Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation

INTRODUCTION — Hypertrophic cardiomyopathy (HCM) is a genetically determined heart muscle disease most often (60 to 70 percent) caused by mutations in one of several sarcomere genes which encode components of the contractile apparatus of the heart. (See "Hypertrophic cardiomyopathy: Gene mutations and clinical genetic testing".)

HCM is characterized by left ventricular hypertrophy (LVH) of various morphologies, with a wide array of clinical manifestations and hemodynamic abnormalities (figure 1). Depending in part upon the site and extent of cardiac hypertrophy, patients with HCM can develop one or more of the following abnormalities:

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

●Diastolic dysfunction

●Myocardial ischemia

●Mitral regurgitation

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 in adults: Supraventricular tachycardias including atrial fibrillation" and "Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death".)

For the majority of patients with HCM, LVH is not progressive, and HCM is compatible with normal longevity in the vast majority with a 1 percent annual mortality rate among nonreferral-based cohorts. A small subset of patients, however, remains at risk for a number of adverse disease-related complications including: sudden death, usually in the absence of symptoms; progressive HF symptoms occasionally associated with systolic dysfunction; and atrial fibrillation with risk of thromboembolic stroke.

The clinical manifestations, diagnosis, and evaluation of HCM will be reviewed here. Other issues such as the natural history and treatment of this disorder are discussed separately. (See "Hypertrophic cardiomyopathy: Natural history and prognosis" and "Hypertrophic cardiomyopathy: Management of patients without outflow tract obstruction" and "Hypertrophic cardiomyopathy: Management of patients with outflow tract obstruction".)

PREVALENCE — The prevalence of HCM in the general population, as determined from echocardiographic studies in a variety of ethnic populations around the world, is 0.2 percent (1 out of every 500 adults) [1-6]. Subsequently, newer techniques (ie, genetic testing, cardiac magnetic resonance [CMR] imaging) have increased recognition of the HCM phenotype and improved clinical diagnosis [7,8]. In the MESA cohort of patients without known cardiovascular disease at baseline, among 4972 patients who underwent CMR screening at baseline, 67 participants (1.4 percent) were found to have unexplained LVH (eg, not related to hypertension, valvular disease, etc), supporting the principle that HCM is likely more common than the 1:500 prevalence derived from general population studies with echocardiography [9]. In addition, prior epidemiologic studies did not take into account autosomal dominant transmission of HCM, with often multiple affected family members for each proband identified. For these reasons, the prevalence of HCM in the general population has been estimated to be closer to 1 out of every 200 adults (0.5 percent) or perhaps even greater [10].

HISTOLOGIC FINDINGS — Histopathology in patients with HCM reveals hypertrophied myocytes arranged in a chaotic and disorganized fashion with a varying amount of interstitial fibrosis intertwined among the myocytes. In addition, the intramural coronary arterioles are structurally abnormal with decreased luminal cross-sectional area and impaired vasodilatory capacity resulting in blunted myocardial blood flow during stress (ie, "small vessel ischemia"). Over time, repetitive bouts of small vessel ischemia lead to myocyte cell death and ultimately repair in the form of replacement fibrosis (picture 1) [11].

CLINICAL MANIFESTATIONS — Many patients with HCM have no or only minor symptoms; thus, affected individuals are often diagnosed as a result of family screening, detection of a murmur during routine examination, or the identification of an abnormal ECG. However, among those who come to clinical attention at referral centers, left ventricular outflow tract (LVOT) gradients and symptoms of dyspnea, fatigue, chest pain, and syncope are the most common clinical manifestations. Patients with mild to moderate limitation usually experience slow progression of symptoms with advancing age in association with a modest deterioration in LV function.

Signs and symptoms — The signs and symptoms of HCM are variable, and there is not a strong correlation between the presence or magnitude of LVOT obstruction, the extent of LV hypertrophy (LVH), and symptoms. Some patients with severe LVOT obstruction remain asymptomatic for many years, while others without LVOT obstruction may have significant limitation.

While many patients with HCM are asymptomatic, others develop one or more of the following symptoms:

●Dyspnea on exertion

●Fatigue

●Atypical or anginal chest pain

●Presyncope and syncope, particularly during or immediately following exertion

●Palpitation

Advanced heart failure (HF) symptoms of orthopnea, paroxysmal nocturnal dyspnea, and edema are uncommon. The frequency of symptoms at diagnosis varies considerably depending on whether the population being studied is a cross section of the overall population or patients at a referral center [2,12,13].

●In a series of 320 patients from three referral centers, transthoracic echocardiography was performed in all patients, with subsequent stress echocardiography only in those whose LVOT gradient was <50 mmHg at rest [12]. The following findings were noted:

•169 patients (59 percent) had New York Heart Association (NYHA) Class II or greater dyspnea at presentation.

•119 patients (37 percent) had a resting LVOT gradient ≥50 mmHg, while 201 patients (63 percent) had a resting LVOT gradient <50 mmHg (mean 4 mmHg). With exercise, 76 (24 percent) developed an LVOT gradient ≥50 mmHg, and 46 (14 percent) developed dyspnea with exertion.

•95 patients (30 percent) were asymptomatic with little or no gradient (≤30 mmHg) at rest or with exertion.

●In a study of 277 outpatients from a regional cohort (nonreferral population) who were followed for eight years, approximately 90 percent were asymptomatic at presentation [13]. During the eight-year follow-up, 69 percent remained asymptomatic or had only mild symptoms, and survival in adults was similar to a normal control age-matched population.

Thus, among patients referred for evaluation of HCM, both HF symptoms and outflow gradients are common, although in many cases exercise testing may be necessary to demonstrate these abnormalities.

The clinical presentation also may be affected by sex. In a review of 969 consecutive patients from the United States and Italy, females were significantly older at presentation than males (47 versus 38 years), more symptomatic (New York Heart Association class 1.8 versus 1.4) (table 1), and more likely to have LVOT obstruction (37 versus 23 percent) [14]. At a mean follow-up of 6.2 years, females had significantly higher rates of progression to NYHA class III or IV and death from HF or stroke.

Symptoms can be induced by a variety of mechanisms which may include LVOT obstruction, impaired myocardial function, brady- or tachyarrhythmias, or impaired filling due to diastolic dysfunction [15]. The importance of these mechanisms may change with time and stage of disease. Some patients, for example, are initially symptomatic because of obstruction. As the myocardial disease worsens over time, the heart may enlarge, obstruction lessens, and symptoms are primarily due to systolic and/or diastolic dysfunction. (See "Hypertrophic cardiomyopathy: Morphologic variants and the pathophysiology of left ventricular outflow tract obstruction", section on 'Pathophysiology and evolution of LVOT obstruction'.)

Heart failure — HF, most commonly manifesting as dyspnea on exertion, is the most common presentation in persons with HCM, occurring in over 90 percent of symptomatic patients [15]. Dyspnea can result from a variety of mechanisms:

●Diastolic dysfunction due to myocardial hypertrophy

●Impaired LV emptying due to LVOT obstruction, resulting in increased LV end-diastolic pressure

●Mitral regurgitation

●Systolic dysfunction in a patient with more extensive myocardial involvement

Paroxysmal nocturnal dyspnea and orthopnea are uncommon presenting symptoms.

Chest pain — Typical exertional chest pain (ie, angina) occurs in 25 to 30 percent of patients with HCM, usually in the setting of a normal coronary arteriogram [16,17]. Some patients also complain of prolonged episodes of atypical chest pain [18]. This chest pain is commonly precipitated or worsened by heavy meals. (See "Outpatient evaluation of the adult with chest pain".)

Several of the pathophysiologic features of HCM predispose to the development of microvascular angina, which may be induced by an increase in myocardial oxygen demand or a reduction in myocardial blood flow and oxygen supply [17]. Factors that increase myocardial oxygen demand include myocyte hypertrophy and increased muscle mass, myocyte disarray (picture 2), and LVOT obstruction and increased wall stress due to elevated diastolic pressures. Factors that reduce myocardial blood flow in HCM, particularly with exertion, include impaired vasodilator reserve, myocardial bridging with systolic and early diastolic compression of intramural vessels, small vessel disease (picture 1) and microvascular dysfunction, myocardial fibrosis, and increased capillary separation and inadequate capillary density [17,19-24].

Many studies have shown that, during pacing or pharmacologic stress, myocardial blood flow is abnormal in patients with HCM and often associated with metabolic evidence for myocardial ischemia [16,19,23,25,26]. Myocardial perfusion in patients with HCM can be assessed using exercise or pharmacologic stress testing. (See 'Exercise testing' below.)

