Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a genetic myocardial disease defined by unexplained left ventricular hypertrophy — a maximal end-diastolic wall thickness of 15 mm or more in any left ventricular segment (or 13 mm or more in a first-degree relative of a patient with confirmed HCM, or in a known pathogenic-variant carrier) that is not explained by another cause of hypertrophy such as hypertension or valvular disease.^[1][2] It is the most common inherited cardiac disease, with an estimated prevalence of approximately 1 in 500 in the general population.^[1] Most cases arise from an autosomal dominant pathogenic variant in a gene encoding a sarcomere protein — most often MYBPC3 (cardiac myosin-binding protein C) or MYH7 (beta-myosin heavy chain) — producing myocyte hypertrophy, disarray, and fibrosis, and classically an asymmetric, septal pattern of hypertrophy.^[1][2]

The pathophysiologic distinction this chapter is organized around is obstructive versus non-obstructive HCM. In obstructive HCM, septal hypertrophy — often combined with systolic anterior motion of the mitral valve — narrows the left ventricular outflow tract (LVOT) and produces a dynamic, load-dependent gradient that worsens with dehydration, exertion, and any medication that reduces preload, reduces afterload, or increases contractility. Significant LVOT obstruction is defined as a peak gradient of 30 mmHg or more at rest, or 50 mmHg or more with provocation (Valsalva or exercise); roughly a third of patients have resting obstruction, a third have obstruction only on provocation, and a third have no obstruction at either.^[2] This distinction directly drives the prescribing-safety theme running through this chapter: which drugs relieve obstructive symptoms, and which — vasodilators, high-dose diuretics, digoxin — make the obstruction worse and should generally be avoided.

Beyond symptom management, this chapter treats sudden cardiac death (SCD) risk stratification as a central safety priority in its own right, independent of symptom burden: HCM can present for the first time as sudden cardiac arrest, most tragically in young, apparently healthy competitive athletes, and identifying who needs specialist evaluation for an implantable cardioverter-defibrillator (ICD) is one of the highest-stakes decisions in this disease.^[2][3] The modern pharmacologic landscape has also genuinely changed: mavacamten, a cardiac myosin inhibitor, is the first therapy that directly targets the underlying sarcomere hypercontractility of obstructive HCM rather than simply slowing the heart down, and is now a guideline-recognized option for patients who remain symptomatic despite a beta-blocker or non-dihydropyridine calcium channel blocker.^[2][4]

Epidemiology

HCM affects roughly 1 in 500 people, making it the most common inherited heart disease, yet it remains substantially underdiagnosed because so many carriers are asymptomatic.^[1] Its public-health significance is disproportionate to its prevalence: HCM is a leading cause of sudden cardiac death in young people, and specifically in young competitive athletes — a large case series of 1,866 young athletes who died suddenly found HCM to be the causative condition in nearly 40% of cases, with almost two-thirds of the affected athletes 17 years of age or younger and still in high school.^[3] Over 80% of these individuals were entirely asymptomatic before their sudden cardiac death, which is exactly why family screening and pre-participation evaluation matter so much — there is often no warning symptom to catch beforehand.^[3]

Typical presentation

• Asymptomatic — a substantial proportion of patients, found incidentally on examination (a murmur), an ECG done for another reason, or through family/cascade screening after a relative's diagnosis.
• Dyspnea on exertion and reduced exercise tolerance, from diastolic dysfunction, dynamic outflow obstruction, or both.
• Angina-like chest pain, which can occur even without epicardial coronary artery disease, from microvascular ischemia and a supply-demand mismatch in the hypertrophied myocardium.
• Palpitations — atrial fibrillation is the most common sustained arrhythmia complicating HCM (see Red Flags/Refer and Common Errors to Avoid).
• Presyncope or syncope, particularly exertional syncope — a genuine red flag that should prompt urgent evaluation rather than reassurance (see Red Flags/Refer).
• Tragically, sudden cardiac death can be the first presentation of HCM, notably in young, previously asymptomatic competitive athletes during or immediately after intense exertion.^[3]

Genetic basis

Most HCM is caused by a pathogenic or likely pathogenic variant in a gene encoding a component of the cardiac sarcomere, inherited in an autosomal dominant pattern with variable penetrance and expressivity — a parent carrying a pathogenic variant has, on average, a 50% chance of passing it to each child, but that child's eventual degree of hypertrophy can range from none to severe.^[1] MYBPC3 and MYH7 together account for the majority of genotype-positive cases; a pathogenic variant is identified on genetic testing in roughly half of clinically diagnosed patients, with the remainder considered "genotype-elusive."^[1]

