Understanding Hypertrophic Cardiomyopathy: A Comprehensive Patient Guide

Table of Contents

• What is Hypertrophic Cardiomyopathy?
• How Common is HCM?
• Genetic Factors and Inheritance
• How HCM is Diagnosed
• Symptoms and Clinical Course
• Understanding Sudden Death Risk
• Treatment Options and Management
• What We Still Don't Know
• Patient Recommendations
• Source Information

What is Hypertrophic Cardiomyopathy?

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disorder caused by a single gene mutation. This condition is incredibly diverse in how it presents and progresses, often misunderstood by doctors, and frequently underrecognized in clinical practice. The disease was first comprehensively described 55 years ago by researchers at the National Institutes of Health, where it was initially called idiopathic hypertrophic subaortic stenosis.

Our understanding of HCM has improved dramatically over the past 15 years, particularly in areas of diagnosis, genetic factors, clinical course, and management. More than 18,000 research studies have been published on this condition, and modern HCM looks very different from the disease described in previous eras. Today, we have better tools for diagnosis, more effective treatments, and improved understanding of how to manage this complex condition.

How Common is HCM?

HCM is diagnosed when imaging tests show a thickened, non-dilated left ventricle without any other cardiac, systemic, metabolic, or syndromic disease causing the thickening. Echocardiography studies show the disease affects approximately 1 in 500 people in the general population. However, when we include both clinical diagnoses and genetic testing of family members, the prevalence increases to about 1 in 200 people.

Researchers estimate that about 750,000 people in the United States may have HCM, but only about 100,000 have actually been diagnosed. This means the vast majority of people with this condition never receive a diagnosis during their lifetime. This underrecognition disproportionately affects women and underserved minorities, with evidence showing black patients may be underreferred for specialized HCM treatments.

HCM has been identified in 122 countries representing approximately 90% of the world's population. It's likely that about 20 million people are affected globally, far more than originally thought. While the disease occurs equally in both sexes and across all ethnic groups, its clinical presentation and genetic basis don't vary significantly based on demographic characteristics.

Genetic Factors and Inheritance

HCM is inherited in an autosomal dominant pattern, meaning if one parent has the genetic mutation, each child has a 50% chance of inheriting it. The condition is associated with mutations in 11 or more genes that encode proteins in the heart's contractile system. The beta-myosin heavy chain and myosin-binding protein C genes are most commonly involved.

Genetic testing has revealed tremendous variety with more than 2,000 different sarcomere mutations identified. Some mutations are known to be disease-causing (pathogenic), while for others the disease-causing potential is uncertain. Many mutations appear only in single families. These genetic insights now allow diagnosis of HCM through laboratory testing in patients who would otherwise be unaware of their genetic status.

However, genetic testing has limitations. The relationship between specific genetic mutations and how the disease presents (genotype-phenotype correlations) has been inconsistent. Single or multiple sarcomere variants cannot reliably predict prognosis and have no specific role in risk assessment. Important management decisions for HCM patients are based solely on clinical criteria rather than genetic results.

Genetic testing is primarily used for family screening, which helps identify family members who are unlikely to inherit HCM as well as affected family members who haven't yet developed left ventricular hypertrophy. These gene carriers typically have no cardiac events or symptoms, and many will never develop HCM but can still pass the mutation to their children.

Currently, only about one third of patients with HCM have pathogenic mutations suitable for family screening. Sporadic (nonfamilial) HCM may be more common than previously thought. Genetic testing can also identify metabolic and storage conditions that mimic HCM, such as Fabry's disease and amyloidosis.

How HCM is Diagnosed

Characterizing the HCM phenotype has been based on almost 50 years of echocardiographic imaging. High-resolution MRI can provide more reliable assessment of left ventricular thickening in some patients and enhanced risk stratification by identifying myocardial fibrosis.

In most clinically diagnosed cases, the left ventricular wall thickness measures 15 mm or more, with an average thickness of 21 mm. Some cases show massive thickening of 30 to 50 mm. Borderline thickness (13-14 mm) often requires differentiation from high blood pressure or athlete's heart. Any left ventricular wall thickness can be consistent with HCM, including normal dimensions in gene carriers.

Greater left ventricular thickness is associated with increased risk of sudden death but not necessarily progression to heart failure. The expression of HCM includes many patterns of thickening that can be diffuse, segmental, focal, or noncontiguous, and can even involve extension into the right ventricle.

For family screening, the preferred approach is diagnostic imaging every 12 to 18 months from ages 12 to 21, since left ventricular thickening commonly develops during adolescence. However, the possibility of delayed appearance of the phenotype into midlife justifies extended imaging surveillance at 5-year intervals.

Echocardiographic assessment with advanced techniques has provided insights into diastolic dysfunction and myocardial mechanics, though these haven't yet substantially affected disease prognosis or management.

Symptoms and Clinical Course

The clinical course of HCM is remarkably diverse. Many patients remain free of significant symptoms and adverse events, don't require major treatment interventions, and have normal or extended lifespans. These patients are increasingly identified incidentally, usually with mild disease expression.

Other patients experience disease progression along specific pathways marked by clinical events that alter the natural history of the disease and require targeted treatments. Approximately 70% of patients have mechanical obstruction to left ventricular outflow, with gradients of 30 mm Hg or more at rest or with physiological provocation.