Patients with HCM who have an acute myocardial infarction appear are more likely to present with non-ST segment elevation myocardial infarction (NSTEMI) rather than STEMI, although patients with HCM who develop STEMI appear to have a lower risk of mortality compared with patients without HCM [27].

Arrhythmias — Both supraventricular arrhythmias, primarily atrial fibrillation (AF), and ventricular arrhythmias occur in HCM. Patients with an arrhythmia may present with palpitations, increasing dyspnea, presyncope, or syncope, with occasional patients presenting with sudden cardiac death due to sustained ventricular arrhythmias.

The arrhythmias associated with HCM, as well as their treatment, are discussed separately. (See "Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation" and "Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death".)

Syncope — Approximately 15 to 25 percent of patients with HCM report at least one syncopal episode. Another 20 percent complain of presyncope. Multiple mechanisms may lead to an inadequate cardiac output or abnormal peripheral vascular reflexes, including [28]:

●AF

●Conduction abnormalities and atrioventricular nodal block [28-32]

●LVOT obstruction

●Ventricular baroreflex activation with inappropriate vasodilatation

●Myocardial ischemia during exertion

Among the reported predictors of syncope in patients with HCM are:

●Age less than 30 years

●Small LV end-diastolic volume and small LV cavity size (irrespective of obstruction and hypertrophy)

●Episodes of nonsustained ventricular tachycardia on 72-hour ambulatory electrocardiographic monitoring [28,33]

Unexplained syncope (ie, not related to neurocardiogenic/vasovagal causes) is considered a marker for increased risk of sudden death, particularly when recent and when occurring in young patients [34].

Acute hemodynamic collapse — Occasional patients with HCM and LVOT obstruction present with acute hemodynamic collapse manifest by HF and severe hypotension, although patients may also experience chest pain, palpitations, lightheadedness, or syncope. Physical examination findings typically include severe hypotension, sinus tachycardia, thready double-impulse peripheral arterial pulse, auscultatory and radiographic evidence of cardiac failure, and systolic murmurs of LV obstruction and mitral regurgitation.

Acute hemodynamic collapse in HCM is usually precipitated by events that acutely increase outflow obstruction, including:

●Decreased preload due to dehydration, diuretics, or an acute reduction in blood volume (eg, hemorrhage, sepsis, peripheral venous pooling, post epidural)

●Decreased afterload due to administration of a vasodilator

●Supraventricular tachycardia, AF, or sinus tachycardia

●Acute mitral regurgitation due to flail mitral valve leaflet or endocarditis

LVOT obstruction is confirmed by urgent echocardiography, which characteristically demonstrates hyperdynamic LV function with a small (underfilled) LV cavity, and systolic anterior motion (SAM) with prolonged SAM-septal contact associated with mitral regurgitation (usually posteriorly directed). (See 'Echocardiography' below.)

Conventional treatment of HF with nitrates, diuretics, and vasodilators may result in further hemodynamic deterioration. The management of acute hemodynamic collapse is discussed in detail separately. (See "Hypertrophic cardiomyopathy: Management of patients with outflow tract obstruction", section on 'Therapies to avoid'.)

End-stage disease — The majority of patients with HCM present with the classic manifestations of HCM, including asymmetric LVH, normal LV systolic function, LVOT obstruction, and related signs and symptoms. However, there is a small subgroup of patients with HCM (approximately 5 to 8 percent) who develop adverse LV remodeling resulting in systolic dysfunction (LV ejection fraction <50 percent) and which can be associated with wall thinning and chamber dilation. This is often referred to as the end-stage (or "burned out") phase of HCM. (See "Hypertrophic cardiomyopathy: Natural history and prognosis", section on 'HCM with LV systolic dysfunction (ejection fraction <50 percent)'.)

Relationship of symptoms to pressure gradient — A pressure gradient between the LVOT and aorta is present in the majority of patients with HCM (75 percent), either at rest or following provocation (waveform 1 and waveform 2). Outflow tract gradients in HCM are dynamic, characterized by spontaneous variability on a day-to-day (or even hourly) basis, and influenced by factors that alter myocardial contractility and loading conditions (eg, dehydration, ingestion of alcohol, or heavy meals). As such, for patients who do not have evidence of LVOT obstruction under resting conditions, an attempt should be made at provoking gradients as the presence of LVOT obstruction will affect management decisions. Exercise (stress) echocardiography using a standard symptom limited Bruce protocol is the preferred method as this mimics most closely the conditions that patients would be experiencing provocable gradients with daily activities. Alternatively, pharmacologic agents (ie, amyl nitrite, dobutamine, isoproterenol) and Valsalva maneuver can also be employed to induce gradients, although these are nonphysiologic maneuvers that may not reflect the true magnitude of outflow gradients experienced during routine daily activities. (See 'Echocardiography' below and 'Exercise testing' below.)

However, despite the presence of LVOT obstruction, there is not a predictable correlation between the degree of LVOT obstruction and symptoms. Some patients with severe LVOT obstruction remain asymptomatic for many years; at the other extreme, cardiac arrest or sudden death may be the initial presentation in those with or without obstruction.

Physical examination — The physical examination in a patient with HCM may be normal or may reveal nonspecific abnormalities such as a fourth heart sound, systolic murmur, and/or an LV lift. Many of the classically described physical examination findings in patients with HCM are associated with LVOT obstruction. Persons with minimal or no LVOT obstruction may have normal or nearly normal physical examinations.

Systolic murmurs — Patients with HCM may develop several types of systolic murmurs, but the two most common are related to LVOT obstruction and mitral regurgitation.

●Significant LVOT obstruction, often due to a combination of LV upper septal hypertrophy and systolic anterior motion (SAM) of the mitral valve, results in a harsh crescendo-decrescendo systolic murmur that begins slightly after S1 and is heard best at the apex and lower left sternal border. The murmur may radiate to the axilla and base, but usually not into the neck. It may reflect both aortic outflow obstruction and mitral regurgitation in patients with a large gradient (waveform 3). (See "Auscultation of cardiac murmurs in adults", section on 'Subvalvular outflow obstruction'.)

●SAM of the mitral valve, or abnormal mitral valve anatomy related to papillary muscle or chordae tendineae abnormalities, can lead to impaired leaflet coaptation and mitral regurgitation, usually with a posteriorly directed jet, which produces a mid-late systolic murmur at the apex. Centrally directed mitral regurgitation, usually associated with primary mitral valve pathology, classically results in a holosystolic murmur heard loudest at the apex which radiates to the axilla. However, if the regurgitant jet is eccentrically directed, the murmur can radiate toward the base of the heart and may be confused with the murmur of LVOT obstruction. (See "Hypertrophic cardiomyopathy: Morphologic variants and the pathophysiology of left ventricular outflow tract obstruction", section on 'Development of mitral regurgitation' and "Auscultation of cardiac murmurs in adults", section on 'Mitral regurgitation'.)

The systolic murmur related to LVOT obstruction in HCM is often similar to that of valvular aortic stenosis and subvalvular aortic stenosis (subaortic stenosis), and differentiating these conditions is difficult on routine auscultation. However, the patient can be asked to perform a series of maneuvers and position changes which can aid in making the correct diagnosis. Maneuvers that affect the degree of LVOT obstruction cause a change in intensity of the outflow tract crescendo-decrescendo murmur (table 2). (See "Hypertrophic cardiomyopathy: Morphologic variants and the pathophysiology of left ventricular outflow tract obstruction".)

●An increase in intensity, due to enhancement of obstruction, is seen with the assumption of an upright posture from a squatting, sitting, or supine position; the Valsalva maneuver; during the more forceful contraction that follows the compensatory pause after a PVC; and following the administration of nitroglycerin.

●A decrease in intensity, due to attenuation of obstruction, is heard after going from a standing to a sitting or squatting position, with handgrip, and following passive elevation of the legs.

The murmur in valvular aortic stenosis does not change substantially, or decreases slightly following the Valsalva maneuver and usually radiates into the neck, while the murmur in subaortic stenosis (most commonly seen in children) tends to decrease following Valsalva maneuver. (See "Physiologic and pharmacologic maneuvers in the differential diagnosis of heart murmurs and sounds".)

Other physical findings — While a number of other physical findings may be observed in patients with HCM, none is pathognomonic for HCM.

