest Survivors 333 Left-Sided Heart Disease 369
Antiarrhythmic Drug Therapy 333 Pulmonary Hypertension Associated
Revascularization 333 with Lung Disease or Hypoxemia 370
 CONTENTS
 ix

Pulmonary Hypertension due to Clinical Findings 397

Chronic Thrombotic or Embolic Disease 370 Symptoms and Signs 397
Prognosis 370 Diagnostic Studies 397
Prognosis & Treatment 399
28. Congenital Heart Disease in Adults 371 Other Acyanotic Congenital Defects 399
Cyanotic Congenital Heart Disease 400
Ian S. Harris, MD & Elyse Foster, MD Tetralogy of Fallot & Pulmonary Atresia VSD 401
General Considerations 371 General Considerations 402
Acyanotic Congenital Heart Disease 400 Clinical Findings 403
Congenital Aortic Valvular Disease 373 Symptoms and Signs 403
General Considerations 373 Diagnostic Studies 403
Clinical Findings 373 Prognosis & Treatment 403
Symptoms and Signs 373 Eisenmenger Syndrome 405
Diagnostic Studies 373 General Considerations 405
Differential Diagnosis 375 Clinical Findings 406
Prognosis & Treatment 375 Symptoms and Signs 406
Pulmonary Valve Stenosis 376 Diagnostic Studies 406
General Considerations 376 Prognosis & Treatment 406
Clinical Findings 377 Transposition of the Great Arteries 409
Symptoms and Signs 377 General Considerations 409
Diagnostic Studies 377 Clinical Findings 410
Prognosis & Treatment 378 Symptoms and Signs 410
Atrial Septal Defect 379 Diagnostic Studies 410
General Considerations 379 Prognosis & Treatment 410
Clinical Findings 380 Tricuspid Atresia 411
Symptoms and Signs 380 General Considerations 411
Diagnostic Studies 381 Clinical Findings 411
Prognosis & Treatment 384 Symptoms and Signs 411
Ventricular Septal Defects 384 Diagnostic Studies 411
General Considerations 384 Prognosis & Treatment 412
Clinical Findings 385 Pulmonary Atresia with Intact Ventricular Septum 401
Symptoms and Signs 385 General Considerations 413
Diagnostic Studies 386 Clinical Findings 413
Prognosis & Treatment 386 Prognosis & Treatment 414
Patent Ductus Arteriosus 388 Other Cyanotic Congenital Heart Defects 414
General Considerations 388 Palliative Surgical Procedures 415
Clinical Findings 389 Genetic Counseling & Pregnancy 415
Symptoms and Signs 389 Recommendations for Exercise &
Diagnostic Studies 389 Sports Participation 415
Prognosis & Treatment 389 Acquired Heart Disease in Adults with
Coarctation of the Aorta 390 Congenital Heart Disease 415
General Considerations 390
Clinical Findings 391 29. Long-Term Anticoagulation for
Symptoms and Signs 391 Cardiac Conditions 417
Diagnostic Studies 391
Prognosis & Treatment 392 Richard D. Taylor, MD & Richard W. Asinger, MD
Ebstein Anomaly 393 General Considerations 417
General Considerations 393 Anticoagulants 417
Clinical Findings 394 Risks of Anticoagulant Therapy 418
Symptoms and Signs 394 Pathophysiology & Etiology 418
Diagnostic Studies 394 Pathogenesis of Intravascular Thrombi 418
Prognosis & Treatment 395 Embolization of Thrombi 419
Congenitally Corrected Transposition of Diagnostic Studies 420
the Great Arteries 396 Treatment of Cardiac Conditions
General Considerations 396 Requiring Anticoagulation 421
 x
 CONTENTS

Atrial Fibrillation 422 Clinical Findings 458

Native Valvular Heart Disease 425 History 458
Prosthetic Heart Valves 426 Symptoms and Signs 458
Left Ventricular Thrombus 427 Physical Examination 458
Aortic Atheroma 429 Diagnostic Difficulties 458
Paradoxical Emboli Associated with Diagnostic Studies 459
Patent Foramen Ovale 429 Treatment 460
Pacemakers, Implantable Cardioverter Pharmacologic Treatment 460
Defibrillators, and Other Intracardiac Devices 429 Surgical Treatment 462
Special Considerations 430 Labor and Delivery 462
Prognosis 463
30. Cardiac Tumors 432
32. Endocrinology & the Heart 464
Bill P.C. Hsieh, MD & Rita F. Redberg, MD, MSc, FACC,
FAHA B. Sylvia Vela, MD & Michael H. Crawford, MD
General Considerations 432 Thyroid & the Heart 464
Metastatic Cardiac Tumors 432 Hyperthyroidism 464
Primary Tumors 432 General Considerations 464
Clinical Findings 437 Clinical Findings 465
Symptoms and Signs 437 Symptoms and Signs 465
Physical Examination 438 Physical Examination 466
Diagnostic Studies 438 Diagnostic Studies 466
Differential Diagnosis 441 Treatment 467
Treatment 441 Prognosis 468
Pharmacologic Therapy 441 Hypothyroidism 468
Radiation 442 General Considerations 468
Surgery 442 Clinical Findings 468
Pericardiocentesis 442 Symptoms and Signs 468
Cardiac Transplantation 442 Physical Examination 469
Prognosis 443 Diagnostic Studies 469
Metastatic Tumors 443 Treatment 470
Primary Tumors 443 Prognosis 470
Cardiac Toxicities from Oncologic Treatments 443 Effect of Heart Disease on Thyroid Function 471
Chemotherapy 443 Cardiovascular Drugs & the Thyroid 471
Radiation 444 Parathyroid & the Heart 472
Hyperparathyroidism 472
31. Cardiovasular Disease in Pregnancy 446 General Considerations 472
Clinical Findings 473
Kirsten Tolstrup, MD, FACC, FASE Symptoms and Signs 473
General Considerations 446 Physical Examination 473
Cardiovascular Physiology of Normal Pregnancy 446 Diagnostic Studies 473
Blood Volume 446 Treatment & Prognosis 473
Cardiac Output 446 Hypoparathyroidism 473
Intravascular Pressures and Vascular Resistance 447 Adrenal & the Heart 474
Etiology & Symptomatology 447 Pheochromocytoma 474
Congenital Heart Disease 447 General Considerations 474
Valvular Heart Disease 450 Clinical Findings 474
Myocarditis 452 Symptoms and Signs 474
Cardiomyopathy 452 Physical Examination 475
Coronary Artery Disease 454 Diagnostic Studies 475
Arrhythmias 455 Treatment 475
Pericardial Diseases 456 Prognosis 476
Pulmonary Hypertension 456 Adrenal Insufficiency 476
Diseases of the Aorta 457 General Considerations 476
Hypertension 458 Clinical Findings 476
 CONTENTS
 xi

Symptoms and Signs 476 Diagnostic Studies 488

Physical Examination 477 Treatment 488
Diagnostic Studies 477 Medical Therapy 488
Treatment 477 Surgical Therapy 488
Cushing Syndrome 477 Myocarditis or Cardiomyopathy 488
General Considerations 477 General Considerations 488
Diagnostic Considerations 478 Clinical Findings 489
Treatment 478 Symptoms and Signs 489
Primary Hyperaldosteronism 478 Diagnostic Studies 489
General Considerations 478 Treatment 489
Diagnostic Considerations 478 Specific Antiinflammatory Therapy 489
Treatment 478 Other Therapy 489
Acromegaly & the Heart 479 Thrombotic Diseases 489
General Considerations 479 General Considerations 489
Clinical Findings 479 Clinical Findings 489
Symptoms and Signs 479 Symptoms and Signs 489
Physical Examination 479 Laboratory Findings 490
Diagnostic Studies 479 Diagnostic Studies 490
Treatment 480 Treatment 490
Growth Hormone Deficiency 480 Specific Antiinflammatory Therapy 490
Carcinoid Tumors & the Heart 480 Other Therapy 490
General Considerations 480 Coronary Artery Disease 490
Treatment 481 General Considerations 490
Diabetes Mellitus & the Heart 481 Clinical Findings 490
General Considerations 481 Symptoms and Signs 490
Clinical Findings 481 Diagnostic Studies 490
Treatment 481 Treatment 491
Estrogens & the Heart 482 Specific Antiinflammatory Therapy 491
Hormone Replacement Therapy 482 Other Therapy 491
Oral Contraceptives 483 Cardiac Arrhythmias & Conduction Disturbances 491
General Considerations 491
33. Connective Tissue Diseases & the Heart 484 Treatment 491
Specific Antiinflammatory Therapy 491
Carlos A. Roldan, MD Other Therapy 491
Systemic Lupus Erythematosus 484 Prognosis 491
General Considerations 484 Rheumatoid Arthritis 492
Valvular Heart Disease 485 Rheumatoid Pericarditis 492
General Considerations 485 General Considerations 492
Valve Vegetations, or Libman-Sacks Clinical Findings 492
Endocarditis 485 Symptoms and Signs 492
Valve Thickening 485 Laboratory Findings 492
Valve Regurgitation 485 Diagnostic Studies 492
Clinical Findings 485 Treatment 493
Symptoms and Signs 485 Prognosis 493
Physical Examination 486 Rheumatoid Valvular Heart Disease 493
Diagnostic Studies 487 General Considerations 493
Treatment 487 Clinical Findings 493
Specific Antiinflammatory Therapy 487 Physical Examination 493
Long-Term Anticoagulation 487 Diagnostic Studies 493
Other Therapy 487 Treatment 493
Pericarditis 487 Rheumatoid Myocarditis 494
General Considerations 487 General Considerations 494
Clinical Findings 488 Clinical Findings 494
Symptoms and Signs 488 Physical Examination 494
Laboratory Findings 488 Laboratory Findings 494
xii
 CONTENTS

Diagnostic Studies 494 General Considerations 501

Treatment & Prognosis 495 Aortitis & Aortic Regurgitation 502
Rheumatoid Coronary Artery Disease 495 General Considerations 502
General Considerations 495 Clinical Findings 502
Clinical Findings 495 Physical Examination 502
Symptoms and Signs 495 Diagnostic Studies 502
Diagnostic Studies 495 Treatment 502
Treatment 495 Medical Therapy 502
Conduction Disturbances 495 Surgical Therapy 502
General Considerations 495 Conduction Disturbances 502
Clinical Findings 496 Clinical Findings 503
Symptoms and Signs 496 Physical Examination 503
Diagnostic Studies 496 Diagnostic Studies 503
Treatment 496 Treatment 503
Rheumatoid Pulmonary Hypertension 496 Specific Antiinflammatory Therapy 503
General Considerations 496 Other Therapy 503
Clinical Findings 496 Mitral Valve Disease 504
Symptoms and Signs 496 Myocardial Disease, Pericardial Disease,
Diagnostic Studies 496 & Bacterial Endocarditis 504
Treatment & Prognosis 496 Prognosis 504
Scleroderma 497 Polymyositis/Dermatomyositis 504
General Considerations 497 General Considerations 504
Coronary Artery Disease 497 Clinical Findings 504
Pathophysiology 497 Myocarditis 505
Clinical Findings 497 Arrhythmias & Conduction Disturbances 505
Symptoms and Signs 497 Coronary Arteritis 505
Diagnostic Studies 497 Valvular Heart Disease 505
Treatment 498 Pericarditis 505
Myocarditis 498 Pulmonary Hypertension, Cor Pulmonale,
General Considerations 498 & Hyperkinetic Heart Syndrome 505
Clinical Findings 499 Treatment & Prognosis 505
Symptoms and Signs 499 Mixed Connective Tissue Disease 505
Diagnostic Studies 499 General Considerations 506
Treatment 499 Clinical Findings 506
Prognosis 499 Symptoms and Signs 506
Conduction Disturbances & Arrhythmias 499 Diagnostic Studies 506
General Considerations 499 Treatment 506
Clinical Findings 499 Prognosis 506
Symptoms and Signs 499
Diagnostic Studies 499 34. The Athlete’s Heart 507
Treatment 500
Prognosis 500 Cedela Abdulla, MD & J. V. (Ian) Nixon, MD, FACC, FAHA
Pericarditis 500 General Considerations 507
General Considerations 500 Physiology of Exercise Training 507
Clinical Findings 500 Acute Responses to Exercise 507
Symptoms and Signs 500 Effects of Systematic Exercise Training 509
Diagnostic Studies 500 Morphologic Responses to Training 510
Treatment 500 Electrocardiography 512
Prognosis 500 Racial Differences in Response to Training 512
Valvular Heart Disease 500 Detraining 512
Secondary Scleroderma Heart Disease 500 Sudden Death in Athletes 513
Ankylosing Spondylitis 501 The Preparticipation Physical Examination 513
 CONTENTS
 xiii

35. Thoracic Aortic Aneurysms & Dissections 516 36. Evaluation & Treatment of
John A. Elefteriades, MD the Perioperative Patient 536
Aneurysms 516 Sanjiv J. Shah, MD
General Considerations 516 Preoperative Risk Assessment 536
Etiology 516 Algorithms 536
Clinical Findings 520
Intermediate Risk Patients 537
Natural History 520
Understanding Cardiac Complications 539
Symptoms and Signs 524
Physical Examination 524 Treatment to Reduce Perioperative Risk 540
Diagnostic Studies 524 β-Blockers 540
Treatment 525 Statins 540
Risks of Aortic Surgery 525 Clonidine 540
Indications and Contraindications 526 Calcium Channel Blockers 540
Surgical Techniques 526 Maintanence of Normothermia 540
Specific Clinical Scenarios and Issues 528 Deep Venous Thrombosis Prophylaxis 540
Aortic Dissection 529 Endocarditis Prophylaxis 540
General Considerations 529 Perioperative Medication Management 541
Terminology 529 Prophylactic Coronary Revascularization 542
Anatomic Classification 531 Special Populations 543
Clinical Findings 531 Vascular Surgery 543
Symptoms and Signs 531
Aortic Stenosis 543
Diagnostic Studies 531
Heart Failure 543
Differential Diagnosis 532
Treatment 533 Pulmonary Hypertension 543
Pharmacotherapy 533 Pacemakers and Defibrillators 543
Surgical Treatment 534
Prognosis 535 Index 545
 Authors
Cedela Abdulla, MD Kuang-Yuh Chyu, MD, PhD
Department of Family Medicine, Memorial Hermann Assistant Professor-in-Residence, Department of Medicine,
Hospital System, Houston, Texas University of California, Los Angeles, California
[email protected] [email protected]
The Athlete’s Heart Unstable Angina/Non-ST Evaluation Myocardial Infarction

