Hypertrophic Cardiomyopathy

Etiology

Familial HCM occurs as an autosomal dominant Mendelian-inherited disorder in approximately 60% of cases. Incomplete penetrance and variable expression can cause unpredictable manifestations, even within the same family. In individuals diagnosed with HCM and a known pathogenic sarcomeric gene variant, the 2 most frequently detected genes are β-myosin heavy chain 7 (MYH7) and myosin-binding protein C3 (MYBPC3), accounting for about 75% of known variant-positive patients.[5] Less common genetic variants encode thin filament proteins, such as troponin T, troponin I, myosin light chains, and actin; TNNI3, TNNT2, TPM1, MYL2, MYL3, and ACTC1 mutations make up a smaller proportion of patients, ranging from 1% to 5%. Over 1500 variants causing HCM have been identified, with most unique to each family. No clear connection has been shown between prognosis and specific gene mutation.

A significant portion of individuals diagnosed with HCM do not have a genetic explanation for their condition; this includes a subset of patients, up to 40% in some studies, who do not have any family members affected by the disease—known as “nonfamilial” HCM. These findings suggest the existence of other yet undiscovered pathophysiological mechanisms that may play a role in the manifestation of HCM pathology.[6] Recent data has also associated abnormal myocardial calcium kinetics with the cause of inappropriate myocardial hypertrophy and specific features of HCM, especially in patients with diastolic functional abnormalities.[7][8][9][10]

Epidemiology

The prevalence of HCM in the general population worldwide is 0.2% (1 in 500 adults), as determined by echocardiographic studies. Morphologic abnormalities are found in approximately 25% of first-degree relatives of patients with HCM. HCM is more common in males than females, although the condition is autosomal dominant, and genetic inheritance does not follow sex predilection. The explanation for this phenomenon may be related to screening strategies, genetics, or hormonal regulation.[11] However, there is evidence that women are diagnosed at an older age and have a worse prognosis, suggesting that diagnosis strategies should be revisited.[2][5] The most common presentation of HCM is in the third decade of life but may be present at any age, from newborns to older individuals.

Pathophysiology

Wall thickening can involve any area of the myocardium, but the interventricular septal wall is the most commonly affected location. In the absence of other conditions that could possibly contribute to left ventricular hypertrophy (LVH), such as severe hypertension or aortic stenosis, HCM is usually diagnosed by echocardiogram.

• HCM in adults is characterized by a left ventricular wall thickness of 15 mm or more, with a septal/posterior wall thickness ratio of over 1.3 in patients who are normotensive or over 1.5 in those who are hypertensive. A wall thickness of 13 to 14 mm can be diagnostic for positive family history, evidence of left ventricular outflow tract obstruction (LVOTO), or electrocardiogram (ECG) abnormalities.[12]                                                                                                                                                          
• In children, hypertrophy is defined as a wall thickness that is at least 2 standard deviations above the mean (z-score ≥2) for age, sex, or body size or LV wall thickness of 13 mm or more.[12]

Five mechanisms contribute to the development of HCM: dynamic LVOTO, mitral regurgitation, diastolic dysfunction, myocardial ischemia, and autonomic dysfunction.

Dynamic LVOTO: Obstruction can occur either at rest or with exercise. About one-third of patients will each have no obstruction, obstruction with exercise, or obstruction at rest. A gradient of 30 mm Hg or more is considered hemodynamically significant and is associated with death and progression to heart failure; however, a gradient of 50 mm Hg or more is regarded as a threshold for surgical and percutaneous intervention, primarily if symptomatic.[5] The gradient can also be provoked by changes in preload and afterload, as later described in the History and Physical section.                                                                                                                      

