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Hypertrophic cardiomyopathy: Natural history and prognosis

Author: Martin S Maron, MD

Section Editor: William J McKenna, MD
Deputy Editor: Brian C Downey, MD, FACC

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2018. | This topic last updated: Feb 21, 2018.

INTRODUCTION — Hypertrophic cardiomyopathy (HCM) is a genetically determined heart muscle disease caused by mutations in one
of several sarcomere genes which encode components of the contractile apparatus. (See "Hypertrophic cardiomyopathy: Gene
mutations and clinical genetic testing".)

HCM is characterized by an enormous diversity in both phenotypic expression and clinical course (figure 1). The location, pattern, and
extent of left ventricular hypertrophy (LVH) are heterogeneous, although the most common location for increased wall thickness is the
basal anterior septum in continuity with the anterior free wall. HCM patients can develop one or more of the following morphologic
abnormalities:

● LV outflow tract obstruction (see "Hypertrophic cardiomyopathy: Morphologic variants and the pathophysiology of left ventricular
outflow tract obstruction")

● Diastolic dysfunction

● Myocardial ischemia

● Mitral regurgitation

● Systolic dysfunction (ie, end-stage; ejection fraction <50 percent)

These structural and functional abnormalities can produce a variety of symptoms, including:

● Fatigue

● Dyspnea

● Chest pain

● Palpitations

● Presyncope or syncope

In broad terms, the symptoms related to HCM can be categorized as those related to heart failure (HF), chest pain, or arrhythmias.
Patients with HCM have an increased incidence of both supraventricular and ventricular arrhythmias and are at an increased risk for
sudden cardiac death (SCD). (See "Hypertrophic cardiomyopathy: Prevalence, pathophysiology, and management of concurrent atrial
arrhythmias" and "Hypertrophic cardiomyopathy: Assessment and management of ventricular arrhythmias and sudden cardiac death
risk".)

For the majority of patients with HCM, LVH is not progressive, and the clinical course is relatively benign. A small subset of patients,
however, will progress to an end-stage form of the disease that is characterized by systolic dysfunction with other adverse LV
remodeling such as LV dilation and wall thinning present in some end-stage patients as well. Such patients are managed according to
the standard approach to patients with HF due to systolic dysfunction. (See "Overview of the therapy of heart failure with reduced
ejection fraction".)

The natural history of HCM will be reviewed here. Other issues such as the clinical manifestations, diagnosis and evaluation, and
treatment of this disorder are discussed separately. (See "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and
evaluation" and "Hypertrophic cardiomyopathy: Medical therapy" and "Hypertrophic cardiomyopathy: Nonpharmacologic treatment of
left ventricular outflow tract obstruction".)

DEVELOPMENT OF HYPERTROPHY

Hypertrophy and fibrosis — HCM can present in infancy and childhood, but more commonly left ventricular hypertrophy (LVH) develops
during the adolescent period [1]. In the majority of HCM patients, LV wall thickness measurements do not typically change once early
adulthood is reached. However, progressive wall thinning may occur in patients with initially severe hypertrophy. In a series of 106
patients with initial wall thickness ≥30 mm, more than 5 mm of wall thinning was seen in 41 of the 71 patients who underwent serial
assessment (58 percent); the duration of follow-up was a significant predictor of thinning [2].
A multitude of pathologic studies in children and young adults with HCM who died suddenly demonstrated that increased wall
thickness is due to myocyte hypertrophy and an expanded extracellular matrix composed of interstitial and replacement fibrosis. [3].
The mechanisms leading to increased collagen matrix in HCM are not well defined but may be mediated by angiotensin II, an
observation supported by studies using genetic mouse models of HCM in which increased interstitial fibrosis was attenuated by an
angiotensin II receptor blocker [4]. (See "Hypertrophic cardiomyopathy: Gene mutations and clinical genetic testing", section on 'Renin-
angiotensin system polymorphisms'.)

The amount and distribution of hypertrophy in patients with HCM may be related to the underlying genetic mutation. In a study
comparing 150 patients with one of the more commonly seen thick filament mutations (eg, myosin heavy chain, myosin binding protein
C) with 80 patients with one of the rarer thin filament mutations (eg, troponin T or I, alpha-tropomyosin, cardiac actin), patients with a
thin filament mutation had significantly less hypertrophy, which was more often in an atypical location (ie, not the basal septum/anterior
wall), and were less likely to have LV outflow tract obstruction [5]. While there was no difference in rate of ventricular arrhythmias or
sudden cardiac death depending on the mutation in this study, patients with a thin filament mutation were more likely to develop severe
heart failure (HF) symptoms. (See "Hypertrophic cardiomyopathy: Gene mutations and clinical genetic testing", section on 'Mutations in
sarcomeric protein genes'.)

A separate study has also shown evidence that serum markers of myocardial fibrosis may be present in HCM family members who
carry a disease causing mutation but no LVH (genotype positive/phenotype negative). Levels of serum C-terminal propeptide of type I
procollagen (PICP) were significantly higher in mutation carriers without LV as compared with controls (31 percent higher). It remains
unresolved whether increases in serum markers of collagen turnover reflect a true increase in myocardial fibrosis in genotype positive
phenotype negative patients. (See "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation", section on
'Cardiovascular magnetic resonance'.)

