Hypertrophic cardiomyopathy (HCM) stands as the most prevalent inherited cardiac condition of a single gene origin, affecting approximately 0.2-0.5% of the general population. In the United States alone, it’s estimated that 750,000 individuals live with HCM, yet a significant diagnostic gap persists with only about 100,000 having received a formal diagnosis. As the approaches to diagnosing and treating HCM advance, it’s crucial for cardiovascular professionals to maintain expertise in recognizing this condition effectively.
History and Physical Examination in HCM Diagnosis
Many individuals with HCM experience no symptoms or only mild symptoms. They often come to medical attention because of a family history suggestive of the condition, the detection of a heart murmur during a routine physical, or an abnormal electrocardiogram (ECG) result. When symptoms are present, they commonly include shortness of breath (dyspnea), fatigue, chest pain, palpitations, lightheadedness (presyncope), and fainting (syncope). Key historical indicators include a gradual decline in exercise tolerance and lightheadedness or syncope occurring during or immediately after physical exertion or in situations of dehydration.
A detailed multigenerational family history is vital during the initial assessment. Clinicians should inquire about relatives with any cardiac diagnoses, reports of “thick” hearts, early-life “heart attack” or stroke, irregular heart rhythms, pacemakers or implantable defibrillators, heart failure, or heart transplantation. A family history of sudden death should prompt specific questions about relatives who died prematurely or unexpectedly, deaths associated with physical activity, and whether autopsy or postmortem genetic testing results are available.
During the physical examination, certain heart sounds should raise suspicion for HCM. These include a harsh crescendo-decrescendo systolic murmur best heard at the lower left sternal border, a mid-to-late systolic apical murmur or a holosystolic apical murmur, and/or a paradoxically split second heart sound (S2).
Confirming the Diagnosis of HCM
The definitive diagnosis of HCM is made when there is evidence of increased thickness in the left ventricle wall, measuring 15 mm or greater, which cannot be explained by other conditions that overload the heart, such as high blood pressure, valve problems, congenital heart defects, or infiltrative cardiomyopathies. A slightly lower threshold of 13 mm is used for diagnosis in relatives of individuals with confirmed HCM or those who are known to carry HCM-related genes. While the basal septum is the most frequently affected area, HCM can manifest in various patterns of asymmetric hypertrophy, including reverse septal curvature, sigmoid septum, neutral septum, midventricular, and apical forms.
Alt: Echocardiogram image showing thickened heart muscle in hypertrophic cardiomyopathy, a key diagnostic indicator.
To assess for and locate any obstruction in the left ventricular outflow tract, continuous-wave Doppler echocardiography should be performed, scanning from the apex to the base of the left ventricle. Care must be taken to differentiate the outflow tract gradient from mitral regurgitation signals, especially when systolic anterior motion of the mitral valve is present. The pressure gradient in the left ventricular outflow tract should be measured at rest. A peak instantaneous gradient of 30 mm Hg or greater at rest is indicative of obstructive HCM. A gradient of 50 mm Hg or more, either at rest or provoked, is generally considered the point at which septal reduction therapy should be considered for patients with symptoms.
Electrocardiogram (ECG) findings in HCM are not specific but can be suggestive. Abnormalities such as localized or widespread repolarization changes (including inverted T-waves), high precordial voltage and left axis deviation (suggesting ventricular hypertrophy), P-wave abnormalities (suggestive of left atrial enlargement), and Q waves in the inferior and/or lateral leads (suggesting depolarization of a hypertrophied septum) should increase clinical suspicion for HCM.
Cardiac magnetic resonance imaging (MRI) offers superior detail in visualizing heart structure and tissues, and in assessing heart chamber volumes compared to echocardiography. Cardiac MRI is particularly valuable in two scenarios: 1) when echocardiography results are not conclusive for diagnosing HCM, and 2) in patients with known HCM where further details on the extent and pattern of hypertrophy or the anatomy of the mitral valve apparatus would aid decisions about septal reduction therapy. Ongoing large-scale studies are investigating the role of contrast-enhanced MRI in predicting sudden death risk in HCM patients.
Alt: Cardiac MRI image illustrating hypertrophic cardiomyopathy with marked thickening of the heart muscle, crucial for detailed diagnosis.