●The first heart sound is typically normal. In patients without severe obstruction, the second heart sound splits normally; however, the split may be paradoxic if there is severe LVOT obstruction. (See "Auscultation of heart sounds".)

●A third or fourth heart sound is common in young patients but rarely heard in later life.

●The arterial or carotid pulse may be brisk in upstroke and bifid; this results from sudden deceleration of blood due to the development of midsystolic obstruction to blood flow and partial closure of the aortic valve. (See "Examination of the arterial pulse".)

●Inspection of the neck veins may reveal a prominent "a" wave. (See "Examination of the jugular venous pulse".)

●There is often a diffuse, forceful LV apical impulse. (See "Examination of the precordial pulsation".)

●A presystolic apical impulse may be felt, reflecting atrial systole.

●A systolic thrill may be appreciated at the apex or lower left sternal border.

●A parasternal lift suggests significant mitral regurgitation and/or pulmonary hypertension.

DIAGNOSTIC EVALUATION — A variety of tests have been used in the evaluation of patients with possible HCM. Appropriate testing as indicated when the diagnosis of HCM is being considered, or when suggestive clinical signs or symptoms are present, can be used:

●To establish the diagnosis of HCM

●To identify the presence or severity of left ventricular outflow tract (LVOT) obstruction

●To identify the presence or severity of mitral regurgitation

●To assess the risk for arrhythmia (both supraventricular and ventricular)

●To assess overall LV function

In addition to performing a comprehensive cardiac history and physical examination and an electrocardiogram (ECG), cardiac imaging to identify LV hypertrophy (LVH) should be performed in all patients. Typically, the presence or absence of LVH can be satisfactorily identified using echocardiography, although another imaging modality such as cardiac magnetic resonance (CMR) may be necessary in persons with nondiagnostic or suboptimal quality echocardiograms. (See 'Echocardiography' below and 'Cardiovascular magnetic resonance' below.)

In persons with ECG and echocardiographic (or CMR) evidence of HCM, ambulatory ECG monitoring and exercise stress testing should be performed for additional prognostic information and risk stratification purposes. Additional testing may not be necessary in an asymptomatic or mildly symptomatic patient; such patients may be discovered because of a positive family history or an abnormal ECG obtained for some other reason. In contrast, a more thorough and detailed evaluation is necessary for symptoms such as syncope, or prior to and following surgical myectomy or septal ablation. (See "Hypertrophic cardiomyopathy: Management of patients without outflow tract obstruction" and "Hypertrophic cardiomyopathy: Management of patients with outflow tract obstruction".)

Electrocardiography — An electrocardiogram (ECG) should be performed in all patients when considering a diagnosis of HCM. ECG testing is the most sensitive routinely performed diagnostic test for HCM, but the ECG abnormalities are not specific to HCM and should prompt further diagnostic evaluation, usually with echocardiography.

A normal ECG is uncommon, seen in less than 10 percent of patients with HCM [6,35-37]. In a cohort of 2485 consecutive patients with HCM who were evaluated at a single center, a normal ECG was seen in only 135 patients (5 percent) [35]. (See "Left ventricular hypertrophy: Clinical findings and ECG diagnosis".)

Typically, the ECG is abnormal with localized or widespread repolarization changes (waveform 4). Prominent voltages with repolarization changes are typical of HCM associated with storage disease (eg, Danon's disease), while prominent voltages in isolation are rare as an ECG manifestation in HCM. Other ECG findings may include [6]:

●Prominent abnormal Q waves, particularly in the inferior (II, III, and aVF) and lateral leads (I, aVL, and V4-V6). These changes reflect septal depolarization of the hypertrophied myopathic tissue. (See "Pathogenesis and diagnosis of Q waves on the electrocardiogram".)

●P wave abnormalities, reflecting left atrial (LA) or biatrial enlargement. The combination of LVH with right atrial enlargement is strongly suggestive of HCM.

●Left axis deviation.

●Deeply inverted T waves (so-called "giant negative T waves") may be seen in the mid-precordial leads (V2 through V4) in patients with the apical variant of HCM. (See "Hypertrophic cardiomyopathy: Morphologic variants and the pathophysiology of left ventricular outflow tract obstruction", section on 'Apical HCM'.)

Echocardiography — Comprehensive transthoracic echocardiography (TTE) with two-dimensional, color Doppler, spectral Doppler, and tissue Doppler imaging should be performed in all patients when considering a diagnosis of HCM. TTE can demonstrate cardiac morphology, systolic and diastolic function, the presence and severity of any LVOT gradient, and the degree of mitral regurgitation (figure 2 and image 1 and movie 1 and movie 2 and image 2) [38-41].

LV hypertrophy — A clinical diagnosis of HCM is confirmed when unexplained increased LV wall thickness ≥15 mm is imaged anywhere in the LV wall [40]. A wall thickness of ≥13 mm may also be considered diagnostic of HCM, particularly when identified in a patient whose family member also has HCM. The most common location for LVH is the basal anterior septum in continuity with the anterior free wall, with the posterior septum (at the mid-LV level) the third most common location. Although LVH often involves a substantial portion of the LV wall, an important minority of patients with HCM (10 percent) have increased wall thickness confined to only one or two LV segments. Although typically asymmetric in distribution, any pattern of LV wall thickening (figure 1) can be seen in HCM, including apical and concentric LVH in a small minority (1 percent).

The distribution of LVH on 2D echocardiography is assessed in a variety of views but primarily in the parasternal short-axis plane [15]. The presence and extent of LVH is evaluated in diastole at the level of the mitral valve and the papillary muscle (movie 3 and movie 4). Parasternal long-axis, and apical 2- and 4-chamber views are also used to integrate the information obtained from the short-axis images (movie 2 and movie 5).

Systolic anterior motion of the mitral valve — Patients with HCM frequently have systolic anterior motion (SAM) of the mitral valve, which positions the mitral valve within the LVOT [6]. SAM of the mitral valve may result in LVOT obstruction when there is contact between the mitral valve and the septum. The greater the duration of mitral-septal contact, the higher the LVOT obstruction (figure 3). The presence of SAM is not a requirement for a diagnosis of HCM.

LVOT obstruction — Echocardiography can be used to accurately measure noninvasively the presence and magnitude of LV outflow gradients using continuous-wave Doppler techniques. The apical long-axis imaging window provides the best views to obtain Doppler estimates of the LVOT pressure gradient, and particular care must be taken to separate the LVOT signals from those due to mitral regurgitation (waveform 3). The aortic valve motion may display early-systolic closure and a "peak and dome" configuration of aortic pressure and velocity, which corresponds to transient mid systolic obstruction and a reduction in stroke volume (image 3).

Outflow tract gradients in HCM are dynamic, characterized by spontaneous variability on a day-to-day (or even hourly) basis, and are influenced by factors that alter myocardial contractility and loading conditions (eg, dehydration, ingestion of alcohol, or heavy meals). Therefore, for patients who do not have obstruction under resting conditions, provoking gradients for the purpose of management decisions is crucial. Exercise (stress) echocardiography using a standard symptom limited Bruce protocol is the preferred method as this mimics most closely the conditions that patients would be experiencing on a daily basis. Alternatively, pharmacologic agents (ie, amyl nitrite, dobutamine, isoproterenol) and Valsalva maneuver can also been employed to induce gradients, although these are nonphysiologic maneuvers which may not reflect the true magnitude of outflow gradients experienced during routine daily activities. (See "Hypertrophic cardiomyopathy: Morphologic variants and the pathophysiology of left ventricular outflow tract obstruction", section on 'Mechanism of LVOT obstruction'.)

A pressure gradient between the LVOT and aorta is present in the majority of patient with HCM (70 to 75 percent) at rest or with provocation [42]. As an example, in a cohort of 201 patients with HCM and no resting LVOT gradient who underwent exercise testing, 106 (53 percent) developed LVOT gradients ≥30 mmHg, including 76 of whom developed gradients ≥50 mmHg [12]. These findings suggest that patients with symptomatic HCM without LVOT obstruction at rest should undergo exercise echocardiography to assess for potential latent obstruction since identification of such obstruction would provide a therapeutic target and may prompt more aggressive medical therapy and consideration of septal reduction therapies. (See "Hypertrophic cardiomyopathy: Management of patients without outflow tract obstruction" and "Hypertrophic cardiomyopathy: Management of patients with outflow tract obstruction".)