The presence of late gadolinium enhancement (LGE) on contrast-enhanced cardiac magnetic resonance (CMR) imaging represents
myocardial fibrosis. In one systemic review of LGE in patients with HCM, which included 1063 patients from four cohorts, 60 percent of
patients had LGE [6]. While the numbers of events were small, those patients with LGE had significantly higher total mortality (odds ratio
[OR] 4.5; 95% CI 1.5-13.0), cardiac mortality (OR 2.9; 95% CI 1.0-8.4), and HF mortality (OR 5.7; 95% CI 1.0-31.1) compared with patients
without LGE. The role of CMR in patients with HCM is discussed in detail separately. (See "Hypertrophic cardiomyopathy: Clinical
manifestations, diagnosis, and evaluation", section on 'Cardiovascular magnetic resonance'.)

Late onset disease — Although most HCM disease expression develops during childhood and adolescence, late-onset disease is
recognized (ie, LVH developing between ages 20 and 50 years) and was first noted in patients with mutations in cardiac myosin binding
protein-C. Most cross-sectional studies of families with mutations in the cardiac myosin binding protein-C gene, which account for
approximately 15 percent of cases of familial HCM, have shown that the proportion of proven carriers of the mutation who have
hypertrophy increases with age [7-10].

In one cross-sectional study of 16 probands and 574 family members at risk, 58 percent of patients aged less than 50 years with a
mutation in the cardiac myosin binding protein C gene had hypertrophy [8]. However, a later age at onset with cardiac myosin binding
protein-C gene mutations has not been noted in all series [11,12]. (See "Hypertrophic cardiomyopathy: Gene mutations and clinical
genetic testing", section on 'Cardiac myosin binding protein-C gene'.)

In contrast to familial early-onset HCM (which results from defects in the beta myosin heavy chain, cardiac troponin T, and alpha
tropomyosin genes in more than 45 percent of cases), elderly-onset HCM is in some series associated with mutations in the cardiac
myosin binding protein-C, troponin I, and alpha myosin heavy chain genes [10]. In addition, the likelihood of identifying any mutation
may be lower in late onset HCM [13].

Additionally, HCM patients who are identified late in life (age >60 years) are at low risk for HCM-related death or adverse events
compared with early-onset disease. Within one cohort of 428 patients presenting at age 60 years or greater who were followed for an
average of six years, 89 percent of the deaths (133 out of 149) were non-HCM related, with HCM-related mortality of only 0.6 percent
per year [14]. In addition, a substantial proportion of elderly HCM patients also had ≥1 conventional risk factors for sudden death. (See
"Hypertrophic cardiomyopathy: Morphologic variants and the pathophysiology of left ventricular outflow tract obstruction", section on
'Obstructive HCM in elderly adults'.)

In a small subset of patients, sigmoid septal morphology (with maximal LV wall thickness ≥15 mm) is part of the phenotypic spectrum
of HCM. A sigmoid shaped basal septum can also be observed in elderly individuals without HCM, but in these cases the maximal wall
thickness of the septum is normal. Among HCM patients, this morphologic subtype appears to be less commonly associated with a
mutation than other morphologic variants. (See "Hypertrophic cardiomyopathy: Morphologic variants and the pathophysiology of left
ventricular outflow tract obstruction", section on 'Sigmoid septal morphology'.)

Relation to restrictive cardiomyopathy — Restrictive cardiomyopathy is characterized by restrictive filling and reduced diastolic volume
of the left and/or right ventricle despite normal or near-normal systolic function and wall thickness [15]. Primary forms are uncommon,
while secondary forms usually present at the advanced stage of an infiltrative disease (sarcoidosis, amyloidosis) or a systemic storage
disease (eg, hemochromatosis). Idiopathic restrictive cardiomyopathy is uncommon, and may be familial and present in children and
young adults. (See "Idiopathic restrictive cardiomyopathy".)

Several observations suggest that idiopathic restrictive cardiomyopathy may be part of the spectrum of familial HCM:
 ● Some cases of restrictive cardiomyopathy have extensive myocyte and myofibrillar disarray at explant or postmortem, findings
similar to those seen in HCM [16,17].

● Some patients with primary restrictive cardiomyopathy have a family history of HCM, and mutations in sarcomeric contractile
protein genes can lead to restrictive and/or HCM within the same family [16-18].

The frequency and clinical significance of this relationship was illustrated in 1226 patients from 688 consecutive HCM families [16]. A
restrictive phenotype was seen in 19 patients (1.5 percent) and was associated with a relatively poor prognosis, with a 44 percent rate
of death, heart transplantation, or implantable cardioverter-defibrillator discharge. Genotyping was feasible in 15 of 16 probands:
mutations were found in eight, four in the beta-myosin heavy chain gene and four in the cardiac troponin I gene. A troponin I mutation
has also been identified in six of nine unrelated individuals transplanted for idiopathic restrictive cardiomyopathy [18]. (See
"Hypertrophic cardiomyopathy: Gene mutations and clinical genetic testing".)