• The likelihood of obstruction is typically determined by the pattern of hypertrophy in the left ventricle, with classical asymmetric left ventricular hypertrophy (LVH) most commonly affecting the basal interventricular septum.                                                                                                                                                          
• LVOTO in HCM can be attributed to 2 main causes. The first is an increase in septal thickness, which narrows the LVOT and leads to abnormal movement of the mitral valve leaflets. Systolic anterior motion (SAM) of the mitral valve is common in HCM and is defined as displacement of the distal anterior mitral valve leaflet into the LVOT.[13] The second cause is alterations in the structure of the mitral valve, such as elongated leaflets and displacement of the papillary muscles and valve apparatus towards the anterior region. These structural changes render the valve liable to unnatural flow vectors. SAM is more common with a hyperdynamic left ventricle; the ejection fraction is often elevated in HCM (>65%).[14]                                 

Mitral Regurgitation: This can be due to LVOTO or SAM of the mitral valve. The regurgitant jet direction can guide the causative mechanism, and SAM is usually directed posteriorly.[5]                        

Diastolic Dysfunction: The presence of LVH in conjunction with myocardial disarray and fibrosis increases left ventricular stiffness. This, in turn, negatively affects myocardial relaxation and diastolic function, ultimately leading to increased intracavitary pressures in both the left ventricle (LV) and left atrium (LA). Delayed inactivation from abnormal intracellular calcium reuptake has also been observed in patients with HCM.

Myocardial Ischemia: Common findings in HCM include myocardial hypertrophy, microvascular dysfunction, impaired coronary flow reserve, and medial and intimal hypertrophy of intramural arterioles. All these factors contribute to a mismatch between myocardial oxygen supply and demand, resulting in myocardial fibrosis.                                          

Autonomic Dysfunction: Autonomic dysfunction in HCM is defined as an abnormal blood pressure response to exercise—specifically, a failure to increase systolic blood pressure by at least 20 mm Hg or a drop in systolic blood pressure during exercise of more than 20 mm Hg from the peak value—is associated with poor prognosis. The proposed mechanism involves the inappropriate firing of stretch-sensitive mechanoreceptors in the LV myocardium, resulting in unreciprocated changes in systemic vascular resistance, which may lead to episodes of presyncope or syncope.

The most common arrhythmia in HCM is atrial fibrillation, present in about 25% of patients, which is 4- to 6-fold higher than in the general population. Atrial fibrillation is poorly tolerated in patients with HCM. Due to decreased LV compliance, up to 35% of left ventricular filling depends on left atrial contraction. The decreased LV filling can lead to lower cardiac output and hypotension.[7] Non-sustained ventricular tachycardia (NSVT) is present in 20% to 30% of patients with HCM. NSVT can lead to ventricular fibrillation—the most common cause of sudden cardiac death (SCD). Potential etiology of the arrhythmias includes interstitial fibrosis, myocyte disarray, and myocardial ischemia.[14]

Histopathology

The histology of HCM provides crucial insights into the structural changes occurring within the myocardium. HCM is characterized by enlarged cardiomyocytes in the heart muscle, which have eosinophilic cytoplasm and box-shaped nuclei. These cells can exhibit unusual shapes, such as Y-shaped branches, frequent side-to-side connections, or a spiraled appearance around a central fibrous core. The resulting disorganized architecture of the heart muscle can lead to myocardial disarray, with bundles of cardiomyocytes arranged at different angles to each other.

The affected areas can be adjacent to areas of normal myocardium in a patchy nature. The disarray is inversely correlated to fibrosis. Fibrosis is seen interstitially and will stain blue with the Masson trichrome stain.[5][14] Microvascular ischemia can cause cell death and replacement fibrosis, while interstitial fibrosis can lead to arrhythmogenic foci. HCM is also associated with intercellular junction abnormalities in the intercalated discs and desmosomes, which can form “huge mega-discs” that likely contribute to diastolic dysfunction and arrhythmias.[5]

History and Physical

Up to 50% of individuals diagnosed with HCM may not experience any symptoms or may only have mild symptoms—especially patients without LVOTO.[12] The patient history should focus on both family and personal history: 