While the vast majority of patients with HCM exhibit an increase or no change in LVOT gradient with exercise, a paradoxical decrease in LVOT gradient following exercise has been reported in a small cohort of patients with HCM [43]. The exact mechanism and clinical implications of this paradoxical decrease in LVOT gradient following exercise are not known.

Left atrium — Increased LA size is associated with greater risk for adverse disease-related events in HCM, including atrial fibrillation (AF). This observation has been demonstrated primarily with 2D echocardiography using transverse linear dimension and subsequently with biplane volumetric assessment (echocardiography or CMR) in which endocardial border of the LA is traced in multiple long-axis views. Given the limitations of 2D techniques in reliably assessing LA morphology, expert opinion in HCM supports employing volumetric assessments. From a clinical management perspective, increased LA size (>48 mm transverse dimension or ≥118 mL chamber volume) can identify patients with HCM at greatest risk for future AF, prompting the need for close surveillance of these patients in order to consider earlier management with anticoagulation for stroke prophylaxis and/or additional drug therapy if AF does occur [44,45].

Systolic function — In the majority of HCM patients, visual assessment of LV systolic function is normal and often hyperdynamic. The emergence of novel echocardiographic techniques such as myocardial strain provides an opportunity to assess intrinsic regional and global myocardial mechanics and function [46,47]. Global longitudinal strain (GLS) is now considered one of the most robust of these techniques, and a number of studies have demonstrated abnormal GLS values in HCM, suggesting that impaired myocardial contractile function is present in this disease despite a normal ejection fraction. In one population of patients with nonobstructive HCM and no evidence of LVOT obstruction at baseline, higher GLS values (ie, less negative) were associated with a greater likelihood of new or progressive HF [48]. However, the precise role of GLS in broad populations of patients with HCM remains to be clarified.

Ambulatory ECG monitoring — Ambulatory ECG monitoring should be performed for 24 to 48 hours in all patients diagnosed with HCM (based on clinical and imaging findings) as part of the risk assessment for ventricular arrhythmias and risk for sudden cardiac death. In addition, in patients with palpitations in whom the etiology is uncertain or if there is suspicion for atrial fibrillation/flutter, ambulatory monitoring should also be considered. The routine use of extended ambulatory monitors >48 hours for the detection of nonsustained ventricular arrhythmias for the purpose of risk stratification is uncertain, although prolonged ambulatory ECG monitoring for up to 14 days may increase detection of nonsustained ventricular arrhythmias [49].

Ambulatory ECG monitoring and continuous loop recorders can identify nonsustained atrial and ventricular arrhythmias in patients with HCM and help to establish whether an arrhythmia is the cause of palpitation or impaired consciousness. Nonsustained ventricular tachycardia on Holter monitoring is associated with an increased risk for SCD, even in the asymptomatic patient. (See "Ambulatory ECG monitoring" and "Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death", section on 'Risk stratification'.)

Exercise testing — We proceed with exercise stress testing in all patients with known or suspected HCM (based on clinical and imaging findings) as part of the risk stratification (ie, abnormal blood pressure [BP] response to exercise) and for the assessment of LVOT gradient. Exercise treadmill testing is the preferred method of stress, rather than using a pharmacologic stress agent, as a maximal treadmill or bicycle exercise stress test provides an objective measurement of functional capacity and information on the integrity of vascular responses and the risk of exercise related ischemia, arrhythmia, and obstruction. In addition, the results of exercise stress testing may lead to a change in patient management (eg, inducible ventricular arrhythmias or inducible LVOT gradient). The decision to add an imaging modality such as echocardiography or myocardial perfusion imaging to the stress test should be based on the usual indications for imaging during stress testing (eg, baseline electrocardiogram is uninterpretable). However, for the assessment of LVOT gradients, echocardiographic imaging should be performed in conjunction with the stress test. (See "Selecting the optimal cardiac stress test".)

Whenever feasible, initial exercise testing should be performed prior to the institution of therapy, although follow-up exercise testing on treatment may be indicated to assess the efficacy of a particular treatment. During exercise, some patients, particularly those who develop angina with marked ST segment changes, AF, hypotension, or large (>100 mmHg) gradients, may be at risk of developing serious ventricular arrhythmia. However, the incidence of sustained VT/VF during exercise testing appears to be very low. (See "Exercise ECG testing: Performing the test and interpreting the ECG results", section on 'Exercise test procedure'.)

Clinically important findings during exercise testing may include:

●Development of symptoms such as angina, dyspnea, palpitation, or presyncope

●An increase in or development of LVOT gradient [12,50]

●Failure of blood pressure to increase appropriately with exercise or exercise-induced hypotension

●Clinically significant arrhythmias (eg, AF, ventricular tachycardia) at maximum exercise or immediately after exercise

●Severe ST segment depression during exercise may reflect myocardial ischemia, particularly if the ST and T of the resting electrocardiogram are normal

●An increase in, or the development of, mitral regurgitation

Myocardial ischemia during exercise testing commonly occurs in the absence of significant coronary artery disease and has been reported to be associated with future risk of adverse cardiac events [51-53]. The pathophysiology of myocardial ischemia is discussed in detail separately. (See "Approach to the patient with suspected angina pectoris", section on 'Pathophysiology'.)

While the majority of exercise testing with imaging will involve echocardiography or SPECT myocardial perfusion imaging, positron emission tomography (PET) at baseline and after infusion of the coronary vasodilator dipyridamole is another method of evaluating myocardial perfusion. The normal increase in myocardial blood flow in response to dipyridamole is impaired in patients with HCM [23,54,55].

Cardiopulmonary exercise testing — In HCM, peak Vo₂, assessed by cardiopulmonary exercise testing (CPET), is reduced in most symptomatic patients and correlates reasonably well with subjective measures of NYHA functional class. A number of longitudinal studies demonstrated that decreased peak Vo₂ is associated with a higher risk for heart failure (HF) progression and death. However, these studies have combined obstructive and nonobstructive patients together making it difficult to determine the clinical relevance of abnormal peak Vo₂ in impacting management specifically within each of these two subgroups of HCM patients.

This point is underscored by the fact that it remains uncertain to what degree results of CPET predict risk of developing HF beyond that predicted by LVOT obstruction, an established and powerful independent determinate of limiting symptoms in HCM. As such, decisions regarding invasive septal reduction treatment for obstructive HCM patients (ie, myectomy or alcohol septal ablation) are based on assessment of a patient's NYHA functional class by history taking. Specifically, there is no peak Vo₂ cutoff point below which it would be justified to recommend invasive septal reduction therapy in an asymptomatic or mildly symptomatic obstructed HCM patient. For this reason, peak Vo₂ values are not considered in the management of obstructive HCM patients unless the extent of limitation, as assessed by the clinical history, is ambiguous, in which case CPET can be employed to aid in helping to clarify the degree of functional disability. This management strategy is supported by the American College of Cardiology/American Heart Association HCM treatment guidelines [40].

In nonobstructive patients with HCM with advanced HF who are being considered for heart transplant, CPET should be considered part of this evaluation. In a similar manner to non-HCM forms of HF, a Vo₂ ≤14 mL/kg/min (or ≤50 percent predicted for age) may add greater weight in determining candidacy for transplant. However, nonobstructive HCM patients who did not demonstrate a peak Vo₂ below this cutoff should not be excluded from transplant consideration since a mismatch may exist in some patients between peak Vo₂ and extent of exercise limitation.

Other tests

Cardiovascular magnetic resonance — We suggest performing CMR in all patients with suspected or diagnosed HCM to most reliably assess LV morphology, including maximal LV wall thickness, as well as to further inform risk stratification with assessment of extent of late gadolinium enhancement (LGE). Given the emerging data supporting extensive LGE on contrast-enhanced CMR as a marker of arrhythmic risk, it is reasonable to consider repeating CMR on a three- to five-year basis in select young and middle-aged patients to re-evaluate for potential progression in LGE, although this strategy is expert opinion and not yet supported by prospective studies. In addition, in patients with HCM being considered for invasive septal reduction therapy in whom the mitral valve and papillary muscle anatomy are not well defined with echocardiography, CMR can be performed to clarify if a patient is better suited for alcohol septal ablation or surgical myectomy.

For the assessment of anatomic structures, CMR imaging may provide additional information beyond that which is available from echocardiography [56-59]. Cardiovascular magnetic resonance, with its high spatial resolution and tomographic imaging capability, has emerged as a technique particularly well suited to characterizing the diverse phenotypic expression of HCM (image 4) [56]. CMR can identify areas of segmental LVH (ie, anterolateral wall or apex) not reliably visualized by echocardiography (or underestimated in terms of extent) (image 5), better characterize structural abnormalities of the mitral valve and papillary muscles, and, when intravenous contrast with gadolinium is used, allow for identification of myocardial fibrosis [56,60-64].