End-stage HCM — A small proportion of patients with HCM (<5 to 7 percent) eventually progress to a stage of disease associated with
adverse LV remodeling with reduced systolic performance (EF <50 percent). In some patients, there is cavity dilation and wall thinning
due to a process of extensive myocardial fibrosis, as demonstrated by histologic examination in hearts removed at time of heart
transplant and on cardiac magnetic resonance imaging with extensive late gadolinium enhancement (figure 2) [2,19-24]. Not all patients
in the end stage will demonstrate cavity dilation or wall thinning, and therefore the unifying definition is considered when a patient
achieves an EF <50 percent.

This phase has been termed "end-stage" or "burned out" HCM. The mechanism is uncertain, but diffuse myocardial ischemia due to
microvascular dysfunction leading to a process of substantial cell death and repair process in the form of myocardial replacement
fibrosis may be important [24,25]. Among a cohort of 30 patients with end-stage HCM who underwent transplantation, histologic review
of the explanted heart revealed extensive myocardial fibrosis averaging 37 percent of the total myocardium [24]. The degree of
microvascular dysfunction assessed by quantitative PET imaging is an independent predictor of clinical deterioration and death [26].
End-stage HCM is associated with a high mortality rate and overall poor prognosis [23,27].

The frequency of progression to a dilated, hypokinetic phenotype was evaluated in a series of 222 patients with HCM who were
prospectively followed for a mean of 11 years [22]. The following findings were noted:

● Eleven patients (5 percent) had a dilated, hypokinetic phenotype at initial evaluation. These patients had a left ventricular ejection
fraction (LVEF) of 32 percent compared with 66 percent in those with typical HCM phenotype.

● Among the 210 patients with a typical phenotype of HCM at initial evaluation, 12 (5.7 percent) progressed to a dilated, hypokinetic
evolution, characterized in part by a decrease in LVEF from 67 percent at initial assessment to 35 percent at last evaluation. The
rate of decline in EF was approximately 0.5 percent per year. These patients, compared with those with HCM and preserved LV
function, were younger and more likely to have had a family history of HCM (61 versus 26 percent) or sudden death (43 versus 19
percent) and had a greater wall thickness at presentation. During follow-up, they had a significantly lower rate of cardiovascular
death-free survival.

The characteristics of end-stage HCM were further evaluated in a retrospective analysis combining three cohorts that included a total
of 1259 patients [23]. End-stage HCM was defined as an LVEF <50 percent. The following findings were noted:

● 44 patients (3.5 percent) were classified as end-stage. Of these, 11 were diagnosed at study entry and 33 during follow-up, with an
annual incidence of 1.1 cases per 100 person-years. The mean age at diagnosis of end-stage was 45 years, but there was a very
wide range (14 to 74 years).

● In patients with LVEF <50 percent, LV remodeling and cavity dilation were common (52 percent).

● The average duration from the onset of HCM symptoms to end-stage HCM was 14 years.

● Once end-stage HCM developed, further deterioration was rapid, and 66 percent of patients progressed to death from progressive
HF, sudden cardiac death, or transplantation over a mean of 2.7 years. Sudden cardiac death occurred at a rate of 11 percent per
year and, among patients awaiting transplant, the incidence of appropriate ICD shocks was 10 percent per year.

● At the time of initial evaluation, the only reliable predictor of end-stage HCM was a family history of end-stage HCM.

Although uncommon, the transition to end-stage HCM represents an ominous change. Early detection of LV dysfunction and/or dilation
should prompt consideration of more aggressive interventions, including standard drug treatment for systolic HF (eg, angiotensin
converting enzyme or aldosterone inhibitors), possibly biventricular pacing, and early consideration for heart transplantation, although
there are little if any data other than expert opinion regarding the efficacy of standard HF drug therapies. In addition, the role of
biventricular pacing in patients with HCM and systolic dysfunction does not appear particularly favorable as a number of small studies
have failed to demonstrate improvements in ejection fraction, HF symptoms, or a decrease in the need for advanced HF therapies
including cardiac transplantation.

● From the Mayo Clinic cohort of 2073 patients with HCM, nine patients were identified with HCM and LVEF <50 percent who had
received cardiac resynchronization therapy (CRT); these patients were matched with control subjects with HCM in a 1:1 fashion
[28]. Over a mean follow-up of 13 years, there was no significant difference in outcomes between the two groups, with five patients
from the CRT group and two from the control group requiring LV assist devices (LVADs) or cardiac transplantation.
 ● Among an Italian cohort of 61 patients with end-stage HCM, 13 underwent CRT (mean age at CRT 49 years, 12 patients with left
bundle branch block, 8 patients with NYHA class II symptoms, 5 with NYHA class III/IV symptoms) [29]. One year following CRT, 7
of the 13 patients had ≥1 NYHA functional class improvement, while the others had no improvement or worsening of symptoms.
Following an average of 5.2 years, there was no significant improvement in symptoms compared with baseline.