• Family history of HCM, sudden cardiac death, unexplained syncope 
• Personal history of chest pain, syncope, unexplained dizziness, palpitations, shortness of breath, chest pain

Shortness of breath and chest discomfort are often caused by underlying diastolic dysfunction and LVOTO. Chest pain can present as typical or atypical angina. Individuals with LVOTO may experience more severe symptoms after consuming a heavy meal (postprandial exacerbation). Dizziness and syncope can occur at rest or during physical exertion, and arrhythmia or dynamic LVOTO can be the underlying causes. Palpitations are also common and may indicate underlying episodes of atrial fibrillation or ventricular arrhythmia. Sudden cardiac death represents the most devastating presenting symptom.

Physical examination findings are characterized by a “jerky” pulse with rapid upstroke and downstroke, a normal S1 and split S2, an S3 due to decompensated heart failure, prominent “a wave” of jugular venous pressure, laterally displaced apical impulse, and double carotid pulse. An S4 is also common with LVH.

A harsh mid-systolic ejection murmur at the left sternal border is affected as follows: 

• Diminished intensity with increased preload (squatting) or afterload (handgrip) 
• Increased intensity with a decrease in preload (Valsalva maneuver, standing) or with any reduction in afterload (vasodilator administration)

Exercise will also increase the murmur. If mitral regurgitation is present, a holosystolic, blowing murmur may be loudest at the apex.

Evaluation

Individuals with a family history of HCM, cardiac symptoms or a cardiac event, a heart murmur revealed during a routine physical examination, or an abnormal 12-lead ECG may require further clinical assessment. To accurately evaluate for HCM, a comprehensive cardiac history, including family history spanning 3 generations, and an extensive physical examination (incorporating special provocative maneuvers such as Valsalva, squat-to-stand, or passive leg raising) are necessary. An ECG and cardiac imaging to identify LVH should be performed in all patients.[15][16][17]

Laboratory testing: Lab testing, including Troponin I and T, can be used to detect suspected ischemic events. Elevation of the natriuretic peptides, especially those of the brain, can also be used as a marker of heart failure. Elevated NT-pro-BNP levels are correlated with LV wall stress and diastolic and systolic dysfunction.                                                                                   

Electrocardiogram: ECG is often abnormal, even if LVOTO is not present. Findings include localized or widespread repolarization changes, prominent Q-waves in the inferior (II, III, and aVF) and lateral (I, aVL, and V4-V6) leads, left atrial or biatrial enlargement, left axis deviation, and deeply inverted T-waves. Prominent Q-waves can represent thickened interventricular septal depolarization.[14]           

Transthoracic echocardiogram: This echocardiogram can demonstrate the typical cardiac morphology of unexplained LVH with a wall thickness of more than 15 mm. About one-third of patients with HCM will also have increased RV wall thickness (>8 mm). As noted above, a septal/posterior wall thickness ratio over 1.3 in normotensive patients or over 1.5 in hypertensive patients is also diagnostic of HCM. Transthoracic echocardiogram (TTE) can also show systolic and diastolic function, the presence and severity of any LVOT gradient, and the degree of mitral regurgitation or SAM (of note, SAM has a specificity of 99% for HCM). Left atrial measurements and pulmonary artery pressures should also be imaged. TTE with contrast can also be performed in patients unable to have a cardiac magnetic resonance imaging scan, such as if an implantable cardioverter-defibrillator (ICD) is present (see Image. Hypertrophic Cardiomyopathy, Echocardiogram).                                                                     

Ambulatory ECG monitoring (Holter): Monitoring should be performed for 24 to 48 hours in all patients diagnosed with HCM for risk assessment of ventricular arrhythmias and sudden death.

