Key
Facts
Diagnosis = unexplained LVHMax LV wall ≥15 mm in any segment not explained by loading (HTN, AS, infiltration); ≥13 mm suffices with a family history of HCM or a pathogenic sarcomere variant; children need age/body-size-adjusted assessment and clinical context.
Obstruction is dynamicLVOT gradient ≥30 mmHg = obstructive; ≥50 mmHg (rest or provoked) is the intervention threshold. Always provoke if resting low.
SCD risk firstEvery new HCM patient needs SCD risk stratification (P.2) — sudden death can be the first event, especially in the young.
Now pharmacologically treatableCardiac myosin inhibitors (mavacamten, aficamten) directly target the hypercontractile sarcomere — a new therapeutic class (P.4).
01
Definition & Genetics
Sarcomeric disease
Diagnosis
- Adults max LV wall ≥15 mm unexplained by loading (HTN/AS); ≥13 mm if FH or genotype positive.
- Distribution commonly asymmetric septal; also apical, concentric, mid-cavity, or apical-aneurysm variants.
- Children use pediatric z-scores and family context. The adult 13-mm family threshold does not apply to children.
Genetics
- Autosomal dominant, sarcomere genes — MYBPC3 & MYH7 most common (~variable penetrance).
- Genetic testing of the proband enables cascade screening of relatives (P.5).
- Phenocopies (treat differently): Fabry, amyloid, PRKAG2, Danon, Noonan.
"Unexplained LVH" is a workup, not a diagnosis Exclude hypertensive heart disease, aortic stenosis, athlete's heart, and infiltrative phenocopies before labeling HCM.
02
Physiology
Obstruction & diastole
Obstructive (HOCM)
- Mechanism septal hypertrophy + systolic anterior motion (SAM) of the mitral valve → dynamic LVOT obstruction + mitral regurgitation.
- Load-dependent worse with ↓ preload/afterload or ↑ contractility (Valsalva, standing, exercise, dehydration, vasodilators).
- Provocation Valsalva, standing, exercise stress echo when resting gradient <50.
Universal features
- Diastolic dysfunction (stiff, hypertrophied LV) → exertional dyspnea even without obstruction.
- Microvascular ischemia, arrhythmia substrate, supply–demand angina.
Symptoms ≠ obstruction
Non-obstructive HCM still causes dyspnea, angina & arrhythmia from diastolic disease & ischemia — treat the symptoms and the risk.
03
Evaluation
Imaging & differential
Core tests
- Echo wall thickness/distribution, SAM, LVOT gradient ± provocation, MR, diastolic function, EF.
- CMR precise wall thickness, LGE (fibrosis → risk), apical aneurysm, phenocopy clues.
- ECG LVH, repolarization changes, deep T-wave inversions (apical).
- Ambulatory monitor ≥24–48 h for NSVT (SCD marker) & AF.
Differentiate from
- Athlete's heart (wall <15, cavity dilates, normal diastole, regresses with detraining).
- Amyloid (low voltage, apical sparing, PYP/screen), Fabry (low T1, α-Gal), AS/HTN.
Get a CMR Beyond confirming phenotype, LGE quantification feeds directly into the SCD decision (P.2).