In the majority of patients with HCM, maximal LV wall thickness measurements obtained by CMR and echocardiography are similar, but discrepancies greater than 10 percent of the maximal LV wall thickness can occur. In instances where the determination of massive LVH would impact management decisions, CMR should be performed to more reliably assess maximal LV wall thickness. (See "Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death", section on 'Established major risk markers'.)

●In a study of 195 patients with HCM who underwent both echocardiography and CMR within a six-month period, maximal LV thickness was similar with both techniques, but in 97 patients (50 percent) there was a ≥10 percent discrepancy in maximal LV wall thickness between the two imaging modalities [65]. In the majority of these instances, echocardiography overestimated maximal LV wall thickness most often due to inclusion of the crista ventricular RV muscle in the short-axis transdimensional measurement of the basal ventricular septum. Less commonly, echocardiography underestimated maximal LV wall thickness, particularly when regional hypertrophy was confined to anterolateral wall, posterior septum, and apex.

●In a study of 48 patients with a suspected or confirmed HCM diagnosis who underwent both echocardiography and CMR, maximal LV thickness was similar with both techniques, but CMR identified areas of thickening in the anterolateral LV free wall in three patients (6 percent) in whom echocardiography showed no areas of hypertrophy, thereby making a new diagnosis of HCM [62]. In addition to identifying areas of hypertrophy that may not be well visualized by echocardiography, a significant number of patients will have discrepant measurement of maximal wall thickness between echocardiography and CMR, particularly patients with massive LVH [66].

In addition to its ability to identify additional regions of LVH not seen with echo, CMR is helpful in characterizing structural abnormalities of the mitral valve (ie, elongation leaflets) and papillary muscles (ie, accessory and apically displaced or anomalous insertion into the mitral valve leaflet) and can more precisely identify the mechanisms responsible for LVOT obstruction [56,61,67,68]. Because of the importance of mitral valve and papillary muscle anatomy in patients with LVOT obstruction who are being considered for invasive septal reduction therapy, CMR should be performed as part of the evaluation [40].

With the intravenous injection of gadolinium, areas of hyperenhancement (ie, late gadolinium enhancement [LGE]) representing myocardial fibrosis within the myocardium can be identified with contrast-enhanced CMR [56,69]. The amount of LGE can be quantified as a percent of the total LV mass. Approximately half of patients with HCM demonstrate LGE, with a diverse pattern and location (not related to a coronary vascular distribution), although most commonly involving hypertrophied segments of the LV wall and at the junctions of the ventricular septum and right ventricular free wall [70].

In a prospective multicenter cohort of almost 1300 patients with HCM who underwent quantitative contrast-CMR, extensive LGE was an independent predictor of sudden death, with ≥15 percent of LV mass conveying a twofold increase in sudden death risk, even among those patients with HCM who do not have conventional sudden death markers [71]. Observational studies have also suggested that patients with HCM and LGE were at greater risk for ventricular tachyarrhythmias on ambulatory 24-hour Holter ECG compared with those without LGE, suggesting that myocardial fibrosis may represent the structural nidus responsible for the generation of potentially lethal reentry ventricular tachyarrhythmias [72]. (See "Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death".)

The independent predictive value of LGE in identifying patients with HCM who are at risk for sudden death is still debated among experts, and therefore management decisions about ICD therapy for primary prevention should not be made based solely on the results of the CMR study [73]. However, substantial LGE also has the potential to resolve complex ICD decision making, acting as an arbitrator in selected patients for whom sudden death risk remains ambiguous even after standard risk stratification, while the absence of LGE is associated with lower risk for adverse events and may provide a measure of reassurance to patients [71]. In addition, preliminary data suggest that the prevalence and extent of late gadolinium enhancement appears similar in children as adults and may also identify young patients at increased risk for adverse disease-related events, although additional studies are necessary to confirm these observations [74]. (See "Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death" and "Hypertrophic cardiomyopathy: Natural history and prognosis", section on 'Hypertrophy and fibrosis'.)

In addition to detecting LVH and myocardial fibrosis, CMR can provide additional information in patients with HCM, including the following:

●Identification and quantification of right ventricular hypertrophy [75]

●Evidence of microvascular dysfunction [76] (see 'Exercise testing' above and "Hypertrophic cardiomyopathy: Natural history and prognosis", section on 'Mortality')

●Assessment of regional myocardial function [60,77,78]

●Assessment of diastolic function [79]

●Subtle structural abnormalities that may precede hypertrophy (eg, myocardial crypts) [80]

Genetic testing for HCM — Routine genetic testing in isolation (ie, without concurrent clinical evaluation with ECG, imaging, etc) is not recommended for the diagnosis of HCM [40,81-83]. However, targeted genetic testing may be useful (in conjunction with clinical evaluation) in two specific scenarios:

●When family history or clinical evaluation raises suspicion for another genetic condition known to cause LVH (ie, Fabry disease, lysosomal storage diseases, etc)

●In first degree family members of a proband with HCM and a definitively identified gene-causing mutation

As of 2019, up to 11 causative genes with over 1500 mutations in genes encoding the thick or thin myofilament proteins of the sarcomere have been reported (figure 4) [84]. In addition, mutations in genes regulating calcium-handling and other components of the sarcomere have been proposed, but with less evidence supporting pathogenicity [85]. Due to this substantial genetic heterogeneity, clinic genetic testing can identify a disease-causing sarcomere protein mutation in less than half of patients with a phenotype of HCM, and disease expression among first-degree family members with HCM can be dramatically different [42,86,87]. In addition, identifying patients with HCM who are at risk for adverse disease-related events including sudden death cannot be predicted based on specific mutations, and specific HCM phenotypes have diverse mutations associated with them, suggesting it is not possible to predict phenotype based on a specific mutation [88]. As a result, management decisions (eg, need for ICD insertion for primary prevention, medical or septal reduction therapy for symptomatic LVOT obstruction, etc) cannot be made solely based on results derived from genetic testing.

The role of genetic testing in assessing for family members at risk for developing HCM is discussed in greater detail elsewhere. (See 'Screening of first-degree relatives' below and "Hypertrophic cardiomyopathy: Gene mutations and clinical genetic testing", section on 'Screening of family members for HCM'.)

Cardiac catheterization — We typically reserve invasive hemodynamic assessment using cardiac catheterization for patients with suspected HCM and one or more of the following situations:

●Persons in whom the additional diagnosis of restrictive cardiomyopathy or constrictive pericarditis is being considered.

●Persons in whom invasive coronary angiography is being performed for the evaluation of obstructive coronary disease.

●Persons in whom a suspicion for LVOT obstruction is present but the clinical and imaging data are discrepant.

●Persons in whom endomyocardial biopsy is indicated to exclude nonsarcomeric disease (eg, Fabry disease, amyloidosis, Danon disease). (See "Hypertrophic cardiomyopathy: Gene mutations and clinical genetic testing".)

●Pre-cardiac transplantation evaluation.

Cardiac catheterization is rarely required for diagnosis or clinical evaluation of HCM. In most patients, echocardiography provides sufficient information regarding cardiac output, LV filling pressure or LA pressure, and LVOT pressure gradient such that cardiac catheterization is not necessary. (See "Differentiating constrictive pericarditis and restrictive cardiomyopathy", section on 'Cardiac catheterization'.)

Pressure gradient — An LVOT gradient is demonstrated in patients with HCM via the measurement of simultaneous LV and aortic pressures using a double lumen pigtail or helical-tip catheter and the side arm of a femoral artery sheath, which contain fluid-filled transducers (waveform 5A-B). For best use of the peripheral pressure, the femoral and ascending aortic pressures should agree within 5 mmHg.

The true pressure gradient across the LVOT is revealed by the careful withdrawal of the catheter from the LV apex to the LVOT under the valve then into the ascending aorta. The most accurate estimation of the intraventricular obstruction is provided by the difference in LV systolic pressures measured at sites distal and proximal to the LV obstruction.

Certain characteristics of the pressure gradient help distinguish HCM from aortic valvular disease. As examples, the LVOT obstruction in HCM, unlike that due to valvular disease, is associated with the following features:

●It is within the LV (intraventricular) (waveform 2).