Differential Diagnosis of HCM
When HCM is suspected, it is crucial to rule out other causes of left ventricular hypertrophy. Systemic hypertension and aortic stenosis are the most common acquired conditions leading to left ventricular hypertrophy. Physiologic remodeling of the heart due to intense physical training can also cause left ventricular wall thickening. However, this “athlete’s heart” is usually distinguishable from HCM through a combination of imaging and functional assessments. In physiologic remodeling, left ventricular wall thickness rarely exceeds 15 mm, and the heart chambers tend to be larger than typically seen in HCM. Additionally, diastolic function, including tissue Doppler measurements, is expected to be normal in physiologic remodeling.
Certain genetic conditions that mimic HCM, known as phenocopies, should also be considered. These include Anderson-Fabry disease (GLA gene), Danon disease (LAMP2), Pompe disease (GAA), AMPK-mediated glycogen storage disease (PRKAG2), amyloidosis (TTR), Friedreich ataxia (FRDA), and myotonic dystrophy (DMPK, ZNF9). Considering inheritance patterns, involvement of other organs (especially neurological, musculoskeletal, and renal systems), and ECG features like pre-excitation can help differentiate these conditions from HCM.
Genetic Testing and Screening for HCM
Patients undergoing genetic testing for HCM should receive genetic counseling from a professional experienced in cardiovascular genetics. This ensures that test results and their clinical implications are properly explained and understood. While genetic testing is not essential for diagnosing HCM, it is recommended for the proband (the first affected family member identified) in cases of atypical presentation or when another genetic syndrome is suspected. Current genetic testing typically involves sequencing a panel of 50-100 genes associated with cardiomyopathies.
Alt: Diagram illustrating genetic testing process for hypertrophic cardiomyopathy, emphasizing its role in diagnosis and family screening.
Genetic testing is also valuable for identifying at-risk first-degree relatives of HCM patients. If a disease-causing genetic variant is found in the proband and affected relatives, family members who do not carry this variant can be excluded from further clinical screening. If genetic testing is not performed or does not identify a causal variant in the proband, ongoing clinical surveillance with ECG and echocardiography every 3-5 years is recommended for relatives.
Summary of HCM Diagnosis
HCM presents with a wide spectrum of clinical scenarios, ranging from asymptomatic individuals identified through family history, murmur, ECG, or echocardiogram findings, to patients with heart failure symptoms due to outflow tract obstruction or restrictive physiology, and even sudden cardiac death. Echocardiography is central to diagnosis, and cardiac MRI is increasingly important, particularly for risk stratification for sudden death. It’s essential to consider genetic phenocopies and physiologic remodeling as part of the differential diagnosis, as these distinctions impact management. As our understanding of the genetic basis of HCM deepens, genetic testing offers valuable insights but should always be paired with genetic counseling to ensure patients and families fully understand the implications of the findings.
Educational grant support provided by: Myokardia.
References
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- Gersh BJ, Maron BJ, Bonow RO, et al.; American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Developed in collaboration with the American Association for Thoracic Surgery, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2011;58:e212-60.
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Clinical Topics: Arrhythmias and Clinical EP, Cardiac Surgery, Cardiovascular Care Team, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Prevention, Valvular Heart Disease, Implantable Devices, Genetic Arrhythmic Conditions, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Aortic Surgery, Cardiac Surgery and Arrhythmias, Cardiac Surgery and Heart Failure, Cardiac Surgery and VHD, Lipid Metabolism, Acute Heart Failure, Heart Transplant, Interventions and Imaging, Interventions and Structural Heart Disease, Interventions and Vascular Medicine, Echocardiography/Ultrasound, Magnetic Resonance Imaging, Hypertension, Mitral Regurgitation
Keywords: Hypertrophy, Left Ventricular, Glycogen Storage Disease Type IIb, AMP-Activated Protein Kinases, Fabry Disease, Genetic Counseling, Mitral Valve, Glycogen Storage Disease Type II, Echocardiography, Stress, Mitral Valve Insufficiency, Friedreich Ataxia, Valsalva Maneuver, Myotonic Dystrophy, Autopsy, Cardiovascular Diseases, Prospective Studies, Prognosis, Diagnosis, Differential, Atrial Fibrillation, Physical Exertion, Systolic Murmurs, Electrocardiography, Cardiomyopathy, Hypertrophic, Death, Sudden, Cardiac, Syncope, Myocardial Infarction, Genetic Testing, Heart Failure, Hypertension, Risk Assessment, Heart Transplantation, Stroke, Dyspnea, Amyloidosis, Counseling, Physical Examination, Fatigue, Pacemaker, Artificial, Magnetic Resonance Imaging, Genotype, Decision Making, Defibrillators, Dizziness, ACCGrantHypertrophicCardiomyopathy