▶
"Red flags" that point away from sarcomeric HCM
Phenocopies need different therapy
| Phenocopy | Clue (ECG / imaging / labs) | Confirm & why it matters |
|---|
| Cardiac amyloid | Low/normal voltage despite thick walls, granular myocardium, apical sparing strain, ↑ native T1/ECV, pleural/pericardial effusions | PYP scan + serum free light chains and serum/urine immunofixation; changes therapy entirely. |
| Fabry disease | Short PR, concentric LVH, low native T1, angiokeratoma, neuropathic pain, proteinuria | α-galactosidase A (men) / GLA gene; enzyme replacement available. |
| PRKAG2 / Danon | Ventricular pre-excitation (WPW) + LVH ± conduction disease; Danon: young men, skeletal myopathy, low EF | Targeted genetics; high pacemaker/transplant need — distinct trajectory. |
| Noonan / RASopathy | LVH + pulmonary stenosis, dysmorphism, short stature, often pediatric | PTPN11 & RAS-pathway panel; syndromic surveillance. |
| Athlete's heart | Wall <15 mm, dilated cavity, normal/supranormal diastole, regresses with detraining | Deconditioning ± CMR; avoid over-diagnosis & unwarranted disqualification. |
| HTN / aortic stenosis | Concentric LVH proportionate to load; valve gradient or chronic HTN history | Treat the load; HCM is a diagnosis of exclusion of secondary causes. |
▶
One-line pathophysiology
Hypercontractile, stiff, obstructive ventricle
From sarcomere to symptoms
Sarcomere-protein variants produce a hypercontractile, poorly relaxing ventricle with myocyte disarray & interstitial fibrosis. Asymmetric septal hypertrophy plus systolic anterior motion of the mitral valve generates dynamic LVOT obstruction and mitral regurgitation; the thick, stiff myocardium causes diastolic dysfunction and microvascular ischemia. Disarray + fibrosis form the substrate for ventricular arrhythmia & sudden death. Cardiac myosin inhibitors target the root hypercontractility — the rest of management reduces obstruction, manages symptoms, and prevents SCD.
Secondary prevention is clear-cut Prior cardiac arrest, VF, or sustained VT → ICD (Class I). The hard work is primary prevention: weigh major risk factors + modern enhancers, estimate risk, and decide via shared decision-making.
A
Primary-prevention risk markers
Adult major markers + modifiers
Major risk factors
- Family history of SCD likely HCM-related in a first-degree or other close relative ≤50 yr.
- Massive LVH maximal wall ≥30 mm.
- Unexplained syncope (non-vasovagal), recent.
- Apical aneurysm with scar or LVEF <50%.
Modifiers when the decision is uncertain
- NSVT give greater weight to longer, faster and repeated runs.
- Extensive LGE on CMR (≈≥15% of LV mass).
- In adults without a major marker, NSVT or extensive LGE may support an ICD (IIb). Pediatric criteria differ.
B
Two pathways to the ICD decision
Both endorsed — use together
Risk-factor approachAHA/ACC 2024
HowPresence of ≥1 major risk factor → ICD is reasonable (IIa) after shared decision-making.
EnhancersNSVT or extensive LGE may support ICD discussion without a major marker (IIb).
ToneIndividualized; avoid reflex implantation without a risk marker.
ESC HCM Risk-SCD5-YEAR SCORE
InputsAge, max wall thickness, LA diameter, max LVOT gradient, FH SCD, NSVT, unexplained syncope.
Output5-yr SCD risk: <4% low · 4–<6% intermediate · ≥6% high → consider ICD.
CaveatDoes not include aneurysm, LGE or EF. Discuss these separately, without adding unvalidated points.
Keep the questions separate: LVOT gradient informs symptoms and is a model input. Obstruction alone is not an AHA/ACC major ICD marker.
C
The seven HCM Risk-SCD inputs — how each is captured
ESC 5-yr model · ages 16+
| Variable | How to measure | Direction & caveats |
|---|
| Age | Years at evaluation | Younger age carries higher relative risk; model validated ≥16 yr. |
| Max LV wall | Greatest end-diastolic thickness, echo or CMR | Continuous input; risk rises then plateaus at extreme thickness. |
| LA diameter | M-mode/2D AP diameter, parasternal long axis | Surrogate for filling pressure & AF risk; use diameter, not volume. |
| Max LVOT gradient | Rest and Valsalva CW Doppler (highest) | Provoked value counts; informs risk, not a standalone SCD driver. |
| FH of SCD | SCD in a first-degree relative <40 yr, or a first-degree relative with HCM at any age | Use the model definition rather than the broader AHA/ACC family-history definition. |
| NSVT | ≥3 beats ≥120 bpm <30 s on Holter | Binary; capture with ≥24–48 h (or extended) ambulatory monitoring. |
| Unexplained syncope | Non-neurocardiogenic, by history | Binary; exclude vasovagal, orthostatic and obstruction-related causes. |
Model excludes apical aneurysm, extensive LGE, and EF<50% — consider these separately in shared decisions, not as extra score points. Do not apply to athletes' physiology, prior SCD/sustained VT (already ICD), metabolic/syndromic phenocopies, or post-myectomy patients.
