Hypertrophic Cardiomyopathy. The Most Common Cause of Sudden Cardiac Death in Young Athletes.

Hypertrophic cardiomyopathy is the most common cause of sudden cardiac death in athletes under 35, and also a condition that the large majority of affected people will never die from suddenly, provided it is identified and managed appropriately. Those two facts sit together in clinical practice. Understanding both is necessary for accurate risk communication and for making sure the condition is not missed in the people who carry it without knowing it.

The Mechanism

HCM is caused by mutations in genes encoding sarcomere proteins, the contractile units of cardiac muscle cells. More than 20 causative genes have been identified. Mutations in MYH7 (beta-myosin heavy chain) and MYBPC3 (myosin binding protein C) together account for the majority of genotype-positive HCM cases. The condition follows autosomal dominant inheritance: each first-degree relative of an affected individual has a 50 percent probability of carrying the mutation.

The genetic mutation produces a cascade of structural and functional abnormalities in the myocardium. At the cellular level, the abnormal sarcomere protein leads to myocyte hypertrophy and disorganization of the normal parallel alignment of muscle fibers, a finding called myocyte disarray on pathology. This disarray is not simply cosmetic: it disrupts the normal electrical propagation through the ventricular myocardium, creating heterogeneous zones of slow conduction and reentry circuits that serve as the substrate for ventricular arrhythmias.

The sarcomere abnormality in HCM does more than cause structural thickening. It fundamentally alters the biophysics of contraction itself. In healthy myocardium, the cross-bridge cycling between actin and myosin is tightly regulated. In HCM, the mutant sarcomere proteins shift the equilibrium toward the “on” state, meaning a greater proportion of myosin heads are available for force generation at any given moment. This hypercontractile state produces more forceful systolic contraction but, paradoxically, impairs the coordinated relaxation that allows the ventricle to fill between beats. The result is a heart that squeezes well but relaxes poorly, a pattern cardiologists call diastolic dysfunction with preserved ejection fraction. This impaired relaxation is the direct mechanism behind exercise intolerance in many HCM patients, even those without significant outflow obstruction.

The macroscopic result is a thickened, stiff left ventricle with impaired relaxation (diastolic dysfunction) and, in approximately 70 percent of HCM patients, obstruction of the left ventricular outflow tract (LVOT). The outflow tract is the path blood takes when the left ventricle ejects blood into the aorta. In obstructive HCM, the thickened septum and abnormal motion of the mitral valve leaflet (systolic anterior motion, or SAM) narrow this pathway during systole, creating a pressure gradient. The obstruction increases with maneuvers that decrease ventricular filling (Valsalva, standing, dehydration) and decreases with maneuvers that increase filling (squatting, leg raise, lying down). This dynamic nature of the obstruction is physiologically important and clinically detectable.

Why Systolic Anterior Motion Occurs

Systolic anterior motion of the mitral valve deserves its own explanation because it is often misunderstood. In obstructive HCM, the thickened interventricular septum narrows the left ventricular outflow tract. The high velocity of blood moving through this narrowed passage, a Venturi effect, creates a zone of low pressure that pulls the anterior leaflet of the mitral valve toward the septum during systole. This is not a primary problem with the mitral valve itself. The valve is structurally normal in most HCM patients. The SAM is a functional consequence of the abnormal ventricular geometry. This matters clinically because treatments aimed at reducing the outflow gradient, whether medications, septal alcohol ablation, or surgical myectomy, can eliminate SAM and with it the associated mitral regurgitation, without the need to repair or replace the mitral valve in most patients.

Microvascular Disease and Fibrosis

A less visible but clinically important component of HCM pathophysiology is abnormality in the coronary microvasculature. The hypertrophied myocardium has increased metabolic demands, but the small arterioles within the thickened walls show abnormal structure and impaired vasodilator reserve. This microvascular dysfunction contributes to angina-like chest pain in HCM patients even in the absence of epicardial coronary artery disease. Over years to decades, repeated episodes of ischemia at the microvascular level, combined with the mechanical stress of the thickened myocardium, drive progressive myocardial fibrosis. This fibrosis appears on cardiac MRI as late gadolinium enhancement and carries independent prognostic weight: patients with more extensive fibrosis carry a higher risk of ventricular arrhythmia and a greater probability of progressing to a burned-out phase of HCM with reduced systolic function.

Sudden cardiac death in HCM occurs from ventricular fibrillation triggered at the disarray substrate, most frequently during intense physical exertion. During vigorous exercise, sympathetic activation shortens the cardiac cycle, increases heart rate, reduces ventricular filling time, and elevates outflow tract gradient in obstructive HCM. These conditions increase the probability that a ventricular ectopic beat will fall during a vulnerable period and initiate reentry VT or VF. This is why the risk of sudden cardiac death in HCM is specifically associated with high-intensity exercise and why competitive athletics carry a different risk profile from recreational activity.

