Hypertrophic Cardiomyopathy: What You Need to Understand

2. What It Is

Hypertrophic cardiomyopathy is defined as left ventricular hypertrophy (maximum wall thickness of 15 mm or above on echocardiography, or 13-14 mm with a positive family history or gene mutation) that cannot be explained by abnormal loading conditions (hypertension, aortic stenosis, athlete’s heart) 5 / Solid .

The key distinction from hypertensive LVH: in HCM, the hypertrophy is:

• Often asymmetric (septal predominance, with septal-to-posterior wall thickness ratio above 1.3-1.5)
• Present in patients without long-standing hypertension
• Associated with a genetic mutation in sarcomere proteins in 40-60% of cases
• Associated with characteristic histological changes (myocyte disarray, interstitial fibrosis, abnormal intramural coronary arteries)

Obstructive vs Non-Obstructive HCM

Approximately 70% of HCM patients have dynamic outflow tract obstruction under provocable conditions; 30-40% have obstruction at rest (resting LVOT gradient above 30 mmHg) 5 / Solid .

The obstruction mechanism: thickened anterior septum creates a narrow LVOT. The anterior mitral valve leaflet is dragged toward the hypertrophied septum during systole (systolic anterior motion, SAM) by the Venturi effect from the hyperdynamic LV. SAM-septal contact both obstructs outflow and creates MR (leaflet distortion during mid-to-late systole). A Valsalva maneuver (which reduces LV volume) accentuates the obstruction; a squatting maneuver (which increases LV volume) reduces it. This dynamic nature is diagnostically important.

Obstruction gradient matters: LVOT gradient above 50 mmHg is associated with worse outcomes and is the threshold for invasive septal reduction therapy 5 / Solid .

3. The Mechanism

Sarcomere protein mutations

The genetic architecture of HCM: autosomal dominant mutations in genes encoding sarcomere proteins cause 40-60% of familial HCM. The most common:

• MYH7 (beta-myosin heavy chain): 15-25% of genotype-positive cases
• MYBPC3 (myosin-binding protein C): 30-40% of genotype-positive cases, usually milder phenotype with later onset
• TNNT2 (troponin T): associated with high SCD risk disproportionate to hypertrophy degree
• TNNI3 (troponin I), TPM1 (tropomyosin)

These mutations cause the sarcomere to be hyperdynamic: increased actin-myosin interaction, faster cross-bridge cycling, and higher calcium sensitivity. The result is hypercontractility of the LV (explaining the high EF and low systolic volumes), but paradoxically impaired relaxation (because the hyperstimulated sarcomere does not efficiently release actin-myosin cross-bridges in diastole), leading to diastolic dysfunction and filling abnormalities.

The hypertrophy is the myocardium’s response to these sarcomere abnormalities, not the primary problem. It is a consequence. This distinction is pharmacologically important: a drug that reduces hypercontractility at the sarcomere level may address the root cause, not just the symptom.

Diastolic dysfunction and HCM

The stiff, hypertrophied, fibrotic LV fills poorly. In HCM, filling pressures are raised in most patients, contributing to exertional dyspnea even in the absence of obstruction. The diastolic dysfunction of HCM is distinct from HFpEF: it coexists with a hypercontractile systole, rather than a normally contracting one. Many HCM patients are in the paradoxical state of simultaneous hyperdynamic systolic function and poor diastolic function.

Myocardial fibrosis and SCD

Late gadolinium enhancement (LGE) on CMR reflects myocardial fibrosis in HCM. The degree of LGE is associated with VT/VF risk. LGE above 15% of LV mass is associated with a 3-5 fold increase in SCD risk 5 / Solid . The fibrotic areas provide a substrate for re-entrant ventricular arrhythmias. The small intramural coronary arteries that are dysplastic in HCM (arteriolar remodeling: medial hypertrophy, luminal narrowing) may cause microvascular ischemia, producing additional arrhythmic substrate.

4. How We Diagnose

Echocardiography

The TTE is the primary diagnostic and monitoring tool. Key measurements:

• Maximum wall thickness (MWT): the single most important measurement. A thickness above 30 mm is itself a risk factor for SCD.
• LVOT gradient at rest and with Valsalva
• Presence of SAM (mitral valve systolic anterior motion)
• Degree of mitral regurgitation
• LV cavity size (most HCM patients have small, hyperdynamic LV cavities)
• Left atrial size (dilated LA from raised filling pressures and MR)
• RV function

Exercise echocardiography: resting LVOT gradient below 30 mmHg does not exclude significant obstruction. With exercise (which reduces LV volume through tachycardia and sympathetic activation), the gradient may exceed 50 mmHg. Exercise echo is appropriate for symptomatic patients with low resting gradient.