Richard W. Asinger, MD Michael H. Crawford, MD

Director of Cardiology Division - HCMC, Professor of Professor of Medicine, Lucy Stern Chair in Cardiology;
Medicine, University of Minnesota Medical School, Interim Chief of Cardiology, University of California,
Minneapolis, Minnesota San Francisco, California
[email protected] [email protected]
Long-Term Anticoagulation for Cardiac Conditions Approach to Cardiac Disease Diagnosis; Chronic Ischemic
Heart Disease; Aortic Stenosis; Aortic Regurgitation; Mitral
Nitish Badhwar, MD Regurgitation; Infective Endocarditis; Restrictive Cardio-
Assistant Clinical Professor of Medicine, University of myopathies; Myocarditis; Syncope; Endocrinology & the
California, San Francisco, California Heart
[email protected]
Ventricular Tachycardia Prakash C. Deedwania, MD
Chief, University of California, San Francisco School of
Andrew J. Boyle, MBBS, PhD Medicine, Cardiology Sections; Veterans Affairs Central
Assistant Clinical Professor of Medicine, University of California Health Care System, San Francisco, California
California, San Francisco, California Congestive Heart Failure
[email protected]
Acute Myocardial Infarction Teresa De Marco, MD
Professor of Clinical Medicine and Surgery; Director, Heart
Robert J. Bryg, MD
Failure and Pulmonary Hypertension; Medical Director,
Professor of Medicine, David Geffen School of Medicine at
Heart Transplantation, University of California, San
UCLA, Los Angeles, California
Francisco, California
[email protected]
[email protected]
Mitral Stenosis
Pulmonary Hypertension
Blase A. Carabello, MD
John P. DiMarco MD, PhD
Professor, Baylor College of Medicine, Houston, Texas
Professor of Medicine; Director, Clinical Cardiac
[email protected]
Electrophysiology Division of Cardiovacular Medicine
Aortic Stenosis
University of Virginia Health System, Charlottesville,
Enrique V. Carbajal, MD Virginia
Assistant Clinical Professor of Medicine, University of [email protected]
California, San Francisco Medical Education Program; Sudden Cardiac Death
Assistant Chief, Cardiology Section, Veterans Affairs
Central California Health Care System, Fresno, John A. Elefteriades, MD
California Professor & Chief, Section of Cardiothoracic Surgery, Yale
[email protected] University School of Medicine, New Haven, Connecticut
Congestive Heart Failure [email protected]
Thoracic Aortic Aneurysms & Dissections
John D. Carroll, MD
Professor of Medicine, Director Cardiac and Vascular Elyse Foster, MD
Center; Chief, Interventional and Clinical Cardiology, Professor of Clinical Medicine and Anesthesia, University of
University of Colorado Hospital, Denver, Colorado California, San Francisco, California
[email protected] [email protected]
Restrictive Cardiomyopathies Congenital Heart Disease in Adults

xiv
 AUTHORS
 xv

Nora Goldschlager, MD Peter R. Kowey, MD

Professor of Clinical Medicine, University of California, San Professor of Medicine, Jefferson Medical College; Chief,
Francisco; Director, Coronary Care Unit, ECG Division of Cardiovascular Diseases, Lankenau Hospital,
Department and Pacemaker Clinic, San Francisco Philadelphia, Pennsylvania
General Hospital, San Francisco, California [email protected]
[email protected] Supraventricular Tachycardias
Conduction Disorders & Cardiac Pacing
Byron K. Lee, MD
William F. Graettinger, MD, FACC, FACP, FCCP Assistant Professor of Medicine, Division of Cardiology,
Professor & Vice-Chairman, Department of Internal University of California, San Francisco, California
Medicine, Chief, Division of Cardiology, University of [email protected]
Nevada School of Medicine, Reno; Chief, Cardiology Supraventricular Tachycardias
Section, VA Sierra Nevada Healthcare System, Reno,
Nevada
Martin M. LeWinter, MD
[email protected] Professor of Medicine & Molecular Physiology and
Systemic Hypertension Biophysics, University of Vermont College of Medicine,
Attending Cardiologist and Director, Heart Failure
Program, Fletcher Allen Health Care, Burlington,
Ian S. Harris, MD Vermont
Assistant Professor of Medicine, Department of Internal [email protected]
Medicine, Division of Cardiology, Adult Congenital Pericardial Disease
Heart Disease Service, University of California School of
Medicine, San Francisco, California David D. McManus, MD
[email protected] Instructor in Medicine, Cardiology Division, Department of
Congenital Heart Disease in Adults Medicine, University of Massachusetts Medical Center,
Worchester, Massachusetts
Brian D. Hoit, MD [email protected]
Professor of Medicine and Physiology and Biophysics, Case Pulmonary Hypertension
Western Reserve University; Director of
Echocardiography, Case Medical Center, University Edward McNulty, MD
Hospitals of Cleveland, Ohio Assistant Clinical Professor of Medicine, University of San
[email protected] Francisco, San Francisco, California
Tricuspid and Pulmonic Valve Disease [email protected]
Cardiogenic Shock
Richard H. Hongo, MD J. V. (Ian) Nixon, MD, FACC, FAHA
California Pacific Medical Center, San Francisco, California Professor of Internal Medicine & Cardiology, Virginia
[email protected] Commonwealth University School of Medicine Director,
Conduction Disorders & Cardiac Pacing Noninvasive Cardiology Services, Pauley Heart Center,
VCU Health System, Richmond, Virginia
Bill P.C. Hsieh, MD [email protected]
Instructor in Medicine, Albert Einstein College of Medicine, The Athlete’s Heart
Montefiori Medical Center, New York, New York
Cardiac Tumors John B. O’Connell, MD
Professor & Chairman, Department of Internal Medicine,
Wayne State University School of Medicine, Detroit,
Allan S. Jaffe, MD
Michigan
Assistant Professor of Medicine & Consultant, Divisions of
[email protected]
Cardiology and Laboratory Medicine, Mayo Clinic,
Myocarditis
Rochester, Minnesota
[email protected] Rajni K. Rao, MD
Acute Myocardial Infarction
Assistant Clinical Professor of Medicine, University of
California, San Francisco, California
[email protected]
Pulmonary Embolic Disease
 xvi
 AUTHORS

Rita F. Redberg, MD, MSc, FACC, FAHA Craig Timm, MD

UCSF School of Medicine, Robert Wood Johnson Professor of Internal Medicine, Associate Dean of
Foundation Health Policy Fellow, Professor of Medicine, Undergraduate Medical Education, University of New
University of California, San Francisco Medical Center, Mexico Health Sciences Center, Albuquerque, New
San Francisco, California Mexico
[email protected] [email protected]
Cardiac Tumors Cardiogenic Shock

Carlos A. Roldan, MD Kristen Tolstrup, MD, FACC, FASE

Associate Professor of Medicine, Cardiology Division, Assistant Director, Cardiac Noninvasive Laboratory,
Veterans Affairs Medical Center and University of New Cedars-Sinai Heart Institute; Associate Professor, UCLA
Mexico, Albuquerque, New Mexico Geffen School of Medicine, Los Angeles, California
[email protected] [email protected]
Connective Tissue Diseases & the Heart Cardiovascular Disease in Pregnancy

Melvin M. Scheinman, MD Subha L. Varahan, MD

Professor of Medicine, Emeritus, Walter H., Shorenstein Fellow Division of Cardiovascular Medicine, University
Endowed Chair in Cardiology, University of California, Hospitals Case Medical Center, Division of
San Francisco, California Cardiovascular Medicine, Department of Medicine,
[email protected] Cleveland, Ohio
Atrial Fibrillation [email protected]
Tricuspid and Pulmonic Valve Disease
Pravin M. Shah, MD, MACC
Chair, Medical Director, Hoag Heart and Vascular Institute,
B. Sylvia Vela, MD
Newport Beach, California
Associate Professor of Clinical Medicine, University of
[email protected]
Arizona College of Medicine; Associate Chief of Staff,
Hypertrophic Cardiomyopathies
Education, Phoenix VA Health Care System, Phoenix,
Arizona
Prediman K. Shah, MD
[email protected]
Shapell and Webb Chair & Director, Division of Cardiology
Endocrinology & the Heart
and Oppenheimer Atherosclerosis Research Center,
Cedar-Sinai Medical Center; Professor of Medicine,
University of California, Los Angeles, California Christian Zellner, MD
[email protected] Cardiology Fellow, University of California, San Francisco,
Unstable Angina/Non-ST Evaluation Myocardial Infarction California
[email protected]
Sanjiv J. Shah, MD Lipid Disorders
Assistant Professor of Medicine, Division of Cardiology,
Department of Medicine; Director, Heart Failure with William A. Zoghbi, MD, FASE, FACC
Preserved Ejection Fraction, Bluhm Cardiovascular William L. Winters Endowed Chair in CV Imaging;
Institute, Northwestern University Feinberg School of Professor of Medicine, Weill Cornell Medical College;
Medicine, Chicago, Illinois Director, Cardiovascular Imaging Institute, The
[email protected] Methodist DeBakey Heart & Vascular Center, Houston,
Heart Failure with Preserved Ejection Fraction; Evaluation & Texas
Treatment of the Perioperative Patient [email protected]
Aortic Regurgitation
Richard D. Taylor, MD
Director, Arrhythmia Management Program, Hennepin
County Medical Center; Assistant Professor of Medicine,
Minneapolis, Minnesota
[email protected]
Long-Term Anticoagulation for Cardiac Conditions
 Preface
Current Diagnosis & Treatment: Cardiology is designed to be a concise discussion of the essential knowledge needed to diagnose
and manage cardiovascular diseases. Current Diagnosis & Treatment: Cardiology cannot be considered a condensed textbook
because detailed pathophysiologic discussions are omitted; there are no chapters on diagnostic techniques; and rare or obscure
entities are not included. Also, it is not a cardiac therapeutics text because diagnostic techniques, prevention strategies, and
prognosis are fully discussed.

INTENDED AUDIENCE
Current Diagnosis & Treatment: Cardiology is designed to be a quick reference source in the clinic or on the ward for the
experienced physician. Cardiology fellows will find that it is an excellent review for Board examinations. Also, students and
residents will find it useful to review the essentials of specific conditions and to check the current references included in each
section for further study. Nurses, technicians, and other health care workers who provide care for cardiology patients will find
Current Diagnosis & Treatment: Cardiology a useful resource for all aspects of heart disease care.

COVERAGE
The 36 chapters in Current Diagnosis & Treatment: Cardiology cover the major disease entities and therapeutic challenges in
cardiology. There are chapters on major management issues in cardiology such as pregnancy and heart disease, the use of
anticoagulants in heart disease, and the perioperative evaluation of heart disease patients. Each section is written by experts in
the particular area, but has been extensively edited to ensure a consistent approach throughout the book and the kind of
readability found in single-author texts.
Since the second edition the book has changed somewhat. Each chapter has been thoroughly revised and the references
updated, often by new authors. A new chapter has been added on heart failure with preserved ejection fraction and the chapters
covering thoracic aortic diseases have been combined into one. My hope is that the book is found useful and improves patient
care. Also, I hope it is an educational tool that improves knowledge of cardiac diseases. Finally, I hope it stimulates clinical
research in areas where our knowledge is incomplete.

Michael H. Crawford, MD

xvii
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  1

1
Approach to Cardiac
Disease Diagnosis
Michael H. Crawford, MD

 General Considerations asleep or recumbent for an hour or more. This symptom is

caused by the redistribution of body fluids from the lower
The patient’s history is a critical feature in the evaluation of
extremities into the vascular space and back to the heart,
suspected or overt heart disease. It includes information
resulting in volume overload; it suggests a more severe
about the present illness, past illnesses, and the patient’s
condition. Third is orthopnea, a dyspnea that occurs imme-
family. From this information, a chronology of the patient’s
diately on assuming the recumbent position. The mild
disease process should be constructed. Determining what
increase in venous return (caused by lying down) before any
information in the history is useful requires a detailed
fluid is mobilized from interstitial spaces in the lower
knowledge of the pathophysiology of cardiac disease. The
extremities is responsible for the symptom, which suggests
effort spent on listening to the patient is time well invested
even more severe disease. Finally, dyspnea at rest suggests
because the cause of cardiac disease is often discernible from
severe cardiac disease.
the history.
Dyspnea is not specific for heart disease, however. Exer-
A. Common Symptoms tional dyspnea, for example, can be due to pulmonary
disease, anemia, or deconditioning. Orthopnea is a frequent
1. Chest pain—Chest pain is one of the cardinal symptoms complaint in patients with chronic obstructive pulmonary
(Table 1–1) of ischemic heart disease, but it can also occur disease and postnasal drip. A history of “two-pillow orthop-
with other forms of heart disease. The five characteristics of nea” is of little value unless the reason for the use of two
ischemic chest pain, or angina pectoris, are pillows is discerned. Resting dyspnea is also a sign of pulmo-
• Anginal pain usually has a substernal location but may nary disease. Paroxysmal nocturnal dyspnea is perhaps the
extend to the left or right chest, the shoulders, the neck, most specific for cardiac disease because few other condi-
jaw, arms, epigastrium, and, occasionally, the upper back. tions cause this symptom.
• The pain is deep, visceral, and intense; it makes the patient
3. Syncope and presyncope—Lightheadedness, dizziness,
pay attention but is not excruciating. Many patients
presyncope, and syncope are important indications of a
describe it as a pressure-like sensation or a tightness.
reduction in cerebral blood flow. These symptoms are non-
• The duration of the pain is minutes, not seconds. specific and can be due to primary central nervous system
• The pain tends to be precipitated by exercise or emo- disease, metabolic conditions, dehydration, or inner-ear
tional stress. problems. Because bradyarrhythmias and tachyarrhythmias
• The pain is relieved by resting or taking sublingual are important cardiac causes, a history of palpitations pre-
nitroglycerin. ceding the event is significant.
2. Dyspnea—A frequent complaint of patients with a vari- 4. Transient central nervous system deficits—Deficits
ety of cardiac diseases, dyspnea is ordinarily one of four such as transient ischemic attacks (TIAs) suggest emboli
types. The most common is exertional dyspnea, which usu- from the heart or great vessels or, rarely, from the venous
ally means that the underlying condition is mild because it circulation through an intracardiac shunt. A TIA should
requires the increased demand of exertion to precipitate prompt the search for cardiovascular disease. Any sudden
symptoms. The next most common is paroxysmal nocturnal loss of blood flow to a limb also suggests a cardioembolic
dyspnea, characterized by the patient awakening after being event.
 2
 CHAPTER 1