The family-screening imperative

Because most familial HCM follows autosomal dominant inheritance, first-degree relatives of every newly diagnosed patient are themselves at risk and should be offered evaluation — this is a core part of management, not an optional add-on.^[1] The CCS 2024 update recommends baseline clinical screening with echocardiography and a resting ECG for first-degree relatives of a patient with a clinical HCM diagnosis. Where a (likely) pathogenic variant has been identified in the family, genetic counselling and testing should be offered to all relatives regardless of age; relatives who test negative for the known familial variant, with a normal baseline clinical screen, can be discharged from further follow-up, while relatives who carry the variant — or come from a genotype-elusive family — need periodic clinical re-screening over time, since expression can emerge later in life.^[1]

Other risk factors and phenocopies

• A family history of HCM, or of unexplained sudden cardiac death at a young age.
• Consider a phenocopy rather than sarcomeric HCM when the clinical picture is atypical — cardiac amyloidosis, Fabry disease, and RASopathy syndromes (e.g., Noonan syndrome) can all produce a similar pattern of unexplained LV hypertrophy and change both management and family counselling.^[2]
• Dynamic worsening factors specific to obstructive HCM — dehydration, heavy exertion (especially in heat), a large meal, alcohol, and any of the medications on the avoidance list below — do not cause the underlying disease but can precipitate or worsen symptoms and the LVOT gradient in a patient who already has it.^[2]

Diagnostic criteria

HCM is diagnosed by a maximal left ventricular end-diastolic wall thickness of 15 mm or more in any myocardial segment on imaging, in the absence of another condition (hypertension, valvular disease, infiltrative disease) sufficient to explain the degree of hypertrophy; the threshold is lowered to 13 mm or more in a first-degree relative of a patient with confirmed HCM, or in a known pathogenic sarcomere-variant carrier, reflecting the lower bar for concern when pretest probability is already high.^[1][2]

Echocardiography — the primary diagnostic tool

Transthoracic echocardiography is the primary tool for both diagnosis and ongoing management. It defines the pattern and maximal thickness of hypertrophy (most often asymmetric septal, though concentric and apical variants occur), assesses systolic anterior motion of the mitral valve and any resulting mitral regurgitation, and — critically — measures the LVOT gradient at rest and with provocation (Valsalva maneuver, and exercise echocardiography if resting and Valsalva gradients are non-diagnostic but obstruction is still suspected). A resting or provoked gradient under 30 mmHg with ongoing exertional symptoms should prompt exercise testing rather than being taken as reassurance that obstruction is not contributing — genuinely provocable obstruction is easy to miss if only a resting, non-provoked study is done.^[2]

Additional investigations

• Cardiac MRI — for further characterization when echocardiographic windows are limited, to clarify the distribution of hypertrophy (e.g., apical HCM, which echo can under-detect), and to assess for late gadolinium enhancement (myocardial fibrosis), which feeds into sudden-cardiac-death risk stratification alongside the clinical risk factors below.^[2]
• 12-lead ECG — frequently abnormal (voltage criteria for LVH, deep or prominent Q waves, T-wave inversion) even before hypertrophy is echocardiographically obvious; used together with echocardiography for family/cascade screening.
• Ambulatory ECG monitoring (24-48 hour Holter or longer) — to detect non-sustained ventricular tachycardia, one of the major sudden-cardiac-death risk factors, and to characterize palpitations or screen for atrial fibrillation.^[2]
• Exercise testing — to assess the blood-pressure response to exercise (an abnormal, blunted, or hypotensive response is a sudden-cardiac-death risk factor) and to unmask a provocable LVOT gradient not present at rest.^[2]
• Genetic testing — offered to the proband to identify a causative variant where possible, which then allows efficient, targeted cascade genetic testing of relatives rather than requiring every relative to undergo lifelong periodic clinical screening (see Risk Factors).^[1]