Exercise stress testing: This can be performed for risk stratification and LVOT gradient assessment. Exercise stress testing with TTE is the preferred method to image the LVOT because this simulates physiologic stress.[18]                                         

Cardiac magnetic resonance: The cardiac magnetic resonance (CMR) is becoming more commonly used to characterize cardiac tissue and structure in patients with HCM and their relatives. With gadolinium, CMR can also detect myocardial fibrosis, an important prognostic indicator. Late gadolinium enhancement (LGE) is present in over 60% of patients with symptomatic HCM and is thought to be a marker for replacement fibrosis.[5]

• The American Heart Association’s (AHA) guidelines suggest using CMR in the following situations:
  • For patients in whom TTE is inconclusive, or images are suboptimal
  • For patients diagnosed with LVH who may have alternative diagnoses, such as Fabry disease, amyloidosis, or athlete’s heart
  • For patients with unclear benefits regarding ICD placement
  • TTE can miss patients with the uncommon apical or anterolateral wall hypertrophy forms of HCM, so CMR is preferred for imaging this variant.
  • To image more subtle structural findings such as myocardial crypts, elongated mitral leaflets, and expanded extracellular space [12]
  • To define the LVOT when planning invasive intraseptal reduction treatments [19][20] 

Some patients may also require additional studies as follows:

• Cardiac catheterization: This catheterization can help characterize cardiac hemodynamics, the degree of left ventricular outflow obstruction, and the coronary vessel anatomy.
• Electrophysiological studies: These studies can help determine the origin of the arrhythmias.

Risk Stratification in Young Athletes and Patients

HCM is a leading cause of sudden cardiac death (SCD) in athletes younger than 35 years (along with congenital anomalies of the coronary arteries and arrhythmogenic right ventricular cardiomyopathy [ARVC]). For most patients with HCM, engaging in mild-to-moderate-intensity recreational exercise can be beneficial. Special attention is paid to athletes because about 25% of SCD cases occur during physical activity, such as sports.[21] Risk stratification for young athletes to evaluate for HCM is performed using ECG and echocardiography. However, these testing modalities have low sensitivity, so CMR has been suggested as a test for all young athletes with a personal history of syncope, a family history of syncope or SCD, or an abnormal or indeterminate echocardiogram.[8] For athletes older than 35 years, coronary artery disease is the most common cause of SCD.

In the United States, HCM and an anomalous origin of coronary arteries are the most common causes of SCD in all patients younger than 35, while in Europe, arrhythmogenic cardiomyopathies (including ARVC) and channelopathies are more common.[22][23] Current guidelines recommend against competitive sports and strenuous exercise, given the association of SCD in young athletes with HCM.[12] However, the prospective, observational LIVE-HCM trial studying the effect of vigorous exercise did not find an association with life-threatening arrhythmia or death. Results from this study found that most significant cardiac events occurred during activities of daily living.[24] Another ongoing trial at Yale University (NCT02549664) is also studying the effect of exercise on patients with HCM. As no well-designed trials have definitively proven that avoiding strenuous exercise helps decrease the chances of SCD, some experts recommend shared decision-making between patients and physicians after fully explaining all possible risks and benefits.[21][22]

Treatment / Management

Treatment strategies for HCM are based on observational data and clinical experience since no large randomized trials have been performed. Pharmacological therapy is the first-line approach to symptomatic HCM. Initial recommended medications include negative inotropic agents, including beta blockers, nondihydropyridine calcium channel blockers, and disopyramide.[25][26](B3)