B. History
Table 1–1. Common Symptoms of
1. The present illness—This is a chronology of the events
Potential Cardiac Origin.
leading up to the patient’s current complaints. Usually phy-
Chest pain or pressure sicians start with the chief complaint and explore the
Dyspnea on exertion patient’s symptoms. It is especially important to determine
Paroxysmal nocturnal dyspnea the frequency, intensity, severity, and duration of all symp-
Orthopnea toms; their precipitating causes; what relieves them; and
Syncope or near syncope what aggravates them. Although information about previous
Transient neurologic defects related diseases and opinions from other physicians are often
Edema valuable, it is essential to explore the basis of any prior
Palpitation
diagnosis and ask the patient about objective testing and the
Cough
results of such testing. A history of prior treatment is often
revealing because medications or surgery may indicate the
nature of the original problem. A list should be made of all
5. Fluid retention—These symptoms are not specific for
the patient’s current medications, detailing the dosages, the
heart disease but may be due to reduced cardiac function.
frequency of administration, whether they are helping the
Typical symptoms are peripheral edema, bloating, weight
patient, any side effects, and their cost.
gain, and abdominal pain from an enlarged liver or spleen.
Decreased appetite, diarrhea, jaundice, and nausea and vom- 2. Antecedent conditions—Several systemic diseases may
iting can also occur from gut and hepatic dysfunction due to have cardiac involvement. It is therefore useful to search for
fluid engorgement. a history of rheumatic fever, which may manifest as Syden-
ham chorea, joint pain and swelling, or merely frequent sore
6. Palpitation—Normal resting cardiac activity usually
throats. Other important diseases that affect the heart
cannot be appreciated by the individual. Awareness of
include metastatic cancer, thyroid disorders, diabetes melli-
heart activity is often referred to by patients as palpitation.
tus, and inflammatory diseases such as rheumatoid arthritis
Among patients there is no standard definition for the type
and systemic lupus erythematosus. Certain events during
of sensation represented by palpitation, so the physician
childhood are suggestive of congenital or acquired heart
must explore the sensation further with the patient. It is
disease; these include a history of cyanosis, reduced exercise
frequently useful to have the patient tap the perceived
tolerance, or long periods of restricted activities or school
heartbeat out by hand. Commonly, unusually forceful
absence. Exposure to toxins, infectious agents, and other
heart activity at a normal rate (60–100 bpm) is perceived as
noxious substances may also be relevant.
palpitation. More forceful contractions are usually the
result of endogenous catecholamine excretion that does 3. Atherosclerotic risk factors—Atherosclerotic cardiovas-
not elevate the heart rate out of the normal range. A cular disease is the most common form of heart disease in
common cause of this phenomenon is anxiety. Another industrialized nations. The presenting symptoms of this
common sensation is that of the heart stopping transiently ubiquitous disorder may be unimpressive and minimal, or as
or of the occurrence of isolated forceful beats or both. This impressive as sudden death. It is therefore important to
sensation is usually caused by premature ventricular con- determine from the history whether any risk factors for this
tractions, and the patient either feels the compensatory disease are present. The most important are a family history
pause or the resultant more forceful subsequent beat or of atherosclerotic disease, especially at a young age; diabetes
both. Occasionally, the individual feels the ectopic beat and mellitus; lipid disorders such as a high cholesterol level;
refers to this phenomenon as “skipped” beats. The least hypertension; and smoking. Less important factors include a
common sensation reported by individuals, but the one lack of exercise, high stress levels, the type-A personality, and
most linked to the term “palpitation” is rapid heart rate truncal obesity.
that may be regular or irregular and is usually supraven-
4. Family history—A family history is important for deter-
tricular in origin.
mining the risk for not only atherosclerotic cardiovascular
7. Cough—Although cough is usually associated with pul- disease but for many other cardiac diseases as well. Congen-
monary disease processes, cardiac conditions that lead to ital heart disease, for example, is more common in the
pulmonary abnormalities may be the root cause of the offspring of parents with this condition, and a history of the
cough. A cardiac cough is usually dry or nonproductive. disorder in the antecedent family or siblings is significant.
Pulmonary fluid engorgement from conditions such as heart Other genetic diseases, such as neuromuscular disorders or
failure may present as cough. Pulmonary hypertension from connective tissue disorders (eg, Marfan syndrome) can affect
any cause can result in cough. Finally, angiotensin-convert- the heart. Acquired diseases, such as rheumatic valve disease,
ing enzyme inhibitors, which are frequently used in cardiac can cluster in families because of the spread of the strepto-
conditions, can cause cough. coccal infection among family members. The lack of a
 APPROACH TO CARDIAC DISEASE DIAGNOSIS
 3

history of hypertension in the family might prompt a more 2. Peripheral pulses—When examining the peripheral
intensive search for a secondary cause. A history of athero- pulses, the physician is really conducting three examina-
sclerotic disease sequelae, such as limb loss, strokes, and tions. The first is an examination of the cardiac rate and
heart attacks, may provide a clue to the aggressiveness of an rhythm, the second is an assessment of the characteristics of
atherosclerotic tendency in a particular family group. the pulse as a reflection of cardiac activity, and the third is
an assessment of the adequacy of the arterial conduit being
 Physical Findings examined. The pulse rate and rhythm are usually deter-
A. Physical Examination mined in a convenient peripheral artery, such as the radial.
If a pulse is irregular, it is better to auscultate the heart;
The physical examination is less important than the history some cardiac contractions during rhythm disturbances do
in patients with ischemic heart disease, but it is of critical not generate a stroke volume sufficient to cause a palpable
value in patients with congenital and valvular heart disease. peripheral pulse. In many ways, the heart rate reflects the
In the latter two categories, the physician can often make health of the circulatory system. A rapid pulse suggests
specific anatomic and etiologic diagnoses based on the phys- increased catecholamine levels, which may be due to cardiac
ical examination. Certain abnormal murmurs and heart disease, such as heart failure; a slow pulse represents an
sounds are specific for structural abnormalities of the heart. excess of vagal tone, which may be due to disease or athletic
The physical examination is also important for confirming training.
the diagnosis and establishing the severity of heart failure, To assess the characteristics of the cardiac contraction
and it is the only way to diagnose systemic hypertension through the pulse, it is usually best to select an artery close to
because this diagnosis is based on elevated blood pressure the heart, such as the carotid. Bounding high-amplitude
recordings. carotid pulses suggest an increase in stroke volume and
1. Blood pressure—Proper measurement of the systemic should be accompanied by a wide pulse pressure on the
arterial pressure by cuff sphygmomanometry is one of the blood pressure measurement. A weak carotid pulse suggests
keystones of the cardiovascular physical examination. It is a reduced stroke volume. Usually the strength of the pulse is
recommended that the brachial artery be palpated and the graded on a scale of 1 to 4, where 2 is a normal pulse
diaphragm of the stethoscope be placed over it, rather than amplitude, 3 or 4 is a hyperdynamic pulse, and 1 is a weak
merely sticking the stethoscope in the antecubital fossa. pulse. A low-amplitude, slow-rising pulse, which may be
Current methodologic standards dictate that the onset and associated with a palpable vibration (thrill), suggests aortic
disappearance of the Korotkoff sounds define the systolic stenosis. A bifid pulse (beating twice in systole) can be a sign
and diastolic pressures, respectively. Although this is the best of hypertrophic obstructive cardiomyopathy, severe aortic
approach in most cases, there are exceptions. For example, in regurgitation, or the combination of moderately severe aor-
patients in whom the diastolic pressure drops to near zero, tic stenosis and regurgitation. A dicrotic pulse (an exagger-
the point of muffling of the sounds is usually recorded as the ated, early, diastolic wave) is found in severe heart failure.
diastolic pressure. Because the diagnosis of systemic hyper- Pulsus alternans (alternate strong and weak pulses) is also a
tension involves repeated measures under the same condi- sign of severe heart failure. When evaluating the adequacy of
tions, the operator should record the arm used and the the arterial conduits, all palpable pulses can be assessed and
position of the patient to allow reproducible measurements graded on a scale of 0 to 4, where 4 is a fully normal conduit,
to be made on serial visits. and anything below that is reduced, including 0—which
If the blood pressure is to be taken a second time, the indicates an absent pulse. The major pulses routinely pal-
patient should be in another position, such as standing, to pated on physical examination are the radial, brachial,
determine any orthostatic changes in blood pressure. Ortho- carotid, femoral, dorsalis pedis, and posterior tibial. In
static changes are a very important physical finding, espe- special situations, the abdominal aorta and the ulnar, subcla-
cially in patients complaining of transient central nervous vian, popliteal, axillary, temporal, and intercostal arteries are
system symptoms, weakness, or unstable gait. The technique palpated. In assessing the abdominal aorta, it is important to
involves having the patient assume the upright position for make note of the width of the aorta because an increase
at least 90 seconds before taking the pressure to be sure that suggests an abdominal aortic aneurysm. It is particularly
the maximum orthostatic effect is measured. Although mea- important to palpate the abdominal aorta in older individu-
suring the pressure in other extremities may be of value in als because abdominal aortic aneurysms are more prevalent
certain vascular diseases, it provides little information in a in those older than 70. An audible bruit is a clue to signifi-
routine examination beyond palpating pulses in all the cantly obstructed large arteries. During a routine examina-
extremities. Keep in mind, in general, that the pulse pressure tion, bruits are sought with the bell of the stethoscope placed
(the difference between systolic and diastolic blood pres- over the carotids, abdominal aorta, and femorals at the
sures) is a crude measure of left ventricular stroke volume. A groin. Other arteries may be auscultated under special cir-
widened pulse pressure suggests that the stroke volume is cumstances, such as suspected temporal arteritis or verte-
large; a narrowed pressure, that the stroke volume is small. brobasilar insufficiency.
 4
 CHAPTER 1

3. Jugular venous pulse—Assessment of the jugular venous 5. Cardiac auscultation—Heart sounds are caused by the
pulse can provide information about the central venous pres- acceleration and deceleration of blood and the subsequent
sure and right-heart function. Examination of the right inter- vibration of the cardiac structures during the phases of the
nal jugular vein is ideal for assessing central venous pressure cardiac cycle. To hear cardiac sounds, use a stethoscope with
because it is attached directly to the superior vena cava a bell and a tight diaphragm. Low-frequency sounds are
without intervening valves. The patient is positioned into the associated with ventricular filling and are heard best with the
semiupright posture that permits visualization of the top of bell. Medium-frequency sounds are associated with valve
the right internal jugular venous blood column. The height of opening and closing; they are heard best with the diaphragm.
this column of blood, vertically from the sternal angle, is Cardiac murmurs are due to turbulent blood flow, are
added to 5 cm of blood (the presumed distance to the center usually high-to-medium frequency, and are heard best with
of the right atrium from the sternal angle) to obtain an the diaphragm. Low-frequency atrioventricular valve inflow
estimate of central venous pressure in centimeters of blood. murmurs, such as that produced by mitral stenosis, are best
This can be converted to millimeters of mercury (mm Hg) heard with the bell, however. Auscultation should take place
with the formula: in areas that correspond to the location of the heart and great
vessels. Such placement will, of course, need to be modified
mm Hg = cm blood × 0.736. for patients with unusual body habitus or an unusual cardiac
Examining the characteristics of the right internal jugular position. When no cardiac sounds can be heard over the
pulse is valuable for assessing right-heart function and precordium, they can often be heard in either the subxiphoid
rhythm disturbances. The normal jugular venous pulse has area or the right supraclavicular area.
two distinct waves: a and v; the former coincides with atrial Auscultation in various positions is recommended
contraction and the latter with late ventricular systole. An because low-frequency filling sounds are best heard with the
absent a wave and an irregular pulse suggest atrial fibrilla- patient in the left lateral decubitus position, and high-
tion. A large and early v wave suggests tricuspid regurgita- frequency murmurs, such as that of aortic regurgitation, are
tion. The dips after the a and v waves are the x and y best heard with the patient sitting.
descents; the former coincide with atrial relaxation and the
A. Heart sounds—The first heart sound is coincident with
latter with early ventricular filling. In tricuspid stenosis the y
mitral and tricuspid valve closure and has two components
descent is prolonged. Other applications of the jugular pulse
in up to 40% of normal individuals. There is little change in
examination are discussed in the chapters dealing with
the intensity of this sound with respiration or position. The
specific disorders.
major determinant of the intensity of the first heart sound is
4. Lungs—Evaluation of the lungs is an important part of the electrocardiographic (ECG) PR interval, which deter-
the physical examination: Diseases of the lung can affect the mines the time delay between atrial and ventricular contrac-
heart, just as diseases of the heart can affect the lungs. The tion and thus the position of the mitral valve when ventricu-
major finding of importance is rales at the pulmonary bases, lar systole begins. With a short PR interval, the mitral valve
indicating alveolar fluid collection. Although this is a signif- is widely open when systole begins, and its closure increases
icant finding in patients with congestive heart failure, it is the intensity of the first sound, as compared to a long PR-
not always possible to distinguish rales caused by heart interval beat when the valve partially closes prior to the onset
failure from those caused by pulmonary disease. The pres- of ventricular systole. Certain disease states, such as mitral
ence of pleural fluid, although useful in the diagnosis of heart stenosis, also can increase the intensity of the first sound.
failure, can be due to other causes. Heart failure most The second heart sound is coincident with closure of the
commonly causes a right pleural effusion; it can cause aortic and pulmonic valves. Normally, this sound is single in
effusions on both sides but is least likely to cause isolated left expiration and split during inspiration, permitting the aortic
pleural effusion. The specific constellation of dullness at the and pulmonic components to be distinguished. The inspira-
left base with bronchial breath sounds suggests an increase in tory split is due to a delay in the occurrence of the pulmonic
heart size from pericardial effusion (Ewart sign) or another component because of a decrease in pulmonary vascular
cause of cardiac enlargement; it is thought to be due to resistance, which prolongs pulmonary flow beyond the end
compression by the heart of a left lower lobe bronchus. of right ventricular systole. Variations in this normal split-
When right-heart failure develops or venous return is ting of the second heart sound are useful in determining
restricted from entering the heart, venous pressure in the certain disease states. For example, in atrial septal defect, the
abdomen increases, leading to hepatosplenomegaly and second sound is usually split throughout the respiratory
eventually ascites. None of these physical findings is specific cycle because of the constant increase in pulmonary flow. In
for heart disease; they do, however, help establish the diag- patients with left bundle branch block, a delay occurs in the
nosis. Heart failure also leads to generalized fluid retention, aortic component of the second heart sound, which results
usually manifested as lower extremity edema or, in severe in reversed respiratory splitting; single with inspiration, split
heart failure, anasarca. with expiration.
 APPROACH TO CARDIAC DISEASE DIAGNOSIS
 5