Differential diagnosis

The most common and clinically important distinction is from athlete's heart — physiologic LV hypertrophy from intense training. Features favouring athlete's heart over HCM include wall thickness that regresses with a period of deconditioning, a normal or enlarged (rather than small) LV cavity, normal diastolic function, no family history of HCM or sudden death, and a normal genetic test; features favouring true HCM include markedly asymmetric hypertrophy, an LV cavity that is small or normal despite the hypertrophy, abnormal diastolic filling, LVOT obstruction, and a positive family history or genetic test. Other considerations include hypertensive heart disease and aortic stenosis (both produce concentric LVH — assess the valve directly), and infiltrative phenocopies such as cardiac amyloidosis and Fabry disease, which can mimic HCM on imaging but require entirely different management.^[2]

• Relieve symptoms of dyspnea, chest pain, and exercise intolerance, whether from outflow obstruction, diastolic dysfunction, or both.
• In obstructive HCM specifically, reduce the LVOT gradient — pharmacologically first, with septal reduction therapy reserved for drug-refractory disease.
• Risk-stratify every patient for sudden cardiac death and refer those with concerning features for specialist evaluation of ICD candidacy — pursued in parallel with symptom management, not only once symptoms become severe.^[2]
• Identify and evaluate first-degree relatives through clinical and, where appropriate, genetic cascade screening.^[1]
• Avoid iatrogenic harm in obstructive HCM specifically — recognize and avoid medications that worsen dynamic outflow obstruction (vasodilators, high-dose diuretics, digoxin).
• Identify and manage complications — atrial fibrillation (with attention to its elevated stroke risk in HCM), progression toward heart failure, and, uncommonly, progression to a "burnt-out," dilated, hypocontractile phase.
• Provide individualized exercise and activity counselling through shared decision-making, rather than blanket restriction.^[2]

• Septal reduction therapy — surgical septal myectomy or alcohol septal ablation — for severe, drug-refractory obstructive symptoms (persistent NYHA class III-IV symptoms, or class II with a hemodynamically significant gradient) despite maximally tolerated medical therapy, including a trial of mavacamten where appropriate. Surgical myectomy is generally preferred in younger, otherwise-healthy candidates and when concomitant cardiac surgery (e.g., mitral valve repair) is needed; alcohol septal ablation is a less invasive, catheter-based alternative more often reserved for older patients, those with significant comorbidity, or where the surgical approach is not feasible or preferred. Both are considered similarly indicated in appropriately selected patients, and outcomes are best at experienced, high-volume HCM centers — refer rather than manage refractory obstruction indefinitely in the community.^[2]
• ICD implantation for patients identified through sudden-cardiac-death risk stratification as appropriate candidates — see the Clinical Decision Algorithm; this is a specialist decision made through shared decision-making once risk factors are identified, not a default response to any single risk feature in isolation.^[2]
• Genetic counselling and cascade family screening for first-degree relatives is itself a core management intervention in a genetic, autosomal-dominant-inherited disease, not an optional adjunct — see Risk Factors.^[1]
• Hydration and avoidance of dehydration (illness with vomiting/diarrhea, excessive heat exposure, alcohol excess) in obstructive HCM specifically, since volume depletion worsens the dynamic gradient the same way a vasodilator or diuretic does.
• Individualized exercise counselling through shared decision-making — see Special Populations/Athletes; the modern approach favours an individualized conversation over blanket restriction from vigorous exercise or competitive sport for most patients with HCM.^[2]
• For atrial fibrillation complicating HCM: rate or rhythm control per standard principles (see the Atrial Fibrillation chapter for drug selection), plus oral anticoagulation, recommended for essentially all HCM patients with clinical atrial fibrillation given their elevated stroke risk (see Common Errors to Avoid).^[2]

Athletes

HCM is a leading cause of sudden cardiac death in young competitive athletes, and it is precisely the combination of intense exertion and an undiagnosed or unmanaged high-risk substrate that makes activity counselling so important.^[3] The field has moved away from a blanket disqualification approach: current guidance favours an individualized shared decision-making conversation between the athlete (and family, where relevant) and a specialist familiar with HCM, weighing the specific risk profile, the sport, and the athlete's own values, rather than universal restriction from vigorous exercise or competitive sport for every patient with an HCM diagnosis.^[2][5] That said, patients with high-risk features — recent unexplained syncope, a prior cardiac arrest, extreme hypertrophy, or other concerning sudden-cardiac-death risk factors — need that specialist conversation before returning to intense competitive training, not a default clearance; this is the same central referral message as Red Flags/Refer, applied specifically to the athletic population where the stakes of getting it wrong are highest.^[5]