Medical Intervention

• Mavacamten is a first-in-class drug approved in 2022 by the Food and Drug Administration that is specifically for the treatment of obstructive HCM. This medicine is the first selective, allosteric, reversible small-molecule adenosine triphosphatase inhibitor of cardiac myosin that functions by blocking the interaction between myosin and actin within cardiac muscle cells, which exerts a negative inotropic effect. This mechanism helps to relieve the obstruction in the left ventricular outflow tract, thereby enhancing blood flow and alleviating symptoms. Mavacamten is presently indicated for the treatment of adults with symptomatic heart failure (New York Heart Association [NYHA] class II and III) due to obstructive HCM. Typical side effects include dizziness, fainting, and shortness of breath. Severe side effects may involve heart failure that requires close monitoring and possible dosage adjustment if the left ventricular ejection fraction drops below 50%.
• Beta-blockers are the first line of management for most HCM cases. Patients should be titrated to a therapeutic dose that provides symptom relief. Beta-blockade failure should not be declared until suppression of the resting heart rate is demonstrated. This approach ensures that patients receive optimal treatment benefits while minimizing the risk of adverse effects. 
• Calcium channel blockers, such as diltiazem and verapamil, are known to alleviate symptoms in patients with obstructive HCM. These drugs can have vasodilating properties, but they can also have negative inotropic and negative chronotropic effects, which may limit their use. Evidence does not support using calcium channel blockers in combination with beta-blockers as a therapy for HCM.       
• Disopyramide is a sodium channel blocker classified as a class Ib antiarrhythmic drug; this is also a potent negative inotropic agent that is used off-label for the treatment of HCM. Disopyramide helps reduce outflow obstruction and associated symptoms. As cytochrome P450 3A4 metabolizes this drug, many drugs, such as calcium channel blockers, can interact with disopyramide and affect its serum levels. Due to the anticholinergic properties of disopyramide, it can potentially cause urinary retention and exacerbate related conditions like glaucoma and myasthenia gravis.
• Diuretics can be given carefully in patients without LVOT obstruction who have refractory heart failure symptoms presenting with volume overload. Volume depletion decreases stroke volume and worsens the LVOT gradient. This can lead to hypotension, lightheadedness, and syncope.
• Certain medications should be avoided or used very cautiously as they can worsen symptoms. These include vasodilators, amlodipine, nifedipine, nitroglycerin, angiotensin-converting enzyme/angiotensin II receptor blockers, and adrenergic receptor β-agonists like dopamine and dobutamine.[27]
• Patients with nonobstructed HCM are usually treated medically.[18][28]
(A1)

Implantable Cardiac-Defibrillator Placement

• The placement of an implantable cardiac-defibrillator (ICD) is considered largely responsible for the improved mortality of HCM over the last 20 years.                    
• Any patient with risk factors for sudden cardiac death should be considered for ICD. Risk factors include the following: recent unexplained syncope, HCM-related SCD in a close relative, thin-walled akinetic or dyskinetic LV apical aneurysm with scarring, frequent or prolonged episodes of ventricular tachycardia on ambulatory monitoring, extensive late gadolinium enhancement on CMR, and massive LVH (>30 mm).                                                           
• Multiple study results have shown primary ICD placement terminates 3% to 4% of malignant tachyarrhythmias per year, and that number rises to 10% for secondary ICD placement (after cardiac arrest).[27]                                 
• Although overall beneficial, the complication rate can be up to 10% per year, including lead fractures and infections.[27] 
• Guidelines for ICD placement in children are less clear as children have less marginal benefit and increased complications from ICDs than adults due to smaller size.[21]

Surgical intervention

Up to 50% of patients with HCM may be refractory to medical treatment.[29] Indications for surgical intervention include New York Heart Association III/IV class symptoms despite optimal medical therapy, syncope related to hemodynamic compromise from LVOT obstruction, or an LVOT gradient of more than 50 mm Hg.

• Septal reduction therapy includes left ventricular septal myectomy, which immediately reduces the outflow tract obstruction. Mitral valve repair or remodeling is sometimes also performed to reduce mitral regurgitation or further relieve LVOTO. Complete heart block requiring a permanent pacemaker is a myectomy complication occurring 1% to 5% of the time. Mortality is low with experienced surgeons.[27]              
• Alcohol septal ablation can also be performed for the same indications and has the added benefit of faster recovery time. However, the LVOT obstruction often takes up to 3 months to show improvement, and results are less uniform than with surgical myectomy. In addition, the risk of complete heart block is higher (10% to 15%), and a post-ablation scar can form, causing an arrhythmogenic focus.[30]                       
• Given that atrial fibrillation is the most common arrhythmia associated with HCM, a Maze procedure is often done in conjunction if a myectomy is required, and it is often successful in decreasing or resolving this arrhythmia.                                                  
• Radiofrequency ablation is a newer technique being studied for left ventricular septal reduction. Results are similarly effective to the more established surgical myectomy and alcohol ablation techniques. The most common adverse effect is pericardial effusion requiring drainage. Further studies of this technique are needed.[29][31] 
• A heart transplant is recommended as a last resort in patients who have failed all medical and surgical treatments (see Image. Hypertrophic Cardiomyopathy Treatment Mapping).[27][32]