A third heart sound occurs during early rapid filling of cause of this murmur is atrioventricular valve regurgitation,
the left ventricle; it can be produced by any condition that but it can also be observed in conditions such as ventricular
causes left ventricular volume overload or dilatation. It can septal defect, in which an abnormal communication exists
therefore be heard in such disparate conditions as congestive between two chambers of markedly different systolic pres-
heart failure and normal pregnancy. A fourth heart sound is sures. Although it is relatively easy to determine that these
due to a vigorous atrial contraction into a stiffened left murmurs represent an abnormality, it is more of a challenge
ventricle and can be heard in left ventricular hypertrophy of to determine their origins. Keep in mind that such condi-
any cause or in diseases that reduce compliance of the left tions as mitral regurgitation, which usually produce holosys-
ventricle, such as myocardial infarction. tolic murmurs, may produce crescendo/decrescendo mur-
Although third and fourth heart sounds can occasionally murs, adding to the difficulty in differentiating benign from
occur in normal individuals, all other extra sounds are signs pathologic systolic flow murmurs.
of cardiac disease. Early ejection sounds are due to abnor- Diastolic murmurs are always abnormal. The most fre-
malities of the semilunar valves, from restriction of their quently heard diastolic murmur is the high-frequency decre-
motion, thickening, or both (eg, a bicuspid aortic valve, scendo early diastolic murmur of aortic regurgitation. This is
pulmonic or aortic stenosis). A midsystolic click is often due usually heard best at the upper left sternal border or in the
to mitral valve prolapse and is caused by sudden tensing in aortic area (upper right sternal border) and may radiate to
midsystole of the redundant prolapsing segment of the the lower left sternal border and the apex. This murmur is
mitral leaflet. The opening of a thickened atrioventricular usually very high frequency and may be difficult to hear.
valve leaflet, as in mitral stenosis, will cause a loud opening Although the murmur of pulmonic regurgitation may sound
sound (snap) in early diastole. A lower frequency (more of a like that of aortic regurgitation when pulmonary artery
knock) sound at the time of rapid filling may be an indica- pressures are high, it is usually best heard in the pulmonic
tion of constrictive pericarditis. These early diastolic sounds area (left second intercostal space parasternally). If structural
must be distinguished from a third heart sound. disease of the valve is present with normal pulmonary
B. Murmurs—Systolic murmurs are very common and do pressures, the murmur usually has a midrange frequency and
not always imply cardiac disease. They are usually rated on a begins with a slight delay after the pulmonic second heart
scale of 1 to 6, where grade 1 is barely audible, grade 4 is sound. Mitral stenosis produces a low-frequency rumbling
associated with palpable vibrations (thrill), grade 5 can be diastolic murmur that is decrescendo in early diastole, but
heard with the edge of the stethoscope, and grade 6 can be may become crescendo up to the first heart sound with
heard without a stethoscope. Most murmurs fall in the 1–3 moderately severe mitral stenosis and sinus rhythm. The
range, and murmurs in the 4–6 range are almost always due murmur is best heard at the apex in the left lateral decubitus
to pathologic conditions; severe disease can exist with grades position with the bell of the stethoscope. Similar findings are
1–3 or no cardiac murmurs, however. The most common heard in tricuspid stenosis, but the murmur is loudest at the
systolic murmur is the crescendo/decrescendo murmur that lower left sternal border.
increases in intensity as blood flows early in systole and A continuous murmur implies a connection between a
diminishes in intensity through the second half of systole. high- and a low-pressure chamber throughout the cardiac
This murmur can be due to vigorous flow in a normal heart cycle, such as occurs with a fistula between the aorta and the
or to obstructions in flow, as occurs with aortic stenosis, pulmonary artery. If the connection is a patent ductus
pulmonic stenosis, or hypertrophic cardiomyopathy. The so- arteriosus, the murmur is heard best under the left clavicle;
called innocent flow murmurs are usually grades 1–2 and it has a machine-like quality. Continuous murmurs must be
occur very early in systole; they may have a vibratory quality distinguished from the combination of systolic and diastolic
and are usually less apparent when the patient is in the sitting murmurs in patients with combined lesions (eg, aortic ste-
position (when venous return is less). If an ejection sound is nosis and regurgitation).
heard, there is usually some abnormality of the semilunar Traditionally, the origin of heart murmurs was based on
valves. Although louder murmurs may be due to pathologic five factors: (1) their timing in the cardiac cycle, (2) where on
cardiac conditions, this is not always so. Distinguishing the chest they were heard, (3) their characteristics, (4) their
benign from pathologic systolic flow murmurs is one of the intensity, and (5) their duration. Unfortunately, this tradi-
major challenges of clinical cardiology. Benign flow mur- tional classification system is unreliable in predicting the
murs can be heard in 80% of children; the incidence declines underlying pathology. A more accurate method, dynamic
with age, but may be prominent during pregnancy or in auscultation, changes the intensity, duration, and character-
adults who are thin or physically well trained. The murmur istics of the murmur by bedside maneuvers that alter hemo-
is usually benign in a patient with a soft flow murmur that dynamics.
diminishes in intensity in the sitting position and neither a The simplest of these maneuvers is observation of any
history of cardiovascular disease nor other cardiac findings. changes in murmur intensity with normal respiration
The holosystolic, or pansystolic, murmur is almost because all right-sided cardiac murmurs should increase in
always associated with cardiac pathology. The most common intensity with normal inspiration. Although some exceptions
 6
 CHAPTER 1

exist, the method is very reliable for detecting such mur- Valsalva maneuver is also frequently used. The patient
murs. Inspiration is associated with reductions in intratho- bears down and expires against a closed glottis, increasing
racic pressure that increase venous return from the abdomen intrathoracic pressure and markedly reducing venous return
and the head, leading to an increased flow through the right to the heart. Although almost all cardiac murmurs decrease
heart chambers. The consequent increase in pressure in intensity during this maneuver, there are two exceptions:
increases the intensity of right-sided murmurs. These (1) The murmur of hypertrophic obstructive cardiomyopa-
changes are best observed in the sitting position, where thy may become louder because of the diminished left
venous return is smallest, and changes in intrathoracic pres- ventricular volume. (2) The murmur associated with mitral
sure can produce their greatest effect on venous return. In a regurgitation from mitral valve prolapse may become longer
patient in the supine position, when venous return is near and louder because of the earlier occurrence of prolapse
maximum, there may be little change observed with respira- during systole. When the maneuver is very vigorous and
tion. The ejection sound caused by pulmonic stenosis does prolonged, even these two murmurs may eventually dimin-
not routinely increase in intensity with inspiration. The ish in intensity. Therefore, the Valsalva maneuver should be
increased blood in the right heart accentuates atrial contrac- held for only about 10 seconds, so as not to cause prolonged
tion, which increases late diastolic pressure in the right diminution of the cerebral and coronary blood flow.
ventricle, partially opening the stenotic pulmonary valve and Isometric hand grip exercises have been used to increase
thus diminishing the opening sound of this valve with the arterial and left ventricular pressure. These maneuvers
subsequent systole. increase the flow gradient for mitral regurgitation, ventricu-
Changes in position are an important part of normal lar septal defect, and aortic regurgitation; the murmurs
auscultation; they can also be of great value in determining should then increase in intensity. Increasing arterial and left
the origin of cardiac murmurs (Table 1–2). Murmurs depen- ventricular pressure increases left ventricular volume,
dent on venous return, such as innocent flow murmurs, are thereby decreasing the murmur of hypertrophic obstructive
softer or absent in upright positions; others, such as the cardiomyopathy. If the patient is unable to perform isomet-
murmur associated with hypertrophic obstructive cardiomy- ric exercises, transient arterial occlusion of both upper
opathy, are accentuated by reduced left ventricular volume extremities with sphygmomanometers can achieve the same
associated with the upright position. In physically capable increases in left-sided pressure.
individuals, a rapid squat from the standing position is often Noting the changes in murmur intensity in the heart beat
diagnostically valuable because it suddenly increases venous following a premature ventricular contraction, and compar-
return and left ventricular volume and accentuates flow ing these to a beat that does not, can be extremely useful. The
murmurs but diminishes the murmur of hypertrophic premature ventricular contraction interrupts the cardiac
obstructive cardiomyopathy. The stand-squat maneuver is cycle, and during the subsequent compensatory pause, an
also useful for altering the timing of the midsystolic click extra-long diastole occurs, leading to increased left ventricu-
caused by mitral valve prolapse during systole. When the lar filling. Therefore, murmurs caused by the flow of blood
ventricle is small during standing, the prolapse occurs earlier out of the left ventricle (eg, aortic stenosis) increase in
in systole, moving the midsystolic click to early systole. intensity. There is usually no change in the intensity of the
During squatting, the ventricle dilates and the prolapse is murmur of typical mitral regurgitation because blood pres-
delayed in systole, resulting in a late midsystolic click. sure falls during the long pause and increases the gradient

Table 1–2. Differentiation of Systolic Murmurs Based on Changes in Their Intensity from Physiologic Maneuvers.

Origin of Murmur
Maneuver Flow TR AS MR/VSD MVP HOCM
Inspiration – or ↑ ↑ – – – –
Stand ↓ – – – ↑ ↑
Squat ↑ – – – ↓ ↓
Valsalva ↓ ↓ ↓ ↓ ↑ ↑
Handgrip/TAO ↓ – – ↑ ↑ ↓
Post–PVC ↑ – ↑ – – ↑
AS, aortic stenosis; Flow, innocent flow murmur; HOCM, hypertrophic obstructive cardiomyopathy; MR, mitral regurgitation; MVP, mitral valve prolapse;
PVC, premature ventricular contraction; TAO, transient arterial occlusion; TR, tricuspid regurgitation; VSD, ventricular septal defect; ↑ or ↓, change in intensity
of murmur; –, no consistent change.
 APPROACH TO CARDIAC DISEASE DIAGNOSIS
 7

between the left ventricle and the aorta, allowing more between ambulances and emergency departments to assess
forward flow. This results in the same amount of mitral and monitor rhythm disturbances. There are two types of
regurgitant flow as on a normal beat with a higher aortic ambulatory ECG recorders: continuous recorders that
pressure and less forward flow. The increased volume during record all heart beats over 24 or more hours and intermittent
the long pause goes out of the aorta rather than back into the recorders that can be attached to the patient or implanted
left atrium. Unfortunately, there is no reliable way of induc- subcutaneously for weeks or months and then activated to
ing a premature ventricular contraction in most patients; it provide brief recordings of infrequent events. In addition to
is fortuitous when a physician is present for one. Atrial analysis of cardiac rhythm, ambulatory ECG recordings can
fibrillation with markedly varying cycle lengths produces the be used to detect ST-wave transients indicative of myocardial
same phenomenon and can be very helpful in determining ischemia and certain electrophysiologic parameters of diag-
the origin of murmurs. nostic and prognostic value. The most common use of
Various rapid-acting pharmacologic agents have been ambulatory ECG monitoring is the evaluation of symptoms
used to clarify the origin of cardiac murmurs. A once- such as syncope, near-syncope, or palpitation for which
popular bedside pharmacologic maneuver was the inhala- there is no obvious cause and cardiac rhythm disturbances
tion of amyl nitrite. Because this produces rapid vasodilata- are suspected.
tion and decreases in blood pressure, it diminishes the The ECG is an important tool for rapidly assessing
murmurs of aortic and mitral regurgitation and ventricular metabolic and toxic disorders of the heart. Characteristic
septal defect and increases systolic flow murmurs (eg, those changes in the ST-T waves indicate imbalances of potassium
caused by aortic stenosis and hypertrophic obstructive car- and calcium. Drugs such as tricyclic antidepressants have
diomyopathy). Patients never liked the unpleasant odor of characteristic effects on the QT and QRS intervals at toxic
amyl nitrite and its popularity has since waned. Other levels. Such observations on the ECG can be life-saving in
pharmacologic maneuvers have occasionally been used to emergency situations with comatose patients or cardiac
clarify the origin of a murmur. These include the infusion of arrest victims.
synthetic catecholamines to increase blood pressure, isopro- Chamber enlargement can be assessed through the char-
terenol to increase the heart rate, and intravenous β-blockers acteristic changes of left or right ventricular and atrial
to decrease the heart rate. With the ready availability of enlargement. Occasionally, isolated signs of left atrial
echocardiography, these more invasive interventions have enlargement on the ECG may be the only diagnostic clue to
also diminished in popularity. mitral stenosis. Evidence of chamber enlargement on the
ECG usually signifies an advanced stage of disease with a
Brennan JM et al. A comparison by medicine residents of physical poorer prognosis than that of patients with the same disease
examination versus hand-carried ultrasound for estimation of but no discernible enlargement.
right atrial pressure. Am J Cardiol. 2007 Jun 1;99(11):1614–6. The ECG is an important tool in managing acute myo-
[PMID: 17531592] cardial infarction. In patients with chest pain that is com-
Marcus GM et al. Usefulness of the third heart sound in predicting
patible with myocardial ischemia, the characteristic ST-T-
an elevated level of B-type natriuretic peptide. Am J Cardiol.
2004 May 15:93(10):1312–3. [PMID: 15135714] wave elevations that do not resolve with nitroglycerin (and
are unlikely to be the result of an old infarction) become the
basis for thrombolytic therapy or primary angioplasty. Rapid
B. Diagnostic Studies resolution of the ECG changes of myocardial infarction after
1. Electrocardiography—Electrocardiography is perhaps reperfusion therapy has prognostic value and identifies
the least expensive of all cardiac diagnostic tests, providing patients with reperfused coronary arteries.
considerable value for the money. Modern ECG-reading Evidence of conduction abnormalities may help explain
computers do an excellent job of measuring the various the mechanism of bradyarrhythmias and the likelihood of
intervals between waveforms and calculating the heart rate the need for a pacemaker. Conduction abnormalities may
and the left ventricular axis. These programs fall consider- also aid in determining the cause of heart disease. For
ably short, however, when it comes to diagnosing complex example, right bundle branch block and left anterior fascic-
ECG patterns and rhythm disturbances, and the test results ular block are often seen in Chagas cardiomyopathy, and
must be read by a physician skilled at ECG interpretation. left-axis deviation occurs in patients with a primum atrial
Analysis of cardiac rhythm is perhaps the ECG’s most septal defect.
widely used feature; it is used to clarify the mechanism of an A newer form of electrocardiography is the signal-aver-
irregular heart rhythm detected on physical examination or aged, or high-resolution, ECG. This device markedly accentu-
that of an extremely rapid or slow rhythm. The ECG is also ates the QRS complex so that low-amplitude afterpotentials,
used to monitor cardiac rate and rhythm; Holter monitoring which correlate with a propensity toward ventricular arrhyth-
and other continuous ECG monitoring devices allow assess- mias and sudden death, can be detected. The signal-averaged
ment of cardiac rate and rhythm on an ambulatory basis. ECG permits a more accurate measurement of QRS duration,
ECG radio telemetry is also often used on hospital wards and which also has prognostic significance of established value in
 8
 CHAPTER 1