High-risk situations to flag
- Apical aneurysm + thrombus arrhythmic substrate and thromboembolic source — consider anticoagulation.
- "Burnt-out" HCM (EF<50%) wall thinning + scar; high arrhythmic risk — treat as advanced disease.
- Extensive LGE (≥15% mass) tips borderline primary-prevention cases toward ICD.
- Children/adolescents use pediatric risk tools (e.g., HCM Risk-Kids); massive LVH, syncope, NSVT & FH still drive decisions.
Device selection & post-implant
- S-ICD attractive in young patients with no pacing/ATP/CRT need and no anti-tachy pacing requirement.
- Transvenous when bradycardia pacing, ATP, or CRT is needed; screen ECG for S-ICD eligibility first.
- Programming high-rate detection & long delays cut inappropriate shocks; minimize unnecessary RV pacing.
- Reassess generator changes are recurring decisions — re-confirm the indication each time.
DECIDE
Secondary prevention → ICD. Primary prevention → estimate risk with the ESC 5-yr score and the AHA/ACC risk-factor + enhancer approach, then choose with the patient. One adult major marker can support an ICD. Isolated NSVT or LGE has a different recommendation strength.
A
Obstructive HCM — stepwise drug therapy
Reduce dynamic obstruction
Step 1 · First-line Non-vasodilating β-blocker (metoprolol, atenolol, bisoprolol) — titrate to symptoms/HR. Avoid vasodilating β-blockers (carvedilol).
Step 2 · If BB inadequate / not tolerated Non-dihydropyridine CCB — verapamil or diltiazem. Caution / avoid with high resting gradient, hypotension, or decompensated HF.
Step 3 · Persistent symptoms Add disopyramide (negative inotrope; monitor QT & anticholinergic effects) or a cardiac myosin inhibitor (mavacamten / aficamten — P.4).
Step 4 · Drug-refractory + gradient ≥50 NYHA III–IV despite optimal drugs → septal reduction therapy at an expert center (P.4).
B
Drugs & situations to avoid in obstruction
They worsen the gradient
AVOIDArterial & venous vasodilators
ACEi / ARB / dihydropyridine CCB / nitrates / hydralazine → ↓ afterload & preload worsen LVOT obstruction.
AVOIDHigh-dose diuretics
Aggressive volume depletion ↓ preload → worse gradient & hypotension. Use cautiously for congestion.
CAUTIONDigoxin & positive inotropes
↑ contractility worsens dynamic obstruction — generally avoid in obstructive HCM.
CAUTIONDehydration & vasodilatory states
Heat, alcohol, sepsis, post-prandial, intense Valsalva → counsel on hydration & triggers.
01
Non-obstructive HCM
Diastolic-dominant disease
- Symptom relief β-blocker or verapamil/diltiazem for angina & dyspnea (rate control aids filling).
- Cautious diuresis for congestion — gentler than in HFrEF.
- If EF falls <50% ("end-stage"/burnt-out) treat as HFrEF with GDMT; evaluate for advanced therapies.
- Vasodilators OK here (no dynamic obstruction) when treating HFrEF physiology.
02
Acute decompensation
Obstructive crisis
- Hypotension from LVOTO assess congestion. Give fluid if underfilled and phenylephrine if needed. Avoid drugs that worsen obstruction.
- Slow the rate β-blocker to lengthen diastole; treat AF promptly (restore sinus).
- Avoid dobutamine, nitroglycerin, high-dose diuretic boluses.
Confirm the shock mechanism Echo-guided loading and vasoconstriction can relieve LVOTO. Pulmonary edema or another shock mechanism changes the plan.