●It may be variable and labile. When obstructive, the aortic pressure has a characteristic "spike and dome" configuration of early LV obstruction.

●The timing and upstroke of the initial LV and the aortic pressure tracings are similar and rapid in upstroke (as compared with slow upstroke in aortic stenosis).

●A premature ventricular complex/contraction (PVC; also referred to a premature ventricular beats or premature ventricular depolarizations) can distinguish aortic stenosis from HCM. (See 'Augmentation of the gradient' below.)

Augmentation of the gradient — The LVOT gradient of HCM can be altered by the following maneuvers (waveform 6):

●Decreasing LV end-diastolic volume (preload) increases the LVOT gradient

●Lowering LA filling pressure increases the LVOT gradient

●Prolonging the length of diastole increases the LVOT gradient

●Increasing the force or duration of ventricular contraction increases the LVOT gradient

●Decreasing aortic outflow resistance (afterload) increases the LVOT gradient

Common maneuvers that have been employed in the cardiac catheterization laboratory to induce intraventricular gradients include:

●Valsalva maneuver – The Valsalva maneuver lowers preload due to reductions in venous return.

●Administration of nitroglycerin, which lowers preload through venodilation.

●Postextrasystolic potentiation – Postextrasystolic potentiation produces an increase in LV inotropic state, which may result in an increase in systolic anterior motion of the mitral valve and LVOT obstruction, and a decreased aortic pulse pressure (Brockenbrough-Braunwald-Morrow sign).

Aortic pressure — The aortic upstroke is usually rapid. There may be a spike and dome-like pattern to the aortic pressure, reflecting the interventricular obstruction and transient reduction in stroke volume that occurs during LV systole. This transient reduction in stroke volume can also be seen on an M-mode echocardiogram of aortic valve movement (waveform 7).

Left ventricular pressure — In addition to the variable elevations in LV pressure, there are LV diastolic abnormalities (similar to those observed in valvular aortic stenosis) that result from LVH and reduced compliance. LV end-diastolic pressure is increased and a prominent "a" wave may be observed (figure 5 and figure 6).

Left atrial or pulmonary capillary wedge pressure — As with valvular aortic stenosis, HCM may be associated with LA hypertrophy and reduced LV compliance resulting from LVH. A marked increase in LA pressure therefore occurs during atrial contraction, which is manifested as an increased "a" wave.

Coronary angiography — Coronary angiography should be performed in patients with apparent anginal chest pain when knowledge of coronary anatomy may affect therapy or when cardiac surgery is planned. Although the epicardial coronary arteries are usually large and normal in patients presenting with angina, coronary artery disease may coexist with HCM and must be ruled out [40,89]. In the absence of obstructive epicardial coronary artery disease, angina may be due to regionally impaired coronary flow and altered coronary flow reserve [90].

Electrophysiology studies — Syncope and presyncope in patients with HCM may be due to arrhythmias, LVOT obstruction, or inappropriate vasodilatation despite an adequate cardiac output. However, an invasive electrophysiology study rarely identifies the underlying mechanism and is not indicated to determine the need for ICD therapy for primary prevention of sudden death. (See "Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death", section on 'Risk modifiers'.)

Plasma BNP — The range of values associated with plasma brain natriuretic peptide (BNP) and N-terminal pro-BNP concentration is quite broad and does not correlate well with HF symptoms in patients with HCM. As a result, we do not order this test as part of the diagnostic or prognostic evaluation of patients with suspected HCM. (See "Natriuretic peptide measurement in heart failure" and "Heart failure: Clinical manifestations and diagnosis in adults".)

DIAGNOSIS — In an individual patient, the diagnosis of HCM may be suspected based on the following: family history of HCM, unexplained symptoms (ie, dyspnea, chest pain, fatigue, palpitations), systolic ejection murmur, and abnormal 12-lead electrocardiogram or syncope (or presyncope). The presence of one or more of these clinical findings should prompt further testing with echocardiography and/or cardiac magnetic resonance imaging to confirm diagnosis. The presence of increased left ventricular (LV) wall thickening ≥15 mm anywhere in the LV wall in the absence of any other identifiable cause such as hypertension or valve disease is consistent with a diagnosis of HCM [42]. Other common findings such as mitral valve systolic anterior motion (SAM) or hyperdynamic LV are not obligatory for an HCM diagnosis. (See 'Differential diagnosis' below.)

Because of the advances in noninvasive imaging, invasive assessments to make the diagnosis of HCM are rarely necessary. On occasion, however, invasive hemodynamic assessment using cardiac catheterization may identify a LV outflow tract gradient which could not be confirmed using noninvasive techniques and may be necessary to exclude coronary artery disease.

While the presence of a pathogenic sarcomeric mutation may be helpful for determining if family members are at risk for developing HCM, genetic testing for HCM should not be performed routinely for diagnostic purposes. (See 'Genetic testing for HCM' above.)

DIFFERENTIAL DIAGNOSIS

Differential diagnosis of LVH — In the patient presenting with left ventricular hypertrophy (LVH), HCM must be distinguished from acquired causes of cardiac hypertrophy. The most common causes are hypertension and aortic stenosis; in a minority, HCM may coexist with either. Among 2472 consecutive patients diagnosed with HCM and LVOT obstruction who underwent septal myectomy at an HCM referral center between 2002 and 2018, 331 patients (13 percent) had postoperative histologic confirmation of an alternative diagnosis (primarily hypertensive heart disease in 280 patients [11 percent] but also storage disorders [mainly Fabry disease] and cardiac amyloidosis) [91]. (See "Clinical manifestations and diagnosis of aortic stenosis in adults", section on 'Diagnostic echocardiography'.)

A rare cause of cardiac hypertrophy is Fabry disease, an X-linked recessive glycolipid storage disease. Although classic multisystem Fabry disease is rare, isolated cardiac involvement may be relatively common in patients with otherwise unexplained concentric LVH (up to 5 percent). In a cohort of 585 patients diagnosed with HCM who subsequently underwent screening for Fabry disease, two patients (0.3 percent) were identified with Fabry disease, leading to family screening that identified 27 new cases of Fabry disease [92]. Given the implications associated with a diagnosis of Fabry disease, in which management strategies differ from sarcomeric HCM including treatment strategies with enzyme replacement therapy, consideration should be made to testing adult patients with presumed sarcomeric HCM for Fabry disease. (See "Fabry disease: Cardiovascular disease", section on 'Ventricular hypertrophy'.)

Other even more uncommon causes of cardiac hypertrophy are metabolic cardiomyopathies in which mutations alter glycogen metabolism in the heart (and other organs). The two most common metabolic myocardial storage cardiomyopathies are PRKAG2 and LAMP2 (Danon cardiomyopathy), both of which demonstrate a clinical phenotype of LVH that mimics the disease expression of "typical" sarcomeric HCM. (See "Lysosome-associated membrane protein 2 deficiency (glycogen storage disease IIb, Danon disease)".)

Hypertension — Long-standing systemic hypertension is the most common cause of LVH, particularly when it has been untreated or incompletely treated. Most persons with hypertension as the cause of LVH will be beyond adolescence, when HCM is most commonly identified. The hypertrophy seen in hypertension, however, rarely leads to wall thicknesses in excess of 1.5 cm. Additionally, hypertension is usually suspected in persons with an extended history of elevated blood pressures (10 or more years), particularly in those with other evidence of end-organ damage due to hypertension (eg, retinopathy, nephropathy).

Aortic stenosis — Valvular AS due to stenosis of a congenital bicuspid aortic valve is more common in younger persons (less than 50 years of age), while in those older than 50 years of age, valvular AS is typically due to atherosclerotic narrowing of the valve. In both situations, concentric LVH develops, which is different than the eccentric hypertrophy seen in HCM. Valvular AS can usually be distinguished from other causes of LVH by echocardiography or invasive cardiac catheterization, which allow for visualization of the restricted leaflet motion. (See "Clinical manifestations and diagnosis of aortic stenosis in adults" and "Clinical manifestations and diagnosis of bicuspid aortic valve in adults", section on 'Aortic stenosis'.)

Valvular aortic stenosis also causes an increased pressure gradient between the LV and aorta. (See 'Valvular aortic stenosis' below.)

Athlete's heart — Highly trained athletes can also develop cardiac hypertrophy (sometimes called "athlete's heart"), resulting in wall thickness measurements in a range that can overlap with those seen in patients with HCM (ie, wall thickness "grey zone" of 13 to 15 mm). As a result, a number of noninvasive measures have been proposed to help differentiate athlete's heart from HCM (figure 7) [56,93].