the stratification of risk of developing sustained ventricular contraction and relaxation which is a measure of myocardial
arrhythmias in postmyocardial infarction patients, patients performance that can be applied to systole and diastole.
with coronary artery disease and unexplained syncope, and Regional differences in myocardial performance can be
patients with nonischemic cardiomyopathy. assessed and used to guide biventricular pacemaker resyn-
2. Echocardiography—Another frequently ordered cardiac chronization therapy.
diagnostic test, echocardiography is based on the use of Because color-flow imaging cannot resolve very high
ultrasound directed at the heart to create images of cardiac velocities, another Doppler mode must be used to quantitate
anatomy and display them in real time on a television screen. the exact velocity and estimate the pressure gradient of the
Two-dimensional echocardiography is usually accomplished flow when high velocities are suspected. Continuous wave
by placing an ultrasound transducer in various positions on Doppler, which almost continuously sends and receives
the anterior chest and obtaining cross-sectional images of ultrasound along a beam that can be aligned through the
the heart and great vessels in a variety of standard planes. In heart, is extremely accurate at resolving very high velocities
general, two-dimensional echocardiography is excellent for such as those encountered with valvular aortic stenosis. The
detecting any anatomic abnormality of the heart and great disadvantage of this technique is that the source of the high
vessels. In addition, because the heart is seen in real time, this velocity within the beam cannot always be determined but
modality can assess the function of cardiac chambers and must be assumed, based on the anatomy through which the
valves throughout the cardiac cycle. beam passes. When there is ambiguity about the source of
Transesophageal echocardiography (TEE) involves the the high velocity, pulsed wave Doppler is more useful. This
placement of smaller ultrasound probes on a gastroscopic technique is range-gated such that specific areas along the
device for placement in the esophagus behind the heart; it beam (sample volumes) can be investigated. One or more
produces much higher resolution images of posterior cardiac sample volumes can be examined and determinations made
structures. Transesophageal echocardiography has made it concerning the exact location of areas of high-velocity flow.
possible to detect left atrial thrombi, small mitral valve Two-dimensional echocardiographic imaging of dy-
vegetations, and thoracic aortic dissection with a high degree namic left ventricular cross-sectional anatomy and the su-
of accuracy. perimposition of a Doppler color-flow map provide more
The older analog echocardiographic display referred to as information than the traditional left ventricular cine-angio-
M-mode, motion-mode, or time-motion mode, is currently gram can. Ventricular wall motion can be interrogated in
used for its high axial and temporal resolution. It is superior multiple planes, and left ventricular wall thickening during
to two-dimensional echocardiography for measuring the size systole (an important measure of myocardial viability) can
of structures in its axial direction, and its 1/1000-s sampling be assessed. In addition to demonstrating segmental wall
rate allows for the resolution of complex cardiac motion motion abnormalities, echocardiography can estimate left
patterns. Its many disadvantages, including poor lateral ventricular volumes and ejection fraction. In addition, val-
resolution and the inability to distinguish whole heart vular regurgitation can be assessed at all four valves with the
motion from the motion of individual cardiac structures, accuracy of the estimated severity equivalent to contrast
have relegated it to a supporting role. angiography.
Doppler ultrasound can be combined with two-dimen- Doppler echocardiography has now largely replaced car-
sional imaging to investigate blood flow in the heart and diac catheterization for deriving hemodynamics to estimate
great vessels. It is based on determining the change in the severity of valve stenosis. Recorded Doppler velocities
frequency (caused by the movement of blood in the given across a valve can be converted to pressure gradients by use
structure) of the reflected ultrasound compared with the of the simplified Bernoulli equation (pressure gradient = 4 ×
transmitted ultrasound, and converting this difference into velocity2). Cardiac output can be measured by Doppler from
flow velocity. Color-flow Doppler echocardiography is most the velocity recorded at cardiac anatomic sites of known size
frequently used. In this technique, frequency shifts in each visualized on the two-dimensional echocardiographic image.
pixel of a selected area of the two-dimensional image are Cardiac output and pressure gradient data can be used to
measured and converted into a color, depending on the calculate the stenotic valve area with remarkable accuracy. A
direction of flow, the velocity, and the presence or absence of complete echocardiographic examination including two-
turbulence. When these color images are superimposed on dimensional and M-mode anatomic and functional visual-
the two-dimensional echocardiographic image, a moving ization, and color, pulsed, and continuous wave Doppler
color image of blood flow in the heart is created in real time. examination of blood flow provides a considerable amount
This is extremely useful for detecting regurgitant blood flow of information about cardiac structure and function. A full
across cardiac valves and any abnormal communications in discussion of the usefulness of this technique is beyond the
the heart. scope of this chapter, but individual uses of echocardiogra-
Tissue Doppler imaging is similar to color-flow Doppler phy will be discussed in later chapters.
except that myocardial tissue movement velocity is interro- Unfortunately, echocardiography is not without its tech-
gated. This allows for the quantitation of the rate of tissue nical difficulties and pitfalls. Like any noninvasive technique,
 APPROACH TO CARDIAC DISEASE DIAGNOSIS
 9

it is not 100% accurate. Furthermore, it is impossible to hours); this allows for use of a larger dose, which results in
obtain high-quality images or Doppler signals in as many as higher energy emissions and higher quality images. Techne-
5% of patients—especially those with emphysema, chest wall tium-99m’s higher energy emissions scatter less and are
deformities, and obesity. Although TEE has made the exam- attenuated less by chest wall structures, reducing the number
ination of such patients easier, it does not solve all the of artifacts. Because sestamibi undergoes considerably less
problems of echocardiography. Despite these limitations, the washout after the initial myocardial uptake than thallium
technique is so powerful that it has moved out of the does, the evaluation of perfusion versus tissue damage
noninvasive laboratory and is now frequently being used in requires two separate injections.
the operating room, the clinic, the emergency department, In addition to detecting perfusion deficits, myocardial
and even the cardiac catheterization laboratory, to help imaging with the SPECT system allows for a three-dimen-
guide procedures without the use of fluoroscopy. sional reconstruction of the heart, which can be displayed in
any projection on a monitor screen. Such images can be
3. Nuclear cardiac imaging—Nuclear cardiac imaging in-
formed at intervals during the cardiac cycle to create an
volves the injection of tracer amounts of radioactive ele-
image of the beating heart, which can be used to detect wall
ments attached to larger molecules or to the patient’s own
motion abnormalities and derive left ventricular volumes
blood cells. The tracer-labeled blood is concentrated in
and ejection fraction. Matching wall motion abnormalities
certain areas of the heart, and a gamma ray detection camera
with perfusion defects provides additional confirmation that
is used to detect the radioactive emissions and form an image
the perfusion defects visualized are true and not artifacts of
of the deployment of the tracer in the particular area. The
photon attenuation. Also, extensive perfusion defects and
single-crystal gamma camera produces planar images of the
wall motion abnormalities should be accompanied by
heart, depending on the relationship of the camera to the
decreases in ejection fraction.
body. Multiple-head gamma cameras, which rotate around
the patient, can produce single-photon emission computed B. Radionuclide angiography—Radionuclide angiogra-
tomography (SPECT) images, displaying the cardiac anat- phy is based on visualizing radioactive tracers in the cavities
omy in slices, each about 1-cm thick. of the heart over time. Radionuclide angiography is usually
done with a single gamma camera in a single plane, and only
A. Myocardial perfusion imaging—The most common
one view of the heart is obtained. The most common
tracers used for imaging regional myocardial blood-flow
technique is to record the amount of radioactivity received
distribution are thallium-201 and the technetium-99m-
by the gamma camera over time. Although volume estimates
based agents, such as sestamibi. Thallium-201, a potassium
by radionuclide angiography are not as accurate as those
analog that is efficiently extracted from the bloodstream by
obtained by other methods, the ejection fraction is quite
viable myocardial cells, is concentrated in the myocardium
accurate. Wall motion can be assessed in the one plane
in areas of adequate blood flow and living myocardial cells.
imaged, but the technique is not as sensitive as other imaging
Thallium perfusion images show defects (a lower tracer
modalities for detecting wall motion abnormalities.
concentration) in areas where blood flow is relatively
reduced and in areas of damaged myocardial cells. If the 4. Other cardiac imaging
damage is from frank necrosis or scar tissue formation, very
A. Chest radiography—Chest radiography is used infre-
little thallium will be taken up; ischemic cells may take up
quently now for evaluating cardiac structural abnormalities
thallium more slowly or incompletely, producing relative
because of the superiority of echocardiography in this regard.
defects in the image.
The chest radiograph, however, is a rapid, inexpensive way to
Myocardial perfusion problems are separated from non-
assess pulmonary anatomy and is very useful for evaluating
viable myocardium by the fact that thallium eventually
pulmonary venous congestion and hypoperfusion or hyper-
washes out of the myocardial cells and back into the circula-
perfusion. In addition, abnormalities of the thoracic skeleton
tion. If a defect detected on initial thallium imaging disap-
are found in certain cardiac disorders and radiographic
pears over a period of 3–24 hours, the area is presumably
corroboration may help with the diagnosis. Detection of
viable. A persistent defect suggests a myocardial scar. In
intracardiac calcium deposits by the radiograph or fluoros-
addition to detecting viable myocardium and assessing the
copy is of some value in finding coronary artery, valvular, or
extent of new and old myocardial infarctions, thallium-201
pericardial disease.
imaging can also be used to detect myocardial ischemia
during stress testing (see section on Stress testing below) as B. Computed tomographic scanning—Computed to-
well as marked enlargement of the heart or dysfunction. The mography (CT) has been applied to cardiac imaging by using
major problem with thallium imaging is photon attenuation ECG gating to account for the motion of the heart. The
because of chest wall structures, which can give an artifactual major application of this technology has been the detection
appearance of defects in the myocardium. of small amounts of coronary artery calcium as an indicator
The technetium-99m-based agents take advantage of the of atherosclerosis in the coronary arterial tree. With the
shorter half-life of technetium (6 hours; thallium 201’s is 73 development of multidetector CT and using intravenous
 10
 CHAPTER 1

contrast agents, noninvasive coronary angiography is possi- oxyglucose are common metabolic tracers used to assess
ble and has a very high negative predictive value for detecting myocardial viability, and acetate containing carbon-11 is
significant coronary artery lesions. Hybrid positron emission often used to assess oxidative metabolism.
tomography (PET) or nuclear SPECT plus CT scanners are The main clinical uses of PET scanning involve the
now available and can provide anatomic and perfusion data. evaluation of coronary artery disease. It is used in perfusion
CT scanning is also very useful for detecting thoracic aorta studies at rest and during pharmacologic stress (exercise
disease, such as dissection and pericardial disease. studies are less feasible). In addition to a qualitative assess-
ment of perfusion defects, PET allows for a calculation of
C. Magnetic resonance imaging—Magnetic resonance
absolute regional myocardial blood flow or blood-flow
imaging (MRI) probably has considerable potential as a
reserve. Positron emission tomography also assesses myo-
technique for evaluating cardiovascular disease. It is excel-
cardial viability, using the metabolic tracers to detect meta-
lent for detecting aortic dissection and pericardial thickening
bolically active myocardium in areas of reduced perfusion.
and assessing left ventricular mass. Newer computer analysis
The presence of viability imply that returning perfusion to
techniques have solved the problem of myocardial motion
these areas would result in improved function of the
and can be used to detect flow in the heart, much as color-
ischemic myocardium. Although many authorities consider
flow Doppler is used. In addition, regional molecular distur-
PET scanning the gold standard for determining myocardial
bances can be created that place stripes of a different density
viability, it has not been found to be 100% accurate. Thal-
in either the myocardium or the blood; these can then be
lium reuptake techniques and echocardiographic and MR
followed through the cardiac cycle to determine structural
imaging of delayed myocardial enhancement have proved
deformation (eg, of the left ventricular wall) or the move-
equally valuable for detecting myocardial viability in clinical
ment of the blood.
studies.
Gadolinium-based contrast agents can be injected intra-
venously to enhance MRI. In delayed images taken after 5. Stress testing—Stress testing in various forms is most
contrast injection (approximately 10 minutes), hyperen- frequently applied in cases of suspected or overt ischemic
hancement of the myocardium suggests irreversible scar heart disease (Table 1–3). Because ischemia represents an
formation. This determination can identify nonviable myo- imbalance between myocardial oxygen supply and demand,
cardium in patients with coronary artery disease. The major exercise or pharmacologic stress increases myocardial oxygen
limitation of cardiac MRI is the length of the studies and the demand and reveals an inadequate oxygen supply (hypoperfu-
relative nonavailabilty of magnetic resonance systems to sion) in diseased coronary arteries. Stress testing can thus
acute patient care areas compared with CT. induce detectable ischemia in patients with no evidence of
D. Positron emission tomography—Positron emission ischemia at rest. It is also used to determine cardiac reserve in
tomography (PET) is a technique using tracers that simulta- patients with valvular and myocardial disease. Deterioration
neously emit two high-energy photons. A circular array of of left ventricular performance during exercise or other
detectors around the patient can detect these simultaneous stresses suggests a diminution in cardiac reserve that would
events and accurately identify their origin in the heart. This have therapeutic and prognostic implications. Although most
results in improved spatial resolution, compared with stress test studies use some technique (Table 1–4) for directly
SPECT. It also allows for correction of tissue photon attenu- assessing the myocardium, it is important not to forget the
ation, resulting in the ability to accurately quantify radioac- symptoms of angina pectoris or extreme dyspnea: light-head-
tivity in the heart. Positron emission tomography can be edness or syncope can be equally important in evaluating
used to assess myocardial perfusion and myocardial meta- patients. Physical findings such as the development of pulmo-
bolic activity separately by using different tracers coupled to nary rales, ventricular gallops, murmurs, peripheral cyanosis,
different molecules. Most of the tracers developed for clinical hypotension, excessive increases in heart rate, or inappropriate
use require a cyclotron for their generation; the cyclotron decreases in heart rate also have diagnostic and prognostic
must be in close proximity to the PET imager because of the value. It is therefore important that a symptom assessment
short half-life of the agents. Agents in clinical use include and physical examination always be done before, during, and
oxygen-15 (half-life 2 minutes), nitrogen-13 (half-life 10 after stress testing.
minutes), carbon-11 (half-life 20 minutes), and fluorene-18
(half-life 110 minutes). These tracers can be coupled to
many physiologically active molecules for assessing various Table 1–3. Indications for Stress Testing.
functions of the myocardium. Because rubidium-82, with a
half-life of 75 seconds, does not require a cyclotron and can Evaluation of exertional chest pain
be generated on-site, it is frequently used with PET scanning, Assess significance of known coronary artery disease
especially for perfusion images. Ammonia containing nitro- Risk stratification of ischemic heart disease
Determine exercise capacity
gen-13 and water containing oxygen-15 are also used as
Evaluate other exercise symptoms
perfusion agents. C-11-labeled fatty acids and 18F fluorode-
 APPROACH TO CARDIAC DISEASE DIAGNOSIS
 11