These subaortic gradients are typically dynamic and can change with physiological conditions such as dehydration, alcohol consumption, or changes in body position. These fluctuations often explain daily variations in symptoms. Outflow obstruction is usually produced by mitral valve systolic anterior motion and septal contact, which also results in mitral regurgitation.

Understanding Sudden Death Risk

HCM was initially described in the context of sudden death, which remains the most visible complication affecting patients with or without obstruction. This is particularly highlighted by media coverage of cardiac arrests in competitive athletes. In cases of sudden death due to ventricular tachyarrhythmias, the unpredictable arrhythmogenic substrate is defined by disorganized myocardial architecture and scarring.

Several clinical markers have been assembled into a risk-stratification algorithm according to management guidelines:

• Family history of HCM-related sudden death (usually a first-degree relative)
• Unexplained fainting (syncope)
• Multiple, repetitive nonsustained ventricular tachycardia
• Massive left ventricular hypertrophy (≥30 mm)
• Left ventricular apical aneurysm
• Extensive late gadolinium enhancement on MRI (≥15% of left ventricular mass)
• End stage disease (ejection fraction <50%)

This strategy has been highly effective for identifying most patients at increased risk for sudden death. Paradoxically, patients with HCM who survive into their seventies and beyond, even those with risk markers, are largely protected from sudden death (rate of 0.2% per year, similar to the general population).

HCM is the most important cause of sudden death on the athletic field in the United States. Intense competitive sports represent a primary risk marker that justifies disqualification of young student athletes with HCM from such activities. However, moderate recreational exercise is acceptable, as there's no evidence it increases susceptibility to dangerous arrhythmias.

Implantable cardioverter-defibrillators (ICDs) have revolutionized sudden death prevention over the past 15 years. These devices effectively terminate ventricular tachycardia or fibrillation at an average rate of 4% per year for primary prevention and 10% per year for secondary prevention after cardiac arrest.

Treatment Options and Management

For 90% of patients with chronic, medication-resistant disability from heart failure, the primary cause is left ventricular outflow obstruction. This leads to markedly elevated left ventricular pressures and secondary mitral regurgitation. Heart failure in HCM patients is often accompanied by pulmonary hypertension and diastolic dysfunction.

The rate at which subaortic gradients at rest lead to progressive heart failure is about 5% per year, though some patients have large gradients with few or no symptoms for long periods, sometimes into advanced age.

Treatment approaches include:

1. Medication therapy as the first option, including AV nodal blocking agents and disopyramide
2. Surgical septal myectomy for eligible patients with obstruction
3. Alcohol septal ablation as a selective surgical alternative
4. Implantable defibrillators for high-risk patients
5. Heart transplantation for advanced heart failure (needed in 2-3% of cases)
6. Antiarrhythmic medications and catheter ablation for atrial fibrillation
7. Anticoagulation therapy to prevent stroke in patients with atrial fibrillation

Transvenous ICDs have largely replaced pharmacological strategies for sudden death prevention and have changed the clinical course for many adult and pediatric HCM patients. The decision to implant a defibrillator requires consideration of device complication rates (3-5% per year), most frequently inappropriate shocks due to supraventricular tachycardia and lead fractures.

What We Still Don't Know

Despite significant advances, several important limitations remain in our understanding of HCM. Genetic testing currently identifies pathogenic mutations in only about one third of patients with HCM, meaning most patients don't have identifiable mutations suitable for family screening. The interpretation of genetic variants of uncertain significance has become increasingly complex with technological advances.

Risk stratification, while improved, isn't perfect. A small minority of patients without conventional risk markers can still experience fatal arrhythmic events, highlighting the need for expanded risk assessment methods. The European sudden death risk score calculator has shown low sensitivity when applied to individual patients, potentially leaving high-risk patients unprotected.

The relationship between specific genetic mutations and disease presentation remains inconsistent, and we cannot reliably predict prognosis based on genetic testing alone. Important management decisions must still be based on clinical criteria rather than genetic results.

Patient Recommendations

If you have been diagnosed with HCM or have a family history of the condition, here are important recommendations:

• Seek care at a specialized HCM center with experience managing this complex condition
• Undergo comprehensive risk assessment including echocardiogram, MRI, and Holter monitoring
• Discuss genetic testing with your cardiologist and genetic counselor
• Screen first-degree family members with clinical imaging and possibly genetic testing
• Avoid intense competitive sports if you have diagnosed HCM with left ventricular hypertrophy
• Maintain moderate recreational activity as approved by your cardiologist
• Report any new symptoms such as chest pain, shortness of breath, palpitations, or fainting
• Discuss ICD implantation if you have risk factors for sudden death
• Consider specialized treatments like surgical myectomy if you have obstructive symptoms
• Participate in regular follow-up care to monitor your condition over time

Source Information

Original Article Title: Clinical Course and Management of Hypertrophic Cardiomyopathy

Authors: Barry J. Maron, M.D.

Publication: The New England Journal of Medicine, 2018;379:655-68

DOI: 10.1056/NEJMra1710575

This patient-friendly article is based on peer-reviewed research from The New England Journal of Medicine.