HCM is present in approximately 1 in 500 adults, making it one of the most common inherited cardiac conditions. Most affected individuals are undiagnosed. Maron et al. documented HCM as the leading structural cause of sudden cardiac death in a registry of 387 competitive athletes, and autopsy studies in young adults who died suddenly frequently identify HCM as the underlying pathology. 5 / Solid

What the Evidence Shows

The EXPLORER-HCM trial, published in The Lancet in 2020, enrolled 251 patients with symptomatic obstructive HCM and randomized them to mavacamten or placebo. Mavacamten is a selective cardiac myosin inhibitor that reduces the number of myosin heads in the force-generating state, directly targeting the underlying sarcomere dysfunction rather than only managing downstream symptoms. At 30 weeks, 37 percent of patients in the mavacamten group met the primary endpoint of improved peak VO2 and NYHA class improvement, compared to 17 percent in the placebo group (p=0.0005). LVOT gradient fell by a mean of 47 mmHg in the mavacamten group versus 10 mmHg in placebo. Olivotto et al., Lancet 2020.

This was the first pharmacological treatment that directly addressed the mechanism of obstructive HCM rather than managing symptoms through heart rate reduction or outflow gradient attenuation. The FDA approved mavacamten (Camzyos) in 2022 for symptomatic obstructive HCM.

On risk stratification for sudden cardiac death, the 2020 AHA/ACC HCM guidelines identify five major risk factors that individually warrant ICD consideration: prior cardiac arrest or spontaneous sustained VT; family history of HCM-related sudden cardiac death; unexplained syncope; massive LV hypertrophy with maximum wall thickness 30 mm or greater; and abnormal blood pressure response to exercise (failure to rise, or a fall, in systolic BP during exercise testing). Ommen et al., Circulation 2020. 5 / Solid

The lifetime sudden cardiac death risk in HCM has declined substantially with modern risk stratification and ICD use. Registry data from specialized HCM centers now show annual sudden death rates of approximately 0.5 to 1 percent per year, with overall HCM-related mortality approaching that of age-matched controls. This is a very different picture from the early HCM literature, which reported annual sudden death rates of 2 to 4 percent, derived from tertiary referral populations that overrepresented the highest-risk patients. The apparent improvement reflects both better treatment and more accurate epidemiology from population-based studies that include the many asymptomatic, lower-risk patients.

Genetic testing identifies a causative mutation in approximately 40 to 60 percent of patients with definite HCM. Identification of a causative variant enables cascade screening of first-degree relatives with genetic testing first, then echocardiography in gene-positive relatives, rather than requiring echocardiographic screening of the entire family. First-degree relatives who do not carry the familial variant can be discharged from cardiac surveillance. Those who carry it but have normal echocardiograms are monitored periodically because clinical expression (phenotypic penetrance) can be delayed into the fourth or fifth decade of life.

The Role of Cardiac MRI

Cardiac magnetic resonance imaging (CMR) has become an essential tool in HCM evaluation and has changed the way risk stratification is done. Echocardiography remains the standard first-line imaging study because of availability and cost, but CMR offers several advantages that echo cannot replicate.

First, CMR provides more accurate and reproducible measurements of wall thickness, particularly in regions of the heart that echocardiography images poorly: the anterolateral wall and the apex. Apical HCM, a variant in which the hypertrophy is concentrated at the left ventricular apex rather than the septum, is frequently missed on echocardiography because the apex sits in an imaging plane that transthoracic echo has difficulty resolving. CMR identifies this variant reliably. The significance is that apical HCM carries specific clinical associations, including a higher rate of atrial fibrillation and, in some series, an elevated risk of apical aneurysm formation.

Second, CMR with gadolinium contrast detects myocardial fibrosis through a technique called late gadolinium enhancement (LGE). Fibrosis is the scar tissue that accumulates in the myocardium over years in HCM, and LGE extent carries independent prognostic information. Briasoulis et al. in a 2015 meta-analysis of studies enrolling over 2,900 HCM patients found that the presence of LGE was associated with a more than twofold increased risk of sudden cardiac death or equivalent events [Briasoulis et al., Heart 2015]. Patients with LGE involving more than 15 percent of LV mass appear to carry a particularly elevated arrhythmic risk, and this threshold increasingly influences ICD decisions in borderline cases where traditional risk factors are equivocal.

Third, CMR can quantify the extent of myocyte disarray indirectly through diffusion tensor imaging sequences, though this remains a research application rather than routine clinical practice.

Atrial Fibrillation in HCM

Atrial fibrillation is the most common sustained arrhythmia in HCM, occurring in 20 to 25 percent of patients over the course of their lives, compared to roughly 3 percent in the age-matched general population [Olivotto et al., JACC 2001]. The mechanisms are multiple. The stiff, poorly relaxing left ventricle transmits elevated filling pressures back to the left atrium, causing progressive atrial enlargement and fibrosis. The atrial fibrosis creates a substrate for atrial arrhythmias in the same way that ventricular disarray creates a substrate for ventricular arrhythmias.