by coronary angiography. In fact, the cardiac catheterization

Table 1–4. Methods of Detecting laboratory has become more of a therapeutic than a diagnos-
Myocardial Ischemia during Stress Testing. tic arena. Once significant coronary artery disease is identi-
fied, a variety of catheter-based interventions can be used to
Electrocardiography alleviate the obstruction to blood flow in the coronary
Echocardiography arteries. At one time, hemodynamic measurements (pres-
Myocardial perfusion imaging
sure, flow, oxygen consumption) were necessary to accu-
Positron emission tomography
Magnetic resonance imaging rately diagnose and quantitate the severity of valvular heart
disease and intracardiac shunts. Currently, Doppler echocar-
diography has taken over this role almost completely, except
Electrocardiographic monitoring is the most common in the few instances when Doppler studies are inadequate or
cardiac evaluation technique used during stress testing; it believed to be inaccurate. Catheter-based hemodynamic
should be part of every stress test in order to assess heart rate assessments are still useful for differentiating cardiac con-
and detect any arrhythmias. In patients with normal resting striction from restriction, despite advances in Doppler echo-
ECGs, diagnostic ST depression of myocardial ischemia has a cardiography. Currently, the catheterization laboratory is
fairly high sensitivity and specificity for detecting coronary also more often used as a treatment arena for valvular and
artery disease in symptomatic patients if adequate stress is congenital heart disease. Certain stenotic valvular and arte-
achieved (peak heart rate at least 85% of the patient’s maxi- rial lesions can be treated successfully with catheter-deliv-
mum predicted rate, based on age and sex). Exercise ECG ered balloon expansion or the deployment of stents. Con-
testing is an excellent low-cost screening procedure for patients genital shunts can also be closed by catheter-delivered
with chest pain consistent with coronary artery disease, normal devices.
resting ECGs, and the ability to exercise to maximal levels. Myocardial biopsy is necessary to treat patients with heart
A myocardial imaging technique is usually added to the transplants and is occasionally used to diagnose selected
exercise evaluation in patients whose ECGs are abnormal or, cases of suspected acute myocarditis. For this purpose, a
for some reason, less accurate. It is also used for determining biotome is usually placed in the right heart and several small
the location and extent of myocardial ischemia in patients pieces of myocardium are removed. Although this technique
with known coronary artery disease. Imaging techniques, in is relatively safe, myocardial perforation occasionally results.
general, enhance the sensitivity and specificity of the tests but 7. Electrophysiologic testing—Electrophysiologic testing
are still not perfect, with false-positives and false-negatives uses catheter-delivered electrodes in the heart to induce
occurring 5–10% of the time. rhythm disorders and detect their structural basis. Certain
Which adjunctive myocardial imaging technology to arrhythmia foci and structural abnormalities that facilitate
choose depends on the quality of the tests, their availability rhythm disturbances can be treated by catheter-delivered
and cost, and the services provided by the laboratory. If these radiofrequency energy (ablation) or by the placement of
are all equal, the decision should be based on patient charac- various electronic devices that monitor rhythm disturbances
teristics. For example, echocardiography might be appropri- and treat them accordingly through either pacing or inter-
ate when ischemia is suspected of developing during exercise nally delivered defibrillation shocks. Electrophysiologic test-
and is profound enough to depress segmental left ventricular ing and treatment now dominate the management of
performance and worsen mitral regurgitation. On the other arrhythmias; the test is more accurate than the surface ECG
hand, perfusion scanning might be the best test to determine for diagnosing many arrhythmias and detecting their sub-
which coronary artery is producing the symptoms in a patient strate, and catheter ablation and electronic devices have been
with known three-vessel coronary artery disease and recur-
rent angina after revascularization.
Choosing the appropriate form of stress is also important
(Table 1–5). Exercise, the preferred stress for increasing Table 1–5. Types of Stress Tests.
myocardial oxygen demand, also simulates the patient’s
normal daily activities and is therefore highly relevant clini- Exercise
cally. There are essentially only two reasons for not choosing Treadmill
exercise stress, however: the patient’s inability to exercise Bicycle
adequately because of physical or psychological limitations; Pharmacologic
Adenosine
or the chosen test cannot be performed readily with exercise
Dipyridamole
(eg, PET scanning). In these situations, pharmacologic stress Dobutamine
is appropriate. Isoproterenol
6. Cardiac catheterization—Cardiac catheterization is now Other
Pacing
mainly used for the assessment of coronary artery anatomy
 12
 CHAPTER 1

more successful than pharmacologic approaches at treating laboratory (assuming, of course, that alternatives are
arrhythmias. available). Poor service cannot be tolerated.
8. Test selection—In the current era of escalating health- Many other situations and considerations affect the
care costs, ordering multiple tests is rarely justifiable, and the choice of tests. For example, a young patient with incapaci-
physician must pick the one test that will best define the tating angina might have a high likelihood of having single-
patient’s problem. Unfortunately, cardiology offers multiple vessel disease that would be amenable to catheter-based
competing technologies that often address the same issues, revascularization. It might be prudent to take this patient
but in a different way. The following five principles should directly to coronary arteriography with an eye toward diag-
be followed when considering which test to order: nosing and treating the patient’s disease in one setting for
maximum cost-effectiveness. This approach, however, pre-
• What information is desired? If the test is not reasonably
sents the risk of ordering an expensive catheterization rather
likely to provide the type of information needed to help
than a less-expensive noninvasive test if the patient does not
the patient’s problem, it should not be done, no matter
have significant coronary disease. If an assessment of left
how inexpensive and easy it is to obtain. At one time, for
ventricular global performance is desirable in a patient
example, routine preoperative ECGs were done prior to
known to need coronary arteriography, the assessment could
major noncardiac surgery to detect which patients might
be done by left ventricular cine-angiography at the time of
be at risk for cardiac events in the perioperative period.
cardiac catheterization. This would avoid the extra expense
Once it was determined that the resting ECG was not
of echocardiography if it was not otherwise indicated. Physi-
good at this, the practice was discontinued, despite its low
cians are frequently solicited to use the latest emerging
cost and ready availability.
technologies, which often have not been proved better than
• What is the cost of the test? If two tests can provide the the standard techniques. It is generally unwise to begin using
same information and one is much more expensive than these usually more expensive methods until clinical trials
the other, the less expensive test should be ordered. For have established their efficacy and cost-effectiveness.
example, to determine whether a patient’s remote history
of prolonged chest pain was a myocardial infarction, the Asch FM et al. Lack of sensitivity of the electrocardiogram for
physician has a choice of an ECG or one of several detection of old myocardial infarction: a cardiac magnetic
imaging tests, such as echocardiography, resting thal- resonance imaging study. Am Heart J. 2006 Oct;152(4):742–8.
lium-201 scintigraphy, and the like. Because the ECG is [PMID: 16996851]
the least expensive test, it should be performed for this Beanlands RS et al; PARR-2 Investigators. F-18-fluorodeoxyglucose
positron emission tomography imaging-assisted management of
purpose in most situations. patients with severe left ventricular dysfunction and suspected
• Is the test available? Sometimes the best test for the coronary disease; a randomized, controlled trial (PARR-2). J Am
patient is not available in the given facility. If it is Coll Cardiol. 2007 Nov 13;50(20):2002–12. [PMID: 17996568]
available at a nearby facility and the patient can go there Budoff MJ et al; American Heart Association Committee on Car-
diovascular Imaging and Intervention; American Heart Associa-
without undue cost, the test should be obtained. If
tion Council on Cardiovascular Radiology and Intervention;
expensive travel is required, the costs and benefits of American Heart Association Committee on Cardiac Imaging,
that test versus local alternatives need to be carefully Council on Clinical Cardiology. Assessment of coronary artery
considered. disease by cardiac computed tomography: a scientific statement
• What is the level of expertise of the laboratory and the from the American Heart Association Committee on Cardiovas-
cular Imaging and Intervention, Council on Cardiovascular
physicians who interpret the tests? For many of the Radiology and Intervention, and Committee on Cardiac Imag-
high-technology imaging tests, the level of expertise ing, Council on Clinical Cardiology. Circulation. 2006 Oct
considerably affects the value of the test. Myocardial 17;114(16):1761–91. [PMID: 17015792]
perfusion imaging is a classic example of this. Some Cheitlin MD et al; American College of Cardiology; American Heart
laboratories are superlative in producing tests of diag- Association; American Society of Echocardiography. ACC/AHA/
nostic accuracy. In others, the number of false-positive ASE 2003 guideline update for the clinical application of echocar-
diography: summary article: a report of the American College of
and false-negative results is so high that the tests are Cardiology/American Heart Association Task Force on Practice
rendered almost worthless. Therefore, even though a Guidelines (ACC/AHA/ASE Committee to Update the 1997
given test may be available and inexpensive and could Guidelines for the Clinical Application of Echocardiography).
theoretically provide essential information, if the qual- Circulation. 2003 Sep 2;108(9):1146–62. [PMID: 12952829]
ity of the laboratory is not good, an alternative test Gibbons RJ et al; American College of Cardiology/American Heart
should be sought. Association Task Force on Practice Guidelines (Committee to
Update the 1997 Exercise Testing Guidelines). ACC/AHA 2002
• What quality of service is provided by the laboratory? guideline update for exercise testing: summary article: a report
Patients are customers, and they need to be satisfied. If a of the American College of Cardiology/American Heart Associ-
laboratory makes patients wait a long time, if it is tardy in ation Task Force on the Practice Guidelines (Committee to
getting the results to the physicians, or if great delays Update the 1997 Exercise Testing Guidelines). Circulation.
occur in accomplishing the test, choose an alternative 2002 Oct 1;106(14):1883–92. [PMID: 12356646]
 APPROACH TO CARDIAC DISEASE DIAGNOSIS
 13

Klocke FJ et al; American College of Cardiology; American Heart filling pressures: a comparative simultaneous Doppler-catheteriza-
Association Task Force on Practice Guidelines; American Soci- tion study. Circulation. 2000 Oct 10;102(15):1788–94. [PMID:
ety for Nuclear Cardiology. ACC/AHA/ASNC guidelines for the 11023933]
clinical use of cardiac radionuclide imaging executive sum- Sampson UK et al. Diagnostic accuracy of rubidium-82 myocardial
mary: a report of the American College of Cardiology/American perfusion imaging with hybrid positron emission tomography/
Heart Association Task Force on Practice Guidelines (ACC/ computed tomography in the detection of coronary artery disease.
AHA/ASNC Committee to Revise the 1995 Guidelines for the J Am Coll Cardiol. 2007 Mar 13;49(10):1052–8. [PMID: 17349884]
Clinical Use of Cardiac Radionuclide Imaging.) Circulation. Sanz J et al. Detection of healed myocardial infarction with
2003 Sep 16;108(11):1404–18. [PMID: 12975245] multidetector-row computed tomography and comparison
Ommen SR et al. Clinical utility of Doppler echocardiography with cardiac magnetic resonance delayed hyperenhancement.
and tissue Doppler imaging in the estimation of left ventricular Am J Cardiol. 2006 Jul 15;98(2):149–55. [PMID: 16828583]
 14


2
Lipid Disorders

Christian Zellner, MD

1. Metabolism—Traditionally, the lipoprotein metabolism

ESSENTIALS OF DIAGNOSIS has been separated into exogenous (ie, uptake of cholesterol
and fat from food) and endogenous pathways (ie, metabolic
 Total serum cholesterol greater than 200 mg/dL. turnover in plasma, liver, and bile) (Figure 2–2). These path-
 LDL cholesterol greater than 100 mg/dL. ways represent simultaneous events that are complementary.
 HDL cholesterol less than 40 mg/dL. Key elements of dietary fat and cholesterol metabolism, and
metabolism of major lipoprotein classes are discussed below.
 Triglycerides greater than 150 mg/dL.
2. Dietary fats—Dietary fats are processed by pancreatic
 Lipoprotein(a) less than 30 mg/dL.
lipase to fatty acids to allow absorption across the intestinal
epithelium, where they are re-esterified to triglycerides. For
further transport they form large chylomicrons, lipoproteins
 General Considerations that also carry esterified cholesterol, apolipoprotein B-48,
Over the last decade, lipid screening has been established as and apo CII (an apolipoprotein that acts as an activator of
a cornerstone of cardiac prevention in guidelines in primary lipoprotein lipase). Chylomicrons are secreted into the lym-
care, cardiology, and many other specialties. Statins, inhibi- phatic system, and eventually enter the bloodstream via the
tors of hydroxymethylglutaryl-coenzyme A (HMG-CoA) thoracic duct. After hydrolysis by lipoprotein lipase, an
reductase have become indispensable in the treatment of enzyme present in the endothelium of many tissues, chylo-
coronary artery disease (CAD) as well as in prevention of microns release fatty acids into peripheral tissues to provide
vascular events in patients at high risk, such as those with immediate energy for muscles or to be stored as fat in
diabetes mellitus. adipose tissue. Similar to the intestinal pathway of chylomi-
crons, VLDL serve as carriers to export triglycerides from the
Lipoproteins and Apolipoproteins liver and are also targets of lipoprotein lipase. After chylomi-
crons and VLDL release most of their triglyceride content,
Esterified cholesterol and triglycerides are insoluble in blood
these smaller particles (called chylomicron remnant, and
and are transported in plasma by lipoproteins. These lipo-
VLDL remnant or IDL) contain a high core concentration of
proteins are known as high-density lipoprotein (HDL) cho-
esterified cholesterol and are considered by many clinicians
lesterol, low-density lipoprotein (LDL) cholesterol, very-low
to be of high atherogenic potential. Chylomicron remnants
density lipoproteins (VLDL), intermediate-density lipopro-
and about half of VLDL remnants are then taken up by the
teins (IDL), and chylomicrons (Figure 2–1). Lipoproteins
liver in an apo E mediated process for subsequent cholesterol
carry characteristic apolipoproteins in their outer layer that
metabolism, while the remaining VLDL remnants act as the
have functional significance (apo A-I for HDL; apo B-100 for
building block for LDL in plasma.
LDL, IDL, and VLDL; and apo B-48 for chylomicrons). For
Turnover of chylomicrons and VLDL is rapid, with VLDL
example, apo B-100 is recognized by the LDL receptor and is
carrying less than 30% of overall plasma triglycerides. Fasting
required for hepatic production and removal of LDL. Other
or zero-fat diets, therefore, lead to prompt improvement in
apolipoproteins, such as apo E and apo CI-CIII, have long
acutely elevated triglycerides in hypertriglyceridemia.
been known to play an important part in lipid metabolism,
while the effects of many apolipoproteins remain incom- 3. Dietary cholesterol—Absorption of dietary or recircu-
pletely understood. lated biliary cholesterol is largely by diffusion across the intes-
 LIPID DISORDERS
 15

