JA CC: H E A R T F AI L U RE VO L. 6, N O .

5, 20 18

ª 2 0 1 8 BY T H E A M E R I C A N C O L L E G E OF C A R D I O L O G Y F O U N DA TI O N

P U B L I S H E D B Y E LS E V I E R

Hypertrophic Cardiomyopathy
Clinical Update

Jeffrey B. Geske, MD, Steve R. Ommen, MD, Bernard J. Gersh, MB, CHB, DP HIL

ABSTRACT

Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiomyopathy, manifesting as left ventricular
hypertrophy in the absence of a secondary cause. The genetic underpinnings of HCM arise largely from mutations of
sarcomeric proteins; however, the specific underlying mutation often remains undetermined. Patient presentation is
phenotypically diverse, ranging from asymptomatic to heart failure or sudden cardiac death. Left ventricular
hypertrophy and abnormal ventricular configuration result in dynamic left ventricular outflow obstruction in most
patients. The goal of therapeutic interventions is largely to reduce dynamic obstruction, with treatment modalities
spanning lifestyle modifications, pharmacotherapies, and septal reduction therapies. A small subset of patients with
HCM will experience sudden cardiac death, and risk stratification remains a clinical challenge. This paper presents a
clinical update for diagnosis, family screening, clinical imaging, risk stratification, and management of symptoms in
patients with HCM. (J Am Coll Cardiol HF 2018;6:364–75) © 2018 by the American College of Cardiology Foundation.

H
ypertrophic cardiomyopathy (HCM) is the is consistent with HCM (2). LVH typically manifests as
most common heritable cardiomyopathy, asymmetric septal hypertrophy, although other pat-
historically believed to affect w1 of 500 terns (apical, concentric, lateral wall, and right ven-
people (Online Ref. 1), with recent investigations sug- tricular) can occur (Online Ref. 2). In first-degree
gesting even greater prevalence (1). Diagnosis can be family members of patients with unequivocal dis-
challenging given phenotypic heterogeneity. Prog- ease, an unexplained wall thickness of $13 mm is
nosis is generally favorable but variable, with sudden sufficient for diagnosis (3).
cardiac death (SCD) and severe congestive heart fail- Distinguishing HCM from the physiological hy-
ure in a small subset of patients. Treatment is multi- pertrophy of athlete’s heart can present a clinical
faceted, requiring individualized care. We present a dilemma, particularly given the recommendation
clinically oriented review of HCM spanning disease against patients with HCM participating in compet-
definition, pathophysiology, family screening, imag- itive sports (2). In elite athletes, LVH >12 mm is
ing assessment, risk stratification, and therapeutic uncommon (1.7%) (Online Ref. 3) and tends to be
approaches (Central Illustration). uniform in distribution without accompanying dia-
stolic dysfunction. Athletic LVH is often accompa-
DE FIN IN G THE D ISE A S E nied by LV chamber dilation (Online Ref. 4), a
finding absent in pathological hypertrophy until
HCM is a diagnosis of exclusion; secondary causes end-stage disease. Mild, late gadolinium enhance-
of left ventricular hypertrophy (LVH) such as sys- ment (LGE) on CMR can be present in a minority of
temic hypertension, valvular and subvalvular aortic athletes (Online Ref. 5); however, extensive LGE
stenosis, and infiltrative cardiomyopathies must be raises suspicion of HCM. Additional clinical clues to
ruled out. A wall thickness of $15 mm by echocardi- the presence of HCM, as opposed to athlete’s heart,
ography, computed tomography, or cardiac magnetic include bizarre electrocardiographic patterns, family
resonance (CMR) in the absence of a secondary cause history of HCM, greater than mild left atrial

From the Department of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota. Dr. Geske is a consultant for MyoKardia, I nc.
Dr. Gershis a consultantfor MyoKardia, Inc., Janssen, Xenon Pharmaceutical, and Sirtex Medical; andis a data safety monitoring board
member of Mount Sinai, St. Lukes, Boston Science Corp., Teva Pharmaceuticals, Janssen R&D, Kowa Research Inst., Duke University,
and Medtronic. Dr. Ommen has reported that he has no relationships relevant to the contents of this paper to disclose.

Manuscript received November 9, 2017; revised manuscript received February 20, 2018, accepted February 21, 2018.

ISSN 2213-1779/$36.00 https://doi.org/10.1016/j.jchf.2018.02.010

JACC: HE A RT FA ILURE V OL. 6, NO. 5, 2018 Geske et al. 365
MA Y 2 0 1 8: 3 6 4 – 75 Hypertrophic Cardiomyopathy: Clinical Update

enlargement, reduced VO2 on exercise testing (wall thinning, cavity dilation, systolic AB BR E V I A T I O N S