Due to the increased risk of ventricular tachycardia noted in end-stage HCM patients, prophylactic ICD implantation for primary
prevention of sudden death should be considered. (See "Overview of the therapy of heart failure with reduced ejection fraction" and
"Indications and contraindications for cardiac transplantation in adults" and "Secondary prevention of sudden cardiac death in heart
failure and cardiomyopathy".)

Phenocopies of sarcomeric HCM — Increased LV wall thickness in a pattern similar to that observed in sarcomeric HCM has also been
observed in other diseases associated with mutations in genes related to carbohydrate metabolism, PRKAG2 and LAMP2 [30,31].
Although these disorders share a similar morphologic expression as patients with sarcomeric HCM, they also have some unique
features and different natural history. Progressive conduction system disease requiring pacemaker implantation is common with
PRKAG2 mutations [30], while progression to end-stage HF and increased risk of VT in early adulthood is common in males (X-linked)
with LAMP2 mutations [31].

The characteristics of these disorders are described separately. (See "Hypertrophic cardiomyopathy: Gene mutations and clinical
genetic testing", section on 'PRKAG2 and LAMP2 genes' and "Lysosome-associated membrane protein 2 deficiency (glycogen storage
disease IIb, Danon disease)".)

Approximately 25 percent of Noonan patients have increased LV wall thickness similar to the pattern of hypertrophy observed in
patients with sarcomeric HCM, while Fabry disease may also mimic HCM. Screening for Fabry disease among patients with suspected
HCM is discussed separately. (See "Fabry disease: Clinical features, diagnosis, and management of cardiac disease".)

SYMPTOMS — The majority of clinically identified patients with HCM have no or minor symptoms [32]. Thus, affected children and
adolescents are often diagnosed during family screening. Patients who are asymptomatic, or have minor symptoms, have a better
prognosis than those with more severe symptoms. (See 'Risk factors' below.)

Patients with mild to moderate limitation may have a stable clinical course with effective therapy, or may experience slow progression
of symptoms with advancing age. Typical symptoms include dyspnea, chest pain, syncope, and palpitations. An in-depth discussion of
the clinical manifestations of HCM is presented separately. (See "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and
evaluation".)

DISEASE-RELATED COMPLICATIONS — The major disease-related complications of HCM are ventricular arrhythmias leading to sudden
death, chest pain, progressive heart failure (HF) symptoms or HF death, atrial arrhythmias including atrial fibrillation, and embolic stroke
[33].

Mortality — In series published in the 1980s, the annual mortality of patients with HCM in referral center populations was 4 to 6 percent
per year [34-38]. However, lower annual mortality rates have been observed in more recent series from large unselected HCM patient
populations (approximately 1 percent or less per year) [32,39-46]. In a report from a referral population of 312 patients, 73 (23 percent)
lived at least 75 years [47]. HCM can now be considered a disease compatible with normal life expectancy for the vast majority of
patients with this disease.

The most comprehensive contemporary data come from a review of 956 adults (mean age 42) seen between 1988 and 2002; the
outcomes were compared with those in natural history studies published between 1960 and 2003 [48]. The following findings were
noted:

● The annual rates of HF death or transplantation and stroke-related deaths were 0.55 and 0.07 percent, respectively.

● Published sudden death rates over the last 10 years of the study were lower than in previously published reports (median 1 versus
2 percent).

● The more recent studies were larger and included less severely affected patients as manifested by fewer patients with NYHA class
III or IV HF (table 1) and fewer patients who underwent septal myectomy.

Similar outcomes have been reported in younger patients. Among a cohort of 474 patients younger than 30 years of age at presentation
(mean age 20.2 years) who were evaluated at two referral centers between 1992 and 2013, the annual HCM-related mortality rate was
0.54 percent per year over an average of 7.1 years of follow-up [44]. Additionally, 63 patients (13 percent of cohort; 1.8 percent per year)
had aborted life-threatening events (including appropriate ICD interventions, resuscitated sudden cardiac arrest, or heart transplant).

The major causes of death in HCM are sudden cardiac death (SCD), HF, and stroke [42,48]. In a review of 744 consecutive and largely
unselected patients, 51 percent of deaths were due to SCD, 36 percent were due to progressive HF, and 13 percent were due to stroke
associated with atrial fibrillation [42]. SCD was most common in young patients, while death from HF or stroke occurred more
frequently in midlife and beyond. Advanced HF has emerged as a significant problem in more patients with HCM due to the
improvements in SCD risk stratification in clinical cardiology practice [45].

In a series of 428 HCM patients presenting at age ≥60 years and followed for close to six years, risk was low for disease related
morbidity and mortality, including sudden death (even with conventional risk factors). Non-HCM related co-morbidities have a greater
impact on survival once HCM patients achieve older age [14].

Risk factors — As noted, patients with HCM have an increased risk of death from several causes (SCD, HF, and stroke). The following
discussion will review factors associated with overall mortality in HCM patients. Because of their potential impact on the decision to
implant a cardioverter-defibrillator, risk factors have also been evaluated for their specific association with SCD. This issue discussed in
detail separately. (See "Hypertrophic cardiomyopathy: Assessment and management of ventricular arrhythmias and sudden cardiac
death risk", section on 'Risk stratification'.)