(PLTP). LDL is taken up in the liver by the LDL receptor. The

0.95
LDL receptor is down-regulated by feedback mechanisms such
VLDL as high hepatic free cholesterol levels, likely one of the causes of
increased LDL levels with high intake of saturated fats. Statins,
1.006
IDL HMG-CoA reductase inhibitors, act by lowering hepatic free
Density, g/mL

cholesterol, leading to increased expression of LDL receptors

Chylomicron
1.02
remnants and subsequent uptake of LDL in the liver.
LDL
5. Lipoprotein(a)—Lipoprotein(a) or Lp(a) is an LDL-like
Chylomicron
1.06 particle containing apo B-100 and apo (a), which has close
structural homology with plasminogen. Lp(a) is not only an
1.10 HDL atherogenic lipoprotein, particularly in patients with ele-
1.20 vated LDL, but it is also prothrombotic because it can
5 10 20 40 60 80 1000 displace plasminogen from its binding sites. Lp(a) can be
elevated in patients with diabetes mellitus, chronic kidney
Diameter, nm
disease, or nephrotic syndrome, but its levels are mainly
▲ Figure 2–1. The density and size-distribution of the determined by genetic factors. Lp(a) does not respond to
major classes of lipoprotein particles. Lipoproteins are statin therapy and is not included in routine lipid panels.
classified by density and size, which are inversely related. Estimated levels by Vertical Auto Profile (VAP) are informa-
HDL, high-density lipoproteins; IDL, intermediate-density tive but need to be confirmed by enzyme-linked immun-
lipoproteins; LDL, low-density lipoproteins; VLDL, very low- osorbent assay (ELISA).
density lipoproteins. (Reproduced, with permission, from
Rader DJ et al. Disorders of Lipoprotein Metabolism. In: AS 6. Genetics—Abnormal lipid levels develop in most
Fauci, E Braunwald, DL Kasper, SL Hauser, DL Longo, JL patients after weight gain, with sedentary lifestyle, or in the
Jameson, J Loscaizo (eds). Harrison’s Principles of Internal presence of other disorders, such as diabetes mellitus and
Medicine, 17th edition. New York: McGraw-Hill; 2008.) renal or thyroid disease. While likely combinations of small
genetic variants (ie, polygenic factors) are responsible for
these lipid changes, only a few patients have known mono-
tinal brush border in the jejunum. It is important to recognize genic defects, the most common of which is familial hyper-
that only half of the intestinal cholesterol is absorbed, mainly cholesterolemia (FH), occurring in 1 in 500 patients. FH is
in the form of recirculated biliary cholesterol, while less than caused by an LDL receptor gene mutation, resulting in
30% comes from dietary cholesterol. Dietary plant sterols elevated plasma cholesterol and premature CAD. The
(phytosterols) or other sterols compete with cholesterol uptake mutant receptor impairs clearance of LDL, but treatment
in this process and lead to cholesterol lowering by way of with statins and other drugs typically remains effective
reduced absorption. This explains why limiting the intake of because of clearance through normal receptors in heterozy-
dietary cholesterol often shows only modest improvement in gous patients. Compound heterozygous states or homozy-
cholesterol levels. After passive diffusion of cholesterol, the gous mutations are infrequent, but always associated with
protein Nieman-Pick C1-like 1 (NPC1L1; inhibited by the severely increased plasma cholesterol, limited response to
drug ezetimibe) is critical in the uptake of sterols and choles- statins, and extensive tendon xanthomas. Because FH is
terol into intestinal enterocytes. In an active process involving diagnosed in most people after their first coronary event,
the adenosine triphosphate–binding cassette (ABC)-Trans- family history of hypercholesterolemia, elevated LDL during
porter ABCG5/G8, sterols and cholesterol are largely trans- childhood, and tendon xanthomas are important clues to
ported back into the gut, while a small amount of free choles- FH and should trigger screening of family members. Early
terol is esterified and transferred into chylomicrons for CAD is also common in familial combined hyperlipidemia
subsequent hepatic uptake. In the liver, cholesterol is either (FCH), a familial disorder characterized by elevated triglyc-
incorporated into VLDL or metabolized into bile acids. Cho- erides and LDL that occurs in 1–2% of the population. A
lesterol can also be synthesized from acetyl-CoA, a process that single gene involved in this disease has not been found, and
is regulated by HMG-CoA and inhibited by statins. the disease is likely polygenic. Typically, patients are identi-
fied after their first cardiac event but do not have tendon
4. LDL and HDL—LDL and HDL are continuously remodeled xanthomas. Although these are examples of common
in plasma, a complex process involving enzymes, transfer genetic disorders associated with lipid abnormalities, cur-
proteins, and receptors. This allows LDL to act as a transporter rent screening and treatment remains centered on lipid
of cholesterol from the liver to target tissues, while HDL carries profiles until genetic testing becomes a clinical reality.
out the opposite function. Most enzymes or proteins affect
both classes and include hepatic lipase (HL), cholesteryl-ester Brunzell JD. Clinical practice. Hypertriglyceridemia. N Engl J
transfer protein (CETP), and phospholipids-transfer protein Med. 2007 Sep 6;357(10):1009–17. [PMID: 17804845]
 16
 CHAPTER 2

Exogenous Endogenous
Dietary lipids
Bile acids
+ LDL
cholesterol

LDLR
Small Liver
intestines Peripheral
tissues

ApoC's ApoE
ApoB

Chylomicron
Chylomicron remnant VLDL IDL

Capillaries Capillaries

LPL LPL
FFA FFA

Muscle Adipose Muscle Adipose

▲ Figure 2–2. The exogenous and endogenous lipoprotein metabolic pathways. The exogenous pathway transports
dietary lipids to the periphery and the liver. The endogenous pathway transports hepatic lipids to the periphery. FFA, free
fatty acids; IDL, intermediate-density lipoproteins; LDL, low-density lipoproteins; LDLR, low-density lipoprotein receptor;
LPL, lipoprotein lipase; VLDL, very low-density lipoproteins. (Reproduced, with permission, from Rader DJ et al. In: AS Fauci,
E Braunwald, DL Kasper, SL Hauser, DL Longo, JL Jameson, J Loscaizo (eds). Harrison’s Principles of Internal Medicine, 17th
edition. New York: McGraw-Hill; 2008.)

 Clinical Findings In addition, a history or symptoms of other diseases associ-

ated with lipid abnormalities (eg, diabetes mellitus, hypothy-
A. History roidism, end-stage renal disease, liver disease), other cardiovas-
History is a critical component of the initial visit, because by cular risk factors, a Framingham Risk Score, and dietary habits
the time patients are referred to a cardiologist, many have (grapefruit juice, red yeast rice) or medication interfering with
already started taking lipid-lowering drugs. It is important to lipid-lowering drugs should be included in the initial history.
ask for lipid profiles obtained before medications were started,
since lipid panels are now routinely included in screening of
B. Physical Examination
healthy adults by primary care physicians or are often offered
at shopping malls or public events. When available, response The physical examination should focus on the cardiovascular
to the initial drug and any adverse effects including myalgias system but manifestations of metabolic diseases are often
and abnormal liver function tests should be noted. Family missed and include abdominal pain (enlarged liver or spleen,
history of early coronary disease or dyslipidemia at a young age gallstones, pancreatitis), corneal changes, and tendon or erup-
suggests a genetic component. A brief diet and exercise review, tive xanthomas. The Achilles tendons are easily palpated while
and recent weight gain or weight loss should also be recorded. examining distal pulses and should resemble a “narrow string
It is important to screen for regular alcohol use as it a frequent of steel.” Broad tendons or tendon xanthomas are found in
cause of elevated triglycerides and weight gain. FH and are typically absent in FCH. Eruptive xanthomas are
 LIPID DISORDERS
 17

found in hypertriglyceridemia and dysbetalipoproteinemia. medial thickness (IMT), coronary artery calcium scores
Other physical findings such as truncal obesity, lipodystrophy, (CACS), and coronary angiography by computed tomogra-
acanthosis, reduced muscle bulk, muscle weakness, myalgia, phy (CTA) estimate subclinical vascular disease burden.
or neuropathy are important clues to metabolic diseases or These tests are not part of ATP III recommendations but
drug side effects. may be useful in individual cases.

C. Laboratory Assessment Expert Panel on Detection, Evaluation, and Treatment of High

Blood Cholesterol in Adults. Executive Summary of the Third
The Third Report of the National Cholesterol Education Report of The National Cholesterol Education Program
Program (NCEP) Expert Panel on Detection, Evaluation, (NCEP) Expert Panel on Detection, Evaluation, and Treatment
and Treatment of High Blood Cholesterol in Adults (Adult of High Blood Cholesterol in Adults (Adult Treatment Panel
Treatment Panel (ATP) III) suggests that a fasting lipid III). JAMA. 2001 May 16;285(19):2486–97. [PMID: 11368702]
profile should be obtained in all adults 20 years of age or Kulkarni KR. Cholesterol profile measurement by vertical auto
profile method. Clin Lab Med. 2006 Dec;26(4):787–802.
older at least once every 5 years. Patients who are acutely ill; [PMID: 17110240]
have significant weight change; are pregnant; or who recently
had a significant illness, myocardial infarction, or stroke  Treatment
should be evaluated at a later time because cholesterol levels
may be suppressed. Because of initial variability between A. LDL Goals
laboratories, the NCEP has established guidelines for stan- Epidemiologic studies suggest that in middle-aged men,
dardization of lipid and lipoprotein measurements. Com- higher LDL (each 1 mg/dL increase is associated with a 1%
pact chemical analyzers for routine office determinations risk increase) and lower HDL (each 1 mg/dL decrease is
should not be used for the initial diagnosis due to reported associated with a 2% risk increase) are important targets in
variability in results but can be useful for subsequent visits. cardiovascular prevention. In patients with established CAD,
In our practice, patients referred for dyslipidemia receive a LDL lowering translates into up to 20% relative-risk reduc-
detailed questionnaire and a laboratory request for a lipid tion. To guide therapy, the NECP has established a classifica-
panel prior to their first visit to facilitate management. tion of LDL, total cholesterol, and HDL levels (Table 2–1).
Lipid panels measure total cholesterol and triglycerides, as The NCEP ATP III identifies LDL as the primary therapeutic
well as LDL, HDL, and VLDL after an overnight fast. Nonfast- target in addition to lifestyle changes and focuses on primary
ing samples primarily affect VLDL and triglycerides, while all prevention in patients with increased risk as well as aggressive
other measurements (including LDL and HDL) remain inter- lipid lowering in patients with established vascular disease.
pretable but are less accurate. Routine lipid panels use precip- Treatment with aspirin, β-blockers, angiotensin-converting-
itation of one fraction of cholesterol (ie, HDL) and measuring enzyme inhibitors in appropriate candidates, smoking cessa-
the remaining cholesterol while adjusting for cholesterol
found in VLDL to estimate LDL. The so-called Friedman
formula: LDL cholesterol = total cholesterol – HDL – triglyc- Table 2–1. ATP III Classification of LDL,
erides/5 is unreliable for triglycerides greater than 400 mg/dL. Total, and HDL Cholesterol (mg/dL).
If direct measurement of LDL is not available, a repeat fasting
sample should be ordered with instructions to fast for at least LDL Cholesterol
12 hours. Newer technologies such as the Berkeley HeartLab < 100 Optimal
Segmented Gradient Gel, the Atherotech VAP (Vertical Auto
100–129 Near or above optimal
Profile), and the LipoScience Nuclear Magnetic Resonance
assess lipid fractions independently. These tests are based on 130–159 Borderline high
the initial discovery of lipoprotein classes in the 1950s using 160–189 High
analytical ultracentrifugation and provide additional informa- ≥ 190 Very high
tion of cholesterol subclasses, although not included in ATP
III guidelines. Direct measurement of LDL and triglycerides Total Cholesterol
using these techniques may be necessary when significant < 200 Desirable
hypertriglyceridemia persists despite fasting. 200–239 Borderline high
Basic screening should also include thyroid function
≥ 240 High
studies, liver function studies, fasting glucose, baseline crea-
tine kinase, and urine analysis. Baseline uric acid levels may HDL Cholesterol
be needed before starting niacin therapy. A host of other < 40 Low
screening tools exist to estimate cardiovascular risk, such as
≥ 60 High
apo B, homocysteine, C-reactive protein (CRP), and lipo-
protein-associated phospholipase A2 (Lp-PLA2). Vascular ATP, adult treatment panel; HDL, high-density lipoprotein; LDL, low-density
studies such as ankle-brachial-index (ABI), carotid intima- lipoprotein.
 18
 CHAPTER 2