(<110% predicted), and hypertrophy regression with dysfunction, and secondary pulmonary hy- AN D A C R O N YM S

activity cessation (4). Regression of LVH with pertension), with poor prognosis (Online
CMR = cardiac magnetic
deconditioning has also been seen in HCM (5). LVH Ref. 10). resonance
secondary to hypertensive heart disease can also
CLINICA L MA NIFES TA TION S HCM = hypertrophic
mimic HCM, often resulting in LVH that is more cardiomyopathy

severe than athlete’s heart (6). In our experience, LGE = late gadolinium
The clinical presentation of HCM varies
hypertension is present in nearly one-half of pa- enhancement
widely. Patients may be completely asymp-
tients with HCM (7), with even greater prevalence in LVH = left ventricular
tomatic and identified incidentally. Atrial hypertrophy
other cohorts (8). In distinguishing between hyper-
fibrillation is present in nearly 1 of 5 patients
tensive heart disease and HCM, the degree of LVH LVOT = left ventricular
(13), accompanied by significant risk of stroke outflow tract
(with LVH >18 mm rarely resulting from hyperten-
(Online Ref. 11) warranting therapeutic anti- SAM = systolic anterior motion
sion alone), pattern of LVH (concentric more likely
coagulation independent of risk stratification SCD = sudden cardiac death
with hypertensive heart disease), as well as the
criteria (Online Ref. 12) (2). Symptoms of HCM VT = ventricular tachycardia
severity and duration of hypertension must be are most commonly exertional dyspnea,
considered; however, differentiating between the 2
chest pain, fatigue, and pre-syncope or syncope. Day-
entities may still present a clinical challenge.
to-day variability in symptom severity and the large
differential diagnosis may result in underrecognized
P A TH OP H Y SIOLO GY
disease or delayed diagnosis. Dyspnea is the result of
elevated left-sided filling pressures from diastolic
The presence of LVH with accompanying myofi-
dysfunction, outflow tract obstruction, mitral regur-
brillar disarray and fibrosis results in some degree of
gitation, and myocardial ischemia (Online Ref. 13).
diastolic dysfunction in virtually all HCM cases
Mechanisms of ischemia encompass increased de-
(Online Ref. 6). Diastolic dysfunction in HCM is
mand (LVH), reduction in myocardial blood supply
secondary to hemodynamic derangements, including
(LVOT obstruction, compression of intramyocardial
prolonged and nonuniform ventricular relaxation,
vasculature), abnormal vasomotor response, and
loss of ventricular suction, decreased chamber
vascular remodeling (Online Ref. 14).
compliance, and abnormal intracellular calcium up-
Large cohorts of patients with HCM have demon-
take (Online Ref. 7).
strated nearly normal life expectancy (Online Ref. 15)
Dynamic LV outflow tract (LVOT) obstruction,
with only a minority experiencing SCD. Recent data
defined as LVOT gradient $30 mm Hg (9), i s a deter-
suggest that women with HCM have worse prognosis
minant of a therapeutic approach to HCM. Approxi-
than men with HCM (7), coinciding with more
mately 70% of HCM patients have LVOT obstruction
obstructive physiology, more mitral regurgitation,
at rest or with provocation (Online Ref. 8). Narrowing
more severe diastolic dysfunction, worse pulmonary
of the LVOT, from septal hypertrophy or abnormal
hypertension, poorer cardiopulmonary exercise per-
subvalvular mitral apparatus, results in turbulent
formance than in men, and more advanced age at
flow that “drags” the redundant mitral valve into the
time of presentation (7,14).
LVOT (drag force), resulting in decreased forward
flow and systolic anterior motion (SAM)-mediated FA MILY S C RE E NIN G AND GE N E TIC S
mitral regurgitation (Online Ref. 9). Obstruction is
associated with increased cardiac morbidity and Although HCM is an inherited cardiomyopathy, the
mortality (9). However, LVOT obstruction in HCM is underlying genetic cause of disease is only found in
labile, varying with fluctuations in volume status, 34% of patients (15). All first-degree family members
autonomic nervous activity, diurnal variation, phar- of HCM patients should undergo disease screening
macotherapy, exercise, general anesthesia, conscious (2). Patients most likely to have positive genetic test
sedation, recent cardioplegia, and physical position, results are those younger than 45 years of age with
even during the course of a single diagnostic maximal wall thickness >20 mm, a family history of
assessment (10). HCM, a family history of SCD, reverse curve septal
Nonobstructive HCM generally carries a favorable morphology, and no systemic hypertension (Figure 1)
prognosis, with symptoms arising from diastolic (15). In those patients without a causative genetic
dysfunction, and large series demonstrating survival mutation (either not assessed or not identified), serial
similar to age- and sex-matched populations (11,12). echocardiographic surveillance of adult first-degree
The exception is “burned out” HCM, wherein the family members is recommended every 5 years, with
phenotype transitions to a dilated cardiomyopathy screening of children beginning at onset of puberty or
366 Geske et al. J A C C : H E A R T F A I L U R E V O L . 6 , N O. 5 , 2 0 18

Hypertrophic Cardiomyopathy: Clinical Update MA Y 2 0 1 8 : 36 4 – 75

CENTRAL ILLUSTRATION Clinical Care of Patients With HCM

Geske, J.B. et al. J Am Coll Cardiol HF. 2018;6(5):364–75.