Various exercise training disciplines appear to have qualitatively and quantitatively different effects on cardiac structure and function. While both endurance and strength training induce increases in LV mass, strength training generally leads to greater hypertrophy. Since athletes with a cardiomyopathy can be at risk of arrhythmias during physical exertion, it is important to exclude such disorders before attributing cardiovascular, electrophysiological, or structural changes to athletic training. (See "Athletes: Overview of sudden cardiac death risk and sport participation", section on 'Hypertrophic cardiomyopathy'.)

Criteria to distinguish HCM from athlete's heart — In individuals with a possible diagnosis of athlete's heart versus HCM, family history, ECG, and LV cavity dimensions may help distinguish HCM from cardiovascular adaptation in an athlete [94,95]. The evidence associated with these findings is discussed in detail separately. (See "Definition and classification of the cardiomyopathies", section on 'Athlete's heart'.)

●ECG – The ECG changes that develop as part of the cardiovascular adaptation in an endurance athlete include sinus bradycardia, increased QRS voltage, tall peaked T wave, J point elevation, and U waves. Pathological Q waves, left axis deviation, and T wave inversion, however, strongly favor a diagnosis of HCM. The combination of Q and S wave amplitude in lead III has been shown to be significantly higher in patients with HCM compared with athletes (0.7 versus 0.2 millivolts, respectively) in one referral cohort [96].

●Extent and pattern of LVH – As noted above, the magnitude of expected LV wall thickening varies with degree and type of athletic training. A finding of a greater degree of LVH than expected for the degree and type of athletic training favors a diagnosis of HCM. In this regard, only high-level endurance training has been associated with LVH of 13 to 15 mm. Of note, the maximal LV wall thickness achieved by female athletes almost never exceeds 14 mm [97].

●LV cavity size – In a study comparing 28 athletes with 25 untrained patients with HCM, athletes had significantly larger LV cavities (end-diastolic measurement of 60 versus 45 mm, respectively), with LV end-diastolic diameter <54 mm distinguishing HCM versus athletes heart with 100 percent sensitivity and specificity in this study [94].

●Doppler and tissue Doppler echocardiography – Depressed Ea velocities found in patients with HCM contrast with the normal or above normal Ea velocities seen in trained athletes who may also have LVH, although Ea velocities for these populations have not been directly compared within a study [98,99].

●Cardiac magnetic resonance (CMR) imaging – CMR can most accurately compare maximal LV wall thickness measurements before and after a period of systematic deconditioning.

•Patients in whom wall thickness regresses greater than 2 mm supports a diagnosis of athlete's heart, while hypertrophy that remains unchanged suggests HCM.

•Baseline measurements prior to deconditioning can also be helpful as patients with HCM have greater LV wall mass and small LV chambers sizes compared with athletes. In one study of CMR in 45 patients with HCM and 734 healthy controls (including 75 percent labelled "athletic"), the ratio of LV end-diastolic volume to LV wall mass was significantly lower in patients with HCM compared with athletes and nonathletes (1.3 compared with 2.4 and 2.3, respectively) [100].

•Additionally, it does not appear that competitive athletes demonstrate late gadolinium enhancement (LGE, which suggests myocardial fibrosis), and therefore the presence of LGE may also provide additional information to confirm a diagnosis of HCM [101,102].

●Functional exercise testing – Lower than expected levels of peak oxygen consumption (Vo₂peak) may aid in the differentiation between HCM and physiologic LVH in an athlete. In a study that compared eight athletic males with genetically proven HCM and mild LVH to eight matched elite athletes with the same LV wall thickness, the elite athletes without HCM had a significantly greater peak Vo₂, anaerobic threshold (percent of the predicted peak Vo₂), and oxygen pulse (mL/beat) than patients with HCM [103]. A peak Vo₂ >50 mL/kg per min or >20 percent above the predicted Vo₂max, an O₂ pulse >20 mL/beat, or an anaerobic threshold >55 percent of the predicted Vo₂max were indicators of physiologic LVH rather than HCM. (See "Cardiopulmonary exercise testing in cardiovascular disease".)

●Genetic testing for HCM can also be considered. The identification of a disease-causing sarcomere mutation in an athlete with a maximal LV wall thickness in the "grey zone" would provide a definitive diagnosis of HCM. (See "Hypertrophic cardiomyopathy: Gene mutations and clinical genetic testing", section on 'Clinical applications of genetic testing'.)

Differential diagnosis of increased LV to aortic gradient — Other than the dynamic subaortic (LV outflow tract [LVOT]) obstruction seen in HCM, several other anatomic and physiologic abnormalities can be associated with increased pressure gradients between the LV and the aorta.

Volume depletion — Patients with significant volume depletion in the setting of normal LV systolic function will often develop hyperdynamic ventricular function in an effort to maintain cardiac output. Hyperdynamic LV function results in more vigorous ejection of blood from the heart at a higher velocity than normal, leading to an intracavitary gradient which may be mistaken for an increased LVOT gradient. An intracavitary gradient is usually suspected from the clinical scenario (eg, hypotension, tachycardia, other signs of hypovolemia) and almost always disappears following fluid resuscitation.

Subaortic stenosis — Fixed subvalvular aortic stenosis (AS) is a congenital abnormality typically caused by a thin membrane of tissue in the LVOT which is typically seen on two-dimensional echocardiography as well as both color and spectral Doppler echocardiography. Fixed subaortic stenosis can usually be distinguished from HCM and valvular AS by echocardiography or invasive cardiac catheterization.

Unlike the dynamic LVOT obstruction seen in persons with HCM, there is typically no evidence of systolic anterior motion of the mitral valve, and the ventricular wall thickness is normal (although long-standing LV hypertension due to a significant gradient across the membrane can lead to concentric LVH). Unlike valvular AS, the aortic valve leaflets are usually normal (although long-standing high-velocity turbulent flow across the membrane over years to decades may result in aortic valve damage). (See "Subvalvar aortic stenosis (subaortic stenosis)".)

Valvular aortic stenosis — In addition to potentially causing LVH, narrowing of the aortic valve opening can lead to a significant pressure gradient between the LV and the aorta. As with subaortic stenosis, valvular AS can usually be distinguished from other pathology by echocardiography or invasive cardiac catheterization. (See 'Aortic stenosis' above.)

GENOTYPE POSITIVE/PHENOTYPE NEGATIVE PATIENTS — With the use of genetic testing, HCM family members who carry a disease-causing sarcomere mutation but without left ventricular hypertrophy (LVH) can now be identified (so-called genotype positive/phenotype negative patients). In approximately 50 percent of these individuals, the ECG will be abnormal. Although these patients have no increased wall thickness, a number of observations have suggested that the myocardium may still not be structurally normal. For example, abnormalities such as myocardial fibrosis by contrast-cardiac magnetic resonance, collagen biomarkers, mitral leaflet elongation, diastolic dysfunction, and blood-filled myocardial crypts have all been shown to occur in gene carriers [104].

The likelihood of developing clinical evidence of HCM with LVH in family members who have a sarcomere mutation is uncertain. Estimates on the likelihood of phenotypic conversion range from annual rates of less than 1 percent to 5 percent.

●Among one cohort of 38 patients at risk for developing HCM but without phenotypic evidence of HCM at their initial evaluation (include 12 genotype-positive, phenotype-negative patients and 26 relatives of an HCM proband in whom gene testing did not identify a specific disease-causing mutation) who had serial follow-up evaluations over a mean of 12 years, two patients (6 percent) subsequently developed phenotypic evidence of HCM [85,105].

●In a cohort of 203 genotype-positive, phenotype-negative patients with serial follow-up over a mean of six years, 21 patients (10 percent) subsequently developed phenotypic evidence of HCM [106]. However, 20 percent of the study patients had achieved >50 years of age without development of LVH, including 5 percent over age 60. In addition, over a mean follow-up of 6 years, no adverse cardiovascular events occurred in the study cohort. These data suggest that it is possible for many genotype-positive, phenotype-negative patients to achieve normal longevity without developing LVH or incurring HCM-related complications.

Clinical follow-up with longitudinal screening should continue based on the current screening recommendations. (See 'Screening of first-degree relatives' below.)

The risk of sudden death in gene carriers is also unknown but considered to be very low, and therefore consideration for prophylactic ICD should be resolved on an individual case basis. However, current society guidelines do not recommend excluding genotype positive/phenotype negative HCM family members from participating in organized competitive sports [107-109].