tion, moderation of alcohol use, increased exercise and LDL goal: < 70 mg/dL for patients with CAD or high risk;
weight loss, as well as incorporation of dietary intervention, (2) Optional LDL goal: < 100 mg/dL for patients with two risk
as outlined in Table 2–2, are strongly advised. factors and moderate risk (10-year CAD risk of 10–20%).
Statin therapy is initiated immediately in patients with The optional LDL goal of < 70 mg/dL should be consid-
established CAD or at high risk; all others will be offered a trial ered in all patients at high risk for subsequent events and
of therapeutic lifestyle changes. When response to lifestyle include history of myocardial infarction, coronary artery or
changes and diet is inadequate, the NCEP recommends the other bypass grafts, stroke, percutaneous coronary interven-
addition of pharmacologic therapy after a few months (Figure tion, and stenting. Treatment with statins, irrespective of
2–3). In patients without overt CAD, the Framingham Risk LDL goals, should be individualized for patients with aortic
Score should be used to estimate 10-year CAD risk (Table 2–3). valve stenosis or prosthesis and chronic kidney disease until
Framingham Risk Score calculators can be found online, as ATP guidelines are revised.
handheld applications, or as part of the ATP III guidelines.
Because it is clear that lifetime risk of CAD remains very high in B. Non-HDL Goals and Hypertriglyceridemia
all individuals, many physicians have adopted a more aggres- Because treating hypertriglyceridemia is not the primary lipid
sive approach to lipid lowering with LDL goals of less than 100 target in patients with CAD, it is frequently overlooked.
mg/dL in patients even considered low risk (10-year CAD risk Elevated triglycerides are common (more than 25% of popu-
of < 10%). The long-term risks, benefits, and costs of such an lation) and often associated with secondary causes (such as
approach will likely be reevaluated in the next ATP revision. obesity; diabetes; renal disease; the metabolic syndrome; and
Treatment decisions are guided by several large-scale clin- a number of drugs, including protease inhibitors and estro-
ical trials that established the role of LDL-lowering and statin gens). Most patients will show borderline high triglyceride
therapy in primary and secondary prevention of cardiac events levels of less than 200 mg/dL, and after achieving their LDL
and stroke. The Heart Protection Study (HPS), Treat-to New goal, lifestyle changes such as smoking cessation, abstinence
Targets (TNT), PROVE-IT, and ASCOT-LLA trials showed from alcohol, increased exercise, weight loss, and reduced
that patients with very low LDL cholesterol and vascular carbohydrate intake are primary treatment strategies in this
disease benefited from statin therapy. These findings have only group of patients. In patients with high triglycerides (> 200
partially been included in the most recent update of the NCEP mg/dL), LDL goals remain the primary treatment target, but
ATP III guidelines and are listed as an “optional” LDL goal lowering non-HDL cholesterol, comprising LDL, IDL, and
of < 70 mg/dL in patients with high-risk features: (1) Optional VLDL, was introduced by ATP III as a secondary treatment
goal in 2001. Non-HDL cholesterol has not been widely
adopted as it is not always reported separately, but non-HDL
Table 2–2. Nutrient Composition of the cholesterol levels can be obtained easily by subtracting HDL
Therapeutic Lifestyle Changes (TLC) Diet. from total cholesterol. This essentially aims to add athero-
genic cholesterol in remnant particles to LDL goals in patients
Nutrient Recommended Intake with elevated triglycerides. Therefore, the non-HDL goal is 30
Saturated fat1 < 7% of total calories
mg/dL higher than the LDL goal. Very high triglyceride levels
(> 500 mg/dL) are rare in the general population but are
Polyunsaturated fat Up to 10% of total calories often associated with recurrent, acute pancreatitis and should
Monounsaturated fat Up to 20% of total calories be suspected with any history of abdominal pain (Table 2–4).
Changes in lifestyle (weight loss, increased physical activity,
Total fat 25–35% of total calories
restriction of alcohol, restriction of dietary fat to 10–20% of
2
Carbohydrate 50–60% of total calories total caloric intake, reduction of high carbohydrate intake)
Fiber 20–30 g/day and drug therapy are almost always required. In general, LDL
cholesterol levels are low and statins are ineffective, but
Protein Approximately 15% of total calories response to niacin or fibrates or in combination with omega-
Cholesterol < 200 mg/day 3 fatty acids is good. A significant number of patients,
however, will not respond to drug therapy due to genetic
Total calories3 Balance energy intake and expenditure
to maintain desirable body weight and mutations in lipoprotein lipase, apo CII or related pathways.
prevent weight gain. A very low-fat diet is critical in these patients and hard to
1
achieve without frequent visits with a dietitian.
Trans fatty acids are another LDL-raising fat that should be kept at a low
Much of moderate hypertriglyceridemia (250–500 mg/dL)
intake.
2
Carbohydrates should be derived predominantly from foods rich in is due to various exogenous or secondary factors (Table 2–5),
complex carbohydrates, including grains, especially whole grains, fruits, and which include alcohol, diabetes mellitus, hypothyroidism,
vegetables. obesity, chronic renal disease, and drugs. Changes in lifestyle
3
Daily energy expenditure should include at least moderate physical activity or treatment of the primary disease process may be sufficient
(contributing approximately 200 kcal/day). to reduce triglyceride levels and high carbohydrate intake and
 LIPID DISORDERS
 19

Visit 1 Visit 2 Visit 3 Visit N

Begin lifestyle Evaluate LDL Evaluate LDL Every Monitor
therapies. 6 response. 6 response. 4–6 adherence
weeks weeks months to TLC.
If LDL goal not If LDL goal not
achieved, achieved,
intensify LDL- consider
lowering adding drug
therapy. therapy.

•Emphasize reduction •Reinforce reduction •Initiate therapy

of saturated fat and in saturated fat and for metabolic
cholesterol intakes. cholesterol intakes. syndrome.
•Encourage moderate •Consider adding •Intensify weight
physical activity. plant stanols and management
•Consider referral sterols. and physical
to a dietitian. •Increase fiber intake. activity.
•Consider referral •Consider
to a dietitian. referral to a
dietitian.

LDL, low-density lipoprotein.

▲ Figure 2–3. Model of steps in therapeutic lifestyle changes (TLC). (Source: Expert Panel on Detection, Evaluation and
Treatment of High Blood Cholesterol in Adults: Executive summary of the Third Report of the NCEP Expert Panel on Detection,
Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285;2491.)

alcohol use are frequently overlooked. Often, however, these

Table 2–3. Risk Factors That Modify patients not only need lifestyle changes, but also statin therapy
LDL–Cholesterol Goals.1 in combination with other lipid-lowering drugs such as
fibrates, niacin, or omega-3 fatty acids.
Major Risk Factors (exclusive of LDL-cholesterol) Hypertriglyceridemia in the presence of elevated LDL with
Cigarette smoking or without low HDL remains a common lipid abnormality in
Hypertension (blood pressure ≥ 140/90 mm Hg or on antihypertensive
patients with CAD, and both LDL and non-HDL cholesterol
medication) goals should be aggressively met to decrease the burden of CAD.
Low HDL-C (< 40 mg/dL)2
C. HDL and Lipoprotein(a)
Family history of premature CAD (CAD in male first-degree relative
< 55 years; CAD in female first-degree relative < 65 years) Low HDL is a strong predictor of CAD and increased
cardiovascular mortality. The major causes of reduced serum
Age (men ≥ 45 years; women ≥ 55 years)
Categories of Risk LDL Goal (mg/dL)
CAD and CAD risk equivalents < 100 Table 2–4. Categories of Triglyceride Levels.
Multiple (2+) risk factors < 130 Category Triglyceride Levels
0–1 risk factor < 160
Optimal < 150 mg dL
1
Diabetes is regarded as a CAD risk equivalent.
Borderline 150–199 mg/dL
2
HDL cholesterol ≥ 60 mg/dL counts as a "negative" risk factor; its presence
removes one risk factor from the total count. High 200–499 mg/dL
CAD, coronary artery disease; HDL, high-density lipoprotein; LDL, low-density
Very high ≥ 500 mg/dL
lipoprotein.
 20
 CHAPTER 2

Table 2–5. Some Acquired Causes of Hyperlipidemia.

Condition Liproprotein Accumulating Lipid Phenotype HDL Level

Diabetes mellitus
Type 1 Chylomicron,VLDL ↑ TG ↓
Type 2 VLDL ↑ TG ↓
Obesity VLDL ↑ TG – or ↓
Alcohol VLDL ↑ TG – or ↑
Oral contraceptives VLDL ↑ TG – or ↑
Hypothyroidism LDL ↑C –
Nephrotic syndrome VLDL, LDL ↑ TG, ↑ C – or ↑
Renal failure VLDL, LDL ↑ TG, ↑ C – or ↓
Primary biliary cirrhosis LDL ↑C
Acute hepatitis VLDL ↑ TG
C, cholesterol; HDL, high-density lipoprotein; LDL, low-density lipoprotein; TG, triglyceride; VLDL, very low-density lipoprotein.
↑, increase; ↓, decrease; –, no change.
Reproduced, with permission, from Frishman WH et al. Lipids and lipoproteins: Atherosclerotic risk and management. In Frishman WH, ed: Medical Management
of Lipid Disorders: Focus on Prevention of Coronary Artery Disease. Armonk, NY: Futura, 1992.

HDL cholesterol are shown in Table 2–6. Low HDL is often Saturated fats typically raise cholesterol, while monounsat-
part of the metabolic syndrome and associated with elevated urated fats (eg, olive oil), and polyunsaturated fats can lower
triglycerides. Attempts should be made to raise low HDL serum cholesterol. The favorable effects of polyunsaturated fat
cholesterol by nonpharmacologic means such as smoking on serum cholesterol have been counterbalanced by evidence
cessation, weight loss, and increased exercise. Drug therapy that high intake not only tends to lower HDL levels but may
should focus initially on LDL goals using statins. When low promote gallstone formation. In most outpatients, diet
HDL is associated with increased VLDL, therapeutic modifi- changes, even after seeing a dietitian, lead to only a 10%
cation of the latter should be considered, and should include decrease in LDL, often with no long-term effects. Very low-fat
fibrates, omega-3 fatty acids, and particularly niacin. Similar diets such as the Dean Ornish Diet, the Pritikin Diet, and most
to low HDL, Lp(a) is independently associated with cardio- vegetarian diets can even lower HDL cholesterol. In contrast,
vascular disease. Statins do not lower Lp(a) but appear to
attenuate pro-atherogenic effects of Lp(a) in the setting of
elevated LDL. ATP III, however, does not suggest a specific
target for LDL cholesterol in patients with elevated Lp(a). Table 2–6. Major Causes of Reduced
Patients are often treated toward a low LDL goal (< 70 mg/ Serum HDL Cholesterol.
dL) because of lack of effective drugs to lower Lp(a), as less
than 30% of patients respond to niacin therapy. Cigarette smoking
Obesity
Lack of exercise
D. Nonpharmacologic Approaches Androgenic and related steroids
Androgens
1. Dietary modification—The NCEP recommends dietary Progestational agents
modification as the first-line treatment for hyperlipidemia Anabolic steroids
(see Table 2–2). It advises a diet that limits cholesterol intake β-Adrenergic-blocking agents
to no more than 200 mg daily (typical US diet is over 400 Hypertriglyceridemia
mg/day) and fat intake of less than 30% of total calories, Genetic factors
saturated fat constituting less than 7% of daily caloric intake Primary hypoalphalipoproteinemia
(typical US diet is over 15% of daily caloric intake). ATP III Reproduced, with permission, from Frishman WH et al: Lipids and lipopro-
also emphasizes the use of plant stanols and sterols and teins: Atherosclerotic risk and managment. In Frishman WH, ed: Medical
viscous (soluble) fiber as therapeutic dietary options to Management of Lipid Disorders: Focus on Prevention of Coronary Artery
enhance lowering of LDL cholesterol. Disease. Armonk, NY: Futura, 1992.
 LIPID DISORDERS
 21

a diet rich in monounsaturated fats such as the Mediterranean agents to treat hypercholesterolemia without concurrent
or South Beach Diets may increase or maintain HDL levels. hypertriglyceridemia.
Trans-fats are formed by commercial hydrogenation pro- Resins interrupt the enterohepatic circulation of bile
cesses, which harden polyunsaturate-rich marine and vege- acids and lead to reduced uptake of biliary cholesterol.
table oils. Lipid profiles are known to be adversely affected by Resins have a synergistic effect when given in combination
a high trans-fat diet, which depresses HDL levels and elevates with statins but are now largely replaced by the cholesterol
LDL levels. Trans-fats are listed on food labels as partially absorption inhibitor ezetimibe. Resins can cause a 5–20%
hydrogenized fats or oils and should be avoided. increase in VLDL levels; hence, they should be restricted to
Saturated fats, such as stearic acid, which contributes patients with normal triglycerides. Cholestyramine and
substantially to the fatty acid composition in beef and in colestipol are powders that must be mixed with water or fruit
plants such as cocoa, have been found to be as effective as juice before ingestion and are taken in two or three divided
oleic acid (monounsaturated fat) in lowering plasma choles- doses with or just after meals. Colestipol is also available in
terol, by replacing other saturated fats. Lean beef, therefore, tablet form for greater ease of administration. Colesevelam is
does not need to be excluded in a low-cholesterol diet. a newer bile acid resin, which may have fewer adverse effects
and drug interactions than older resins due to its novel
2. Exercise—Physical inactivity is a modifiable risk factor, structure and higher affinity for bile acids. It should be noted
and daily exercise is recommended as an adjunct to dietary that all bile acid sequestrants could decrease absorption of
modification for the initial treatment of hyperlipidemia. some antihypertensive agents, including thiazide diuretics
More recently, the benefits of combined resistance and and β-blockers. As a general recommendation, all other
aerobic exercise have become apparent and should be drugs should be administered either 1 hour before or 4 hours
encouraged in every patient. Walking of at least 5000 steps after the bile acid sequestrant. The response to therapy is
daily or a goal exercise of 1500 calories weekly should be variable in each individual, but a 15–30% reduction in LDL
recommended to all patients. Regular physical activity cholesterol may be seen with colestipol (20 g/day), cholesty-
reduces VLDL and triglyceride levels in most, and, in some, ramine (16 g/day), or colesevelam (3.8 g/day) treatment. The
lowers LDL and raises HDL. It also can lower blood pressure, fall in LDL concentration becomes detectable 4–7 days after
reduce insulin resistance, and favorably influence cardiovas- the start of treatment, and approaches 90% of maximal effect
cular function, but likely requires a modest degree of associ- in 2 weeks. The initial dose should be 4 g of cholestyramine,
ated weight loss to achieve sustained benefits. 5 g of colestipol, or 1.88 g of colesevelam twice a day, and if
there is an inadequate response, the dosage can be titrated
E. Pharmacologic Therapy upward accordingly. Using more than the maximum dosage
does not increase the antihypercholesterolemic effect of the
Table 2–7 summarizes the medications available to treat drug appreciably, but because it does increase side effects, it
hyperlipidemia. decreases compliance. Because resins are virtually identical
1. Omega-3 fatty acids (fish oil)—Omega-3 fatty acids in action, the choice is based on potential drug interactions
are found in cold-water fish (salmon, Arctic char). Eicosa- and patient preference, specifically taste and the ability to
pentaenoic acid (EPA) and docosahexaenoic acid (DHA) are tolerate the ingestion of bulky material.
the active compounds and sold as part of many dietary 3. Cholesterol absorption inhibitors—Ezetimibe, the first
supplements. Purified EPA and DHA have recently become drug in this class, inhibits the absorption of cholesterol and
available by prescription to avoid concerns about contami- phytosterols through the intestinal brush border and interrupts
nation with mercury or other environmental toxins. The the enterohepatic recirculation of sterols from bile. Ezetimibe
pathways by which DHA and EPA lower triglycerides are not lowers LDL but does not affect triglycerides. When used with
completely understood and doses of at least 3–4 g per day are resins, its absorption is reduced, while use of fibrates increases its
needed for significant triglyceride lowering. Omega-3 fatty blood concentration. Ezetimibe should be avoided in pregnant
acids can used in combination with statins, fibrates, and or lactating women and in patients with liver disease, and used
niacin without significant side effects, but frequently with caution in patients receiving cyclosporine. As a monother-
increase LDL in higher doses. Unpleasant aftertaste and soft apy of 10 mg daily, it reduces cholesterol by 15–20% and is
stools often limit the compliance with higher doses, and liver synergistic with statin therapy. Although side effects are uncom-
function studies should be monitored. High-dose fish oil mon, when ezetimibe is given in combination with statins, liver
may affect platelet function when given in combination with function studies can become elevated. Rare cases of thrombocy-
aspirin and other platelet-antagonists, although no clear topenia, pancreatitis, and arthralgias have been reported.
association with increased bleeding risk has been found.
4. Fibrates—Fibrates are a class of drugs that activate the
2. Bile acid sequestrants—The bile acid-binding resins nuclear peroxisome proliferator activated receptor alpha.
cholestyramine, colestipol, and colesevelam (WelChol) are Fibrates inhibit the production of VLDL while enhancing
used as second-line therapy and in combination with other VLDL clearance, as a result of the stimulation of lipoprotein
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