Clinical care of patients with HCM encompasses family screening, symptom alleviation, and SCD risk stratification. Family screening entails
either genetic testing or serial echocardiographic surveillance. Symptom alleviation begins with lifestyle modifications, accompanied by
medical therapy (typically beta receptor antagonists and calcium channel antagonists). For obstructive HCM with limiting symptoms re-
fractory to medical therapies, septal reduction therapy is indicated. Selection of ASA or myectomy is patient-specific with shared decision
making. SCD risk stratification should use guideline recommendations (such as European Society of Cardiology HCM Risk-SCD Calculator
[26] and American College of Cardiology Foundation/American Heart Association risk strati fication algorithm [2]) and include shared decision
making regarding ICD insertion. ASA ¼ alcohol septal ablation; HCM ¼ hypertrophic cardiomyopathy; ICD ¼ implantable cardioverter-
defibrillator; SCD ¼ sudden cardiac death.
JACC: HE A RT FA ILURE V OL. 6, NO. 5, 2018 Geske et al. 367
MA Y 2 0 1 8: 3 6 4 – 75 Hypertrophic Cardiomyopathy: Clinical Update

F I G URE 1 Predictive Model for Positive Genetic Assessment

Clinical markers of a positive genetic test for HCM include increased wall thickness, septal morphology, family history (Hx), younger age, and
lack of systemic hypertension diagnosis (Dx). Reprinted with permission from Bos et al. (15). FH ¼ family history; HCM ¼ hypertrophic
cardiomyopathy; MLVWT ¼ maximum left ventricular wall thickness; SCD ¼ sudden cardiac death.

initiation of competitive sports and performed every for this mutation becomes the preferred method of
12 to 18 months (2). Reduced mitral annular tissue family screening.
Doppler velocities may precede development of LVH Family members who are found to have a caus-
(Online Ref. 17). Strain and strain rate imaging may ative mutation but who lack LVH present a unique
also provide incremental value in identification of clinical challenge and a major area of ongoing
subclinical HCM (Online Ref. 18). A single echocar- investigation. Expectant clinical follow-up is rec-
diographic screening evaluation for HCM is not suf- ommended, with data for SCD risk stratification and
ficient to exclude the diagnosis, given the potential competitive sports participation lacking. As cardiac
for late-onset phenotypic changes. Although HCM can imaging and perhaps biomarkers advance, subclini-
be newly diagnosed in the elderly, our approach is to cal disease in patients previously believed to be
discontinue screening surveillance within the sev- genotype-positive and phenotype-negative may
enth decade of life, after 1 or more negative echo- become apparent.
cardiographic study results, given the low yield of
screening and reassuring clinical profile of HCM of the ROLE OF IMA GIN G
elderly (Online Ref. 19).
The genetic basis of HCM is most well defined by ECHOCARDIOGRAPHY. Transthoracic echocardiog-
autosomal dominant mutations in sarcomere or raphy remains the mainstay of cardiac imaging in
sarcomere-associated proteins, in which beta- HCM. An organized assessment is essential, as out-
myosin heavy chain and myosin binding protein C lined below.
are the proteins most frequently identified (Online Demo nst r at e severit y a nd d i s t r i b ut i o n of
Ref. 16). Genetic phenocopies such as Fabry dis- LVH. LVH is the hallmark of HCM diagnosis. LVH
ease, amyloidosis, Danon disease, and Friederich’s severity plays an important role in prognostication
ataxia must also be considered (Table 1). Genetic and SCD risk assessment decision making. A step-
assessment is complex because, in addition to issues wise increase in SCD risk is associated with
such as incomplete penetrance, variable expressiv- increasing wall thickness, with a cutoff of $30 mm
ity, and incomplete or inaccurate family history as “massive” hypertrophy (Online Ref. 20). Defined
assessment, the true prevalence of de novo muta- from a long-axis view, septal morphology is catego-
tions remains unclear. The clinical role of genetic rized as sigmoid, reverse curve, neutral, or apical
testing in HCM largely centers on family screening; (Online Ref. 21). Apical HCM, once believed to be a
if a causative genetic mutation is identified, testing “benign” variant of HCM, has outcomes equivalent
368 Geske et al. J A C C : H E A R T F A I L U R E V O L . 6 , N O. 5 , 2 0 18

Hypertrophic Cardiomyopathy: Clinical Update MA Y 2 0 1 8 : 36 4 – 75

TABL E 1 Genetic and Molecular Basis of Disease for HCM and Phenocopies

Disease Gene Locus Protein Frequency (%)