Age at diagnosis — The excess death rate appears to vary with the age of the patient at diagnosis.

● Among 1085 patients with idiopathic HCM (not associated with another syndrome) who were enrolled in the Pediatric
Cardiomyopathy registry between 1990 and 2009, the risk of death or cardiac transplantation after two years of follow-up was
markedly and significantly higher for patients diagnosed prior to one year of age (21 percent compared with 3 percent for patients
diagnosed after age one year) [49].

● In a review of 277 outpatients who were followed for eight years, the mean age of death from HCM was 56 years [32]. The annual
mortality compared with the general population was substantially increased in those identified during childhood (1.3 versus 0.08
percent) but not in those identified in adulthood (2.2 versus 1.9 percent).

● Similar data on survival in adults were noted in a series from the Mayo Clinic in which 37 patients with HCM and a mean age of 59
years had one and five year survival rates (95 and 92 percent) that did not differ from an age and sex matched population without
HCM [41]. However, some mutations associated with late onset disease do not have a benign course [19]. (See 'Late onset disease'
above.)

Female gender — Although HCM occurs equally in both sexes and with generally similar phenotypic expression, there is under-
recognition of the disease among women [50]. In addition, women often are diagnosed later than men and with more advanced
symptoms at the time of diagnosis [50,51]. Women do not appear to be at greater risk for sudden death or other adverse disease-
related events compared with men with HCM [42,50]. In a single-center cohort of 3673 patients with HCM (1661 [45 percent] women)
followed for a median of 11 years, female gender was associated with a higher overall mortality (adjusted hazard ratio [HR] 1.13, 95% CI
1.03-1.22) [51].

Symptom status — The presence of symptoms in patients with HCM is associated with worse outcomes compared with
asymptomatic patients with HCM [32,47,52-54]. In the above report of 277 outpatients, 90 percent were asymptomatic at presentation;
during the eight year follow-up, 69 percent remained asymptomatic or had only mild symptoms, while 25 percent had incapacitating
symptoms or died [32]. Factors that increased the likelihood of HCM-related death included advanced symptoms at diagnosis; other
adverse risk factors were atrial fibrillation associated with an embolic stroke, basal outflow obstruction ≥30 mmHg, and marked left
ventricular hypertrophy >25 mm. Similar findings were noted in a series of 128 adults with HCM (followed for 9 to 11 years), among
whom the 58 patients who were asymptomatic at presentation had a lower annual cardiac mortality than those with symptoms (0.9
versus 1.9 percent) that was entirely due to a lower annual rate of sudden death (0.1 versus 1.4 percent) [52].

Many patients who report a lack of symptoms or only minimal symptoms may actually be limiting activity (consciously or
unconsciously) to avoid the development of symptoms. Among a single-center cohort of 426 asymptomatic or minimally symptomatic
patients with HCM who underwent exercise stress echocardiography, 82 percent of patients failed to reach their age-predicted
metabolic equivalents (METs) during exercise stress testing [55]. During an average follow-up of 8.7 years, the risk of death, appropriate
implantable cardioverter-defibrillator shock, or HF admission was significantly lower for patients who achieved greater workloads
during exercise (1 percent in patients achieving >100 percent age-predicted METs versus 12 percent in patients who achieved <85
percent of age-predicted METs). (See "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation", section on
'Exercise testing'.)

Not surprisingly, the mortality risk is markedly increased in patients who develop severe symptoms (NYHA class III or IV), (table 1). (See
'Heart failure' below.)

Obstruction — Regardless of the presence of symptoms, left ventricular outflow tract (LVOT) obstruction at rest which is ≥30
mmHg is an independent predictor of progressive HF symptoms, HF, and stroke death in patients with HCM. In a multicenter study of
1101 patients with HCM, 273 (25 percent) had LVOT obstruction at rest with a peak gradient ≥30 mmHg [53]. At a mean follow-up of six
years, 127 patients (12 percent) died, and 216 surviving patients (20 percent) had progression to NYHA class III or IV HF (table 1). After
adjusting for age, gender, HF at entry, presence of atrial fibrillation, and LV wall thickness ≥30 mm, patients with LVOT obstruction had a
higher rate of HCM-related mortality (relative risk 1.6, 95% CI 1.1-2.4).

A subsequent report of 526 consecutive patients with HCM, 141 of whom (27 percent) had LVOT obstruction, noted that the prognostic
value of LVOT obstruction varied with the severity of symptoms during mean follow-up of 4.5 years [54]. At initial evaluation, LVOT
obstruction was a significant predictor of mortality among patients with no or mild symptoms at presentation (adjusted HR 2.4).
However, after the onset of severe symptoms, NYHA functional class becomes the dominant marker of prognosis, independent of the
LVOT gradient.

