Abstract:
The latest guidelines from the American Heart Association and the American College of Cardiology have brought many novelties and revisions of previous recommendations concerning various aspects of the diagnosis and management of hypertrophic cardiomyopathy. These new recommendations adopt new approaches in terms of diagnosis and initial evaluation, prognosis and sudden cardiac death risk assessment, as well as patient selection for implantable cardioverter-defibrillator placement. The novel therapeutic agents, cardiac myosin inhibitors, have also figured in the new guidelines, emphasizing their mechanism of action, indications and contraindications.
Introduction:
Cardiomyopathies represent a group of heart diseases that primarily affect the myocardium. These conditions can be divided into various entities depending on their morphologic and/or functional features. Hypertrophic cardiomyopathy is a complex disease with numerous clinical presentations, heterogeneous genetic profiles, intricate prognostic factors and potentially life-threatening complications that require thorough diagnostic work-up, risk assessment and a comprehensive treatment plan. Hence the need for regularly updated guidelines to ensure continuous revision and reevaluation of the different approaches for optimal management of this disease.
Definitions, epidemiology, etiology and genetics:
Epidemiology:
Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease, with prevalence estimates ranging from 1 in 200 to 1 in 500 individuals globally. HCM is typically inherited in an autosomal dominant manner, but a family history is not always necessary for diagnosis. It affects both sexes equally, but women are diagnosed less frequently than men. Prevalence varies by race and ethnicity, potentially reflecting social disparities in access to healthcare.
Definitions:
For this guideline, hypertrophic cardiomyopathy (HCM) is defined as a heart-specific disease characterized by left ventricular hypertrophy (LVH) without any other cardiac, systemic, or metabolic cause. A clinical diagnosis in adults can be made through imaging, typically 2D echocardiography or CMR showing a maximum end-diastolic wall thickness of ≥15 mm in the left ventricle, in the absence of other causes of hypertrophy.
Etiology
In the early 1990s, DNA sequencing in families with hypertrophic cardiomyopathy (HCM) revealed that damaging variants in sarcomere protein genes were linked to left ventricular hypertrophy (LVH), leading to HCM being recognized as a potentially monogenic disease, with an autosomal dominant pattern of inheritance.
Currently, variants in at least eight genes related to cardiac sarcomere proteins have been implicated in causing LVH, which is essential for HCM diagnosis. Approximately 30% to 60% of patients with HCM have identifiable pathogenic genetic variants, while a significant portion lacks any known genetic cause, including up to 40% of patients with “nonfamilial” HCM. This suggests that other mechanisms may contribute to HCM’s phenotypic expression.
The two most common genes associated with pathogenic variants in HCM are MYH7 and MYBPC3, found in most variant-positive patients. Other genes like TNNI3, TNNT2, and TPM1 account for smaller percentages (1%-5%).
These genetic alterations can trigger myocardial changes resulting in hypertrophy and fibrosis, leading to a small, stiff ventricle with impaired function despite preserved left ventricular ejection fraction (LVEF). Additionally, some clinical features of HCM, such as abnormal coronary arteries and congenital valve anomalies, do not appear to be directly linked to sarcomere variants.
Pathophysiology:
Left Ventricular Outflow Tract Obstruction
Left ventricular outflow tract obstruction (LVOTO) is common in patients with hypertrophic cardiomyopathy (HCM) and is primarily caused by systolic anterior motion (SAM) of the mitral valve. Obstruction is defined by a peak LVOT gradient of ≥30 mm Hg, with gradients ≥50 mm Hg typically associated with symptoms, prompting consideration of advanced pharmacological or invasive therapies if standard treatments are ineffective.
Diastolic Dysfunction
Hypertrophic cardiomyopathy (HCM) is characterized by features such as altered ventricular load, high intracavitary pressures, impaired left ventricular (LV) compliance due to hypertrophy and fibrosis, altered energetics, microvascular ischemia, and delayed calcium reuptake, all of which contribute to diastolic dysfunction. Notably, young carriers of pathogenic sarcomere gene variants may exhibit impaired relaxation even with normal LV wall thickness, indicating that diastolic abnormalities can be an early sign of these variants.
In some patients, increased stiffness and severe hypertrophy can significantly reduce ventricular cavity size and stroke volume, potentially leading to restrictive physiology. Diastolic dysfunction may decrease exercise capacity and worsen prognosis independently of left ventricular outflow tract obstruction (LVOTO). To determine if exercise intolerance or symptoms stem from diastolic dysfunction, invasive testing may be necessary. Additionally, impaired myocardial relaxation can increase reliance on atrial systole for ventricular filling, making some patients more susceptible to poor tolerance of atrial fibrillation or similar arrhythmias.