Pregnancy

Pregnancy in a patient with HCM needs specialist co-management by cardiology and maternal-fetal medicine, ideally planned in advance with pre-pregnancy counselling given the disease's inheritance pattern. Beta-blockers are generally continued through pregnancy for symptom and arrhythmia control, with attention to fetal growth monitoring. Mavacamten is not established as safe in pregnancy — animal data suggest potential fetal harm and there are no adequate human data, which is why pregnancy must be excluded before starting it in a patient of reproductive potential, and effective contraception must be used during treatment and for 4 months after the last dose; mavacamten can also reduce the effectiveness of some combined hormonal contraceptives, which needs to be accounted for when selecting a method.^[4] Avoid initiating disopyramide in pregnancy where possible given its anticholinergic profile and limited safety data; if a rhythm-control or negative-inotrope strategy is genuinely needed, decide jointly with the specialist team. As in any obstructive HCM patient, avoid vasodilators, high-dose diuretics, and digoxin for the same hemodynamic reasons described above.

Pediatric and genotype-positive children

Children carrying a familial pathogenic variant, or from a genotype-elusive family, need periodic clinical re-screening through childhood and adolescence as expression of the disease can emerge with growth — a single normal childhood echocardiogram does not rule out later development of HCM.^[1] Pediatric HCM and sudden-cardiac-death risk stratification is a specialist area; refer to pediatric cardiology rather than extrapolating adult risk thresholds directly.

Renal and hepatic impairment

Adjust verapamil, diltiazem, and disopyramide doses for renal or hepatic impairment per standard references and the Drug Database — disopyramide in particular is substantially renally cleared and needs real caution and dose reduction in renal impairment. Consult the CAMZYOS product monograph and a pharmacist for mavacamten dosing considerations in hepatic impairment given its CYP-dependent metabolism.^[4]

Older adults

Consider a hypertensive or, less commonly, an infiltrative phenocopy (cardiac amyloidosis) more actively in an older adult with newly identified LV hypertrophy, since amyloidosis becomes considerably more common with age and changes management substantially — see Assessment/Diagnosis.^[2]

• Routine follow-up echocardiography approximately every 1-2 years in stable, asymptomatic patients, and more frequently with new or worsening symptoms, a medication change, or after septal reduction therapy.
• For patients on mavacamten: strict adherence to the REMS-style echocardiographic monitoring schedule (baseline, 4, 8, and 12 weeks, then approximately every 12 weeks, or sooner after a dose change or the addition/removal of an interacting CYP2C19/CYP3A4 drug) is a condition of continued treatment, not an optional add-on — confirm the patient understands that missed monitoring visits can mean an interruption in therapy.^[4]
• Reassess sudden-cardiac-death risk factors periodically, not only at diagnosis — a new syncopal event, a new family history of sudden death, or NSVT newly detected on monitoring should trigger re-referral even in a patient previously considered lower risk.^[2]
• Confirm first-degree relatives have actually completed the recommended screening — this is easy to lose track of over time and is a genuine, correctable gap in care.^[1]
• For patients anticoagulated for HCM-associated atrial fibrillation: routine renal function and adherence checks per the Atrial Fibrillation chapter.
• Patient education — teach patients to recognize and promptly report exertional presyncope/syncope, palpitations, and worsening dyspnea; reinforce hydration and avoidance of dehydration-provoking situations (illness, extreme heat, excess alcohol) specifically in obstructive HCM; explain, in plain language, why an otherwise-ordinary medication (an ACE inhibitor for blood pressure, a diuretic, digoxin) may need to be avoided or used cautiously, so patients understand this is disease-specific rather than overcaution; and discuss the implications of the diagnosis for family members, including how to raise genetic counselling and screening with relatives.
• For a patient with a new ICD: confirm device follow-up is arranged, counsel on recognizing signs of a device or lead complication, and set realistic expectations for driving-restriction and activity guidance in the immediate post-implant period per local/provincial requirements.