Pharmacologic therapy (eg, beta blockers) can improve symptoms due to LVOT obstruction. Nonpharmacologic approaches (eg,
surgical myectomy and nonsurgical septal ablation) are warranted in patients with NYHA class III/IV limiting symptoms (table 1)
despite maximum tolerated drug therapy, and they are highly effective at improving functional limitation and restoring quality of life by
abolishing outflow gradients. (See "Hypertrophic cardiomyopathy: Medical therapy" and "Hypertrophic cardiomyopathy:
Nonpharmacologic treatment of left ventricular outflow tract obstruction".)

Coronary disease and stress-induced ischemia — The adverse effect of coronary artery disease (CAD) on prognosis in HCM was
illustrated in a study of 433 adult patients [56]. Severe CAD was defined as the presence of a single luminal stenosis of ≥50 percent in
the left main coronary artery, ≥70 percent in other major epicardial branches, or two stenoses of ≥50 percent. Ten-year overall survival
was 46 percent, 71 percent, and 77 percent for patients with severe, mild-to-moderate, and no coronary artery disease, respectively. The
risk of death with severe CAD and HCM far exceeds historical death rates of CAD patients with normal LV function (eg, 12-year survival
of 73 percent in the CASS registry) [57]. In addition, the presence of coexistent CAD in patients who died suddenly without HCM risk
factors suggests that this particular comorbidity is prognostically important, although selection bias in the data makes it difficult to
draw definitive conclusions regarding the impact of these risk factors on each other [58].

In HCM, exercise testing provides an objective measure of the patient's physical limitations and exercise stress testing can detect
important abnormalities such as arrhythmia, exercise-induced hypotension, or ischemia. Marked (>5mm) ST segment depression is
common in HCM patients due to microvascular ischemia and therefore is not specific for detection of obstructive epicardial CAD. (See
"Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation", section on 'Exercise testing'.)

Stress-induced ischemia is associated with an increased risk of cardiac events and perhaps reduced survival [59-61]. If often occurs in
the absence of significant angiographic CAD in patients with HCM and may reflect coronary microvascular dysfunction [25,26,62].

In a series of 158 older HCM patients (age 18 to 88) who were referred for stress testing with nuclear imaging, the nuclear images were
abnormal (with fixed and/or reversible defects) in 62 percent of patients and, of 47 patients who underwent coronary angiography after
rMPI, only 10 had significant CAD [59]. Ten-year survival was significantly lower in those with abnormal (with fixed and/or reversible
defects) SPECT images (67 versus 90 percent with a normal test) and in those with reversible defects (64 versus 90 percent without
reversible defects). Given the low specificity for nuclear imaging to detect significant CAD in patients with HCM, CT angiography or
coronary catheterization should be considered if a patient's pretest probability of CAD is moderate to high.

Heart failure — Progression to NYHA class III or IV HF (table 1) occurs in a minority of patients with HCM and is most often due to LVOT
obstruction [19,53,54]. Progression to severe HF symptoms is associated with a marked increase in cardiovascular mortality,
particularly for HCM patients without LVOT obstruction. In different observational studies, patients with obstruction had a higher rate of
progression to NYHA class III or IV or death from HF or stroke (relative risk 2.7, 95% CI 2.0-3.5) [53]. For patients with LVOT obstruction
who progress to NYHA class III/IV, relief of obstruction with myectomy or alcohol septal ablation is associated with substantial
improvement in symptoms and normal life expectancy.

It has been estimated that mortality in HCM is due to progressive HF in approximately one-third of patients, the majority of whom have
the non-obstructive form of the disease [42]. Some patients develop a clinical picture similar to a dilated cardiomyopathy. Alternative
diagnoses should always be considered when LV systolic dysfunction is seen together with significant hypertrophy. Amyloid
cardiomyopathy and primary metabolic disorders such as Fabry disease, glycogen storage disease, and mitochondrial disease may
present with these findings. (See 'Mortality' above and 'End-stage HCM' above and 'Phenocopies of sarcomeric HCM' above and
"Evaluation of the patient with suspected heart failure".)

Treatment in these patients is the same as for any patient with systolic dysfunction, although there are no long-term data on the
efficacy of angiotensin converting enzyme inhibitors or other vasodilators in HF associated with HCM. Patients with NYHA class III/IV
symptoms refractory to medical therapy and obstruction ≥50 mmHg (at rest or with provocation) are candidates for invasive septal
reduction therapy with surgical myectomy or alcohol septal ablation [63,64]. (See "Overview of the therapy of heart failure with reduced
ejection fraction" and "Hypertrophic cardiomyopathy: Nonpharmacologic treatment of left ventricular outflow tract obstruction".)

Arrhythmias — HCM is associated with both atrial and ventricular arrhythmias (figure 3). These issues are discussed in detail
separately. (See "Hypertrophic cardiomyopathy: Prevalence, pathophysiology, and management of concurrent atrial arrhythmias" and
"Hypertrophic cardiomyopathy: Assessment and management of ventricular arrhythmias and sudden cardiac death risk".)

Stroke — Stroke and systemic embolic events are known complications of HCM, but there are few data about frequency and predictors
of occurrence [65,66].