Differential Diagnosis

For a correct diagnosis of HCM to be made, other diagnoses must be excluded first, including the following:

Fabry disease: This disease is transmitted through X-linked inheritance and is caused by an α-galactosidase deficiency characterized by angiokeratomas and peripheral neuropathies.

LEOPARD syndrome: Patients with this syndrome exhibit multiple lentigines.

Amyloidosis: Patients with ventricular hypertrophy due to amyloidosis will most likely have bilateral carpal tunnel syndrome, nephrotic syndrome, or skin abnormalities. The ECG may show an arteriovenous block, and the echocardiogram may show a “sparkling” appearance.

Danon disease: This is an X-linked lysosomal glycogen-storage disease with the clinical triad of skeletal myopathy, cardiomyopathy, and intellectual disability.

Friedrich ataxia: This is the most common cause of inherited ataxia caused by a mutation in the frataxin gene, a mitochondrial protein found in neurons and cardiomyocytes. Ataxia, dysarthria, and other cerebellar signs usually become prominent during childhood. 

Aortic stenosis or insufficiency/pulmonary hypertension: These clinical entities combine LVH with aortic valve or pulmonary artery changes and can cause symmetric or asymmetric LVH, similar to HCM. Abnormalities may be detectable on echocardiogram.   

Athlete’s heart: A history of athletic achievement and strenuous training should help in differential diagnosis. An echocardiogram may show a low-normal ejection fraction, and all the heart chambers may be enlarged instead of just the LV. Contractility reserve is increased, but this may not be apparent on echocardiography. CMR is a valuable tool to differentiate this from HCM, as athlete’s heart will not show LGE (late gadolinium enhancement).[33][34]

Hypertensive heart disease: Diffuse atherosclerotic changes and a history of essential hypertension should suggest the diagnosis. HCM is also associated with systolic anterior motion, late gadolinium enhancement, and preferential involvement of the apical, anterolateral free wall or posterior septum, which is usually not seen in hypertensive heart disease.

Prognosis

Understanding the prognosis of HCM is essential for guiding patient care and counseling. Factors such as age of onset, genetic mutations, degree of hypertrophy, presence of symptoms, and complications significantly influence the long-term outlook. A nuanced understanding of these prognostic indicators is crucial for clinicians to tailor treatment strategies and optimize patient outcomes.

• Previously, mortality rates of 1% to 4% were reported in patients with HCM. With appropriate treatment, these numbers are now thought to be closer to 0.5%.                                                                                              
• Even though many patients with HCM are asymptomatic, the first clinical presentation may be sudden death from malignant arrhythmias.                                                                                                                   
• Increased left atrial size (transverse linear dimension >48 mm or volume >118 mL) is correlated with an increased risk of death, heart failure, and atrial fibrillation.[5]

Complications

Complications of HCM pose significant challenges in case management and prognostication. Understanding the diverse array of complications associated with HCM is essential for clinicians to implement appropriate preventive measures and therapeutic interventions, ultimately improving patient outcomes and quality of life.

These complications encompass a spectrum of cardiovascular events, including the following:

• Ventricular arrhythmias
• Congestive heart failure
• Infective endocarditis of the mitral valve
• Atrial fibrillation
• Embolic phenomenon
• Sudden death