Mitral Regurgitation
Mitral regurgitation (MR) in hypertrophic cardiomyopathy (HCM) can arise from systolic anterior motion (SAM) or from primary leaflet abnormalities, both of which contribute to symptom burden. Common primary mitral valve issues include excessive leaflet length, anomalous papillary muscle insertion, and anteriorly displaced papillary muscles. The characteristics of the MR jet can help identify its cause: MR due to SAM typically presents as a mid-to-late sysMitral regurgitation (MR) in hypertrophic cardiomyopathy (HCM) can arise from systolic anterior motion (SAM) or from primary leaflet abnormalities, both of which contribute to symptom burden. Common primary mitral valve issues include excessive leaflet length, anomalous papillary muscle insertion, and anteriorly displaced papillary muscles.
Myocardial Ischemia
Patients with hypertrophic cardiomyopathy (HCM) may experience myocardial ischemia due to a mismatch between oxygen supply and demand. Common findings include myocardial hypertrophy, microvascular dysfunction, and reduced density of intramural arterioles. These issues can be worsened by hyperdynamic systolic function and left ventricular outflow tract obstruction (LVOTO), leading to high intracavitary pressures. Blunted coronary flow reserve can occur even without epicardial stenosis, but severe coronary atherosclerosis can worsen this mismatch and is linked to poorer outcomes. Apical myocardial ischemia may contribute to the development of left ventricular apical aneurysms, increasing the risk of heart failure, stroke, and arrhythmias. Additionally, myocardial bridging—a congenital anomaly causing compression of an epicardial coronary artery—may impair blood flow and occasionally lead to ischemia in some patients.
Diagnosis & initial work-up :
The diagnosis of hypertrophic cardiomyopathy (HCM) is based on a combination of clinical evaluation, imaging, and genetic testing. In adults, the diagnosis is confirmed when imaging, such as 2D echocardiography or cardiovascular magnetic resonance (CMR), reveals a left ventricular wall thickness of ≥15 mm. In certain cases, particularly in individuals with a family history of HCM or a positive genetic test, hypertrophy as low as 13–14 mm may be considered diagnostic. For children, the diagnosis takes into account body size and growth, with body surface area-adjusted z-scores ≥2 being diagnostic in those with a genetic predisposition or family history, while z-scores >2.5 are more appropriate for asymptomatic children without such factors.
HCM presents with considerable phenotypic variability. Hypertrophy often affects the basal anterior septum, but it can involve other areas of the left ventricle. Associated features include systolic anterior motion (SAM) of the mitral valve, hyperdynamic left ventricular function, and abnormalities like hypertrophied papillary muscles, myocardial crypts, or elongated mitral valve leaflets. Echocardiography remains the cornerstone for diagnosing HCM, providing critical insights into wall thickness, left ventricular outflow tract obstruction (LVOTO), and mitral valve abnormalities. Cardiovascular magnetic resonance (CMR) is often used as an adjunct, especially when echocardiographic visualization is limited, and it can identify late gadolinium enhancement (LGE), indicative of myocardial fibrosis. Genetic testing plays an important role, particularly in familial cases, by identifying pathogenic sarcomeric mutations such as those in MYH7 and MYBPC3 genes. Screening of first-degree relatives is essential, and early detection in genotype-positive individuals is crucial for effective management.
Differentiating HCM from conditions like athlete’s heart, hypertensive cardiomyopathy, and infiltrative diseases (e.g., Fabry disease, amyloidosis) can be challenging. Advanced imaging and specific clinical markers help clarify the diagnosis. For at-risk individuals, such as those with a family history or genetic predisposition, regular clinical evaluation and imaging are recommended to detect disease progression and initiate timely intervention.
Natural history & complications :
The natural history of HCM is highly variable, ranging from asymptomatic cases to severe complications that significantly impact morbidity and mortality. While many individuals with HCM can lead normal lives without symptoms or major interventions, others experience complications such as sudden cardiac death (SCD), heart failure (HF), and atrial fibrillation (AF). SCD remains a critical risk, particularly in individuals with severe left ventricular hypertrophy (LVH), a family history of SCD, or unexplained syncope. Heart failure may result from progressive LVOTO, diastolic dysfunction, or the development of systolic dysfunction in advanced stages of the disease. Atrial fibrillation is common and carries a high risk of thromboembolic stroke, adding to the burden of morbidity.