● Stroke and systemic embolic events were examined in a community-based cohort of 900 patients followed for 7.7 years [65]. The
prevalence rate of stroke or peripheral embolization was 6 percent (incidence 0.8 percent per year); 41 percent of patients with a
stroke died or were permanently disabled. Most of the events (72 percent) occurred in patients over age 50 and, in those over age
60, the incidence was 1.9 percent per year. With a multivariate analysis, embolic events were also associated with atrial fibrillation,
which was present in 88 percent of those who had a stroke, and congestive symptoms. In spite of the relative paucity of data,
expert opinion is generally to have a low clinical threshold to initiate anticoagulation for stroke prophylaxis in patients with HCM
and atrial fibrillation due to the high observed risk of stroke.

● Similar findings were reported from a Japanese cohort of 593 patients with HCM (including 431 without known atrial fibrillation at
baseline) who were followed for an average of 10.7 years, during which time the stroke/systemic embolic event rate was 1 percent
per year [66]. Older age and larger left atrial size were markers of greater risk of stroke among patients without identified atrial
fibrillation.
Infective endocarditis — Antibiotic prophylaxis was recommended in the past in HCM patients with outflow gradients and/or mitral
valve abnormalities. However, the 2007 AHA guideline for the prevention of infective endocarditis made major revisions, including the
recommendation that prophylaxis is NOT indicated in patients with HCM with latent or resting obstruction or mitral valve disease [67].
(See "Antimicrobial prophylaxis for the prevention of bacterial endocarditis".)

Infective endocarditis appears to be uncommon in HCM. Among a large, referral-based cohort with HCM, only 30 patients were
diagnosed with infective endocarditis over an 11-year period (2006 to 2016), occurring equally in patients with and without LVOT
obstruction and with similar rates of mitral and aortic valve involvement [68]. While embolic complications occurred in 10 patients (33
percent) and 11 patients (37 percent) required surgery, one-year mortality was low (7 percent).

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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients.
(You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

● Basics topics (see "Patient education: Hypertrophic cardiomyopathy in adults (The Basics)" and "Patient education: Hypertrophic
cardiomyopathy in children (The Basics)")

● Beyond the Basics topic (see "Patient education: Hypertrophic cardiomyopathy (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

● Phenotypic expression of hypertrophic cardiomyopathy (HCM) with LV hypertrophy usually occurs during adolescence with wall
thickness measurements that remain stable throughout life in the majority of patients. However, early onset disease in HCM can
occur in infancy and early childhood, and late-onset disease occurring in mid-life has also been recognized. (See 'Development of
hypertrophy' above.)

● A small proportion of patients with HCM (<5 percent) will develop the high-risk phenotype of end-stage disease, associated with
reduced systolic function (EF <50 percent). In some cases, there is relative left ventricular dilation and wall thinning, with greater
resemblance to the morphologic and functional features of dilated cardiomyopathy. End-stage disease raises consideration for
aggressive therapy, including consideration for primary prevention ICD, conventional heart failure (HF) therapy, and early
consideration for transplant evaluation. (See 'End-stage HCM' above.)

● HCM is compatible with normal life expectancy for the majority of patients, with annual mortality rates of referral-based HCM
populations of 1 percent, with the major causes of death being sudden cardiac death (SCD), HF, and stroke. SCD is more common
in young patients, while death from HF or stroke is more common in mid-life and beyond. (See 'Mortality' above.)

● Progression to NYHA class III or IV HF (table 1) occurs in a minority of patients with HCM and is most often associated with left
ventricular outflow tract obstruction (≥30 mmHg). Progression to severe HF symptoms is associated with a marked increase in
cardiovascular mortality, particularly in non-obstructed HCM patients. In patients with obstruction and class III/IV symptoms, relief
of the gradient is associated with substantial improvement in HF symptoms and normal longevity. (See 'Heart failure' above.)

● HCM is associated with an age-related increase in the prevalence of supraventricular arrhythmias, particularly atrial fibrillation. (See
"Hypertrophic cardiomyopathy: Prevalence, pathophysiology, and management of concurrent atrial arrhythmias" and "Hypertrophic
cardiomyopathy: Assessment and management of ventricular arrhythmias and sudden cardiac death risk".)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Perry Elliott, MD, who contributed to an earlier
version of this topic review.

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Topic 4916 Version 23.0

GRAPHICS

Morphologic variants of hypertrophic cardiomyopathy

HCM typically presents with asymmetric or localized areas of LV hypertrophy, which are
diagrammed in B to E.
(A) Normal LV wall thickness.
(B) ASH.
(C) Sigmoid septum, which is more common in older adults.
(D) Midcavity hypertrophy associated with midcavity obstruction.
(E) Predominantly free wall hypertrophy, an unusual pattern in HCM.
(F) LV wall thinning (associated with low LV ejection fraction) and biatrial enlargement.
(G) Predominantly apical LV hypertrophy.
(H) Severe concentric hypertrophy with cavity obliteration.
(I) Biventricular hypertrophy.
(J) Mild to moderate symmetric hypertrophy.

ASH: asymmetrical septal hypertrophy; HCM: hypertrophic cardiomyopathy; LV: left ventricular.