Hypertrophic cardiomyopathy
HCM: myofilament mutation MYBPC3 11p11.2 Cardiac myosin-binding protein C 15–25
MYH7 14q11.2–q12 b-Myosin heavy chain 15–25
TNNI3 19p13.4 Cardiac troponin I <5
TNNT2 1q32 Cardiac troponin T <5
TPM1 15q22.1 a-Tropomyosin <5
MYL2 12q23–q24.3 Ventricular regulatory myosin light chain <2
ACTC 15q14 a-Cardiac actin <1
MYH6 14q11.2–q12 a-Myosin heavy chain <1
MYL3 3p21.2–p21.3 Ventricular essential myosin light chain <1
TNNC1 3p21.3–p14.3 Cardiac troponin C <1
TTN 2q24.3 Titin <1
HCM: Z-disc mutation LBD3 10q22.2–q23.3 LIM binding domain 3 (alias: ZASP) 1–5
ACTN2 1q42–q43 a-Actinin 2 <1
ANKRD1 10q23.33 Ankyrin repeat domain 1 (alias: CARP) <1
CSRP3 11p15.1 Muscle LIM protein <1
MYOZ2 4q26–q27 Myozenin 2 <1
TCAP 17q12–q21.1 Telethonin <1
VCL 10q22.1–q23 Vinculin/metavinculin <1
HCM: calcium-handling JPH2 20q12 Junctophilin-2 <1
PLN 6q22.1 Phospholamban <1
Hypertrophic cardiomyopathy phenocopies
Barth syndrome/left ventricular DTNA 18q12 a-Dystrobrevin –
noncompaction TAZ Xq28 Tafazzin (G4.5) –
Danon disease/Wolff-Parkinson-White LAMP2 Xq24 Lysosome-associated membrane protein 2 –
syndrome
Fabry’s disease GLA Xq22 a-Galactosidase A –
Forbes disease AGL 1p21 Amylo-1,6-glucosidase –
Friedreich’s ataxia FXN 9q13 Frataxin –
Noonan syndrome KRAS 12p12.1 v-Ki-ras2 Kirsten rat sarcoma viral oncogene –
homolog
SOS1 2p22–p21 Son of sevenless homolog 1 –
Noonan syndrome, PTPN11 12q24.1 Protein tyrosine phosphatase, non-receptor –
LEOPARD syndrome type 11, SHP-2
RAF1 3p25 V-RAF-1 murine leukemia viral oncogene –
homolog 1
Pompe disease GAA 17q25.2–q25.3 a-1,4-glucosidase deficiency –
Wolff-Parkinson-White syndrome/HCM PRKAG2 7q35–q36.36 AMP-activated protein kinase –

Adapted with permission from Ginsburg (48).

to those of other morphologies (16,17). Septal shape Characteristics of the mitral valve and subvalvular
guides the approach and type of septal reduction apparatus and mitral hemodynamics. Abnormalities of
therapy (SRT). If septal morphology or severity of the mitral valve and mitral apparatus are common
LVH is unclear, contrast-enhanced imaging should in HCM, with leaflets longer than those in control
be administered. We favor use of contrast for all patients, independent of wall thickness or mass
patients with apical HCM to assess for apical aneu- index (Online Ref. 23). Numerous papillary muscle
rysms, consistent with guidelines (2). Strain assess- abnormalities have been described (Online Ref. 24).
ment provides additional insights into myocardial In LVOT obstruction, mitral valve SAM produces a
mechanics and helps distinguish them from pheno- dynamic, eccentric, posteriorly directed jet of
copies such as cardiac amyloidosis (wherein regurgitation. Other mechanisms of regurgitation
amyloidosis presents a pattern of relatively well must also be contemplated, especially if the jet is
preserved apical strain with significant basal not posteriorly directed. Transesophageal echocar-
impairment) (Online Ref. 22). diography should be considered if the underlying
JACC: HE A RT FA ILURE V OL. 6, NO. 5, 2018 Geske et al. 369
MA Y 2 0 1 8: 3 6 4 – 75 Hypertrophic Cardiomyopathy: Clinical Update

mechanism is unclear (2), because intrinsic mitral

F I G URE 2 Stepwise Approach to Defining Obstructive Physiology
pathology may alter the therapeutic approach. Our
experience is that mitral valve interventions are
infrequently required during myectomy (<4%) (18),
although in some cohorts, concomitant mitral valve
procedures are more common (Online Ref. 25).
Assess for obstruction, including with provocation. The dy-
namic nature of LVOT obstruction in HCM adds
complexity to imaging assessment. A systematic
approach to provocation should be used (Figure 2). All
maneuvers may be required to provoke dynamic
obstruction in symptomatic patients (19). Maximum
instantaneous LVOT gradient at echocardiography
has excellent correlation with peak-to-peak gradient
assessment at cardiac catheterization (Online
Ref. 26). Obstruction can occur at the midventricular
level or with multiple levels of obstruction (Online Although a gradient of 30 mm Hg constitutes the presence of obstruction, a gradient of
50 mm Hg (severe obstruction) is used as the cutoff for this decision-making algorithm.
Ref. 27), including in series with fixed valvular
If a gradient of 50 mm Hg is not present at rest, a Valsalva maneuver is performed. At
obstruction (Online Ref. 28).
Mayo Clinic, the next assessment is amyl nitrite inhalation. If clinical evaluation there-
E v a l ua t e di a s t o l i c d y s f u n c t i o n. Conventional
after suggests obstructive symptoms despite absence of obstruction on initial as-
echocardiographic measurements of diastolic func- sessments, then exercise and/or isoproterenol administration during comprehensive
tion, such as E/e0 ratio and left atrial volume index, hemodynamic catheterization is warranted.