Genetic factors strongly influence the clinical course, with sarcomeric mutations linked to earlier onset and more severe manifestations. However, the specific genotype often cannot reliably predict individual prognosis due to significant phenotypic variability. Some patients are diagnosed later in life with milder forms of the disease, while early-onset cases tend to follow a more aggressive clinical course. Advances in risk stratification have improved the management of HCM, particularly the use of tools to identify individuals at high risk for SCD. Implantable cardioverter-defibrillators (ICDs) have significantly reduced SCD-related mortality, shifting the focus to managing heart failure and AF as the leading causes of morbidity and mortality.
The presence of comorbidities, such as obesity, hypertension, diabetes, and obstructive sleep apnea, exacerbates the progression of HCM and worsens outcomes. Comprehensive management of these risk factors is critical to improving long-term prognosis. Contemporary therapies, including novel pharmacological agents like myosin inhibitors and interventions such as surgical septal myectomy or alcohol ablation, provide effective symptom relief and improve quality of life. Regular follow-up is essential to monitor disease progression, assess the development of complications, and optimize treatment strategies.
Sudden cardiac death risk assessment strategies in patients with HCM:
Sudden cardiac death (SCD) is one of the greatest burdens associated with HCM, especially in younger patients. This particularly frequent and feared complication of the disease can be prevented using implantable cardioverter-defibrillators (ICD) following a thoroughly careful risk assessment of SCD using various tools to estimate the 5-year risk, which is then integrated in a more general shared-decision approach in which the patient’s preferences and life goals are to be taken into consideration. This strategy has thus become an integral component of the management of HCM patients.
The goal of SCD risk assessment is to identify high-risk patients that may benefit from ICD placement, and distinguish them from those with a much lower risk and in whom further investigations may be recommended. Clinicians must make sure that such evaluation is individualized to each patient, emphasizing the shared-decision approach mentioned previously. Risk assessment in adults slightly differs from children.
In every adult patient with HCM, a noninvasive risk assessment at initial work-up and annually or every 2 years that includes a thorough personal and family history, echocardiography, and ambulatory ECG monitoring is highly recommended. The following risk factors must be carefully assessed: a personal history of resuscitated cardiac arrest, sustained (>30 seconds or associated with hemodynamic instability) ventricular arrhythmias or syncope suspected clinically to be of arrhythmic origin, a 1st degree family history of early (
50 years of age) HCM-related SCD, cardiac arrest, or sustained ventricular arrhythmias, echocardiography findings including maximal left ventricular (LV) wall thickness ( 30 mm), systolic dysfunction with an ejection fraction <50% and left ventricular apical aneurysm, as well as non-sustained episodes of ventricular tachycardia (VT) on continuous ECG monitoring. This initial evaluation identifies patients with high-risk, in which an ICD placement is recommended, and low-risk patients that warrant careful follow-up. A subset of patients whose risk is not elucidated despite initial assessment, or in whom a decision to intervene remains unclear after standard assessment, contrast-enhanced cardiac MRI is indicated for more detailed evaluation of the same parameters seen on echocardiography, with the appraisal of the extent of myocardial fibrosis with late Gadolinium enhancement (LGE), which correlates with a higher risk of ventricular arrhythmias. Another argument that can be useful while discussing the decision for ICD placement is the estimated 5-year SCD risk, which can be calculated after obtaining left atrial diameter and maximal left ventricle outflow tract (LVOT) gradient.
Risk evaluation in children uses a combination of adult components and some pediatric specificities. These specificities include genotype (i.e.: identification of a pathogenic or a likely pathogenic variant of sarcomeric genes) and echocardiography-derived parameters that include LV wall diameter z-scores (compared to mean values), left atrial diameter z-score and maximal instantaneous LVOT gradient.
Selecting patients for ICD placement must be conducted through personalized risk evaluation that takes into consideration the clinical profile of the patient, but also their personal choices and life goals. A considerate discussion of the estimated risks and benefits of the intervention is recommended to obtain optimal participation of the fully informed patient in the decision-making process. The patient must also be educated on the potential long-term and short-term complications of ICD placement. This procedure is recommended in patients who have endured a cardiac arrest or sustained VT, and it is reasonable (after a thorough discussion) in patients with 1 major risk factor for SCD. ICD placement decisions in children must take into consideration the relatively high risk of long-term complications. However, this intervention should not be performed in patients without risk factors for SCD, or for the single purpose of engaging in competitive sports.