Graphic 58156 Version 4.0

Hypothetical model for the pathogenesis of the end-stage phase of
hypertrophic cardiomyopathy with left ventricular wall thinning and
cavity enlargement

LV: left ventricular.

* Indicates the following possibilities: 1) enhanced myocardial oxygen requirements and reduced
myocardial capillary density relative to marked left ventricular hypertrophy (LVH); and 2) increased
diastolic wall tension and coronary vascular resistance resulting from abnormal LV relaxation and
impaired filling.

Redrawn from Maron BJ, Spirito P, Am J Cardiol 1998; 81:1339.

Graphic 81390 Version 2.0

NYHA and other classifications of cardiovascular disability
New York Heart Association
Class
functional classification [1]
I Patients with cardiac disease but
without resulting limitations of physical
activity. Ordinary physical activity does
not cause undue fatigue, palpitation,
dyspnea, or anginal pain.
II Patients with cardiac disease resulting
in slight limitation of physical activity.
They are comfortable at rest. Ordinary
physical activity results in fatigue,
palpitation, dyspnea, or anginal pain.
III Patients with cardiac disease resulting
in marked limitation of physical activity.
They are comfortable at rest. Less than
ordinary physical activity causes
fatigue, palpitation, dyspnea, or anginal
pain.
IV Patients with cardiac disease resulting
in inability to carry on any physical
activity without discomfort. Symptoms
of cardiac insufficiency or of the
anginal syndrome may be present even
at rest. If any physical activity is
undertaken, discomfort is increased.
NYHA: New York Heart Association.
References:
1. The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels, 9th ed, Little, Brown & Co,
Boston, 1994. p.253.
2. Campeau L. Grading of angina pectoris. Circulation 1976; 54:522.
3. Goldman L, Hashimoto B, Cook EF, Loscalzo A. Comparative reproducibility and validity of systems for assessing cardiovascular functional class: Advantages of a new
specific activity scale. Circulation 1981; 64:1227.
Graphic 52683 Version 13.0
Canadian Cardiovascular
Society functional
classification [2]
Ordinary physical activity, such as
walking and climbing stairs, does not
cause angina. Angina with strenuous or
rapid prolonged exertion at work or
recreation.
Slight limitation of ordinary activity.
Walking or climbing stairs rapidly,
walking uphill, walking or stair climbing
after meals, in cold, in wind, or when
under emotional stress, or only during
the few hours after awakening. Walking
more than two blocks on the level and
climbing more than one flight of
ordinary stairs at a normal pace and in
normal conditions.
Marked limitation of ordinary physical
activity. Walking one to two blocks on
the level and climbing one flight in
normal conditions.
Inability to carry on any physical activity
without discomfort. Anginal syndrome
may be present at rest.
Specific activity scale [3]
Patients can perform to completion any
activity requiring ≥7 metabolic
equivalents, eg, can carry 24 lb up eight
steps; do outdoor work (shovel snow,
spade soil); do recreational activities
(skiing, basketball, squash, handball,
jog/walk 5 mph).
Patients can perform to completion any
activity requiring ≥5 metabolic
equivalents, eg, have sexual intercourse
without stopping, garden, rake, weed,
roller skate, dance fox trot, walk at 4
mph on level ground, but cannot and do
not perform to completion activities
requiring ≥7 metabolic equivalents.
Patients can perform to completion any
activity requiring ≥2 metabolic
equivalents, eg, shower without
stopping, strip and make bed, clean
windows, walk 2.5 mph, bowl, play golf,
dress without stopping, but cannot and
do not perform to completion any
activities requiring >5 metabolic
equivalents.
Patients cannot or do not perform to
completion activities requiring >2
metabolic equivalents. Cannot carry out
activities listed above (specific activity
scale III).
Pyramid profile of risk stratification model currently used to identify patients at the highest sudden cardiac death (SCD) risk who
may be candidates for an implantable cardioverter-defibrillator (ICD)

Major and minor risk markers appear in boxes at the left. At the right are the results of ICD therapy in 730 children, adolescents, and adults assembled from two registry
studies.

BP: blood pressure; CAD: coronary artery disease; EF: ejection fraction; ICD: implantable cardioverter-defibrillator; LV: left ventricular; LGE: late gadolinium enhancement; LVH: left
ventricular hypertrophy; NSVT: nonsustained ventricular tachycardia; SD: sudden death; VT/VF: ventricular tachycardia/ventricular fibrillation.
* Extensive LGE is a novel primary risk marker that can also be used as an arbitrator when conventional risk assessment is ambiguous.
¶ SD events are uncommon after 60 years of age, even with conventional risk factors.

Reproduced from: Maron B, Ommen S, Semsarian C. Hypertrophic cardiomyopathy: Present and future, with translation into contemporary cardiovascular medicine. J Am Coll Cardiol
2014; 64:83. Illustration used with the permission of Elsevier Inc. All rights reserved.

Graphic 99534 Version 2.0

Contributor Disclosures
Martin S Maron, MD Nothing to disclose William J McKenna, MD Nothing to disclose Brian C Downey, MD, FACC Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through
a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced
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