exhibit wide scatter in their relationship to invasively

assessed left atrial pressures, such that it is not
possible to accurately predict filling pressures for any
given individual (Online Refs. 7,29). Consequences of CMR is performed by direct tracing of myocardial
diastolic dysfunction, such as pulmonary hyperten- borders and is not reliant upon the geometric as-
sion, are associated with worse survival (20). Char- sumptions used in echocardiography. Although
acterization of diastolic strain, including quantitation contrast echocardiography can detect apical aneu-
of untwist, may provide further insight into abnor- rysms, which increase risk of ventricular arrhythmias
malities of diastolic filling in HCM (Online Ref. 30). and intracardiac thrombus (Online Ref. 31), CMR
CARDIAC CMR. It is our practice that all patients with provides better identification (17).
suspected or known HCM undergo at least 1 CMR Perhaps the greatest additive value of CMR for
procedure, given its multifaceted role in diagnosis, HCM is tissue characterization. Sequences such as
risk stratification, and treatment (Figure 3) (21). myocardial nulling and T2* assessment help exclude
Cardiac magnetic resonance offers distinct advan- phenocopies such as cardiac amyloidosis and hemo-
tages over echocardiography, with superior spatial chromatosis. LGE sequences provide in vivo defini-
resolution and accurate volumetric assessment of all tion of myocardial fibrosis (23). However, this
cardiac chambers. Furthermore, images are indepen- relationship is complex, as LGE is not a specific
dent of body habitus, chest wall geometry, and pul- finding for HCM, it does not detect diffuse interstitial
monary parenchymal disease, which limit expansion, and presence of LGE may represent het-
echocardiographic acoustic windows. Notably, image erogeneous amounts of fibrosis (not just replacement
quality in CMR is dependent upon cardiac and respi- fibrosis) (Online Ref. 32). Extensive LGE portends an
ratory gating, with need for prolonged breath hold for adverse prognosis in HCM, with multiple studies
some image sequences. Lack of portability, cost, and demonstrating correlations with increased wall
patient accessibility may limit its use. Gadolinium- thickness, exercise test evidence of ischemia, reduc-
based contrast, necessary for LGE, is contraindicated tion in ejection fraction, nonsustained ventricular
in renal failure, given the risk of nephrogenic sys- tachycardia (VT), and mortality (Online Ref. 33)
temic fibrosis. (23,24). Prevalence of LGE is as high as 80% in HCM
Differences exist in measurements of maximal LVH (Online Ref. 34). In a large, multicenter, international
between echocardiography and CMR (22). This prospective study, quantitation of $15% LGE (visual
discordance may relate to multiplanar reformatting or quantification by a single author) demonstrated a 2-
inherent differences between the modalities, with fold increase in SCD events and enhanced SCD event
uncertain clinical impact. Calculation of LV mass by risk modeling (24). Although multiple methods have
370 Geske et al. J A C C : H E A R T F A I L U R E V O L . 6 , N O. 5 , 2 0 18

Hypertrophic Cardiomyopathy: Clinical Update MA Y 2 0 1 8 : 36 4 – 75

FIG URE 3 Clinical Utility of CMR in HCM

CMR augments diagnosis of HCM by differentiating from phenocopies and allowing visualization of anatomy obscured from echocar diography.
Clinical decision making in SCD risk stratification and management, including SRT, can be influenced by anatomy and tissue characterization.
Adapted with permission from Maron and Maron (21). CMR ¼ cardiac magnetic resonance; LGE ¼ late gadolinium enhancement; LVH ¼ left
ventricular hypertrophy; SRT ¼ septal reduction therapy; other abbreviations as in Figure 1.

been proposed to measure LGE, quantitation remains corresponding to rates of SCD of w10%/year (Online
challenging given heterogenous patterns and signal Refs. 38,39). Implantable cardioverter-defibrillator
intensity. Furthermore, LGE images depend on the (ICD) insertion for secondary prevention carries a
specific CMR device vendor, imaging technique, type Class I indication in the American College of Cardi-
and volume of contrast, time of acquisition after in- ology Foundation (ACCF)/American Heart Associa-
jection, and reliability of the inversion time. tion (AHA) guidelines and a similarly strong
T1 mapping is a CMR technique whereby the value recommendation in European Society of Cardiology
of native and post-contrast T1 relaxation can be (ESC) guidelines (2,3). Risk stratification for primary
quantified and potentially used to assess myocardial prevention is more complex, with some variability
fibrosis. T1 mapping shows promise in discriminating between guidelines.
HCM from athlete’s heart and hypertensive heart
FAMILY HISTORY OF SCD. Although definitions of a
disease (Online Refs. 35,36) and holds promise for
positive family history vary, there is clear recognition
SCD risk assessment in the future.
that SCD events in first-degree family members impart
SU D D EN CA R DIA C DEATH increased risk of SCD (Online Refs. 40,41) (26). Because
RISK S TR A TIFIC A TION of the familial clustering of risk, family history is given
a Class IIa recommendation for ICD insertion in ACCF/
Although SCD is infrequent in HCM (w1% per year), AHA guidelines and is included in the HCM Risk-SCD
it is a devastating complication, and risk stratifica- Calculator (European Society of Cardiology website)
tion is actively being refined (Online Ref. 37) (2). SCD (2,3,26). One proposed mechanism is that of high-risk
results from ventricular arrhythmias caused by genetic mutations, although studies attempting to
autonomic overactivity secondary to LVOT obstruc- correlate “malignant” mutations with SCD have shown
tion, microvascular ischemia, myocardial fibrosis, mixed results, thereby rendering mutation-specific
and myocyte disarray (Figure 4) (25). The greatest risk with little clinical utility (27,28). Because under-
risk factor for SCD is a personal history of cardiac standing of the genetic basis of HCM continues to
arrest, ventricular fibrillation, or sustained VT, evolve, this may warrant reassessment.
JACC: HE A RT FA ILURE V OL. 6, NO. 5, 2018 Geske et al. 371
MA Y 2 0 1 8: 3 6 4 – 75 Hypertrophic Cardiomyopathy: Clinical Update