Management of HCM:
Treating HCM is in most cases limited to symptomatic management. Symptoms could be due to various factors, the most common of which are LVOT obstruction, heart failure, atrial fibrillation and ventricular arrhythmias. Available therapies include pharmacologic agents and invasive procedures. Lifestyle changes also play a key role in the management of HCM.
The pharmacologic treatment of symptomatic obstructive HCM targets dynamic LVOT obstruction and involves the use of non-vasodilating beta-blockers titrated to maximally tolerated dose as 1st line therapy, to prevent disproportionate increase in the LVOT. If symptoms persist, substitution with a nondihydropyridine calcium channel blocker like verapamil or diltiazem is recommended. If symptoms do not improve despite trial of both medications, adding the cardiac myosin inhibitor Mavacamten, Disopyramide (an atrioventricular nodal blocking agent), or septal reduction therapy is recommended. Cardiac Myosin inhibitors are a novel therapeutic class that acts by reducing myocardial contractility thus alleviating the LVOT pressure gradient which leads to symptom improvement(g). Patients with obstruction HCM presenting with acute hypotension resistant to intravenous fluids, administration of phenylephrine intravenously alone or in association with a beta-blocker is recommended. Vasodilators such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and dihydropyridine calcium channel blockers) as well as digoxin can worsen symptoms by increasing the LVOT pressure gradient. Verapamil and diltiazem should be avoided in patients with signs of decompensated congestive heart failure.
Invasive interventions aimed at reducing the LVOT obstruction include extended septal myectomy (ESM) through a transaortic approach and alcohol septal ablation. Patients with symptoms attributable to LVOT obstruction and who have not responded to medications should benefit from septal reduction therapy (SRT) in a specialized center. This procedure is also recommended in patients with obstructive HCM who have associated cardiac disease requiring surgical treatment. However, in patients with asymptomatic HCM and normal exercise capacity, SRT should be avoided. Mitral valve replacement should not be performed to improve symptoms of LVOT obstruction.
Management of non obstructive HCM depends on the clinical profile of the patient. Patients with non obstructive HCM with preserved EF and symptoms of dyspnea and angina should be treated with beta blockers or nondihydropyridine calcium channel blockers. Oral diuretics can be added in cases where symptoms persist despite the use of 1st line medications. Those with HCM and associated systolic dysfunction (LVEF < 50%) should benefit from guideline-directed medical management of heart failure with reduced EF (HFrEF), as well as a thorough diagnostic work-up to exclude concomitant causes of systolic dysfunction, especially coronary artery disease. In such patients, cardiac myosin inhibitors and negative inotropic agents are to be discontinued. Since a reduced EF is a risk factor for SCD, placement of an ICD should be discussed with patients.
HCM patients with associated clinical atrial fibrillation (AF) should receive adequate anticoagulation with direct-acting oral anticoagulants (DOACs) or vitamin K antagonists regardless of their CHADS-VASc score. Those with associated subclinical AF of >24 hours’ duration for each episode should be managed the same way as patients with clinical AF. The preferred medications for rate control in these patients are beta blockers, verapamil and diltiazem.
According to the latest AHA/ACC 2024 guidelines, systematic restriction from vigorous physical exercise or competitive sports is no longer indicated. Mild- to moderate-intensity recreational exercise helps improve cardiorespiratory health and overall quality of life. Though it is permissible, a thorough evaluation and shared decision-making by an expert professional is highly advised.
Conclusion:
The updated 2024 AHA/ACC guidelines for the diagnosis and management of hypertrophic cardiomyopathy have included many modifications and novelties that are, but not limited to the insightful prognostic value of the exercise stress testing in pediatric patients, criteria for patient selection for ICD placement, the arrival of novel therapeutic agents that inhibit cardiac myosin, their contraindications in pregnant women and in patients with systolic dysfunction, as well as the absence of benefit of physical exercise restriction. Further studies are required to evaluate the implementation of these changes in everyday practice.
References:
Circulation. 2024;149:e1239–e1311. DOI: 10.1161/CIR.0000000000001250
Ostrominski, J, Guo, R, Elliott, P. et al. Cardiac Myosin Inhibitors for Managing Obstructive Hypertrophic Cardiomyopathy: JACC: Heart Failure State-of-the-Art Review. J Am Coll Cardiol HF. 2023 Jul, 11 (7) 735–748.
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