Cardiac MRI

CMR provides:

• More accurate wall thickness measurement than echo (particularly for anterolateral and apical walls, where echo underestimates thickness due to foreshortening)
• Apical HCM identification (a specific variant with apical thickening that is frequently missed on echo): this is more common in Asian populations
• LGE quantification for SCD risk stratification
• T1 mapping for diffuse fibrosis assessment

CMR is the gold standard for HCM evaluation and should be performed in all newly diagnosed patients or when echo is inadequate.

Genetic testing

Genetic testing is recommended for all patients with HCM. If a sarcomere mutation is identified, cascade screening of first-degree relatives is recommended. Approximately 40-60% of probands with HCM will have a definite pathogenic or likely pathogenic sarcomere variant. Negative genetic testing does not rule out HCM; it means a mutation was not found (or a currently unclassified variant of uncertain significance was found).

Genetic testing informs: family screening, prognosis (some mutations carry higher SCD risk), and pharmacological considerations (mavacamten targets the myosin head and may have differential efficacy by mutation type).

5. The Evidence

SCD risk stratification

The primary clinical challenge in HCM is SCD risk stratification. The American College of Cardiology (ACC) 2020 HCM guidelines (Ommen SR, et al., Circulation 2020; 10.1161/CIR.0000000000000937) recommend risk stratification at diagnosis and every 1-2 years.

Major SCD risk factors (Class I or IIa indications for ICD consideration):

• Prior cardiac arrest or sustained VT
• Spontaneous non-sustained VT (NSVT) on ambulatory monitoring
• Maximum wall thickness above 30 mm
• First-degree relative with HCM-related sudden death
• Unexplained syncope within the preceding 6 months
• Abnormal blood pressure response to exercise (failure to rise, or fall, during exercise stress testing)
• LGE above 15% of LV mass on CMR

The European Society of Cardiology HCM Risk-SCD calculator (Siontis KC, et al.; 10.1093/eurheartj/ehv459) provides a 5-year predicted SCD probability. A score above 6% at 5 years is considered high risk warranting ICD consideration 5 / Solid .

ICD is the only intervention proven to prevent SCD in HCM. It does not treat symptoms. It does not reduce obstruction. Its role is survivability from an otherwise fatal arrhythmic event.

Pharmacological treatment: disopyramide and beta-blockers

Disopyramide (a class IA antiarrhythmic with negative inotropic properties) reduces LVOT obstruction and symptom burden in obstructive HCM 4 / Promising . It works by reducing contractility and slowing early LV ejection, reducing the Venturi effect that drives SAM. Anticholinergic side effects (urinary retention, dry mouth, blurred vision) limit tolerability in older patients. Disopyramide is typically used in combination with a beta-blocker or verapamil (to control the AF that disopyramide can promote by increasing AV conduction at atrial level).

Beta-blockers reduce heart rate, decrease LVOT gradient by increasing LV filling time, and improve diastolic function. They are the most commonly used first-line agents for symptom management in HCM. Non-vasodilating beta-blockers (metoprolol, atenolol, nadolol) are preferred.

Verapamil: for patients intolerant of beta-blockers, verapamil provides rate reduction and some negative inotropic effect. It should not be used in patients with high resting LVOT gradients or severe pulmonary hypertension.

EXPLORER-HCM: mavacamten (2020)

The EXPLORER-HCM trial enrolled 251 patients with obstructive HCM (resting or Valsalva LVOT gradient above 50 mmHg, NYHA II-III) and randomized them to mavacamten (Camzyos) versus placebo for 30 weeks 5 / Solid 31792-X).

Mavacamten is a selective cardiac myosin inhibitor. It reduces the number of myosin heads in the force-producing state during systole (reducing excess cross-bridge formation), decreasing hypercontractility at the sarcomere level without reducing EF to pathological levels in most cases.

Results: 37% of mavacamten patients achieved the primary endpoint (reduction of peak VO2 by 1.5 mL/kg/min or more AND improvement of NYHA class by 1 or more, compared to 17% for placebo, p = 0.0005). LVOT gradient fell dramatically: mean reduction of 47 mmHg from baseline in the mavacamten group versus 10 mmHg for placebo. Mean post-exercise LVOT gradient: 24 mmHg in mavacamten versus 68 mmHg for placebo.