SYNCOPE AND LVOT OBSTRUCTION. Syncope and

F I G URE 4 Cause of Ventricular Arrhythmia in HCM
pre-syncope occur in 1 of 4 HCM patients, with
mechanisms including supraventricular arrhythmia,
sinus node dysfunction, complete heart block, ven-
tricular arrhythmia, LVOT obstruction, inappropriate
vasodilation, volume depletion, and diastolic dysfunction-
mediated hypotension (Online Ref. 42). Unexplained, non-
neurocardiogenic syncope, partic- ularly if recent
(<6 months), corresponds to an
increased risk of SCD (Online Ref. 43) (26). Both
ACCF/AHA guidelines (Class IIa) and ESC guidelines
include unexplained syncope in ICD decision making.
LVOT obstruction has been linked to SCD (Online
Ref. 44) and is a component of the HCM Risk-SCD
Calculator (26); however, our practice is to minimize
the contribution of this factor to ICD decision making,
given the marked lability of LVOT obstruction (Online
Ref. 45) (10). The combination of abnormal cellular substrate, ischemia, ventricular anatomy, hemo-
dynamics, known rhythm disturbances, and family history contribute to ventricular
WALL THICKNESS AND LGE. Severity of LVH corre-
arrhythmogenesis. Patients with history of cardiac arrest are at highest risk for future
sponds to increased risk (Online Refs. 20,46) with
cardiac arrest. Massive hypertrophy, family history of SCD, and unexplained syncope are
massive hypertrophy portending sufficient risk to risk factors more heavily weighted by American College of Cardiology Foundation/
warrant a Class IIa recommendation for ICD insertion American Heart Association guidelines, with other risk factors contributing to overall risk

in ACCF/AHA guidelines (2). However, a binary cutoff stratification. Adapted with permission from Ommen and Gersh (25). LA ¼ left atrium;

for decision making ignores the stepwise increase in LV ¼ left ventricular hypertrophy; LVOT ¼ LV outflow tract; VT ¼ ventricular tachy-
cardia; other abbreviations as in Figure 1.
risk of gradations of LVH. Use of LVH as a continuous
variable within the HCM Risk-SCD Calculator likely
provides a more inclusive assessment of risk in this
regard (26). Extent of LGE correlates with wall thick- fall in systemic vascular resistance, which may result
ness, although remains an independent risk prog- from autonomic dysfunction and dynamic obstruc-
nosticator (24). Currently neither ACCF/AHA tion (Online Ref. 40). In younger patients, an
guidelines nor the HCM Risk-SCD Calculator incor- abnormal blood pressure response to exercise corre-
porate LGE (2,26). sponds to increased SCD risk (Online Ref. 50).
NONSUSTAINED VT. Incidence of nonsustained VT Left atrial size serves as a barometer of chronic
has been reported in 20% to 46% of HCM patients elevation in left atrial pressure, the sum total of
(Online Refs. 38,39). Nonsustained VT portends abnormal diastolic function, mitral regurgitation, and
increased risk of SCD (Online Refs. 47,48) (26); how- atrial arrhythmias (Online Ref. 29). Left atrial
ever, given its high frequency is not sufficient to enlargement has been associated with adverse out-
warrant ICD insertion in isolation (2,3). Moreover, comes and increased SCD risk (Online Refs. 43,51)
robust data regarding the impact of rate and duration (26). However, recent data would suggest atrial
on risk are lacking. fibrillation is not a risk factor for SCD (30).
Ventricular apical aneurysms have been correlated
OTHER RISK FACTORS. Although SCD can occur at
with an increased risk of SCD in some series (Online
any age, elderly patients with HCM have “weathered
Ref. 52) (17) and may warrant targeted therapies
the test of time” and generally have a benign clinical
(Online Ref. 53).
course (29). This observation may also reflect selec-
tion bias, wherein hypertensive heart disease of the SUMMATIVE APPROACH TO SCD RIS K
elderly is labeled as HCM, as opposed to a more pure STRATIFICATION. Patients with HCM and prior car-
form of HCM in the young. Patients with HCM iden- diac arrest should undergo ICD insertion unless it is
tified at young age may carry higher SCD risk and contrary to goals of care. For primary prevention, one
have greater potential for altered prognosis from accessible approach to risk stratification is the HCM
aborted VT (Online Ref. 43) (26). Risk-SCD Calculator that incorporates age, extent of
Abnormal blood pressure response to exercise oc- LVH, left atrium size, LVOT gradient, family history
curs in more than 1 of 3 of HCM patients (Online of SCD, nonsustained VT, and unexplained syncope
Ref. 49). The mechanism relates to an exaggerated to predict 5-year SCD risk (26). The HCM Risk-SCD
372 Geske et al. J A C C : H E A R T F A I L U R E V O L . 6 , N O. 5 , 2 0 18

Hypertrophic Cardiomyopathy: Clinical Update MA Y 2 0 1 8 : 36 4 – 75

F I G URE 5 Comparison of Septal Reduction Therapies

Selection of SRT must be individualized, with consideration of patient demographics, anatomy, coexistent structural heart disease, institu-
tional experience, and decision making shared with the patient. Adapted with permission from Gersh and Nishimura (41). Abbreviations as in
Figure 1.