Atrial fibrillation in HCM is not benign. The loss of atrial contraction eliminates the active filling contribution to the stiff LV, which can produce abrupt and severe hemodynamic deterioration in patients who are heavily dependent on that “atrial kick” for adequate stroke volume. Rapid ventricular rates during AF compound the problem by shortening diastolic filling time further. Patients with HCM who develop AF frequently present with sudden worsening of symptoms out of proportion to what would be expected from AF in a structurally normal heart. Rate control and rhythm control decisions in HCM-related AF follow the same general framework as in other patients, but the threshold to pursue rhythm control is lower given the hemodynamic sensitivity.

Stroke risk in HCM-related AF is also elevated. The 2020 AHA/ACC HCM guidelines recommend anticoagulation for HCM patients with AF regardless of CHA2DS2-VASc score, because the combination of structural heart disease, diastolic dysfunction, and atrial fibrosis creates a prothrombotic milieu beyond what the CHA2DS2-VASc calculator was designed to capture.

Athlete Screening and the Overlap Problem

Athlete screening for HCM presents a specific challenge. The ECG abnormalities seen in HCM (left ventricular hypertrophy by voltage, ST changes, T-wave inversions) overlap with normal athletic ECG adaptations, requiring expertise to distinguish. Echocardiography is more specific but expensive at scale. Most major sports governing bodies in Europe (UEFA, International Olympic Committee) require 12-lead ECG as part of preparticipation screening. US guidelines have historically recommended history and physical examination only, with ECG optional. The debate about universal ECG screening in US athletes continues, with cost-effectiveness arguments on both sides.

The wall thickness overlap between HCM and athlete’s heart (physiological cardiac adaptation) typically falls in the 12 to 15 mm range. Features that favor HCM over athlete’s heart include asymmetric hypertrophy (septum-to-posterior wall ratio above 1.5), small left ventricular cavity size, diastolic dysfunction on echo, family history, female sex, and failure of wall thickness to decrease with deconditioning. When the distinction cannot be made with imaging alone, genetic testing and cardiopulmonary exercise testing can help.

An athlete with physiological hypertrophy will show normal or supranormal diastolic filling on echocardiography, normal peak oxygen uptake on exercise testing, and wall thickness that regresses at least partly with 3 months of detraining. An HCM patient with wall thickness in the same numeric range will typically show impaired diastolic relaxation, a relatively reduced exercise capacity for their training level, and no regression of wall thickness with deconditioning. Getting this distinction right is the difference between allowing a healthy athlete to continue competing and wrongly clearing a person with HCM for high-intensity sport.

What to Do This Week

1. If you have a first-degree relative who has been diagnosed with HCM, request a referral to a cardiologist familiar with inherited cardiac conditions for echocardiography and genetic counseling. Do not wait for symptoms to develop. The condition can be completely asymptomatic until a serious event.

2. If you have been told you have a heart murmur, particularly one described as louder when you stand up or bear down, ask your physician specifically whether an echocardiogram has been done to exclude HCM. A murmur that worsens with Valsalva is a classic sign of obstructive HCM and requires echocardiographic evaluation.

3. If you participate in competitive athletics or high-intensity recreational sport and you have experienced exertional chest discomfort, near-syncope (feeling faint during exercise), or unexplained palpitations during activity, seek cardiac evaluation before returning to that activity level. Attributing those symptoms to fitness level or dehydration without a structural cardiac evaluation is an avoidable risk.

4. If HCM has been diagnosed in you and you have not had a cardiac MRI with gadolinium contrast, ask your HCM specialist about it. The extent of late gadolinium enhancement (fibrosis) on CMR adds independent prognostic information to echocardiographic risk stratification and influences ICD decisions in borderline cases.

5. Keep a symptom log if you have known HCM: date, activity at onset, symptom description, duration, and resolution. This log provides objective data for risk re-stratification at annual follow-up visits and helps distinguish stable symptoms from new ones that warrant earlier evaluation.

6. If you have HCM and have not been screened for atrial fibrillation, ask your cardiologist whether a Holter monitor or extended rhythm recording is indicated. AF in HCM can be paroxysmal and asymptomatic, and identifying it changes your anticoagulation management in a way that reduces stroke risk.

7. Ask specifically whether your cardiologist has expertise in HCM. Not all cardiology practices see sufficient HCM volume to maintain current expertise in risk stratification, mavacamten prescribing, or the athlete-versus-HCM distinction on echocardiography. Major medical centers with dedicated inherited cardiac disease programs or HCM programs see this condition frequently enough to apply the evidence base accurately.

HCM is manageable for most people who have it. The patients at genuine high risk of sudden cardiac death can be identified with available tools and protected with an ICD. The challenge is identifying the condition in the people who do not yet know they carry it, which means taking family history seriously and pursuing echocardiographic evaluation when the clinical context warrants it.

The Signal Check is fifteen questions mapping the cardiovascular risk pattern across the physiological domains most commonly missed in standard screenings. It produces a specific starting point for your next clinical conversation.