Mavacamten received FDA approval in April 2022 for symptomatic obstructive HCM (NYHA Class II-III) under priority review. It is the first approved pharmacological therapy targeting the underlying sarcomere hypercontractility in HCM.

Safety concern: mavacamten reduces systolic function. In a small proportion of patients, the EF can fall below 50% (LVEF reduction). The REMS program (Risk Evaluation and Mitigation Strategy) requires echocardiographic monitoring of LVEF before and during therapy. Dose reductions are mandated if EF falls below 50%.

VALOR-HCM: mavacamten as an alternative to septal reduction therapy (2022)

VALOR-HCM enrolled 112 patients with obstructive HCM who were guideline-eligible for septal reduction therapy (SRT, i.e., had severe symptoms, LVOT gradient above 50 mmHg on treatment, and were willing to undergo surgery or ablation). These patients were randomized to mavacamten versus placebo for 16 weeks, with SRT offered to all at 16 weeks if still indicated.

At 16 weeks, only 17.9% of patients in the mavacamten group remained guideline-eligible for SRT, compared to 76.8% for placebo (p < 0.0001) 5 / Solid . Mavacamten significantly delayed or eliminated the need for invasive SRT in many patients. This changed the clinical algorithm: before referring a patient for myectomy or alcohol septal ablation, a trial of mavacamten is now reasonable.

Septal reduction therapy: surgery vs alcohol ablation

For patients with obstructive HCM who remain severely symptomatic (NYHA III-IV) despite maximal medical therapy, septal reduction therapy is indicated.

Surgical septal myectomy (Morrow procedure): Transaortic resection of a rectangular trough of hypertrophied septum, performed under cardiopulmonary bypass. This is the gold standard intervention. At experienced centers (more than 50 myectomies per year), operative mortality is less than 0.5% and successful relief of obstruction is achieved in 90-95% of patients 5 / Solid . Long-term outcomes are excellent: most patients achieve NYHA Class I-II symptoms and the gradient is eliminated.

Center volume matters enormously for myectomy outcomes. High-volume myectomy centers in the United States: Mayo Clinic (Rochester, MN), Cleveland Clinic, Brigham and Women’s (Boston), Hypertrophic Cardiomyopathy Center at Tufts Medical Center. In Illinois: Northwestern Memorial Hospital (Chicago), University of Chicago.

Alcohol septal ablation (ASA): Catheter-based injection of absolute ethanol into the first septal perforator artery, causing a controlled septal MI that reduces septal mass. This is a less invasive alternative for patients who are not surgical candidates. Gradient reduction is comparable to surgery at experienced centers 4 / Promising . Limitations: requires a suitable septal perforator anatomy; complete heart block complicating the ablation requires permanent pacemaker in 10-20% of patients. ASA creates scar, which may increase arrhythmic risk; surgery does not create scar.

The 2020 ACC guidelines recommend myectomy over ASA as the preferred SRT at experienced surgical centers for patients who are good surgical candidates 5 / Solid .

6. The Patient Experience

The athlete with HCM

The question of athletic participation in HCM is among the most emotionally charged decisions in sports cardiology. The 2020 AHA/ACC guidelines took a more permissive stance than earlier guidelines, recommending shared decision-making for athletes with HCM rather than categorical disqualification 5 / Solid . Key considerations:

• Athletes without obstructive HCM, without high SCD risk factors, and with preserved exercise capacity may participate in competitive sports after informed shared decision-making.
• Athletes with obstructive HCM, high SCD risk factors, or prior arrhythmic events carry higher risk; restriction or ICD implantation before return to competition is discussed.
• Access to AEDs at training and competition venues is mandatory for any HCM athlete who returns to play.

The basketball player from the opening scene: he was disqualified from competitive Division I play based on the severity of his obstruction and his prior arrest. He received an ICD. He returned to recreational basketball 14 months later after myectomy and ICD implant, gradient resolved.

Living with an ICD for HCM

The ICD decision in HCM is emotionally complex. The patient is typically young (20s-50s), often asymptomatic between risk stratification visits, and is asked to accept a device implanted for prevention of an event that may never occur. The shock itself, if it fires appropriately, is painful and traumatic. Inappropriate shocks (from sensing exercise-induced tachycardia, oversensing, or T-wave oversensing) occur in 5-10% per year with older devices; modern devices have improved algorithms that significantly reduce inappropriate shock rates.