Calculator is not designed for use in pediatric patients (31). There are ongoing prospective studies for
or competitive athletes, nor has it been as well stud- further evaluation (LIVE-HCM [Exercise in Genetic
ied following SRT. ACCF/AHA guidelines more Cardiovascular Conditions]; NCT02549664; and RESET-
heavily emphasize risk associated with massive hy- HCM [Study of Exercise Training in Hyper- trophic
pertrophy, unexplained syncope, and family history Cardiomyopathy]; NCT01127061). Participa- tion in
of SCD, providing a Class IIa recommendation for ICD competitive sports is discouraged by guidelines (2),
insertion in these patients (2). Even with these although recent data are available to support
guidelines, clinical judgment remains paramount. individualized decision making regarding sports
Following comprehensive risk stratification, de- participation (32). Beyond exercise, avoid- ance of
cisions regarding ICD insertion should occur in the excess alcohol or stimulant consumption, dehydration,
setting of shared decision making, with the knowl- and temperature extremes (e.g., saunas and hot
edge that ICD insertion is the only therapy known to tubs) are recommended. Use of phosphodiesterase
prolong life in HCM (Online Ref. 54). The availability inhibitors for erectile dysfunc- tion may result in
of subcutaneous defibrillators virtually eliminates hemodynamic instability in the setting of LVOT
lead-associated cardiac complications in patients obstruction, and therefore cautionis advised.
without anticipated pacing need.
PHARMACOLOGI CAL THERAPIES. The goal of medi-
TRE A TME N T OF SY MP TOMS cal therapies in HCM is symptom reduction, with no
clear role for medical therapies in asymptomatic pa-
LIFESTYLE ADJUSTMENT. Regardless of symptom tients outside of treatment of comorbidities inde-
status, lifestyle optimization is recommended at pendent of HCM (hypertension, obesity, and other
HCM diagnosis. Patient education is fundamental to factors) (2). Pharmacotherapies in HCM are largely
treatment, as there are often misconceptions. Cur- directed at reducing LVOT obstruction.
rent ACCF/AHA guideline recommendations Initial assessment should include re-evaluation of
encourage low-intensity aerobic activities to achieve medications that worsen dynamic LVOT obstruction,
and maintain cardiovascular fitness (2). Recent data including digitalis, vasodilators, and diuretics. Beta-
support moderate intensity exercise, although study receptor antagonists are the mainstay of therapy;
size was insufficiently powered to evaluate safety
JACC: HE A RT FA ILURE V OL. 6, NO. 5, 2018 Geske et al. 373
MA Y 2 0 1 8: 3 6 4 – 75 Hypertrophic Cardiomyopathy: Clinical Update

negative inotropy reduces dynamic LVOT obstruc- isolated to the LVOT, transaortic septal myectomy
tion, whereas negative chronotropy prolongs diastole alone may be sufficient. In more complex obstruction,
(which may improve filling hemodynamics) and transapical myectomy or combined transaortic and
blunts adrenergic mediated tachycardia (2). In con- transapical myectomy may be necessary to relieve
cert, these effects minimize ischemic supply–demand obstruction (Online Ref. 66). The role of mitral valve
mismatch. Nondihydropyridine calcium receptor an- surgery accompanying myectomy remains contro-
tagonists are an alternative to beta receptor antago- versial, with some practitioners advocating in-
nists if there are unacceptable side effects or terventions when a lesser degree of hypertrophy is
inadequate symptom relief. Concomitant calcium and present, whereas we favor avoiding mitral valve in-
beta receptor antagonists may be administered, terventions when possible (18,34,35).
although this increases risk of high-grade atrioven- ASA is a newer technique than myectomy, first
tricular block and sinus node dysfunction. Dis- performed in 1994 (Online Ref. 65), with favorable
opyramide, a Class Ia antiarrhythmic with negative intermediate-term prognosis (36,37). Alcohol is
inotropic effects, can be used alone or in conjunction injected antegrade into the septal perforator coronary
with other therapies (Online Ref. 55); we favor the arteries, creating a targeted septal myocardial infarct.
latter. Initiation of disopyramide requires hospitali- Angiographic and echocardiographic intracoronary
zation to monitor proarrhythmic effects. In our contrast dye injections are used to identify adequate
experience, disopyramide often results in significant septal perforators and the supplied myocardium
anticholinergic side effects, and patients have expe- (Online Ref. 67). Smaller volumes of alcohol and
rienced drug access issues. Other therapeutic agents slower injections may reduce the incidence of post-
for HCM are being explored. The role of perhexiline, a procedure heart block (Online Ref. 68). Given the
weak calcium channel antagonist with potent inhibi- rapid development of ASA, the lack of randomized
tion of carnitine palmitoyltransferase-1 and anti- controlled trials, and the established role of myec-
inflammatory properties, remains poorly defined in tomy, there remains considerable debate as to who is
HCM (Online Ref. 56). There are ongoing in- best served by ASA (38,39).
vestigations of medical therapies that may reduce Comparison of ASA and myectomy is challenging
LVH (such as aldosterone receptor blockers) (33), given lack of feasibility for a randomized controlled
although no clinical role is yet established in HCM. trial (Online Ref. 69); therefore, highest levels of evi-
INVASIVE THERAPIES. Dual-chamber pacing with dence are currently single-center cohort studies, meta-
optimized atrioventricular delay reduces LVOT analyses, and registry experiences (Figure 5) (40,41).
obstruction in some HCM patients (Online Operative risk of sternotomy and cardiopul- monary
Refs. 57,58). Right ventricular apical pacing likely al- bypass may be prohibitive for septal myec- tomy.
ters septal activation, changing the LVOT configura- Similarly, septal perforator anatomy and coronary
tion during systole. Reductions in LVOT gradient artery disease may preclude ASA. Myectomy
through pacing are only modest, and accurate pre- consistently results in more gradient reduction than
dictors of therapeutic response are unclear (Online ASA (Online Ref. 70). Coexistent primary valvular
Ref. 59). Although initial studies were promising, disease (including mitral valve disease other than
subsequent randomized controlled data suggest a SAM), multiple levels of obstruction, and other
significant placebo effect with long-lasting results structural heart disease mandate surgical myectomy.
seen only in a minority of patients (Online Myectomy is more efficacious in younger patients
Refs. 60,61). Therefore, SRT remains the treatment (<65 years of age) (Online Ref. 71) with higher resting
of choice for obstructive HCM with symptoms not gradients (42) and those with greater septal thickness
adequately relieved by medical therapy. (>18 mm) (42). In experienced centers, intermediate-
Septal myectomy is the most well-established term mortality following ASA is comparable to that
invasive therapy in HCM, pioneered in the 1950s after myectomy (Online Refs. 70,72) (42), but data for
(Online Refs. 62,63). Myectomy results in long-term long-term results (>10 years) are less certain. Concern
symptomatic benefit and is the gold standard of SRT has been raised for increased arrhythmogenic risk
according to ACCF/AHA guidelines (2), whereas ESC related to post-ASA scar (Online Refs. 73,74). Recent
guidelines provide equivalent recommendations to series suggest that rates of SCD after ASA, although
alcohol septal ablation (ASA) (3). Surgical technique statistically higher, are low overall (39,43–45). The
has evolved to an extended septal myectomy, need for permanent pacemaker implantation post-
wherein the initial incision is continued leftward to- SRT is dependent upon pre-existing conduction disease;
ward the mitral apparatus and apically toward the ASA frequently results in right bundle branch block,
papillary muscles (Online Ref. 65). If obstruction is whereas myectomy creates a left bundle branch
374 Geske et al. J A C C : H E A R T F A I L U R E V O L . 6 , N O. 5 , 2 0 18