SCREENING OF FIRST-DEGREE RELATIVES — HCM is an autosomal dominant disorder, and most (but not all) mutations have a high degree of penetrance. As a result, first-degree family members of an affected individual should be evaluated for possible inheritance of the disease (algorithm 1). We agree with the recommendations of others that the components of family screening should include history, physical examination, electrocardiography (ECG), and echocardiography [38,40,110]. Screening is not routinely recommended before the age of 12 years unless the child has a high-risk family history or is participating in intense competitive sports. We do not recommend routine genetic screening of first-degree relatives unless a definite HCM-causing mutation has been identified in the index case. Additionally, while some experts recommend genetic testing in first-degree relatives for the pathogenic mutation identified in the proband prior to performing clinical evaluation with ECG and echocardiography, UpToDate experts recommend only offering cascade genetic testing of family members after initial comprehensive clinical evaluation to determine if HCM is present.

Among first-degree adult relatives of patients with HCM, otherwise unexplained echocardiographic and ECG abnormalities identified during screening examinations have a high probability of reflecting the expression of HCM [111]. First-degree relatives who are children, however, may have HCM identified at a younger age, in particular when a family member has had a childhood presentation with HCM. In a cohort of 1198 consecutive children ≤18 years of age (mean age 8 years, 80 percent who were ≤12 years of age) referred for screening following diagnosis of HCM in a first-degree relative, 57 patients (4.8 percent) were diagnosed with HCM at a mean age of 10 years, either at initial screening (n = 32) or during serial evaluations (n = 25) [112]. However, whether earlier routine screening with echocardiography in pre-adolescent family members ultimately improves clinical outcomes remains unresolved.

Family members who have a normal evaluation should not necessarily be assumed to be free of risk:

●Because hypertrophy usually develops during adolescence, clinical evaluation should be repeated annually from 12 to 18 years of age.

●Due to the possibility of delayed-onset hypertrophy, it is recommended that adult family members with normal ECGs and echocardiograms who are over the age of 18 be reevaluated approximately every five years. There may be a role for tissue Doppler echocardiography in such patients, where abnormalities in contraction and relaxation velocities can suggest pre-clinical myocardial dysfunction [113-115]. However, these abnormalities are not considered diagnostic for HCM and rarely precede the development of ECG abnormalities.

The identification of gene mutations for HCM has led to interest in the development of DNA-based testing of patients with HCM and screening of family members. Genetic screening may accurately define the risk of disease development, but it is not universally available and presents additional possible concerns. Additionally, not all persons with a genotype-positive mutation will have the HCM phenotype identified by ECG or echocardiography. The issue of genetic testing and screening for HCM with genetic testing is discussed in greater detail separately. (See "Hypertrophic cardiomyopathy: Gene mutations and clinical genetic testing", section on 'Screening of family members for HCM'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cardiomyopathy".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

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 topic (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

●Prevalence – Hypertrophic cardiomyopathy (HCM) is a genetic cardiomyopathy caused by mutations of the cardiac sarcomere, resulting in heterogeneous phenotypic expression with respect to the extent, location, and distribution of left ventricle (LV) wall thickening as well as a diverse clinical course including sudden death, heart failure, and stroke. The prevalence of HCM in the general population may be as common as 1 in 200 adults. (See 'Introduction' above and 'Prevalence' above.)

●Histologic findings – Histopathology in patients with HCM reveals disorganized myocyte architecture, including hypertrophied myocytes in a disarray pattern with bizarre-shaped nuclei, abnormal intramural coronary arteries, and interstitial as well as replacement fibrosis (picture 1). (See 'Histologic findings' above.)

●Clinical manifestations – While many patients with HCM remain asymptomatic, it is not uncommon for patients to develop one or more of the following symptoms: dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea, chest pain, palpitations, presyncope/syncope, postural lightheadedness, fatigue, or edema. (See 'Signs and symptoms' above.)

•The physical examination in HCM may be normal or may reveal nonspecific abnormalities such as a fourth heart sound, systolic murmur, and/or an LV lift. Patients with LV outflow tract (LVOT) obstruction may have a harsh crescendo-decrescendo systolic murmur, which develops slightly after S1 and is heard best at the apex and lower left sternal border. Several physical exam maneuvers can affect the degree of obstruction, resulting in a change in murmur intensity.

●Diagnostic evaluation – The evaluation for HCM in an individual patient may be prompted by a family history of HCM, systolic ejection murmur, abnormal 12-lead electrocardiogram showing otherwise unexplained evidence of LV hypertrophy (LVH), and clinical symptoms including syncope. In addition to performing a comprehensive cardiac history and physical examination and an electrocardiogram (ECG) in all patients with suspected HCM, cardiac imaging to identify LVH should be performed. (See 'Diagnostic evaluation' above.)

•ECG – Although the ECG is abnormal in 90 percent of patients with HCM (waveform 4), no specific pattern is diagnostic. Typically, the ECG shows repolarization abnormalities but also may include prominent abnormal Q waves, P wave abnormalities, left axis deviation, and deeply inverted T waves. (See 'Electrocardiography' above.)

•Echocardiography – Two-dimensional echocardiography can be used to reliably diagnose patients with HCM when an area of increased LV wall thickness is imaged anywhere in the LV wall in the absence of another cause. Echocardiographic findings suggestive of HCM include LVH (particularly when asymmetric and involving the septum or anterolateral wall), systolic anterior motion of the mitral valve leaflets, particularly with septal contact resulting in an associated subaortic LVOT gradient. In addition, we suggest performing cardiovascular magnetic resonance (CMR) in all patients with suspected or diagnosed HCM to most reliably assess LV morphology, including maximal LV wall thickness, as well as to further inform risk stratification with assessment of extent of late gadolinium enhancement (LGE). (See 'Echocardiography' above and 'Cardiovascular magnetic resonance' above.)

•Exercise testing – The majority of patients with HCM have LVOT obstruction under resting conditions or following exercise. Because the identification of a provocable LVOT gradient may result in additional treatment options for heart failure symptoms (ie, disopyramide, septal reduction therapy), we proceed with exercise stress testing in all patients with known or suspected HCM, without resting LVOT obstruction, as part of the initial HCM evaluation. Exercise should be performed as the stress agent rather than using a pharmacologic stress agent, as a maximal treadmill or bicycle exercise stress test provides an objective measurement of functional capacity and information on the integrity of vascular responses and the risk of exercise related ischemia, arrhythmia, and obstruction. (See 'Exercise testing' above.)

•Genetic testing – Genetic testing is available for clinical use but is predominately reserved for identifying patients who may have a disease which appears phenotypically similar to sarcomere HCM, such as Fabry disease or a lysosomal/glycogen storage disease, or to help identify family members who may be at risk of developing HCM. (See 'Genetic testing for HCM' above.)

●Diagnosis – The diagnosis of HCM can usually be made following echocardiography and/or CMR imaging, and invasive diagnostic assessments are rarely necessary. We typically reserve invasive hemodynamic assessment using cardiac catheterization for patients with suspected HCM to exclude obstructive coronary artery disease, distinguish pericardial constriction from severe restrictive physiology, to perform endomyocardial biopsy to exclude nonsarcomeric causes of HCM, or for pre-cardiac transplant assessment. (See 'Diagnosis' above.)

●Differential diagnosis – In the patient presenting with LVH, HCM must be distinguished from acquired causes of cardiac hypertrophy, including hypertension, aortic stenosis, cardiac amyloid, and athlete's heart or other genetic heart diseases which phenotypically mimic sarcomeric HCM (Anderson-Fabry and glycogen storage disease). Other than the dynamic subaortic (LVOT) obstruction seen in HCM, several other anatomic and physiologic abnormalities can be associated with increased pressure gradients between the LV and the aorta, including volume depletion, subaortic stenosis, and valvular aortic stenosis. (See 'Differential diagnosis' above.)

●Testing of first-degree relatives – HCM is an autosomal dominant disorder, and some mutations have a high degree of penetrance. As a result, first-degree family members of an affected individual should be evaluated for possible inheritance of the disease. The components of family screening should include history, physical examination, electrocardiography (ECG), and echocardiography. We do not recommend routine genetic screening of first-degree relatives unless a definite HCM-causing mutation has been identified in the index case. (See 'Screening of first-degree relatives' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledges Perry Elliott, MD, who contributed to earlier versions of this topic review.