Psychological support for young HCM patients receiving ICDs is recommended but often not systematically provided.

The diagnosis gap in women

The sex difference in HCM surgical referral is documented and concerning. Women with HCM are referred for septal myectomy at lower rates than men, despite having equivalent or greater symptom burden 5 / Solid . The reasons are multifactorial: women present later in the disease course, have smaller body habitus (smaller LV dimensions making surgical assessment more difficult), and may have their symptoms underestimated or attributed to other causes. Awareness of this gap is needed for both patients and physicians.

7. Decisions and Trade-Offs

When to initiate mavacamten vs proceed to SRT

Mavacamten changed the clinical sequence for obstructive HCM. The algorithm before VALOR-HCM: start beta-blocker, uptitrate, add disopyramide, if still NYHA III-IV and gradient above 50 mmHg, refer for SRT. The algorithm after VALOR-HCM: include a 16-week trial of mavacamten before committing to SRT. For a patient who achieves NYHA Class II symptoms and gradient below 50 mmHg on mavacamten, deferring SRT is appropriate. For a patient who does not respond adequately to mavacamten (still NYHA III-IV, still high gradient), SRT should not be delayed.

Mavacamten is not free of complexity. Monthly echocardiography for the first three months, then every 3 months, is required per the REMS program. Drug interactions matter: CYP2C19 inhibitors (fluconazole, omeprazole) increase mavacamten levels; CYP3A4 inducers (rifampin, phenytoin) decrease them. Cost is approximately $68,000/year at launch.

ICD timing and SCD risk thresholds

The 2020 ACC guidelines moved away from a rigid 5-year SCD risk calculator toward a more individualized multifactorial assessment. A patient with a single major risk factor (maximum wall thickness 30 mm alone, or single family member with SCD alone) may have a 5-year calculated risk of 3-4%, below the traditional ICD threshold. But a 25-year-old with this single risk factor has a 40-50-year risk horizon; the lifetime risk of SCD is different from the 5-year risk.

The decision to implant an ICD in HCM requires a genuine shared decision-making conversation about the uncertainty of risk, the psychological burden of device therapy, and the protection the device provides.

End-stage HCM: the burned-out phase

Approximately 3-5% of HCM patients develop an end-stage burned-out phenotype: the hypertrophied myocardium becomes replaced by fibrosis, EF falls below 50% and eventually below 35%, and the clinical picture becomes indistinguishable from dilated cardiomyopathy 5 / Solid . At this stage, the four-drug HFrEF protocol is appropriate and ICD is indicated based on EF threshold. LVAD or cardiac transplantation is an option for end-stage HCM patients, with transplant outcomes comparable to non-HCM dilated cardiomyopathy.

8. The SDE Synthesis

HCM is the most common inherited cardiac condition in the United States, yet it is often diagnosed only after a sentinel event (syncope, cardiac arrest) because systematic screening of asymptomatic family members is not universally performed. The SDE platform’s approach to HCM focuses on three levels.

Level 1: Family screening. When an HCM proband is identified, first-degree relatives (parents, siblings, children) should be screened with echocardiography and, once a pathogenic variant is identified in the proband, with genetic testing. The SDE Audit facilitates this cascade screening process, providing a structured pathway for family members who may be at five different hospitals in two states.

Level 2: Risk stratification and monitoring. For patients with established HCM, annual echocardiography and risk factor assessment is the standard. Ambulatory monitoring for NSVT (a risk factor for SCD) and exercise testing for BP response are components of the standard surveillance. The SDE Cohort provides the tracking infrastructure to ensure these evaluations occur on schedule and that risk stratification is updated annually.

Level 3: Access to expertise. HCM is a disease where center volume determines outcome. The SDE Executive tier provides facilitation for referral to HCM centers of excellence for patients who need myectomy evaluation, advanced genetic counseling, or athlete evaluation and sports cardiology consultation. In Illinois, Northwestern Memorial Hospital and the University of Chicago operate dedicated HCM programs. For patients in central or downstate Illinois, travel to Chicago is the pathway; SDE Executive coordinates that process.

The basketball player is alive because an AED was in the gym and a trainer knew how to use it. That is a separate story. But the family members who were told they “had a heart condition” are the SDE story. Three of them now have echocardiograms. Two have mutations. One has an ICD. None of them collapsed on a basketball court.

That is what systematic screening does.