Hypertrophic Cardiomyopathy: Clinical Update MA Y 2 0 1 8 : 36 4 – 75

block. Procedural risk and shared decision making define the disease in some patients, many others with
with informed patient preferences should be pursued. phenotypic manifestation are left without identified
Institutional experience is a critical driver of out- genetic mechanisms. This remains an area of intense
comes for SRT (2,46). Myectomy mortality rates in investigation. With the rapid pace of technological
less experienced centers are as high as 14% (Online change and the use of other models, such as human
Ref. 75), whereas in centers with experienced staff, induced pluripotent stem cells (Online Ref. 80), we
the risk of death is well below 1%, accompanied by remain hopeful for significant future breakthroughs.
excellent reduction of LVOT gradient, symptomatic Much is known about the impact of treatment of
improvement, and long-term post-operative survival symptoms and prevention of adverse outcomes in
similar to that in the general population (Online patients with established disease; however, there are
Ref. 76). Similarly, operator experience affects out- a striking lack of data for interventions for early onset
comes in ASA (42), and institutional experience must disease. As diagnostic techniques become more sen-
be considered during decision making. sitive for HCM, there is a need for therapies to pre-
NOVEL PROCEDURAL APPROACHES. In severely vent disease progression or promote regression of
symptomatic patients with HCM, small LV cavity, hypertrophy.
and nonobstructive physiology, apical myectomy to Given the genotypic and phenotypic diversity
enlarge the LV improves symptoms for patients who within HCM, defining discrete populations for study
would otherwise be relegated to cardiac trans- is necessary. As patient cohorts with adverse prog-
plantation (Online Refs. 77,78). Resection of apical nosis are identified, clinical practice must tailor
aneurysms or apical pouch radiofrequency ablation treatment of high-risk patient subsets. Continued
may provide dramatic relief of recurrent ventricular study of long-term outcomes of SRT is needed to
arrhythmia (Online Refs. 52,53,79). Percutaneous inform decision making and selection of SRT
mitral valve repair to limit SAM is a novel approach approach. Beyond this, novel percutaneous ap-
to treating LVOT obstruction in drug-refractory pa- proaches to improve hemodynamics require further
tients with obstructive HCM who are not candidates study. Further refinement of SCD risk stratification
for SRT (47). Such percutaneous techniques may and unifying practice guideline updates to reflect
alter the landscape of interventional therapy for interim advances in risk assessment remain
HCM. paramount.

FU TU RE DIR E C TION S
ADDRESS FOR CORRESPONDENCE: Dr. Jeffrey B.
There remain large gaps in understanding of the ge- Geske, Department of Cardiovascular Diseases, Mayo
netic underpinning of HCM. Although genes encoding Clinic, 200 First Street SW, Rochester, Minnesota 55905.
sarcomere and sarcomere-associated proteins do E-mail: [email protected].

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