1. Persistent obstructive symptoms despite an optimized, maximally tolerated beta-blocker: switch to or add a non-dihydropyridine calcium channel blocker (if not already combined), or add disopyramide with an AV-nodal blocking agent already on board.
2. Persistent NYHA class II-III symptoms despite an optimized beta-blocker or calcium channel blocker: this is the specific population mavacamten is approved for — refer to or coordinate with a prescriber enrolled in the monitoring program rather than continuing to escalate the same drug class indefinitely.^[4][2]
3. Mavacamten with an LVEF that falls under 50% at a monitoring visit: interrupt therapy per the product monograph; an LVEF of 30% or under, or clinically significant heart failure symptoms, means permanent discontinuation.^[4]
4. Severe, drug-refractory obstructive symptoms despite optimized medical therapy, including a mavacamten trial where appropriate: refer to an experienced center for septal reduction therapy (myectomy or alcohol septal ablation) rather than continuing to add or increase medication doses indefinitely.^[2]
5. New sudden-cardiac-death risk factors identified on follow-up (new syncope, new family history, NSVT on monitoring, worsening LVEF): re-refer for specialist ICD-candidacy reassessment — risk stratification is not a one-time determination made only at diagnosis.^[2]
6. Atrial fibrillation not adequately rate- or rhythm-controlled with first-line therapy: escalate per the Atrial Fibrillation chapter's principles, keeping in mind that digoxin is not an appropriate rate-control choice in obstructive HCM and that anticoagulation should already be in place regardless of the CHA2DS2-VASc score.

• Prescribing a vasodilator (nitrate, ACE inhibitor/ARB, dihydropyridine calcium channel blocker), a high-dose diuretic, or digoxin in a patient with obstructive HCM without recognizing that each can worsen dynamic LVOT obstruction and precipitate genuine hemodynamic compromise.^[2]
• Treating exertional syncope in a patient with known or suspected HCM as a routine vasovagal event rather than a red flag warranting urgent specialist evaluation.^[2]
• Assuming a family history of sudden death is "the other relative's problem" rather than a major sudden-cardiac-death risk factor for the patient currently in front of you.^[2]
• Initiating mavacamten outside the required REMS-style monitoring program, or without a baseline echocardiogram confirming LVEF is 55% or higher.^[4]
• Missing a clinically important drug interaction with mavacamten — starting a strong CYP2C19 inhibitor, or a moderate-to-strong CYP2C19/CYP3A4 inducer, without recognizing the contraindication, or combining mavacamten with disopyramide, verapamil, or diltiazem without recognizing the additive risk of excessive negative inotropy.^[4]
• Combining a non-dihydropyridine calcium channel blocker with a beta-blocker in obstructive HCM without real caution — this combination is not well supported by evidence and carries a genuine additive hypotension/bradycardia risk.^[2]
• Adding disopyramide without an AV-nodal blocking agent already on board, risking an enhanced ventricular rate if atrial fibrillation or flutter develops.^[2]
• Using digoxin for rate control of atrial fibrillation in obstructive HCM — its positive inotropic effect directly worsens the outflow gradient, unlike its use in a structurally normal heart.^[2]
• Withholding anticoagulation in an HCM patient with atrial fibrillation because a calculated CHA2DS2-VASc score looks low — HCM itself confers a sufficiently elevated stroke risk that anticoagulation is recommended for essentially all HCM patients with clinical atrial fibrillation, independent of the score.^[2]
• Applying a blanket "no exercise" rule to every patient with HCM rather than having the individualized, shared decision-making conversation the current evidence actually supports for most patients.^[2][5]
• Missing the opportunity to offer first-degree relatives clinical and, where appropriate, genetic screening after a new HCM diagnosis.^[1]

How to use this table: Doses are adult doses and require patient-specific confirmation (renal/hepatic function, weight, allergy history). Pediatric dosing is weight-based per the current product monograph unless stated. Drug pricing is intentionally omitted. Select any drug name to open its complete Pharmasist Drug Database page.

Beta-Blockers — First-Line Symptom Management

Non-vasodilating agents; titrate fully to symptom relief and heart-rate response before concluding beta-blockade has failed.

Non-Dihydropyridine Calcium Channel Blockers

Alternative to a beta-blocker if not tolerated or not effective; avoid routinely combining the two.

Add-On Negative Inotrope

Reserved for obstructive HCM symptoms persisting despite an optimized beta-blocker or non-dihydropyridine calcium channel blocker.

Cardiac Myosin Inhibitor — Disease-Targeted Therapy

The first therapy to directly target the sarcomere hypercontractility underlying obstructive HCM; available only through a structured, REMS-style monitoring program given the risk of reducing LVEF.

Medications to Avoid or Use With Real Caution in Obstructive HCM

Each of these is an otherwise routine cardiovascular drug — the harm here comes specifically from worsening dynamic LVOT obstruction, not from the drug being inherently unsafe.