C
Negative-inotrope agents — dosing & cautions
Titrate to symptoms, HR & gradient
| Agent | Typical dosing | Mechanism / role | Watch / avoid |
|---|
| Metoprolol BB | 25–100 mg BID (or succinate qd) | First-line; slows HR, lengthens diastole, blunts exercise gradient | Bradycardia, fatigue; use non-vasodilating BBs. |
| Bisoprolol / Atenolol | 5–10 mg qd / 25–100 mg qd | Alternative β-blockers | Avoid carvedilol (α-blockade → vasodilation). |
| Verapamil CCB | 120–480 mg/d (SR) | 2nd-line if BB not tolerated; improves diastolic filling | Avoid with high gradient, hypotension, decompensated HF. |
| Diltiazem | 120–360 mg/d | Non-DHP CCB alternative to verapamil | Same cautions as verapamil; negative dromotropy. |
| Disopyramide +BB/CCB | ~400–600 mg/d (with AV-nodal agent) | Potent negative inotrope; lowers resting gradient | QT prolongation; anticholinergic (dry mouth, urinary retention, glaucoma); pair with rate-controlling agent for AF. |
| Phenylephrine acute | IV bolus / infusion | Pure α-agonist for obstructive hypotensive crisis | For the acute setting only; combine with volume. |
Doses are illustrative ranges — individualize and consult current labeling. Myosin inhibitors (mavacamten, aficamten) are detailed on P.4 & P.6.
A
Cardiac myosin inhibitors
Target the hypercontractile sarcomere
EXPLORER-HCM
Mavacamten · Camzyos (BMS)
Olivotto · Lancet 2020
N = 251
DesignPhase 3 RCT, mavacamten vs placebo, 30 wk, symptomatic obstructive HCM (NYHA II–III).
PrimaryComposite: ↑ peak VO₂ and ≥1 NYHA class improvement (or large VO₂ rise + stable NYHA).
Result37% vs 17% met primary; large falls in LVOT gradient, NT-proBNP & symptom/QoL scores.
Bottom lineFirst-in-class; FDA-approved 2022 for symptomatic obstructive HCM. Dispensed via REMS.
VALOR-HCM
Mavacamten · SRT-eligible
Desai · JACC 2022
N = 112
Pop'nSeverely symptomatic obstructive HCM referred for septal reduction therapy.
ResultAt 16 wk, far fewer mavacamten patients still met SRT criteria / proceeded to SRT vs placebo; sustained over follow-up.
Bottom lineCMIs can defer or avoid invasive SRT in many — but require ongoing echo surveillance.
SEQUOIA-HCM
Aficamten · Cytokinetics
Maron · NEJM 2024
N = 282
DesignPhase 3 RCT, next-gen myosin inhibitor aficamten vs placebo, 24 wk, obstructive HCM.
ResultImproved peak VO₂, NYHA class, LVOT gradient & KCCQ. MAPLE-HCM improved exercise capacity versus metoprolol monotherapy. Neither trial compares aficamten directly with mavacamten.
Bottom lineUS-approved as MYQORZO in December 2025 for adults with symptomatic obstructive HCM. Separate REMS and dosing algorithm (P.6).
Using a CMI safely Use the agent-specific label and serial echo (P.6). The drugs have different interruption thresholds. Both require REMS, medication-interaction review and pregnancy precautions.
B
Septal reduction therapy (SRT)
Refractory symptoms + gradient ≥50 mmHg
Surgical MyectomyGOLD STANDARD
ForMost patients; younger, concomitant valve/papillary disease, very thick septum.
OutcomeDurable gradient relief; mortality <1% at experienced centers.
RiskAV block/PPM, VSD (rare), surgical morbidity.
Alcohol Septal AblationPERCUTANEOUS
ForSelected anatomy, higher surgical risk, suitable septal perforator.
OutcomeEffective in many; more residual/recurrent gradient & repeat procedures than myectomy.
RiskHeart block needing PPM (~10%), scar-related arrhythmia.
Indication for SRT: NYHA III–IV (or recurrent exertional syncope) with LVOT gradient ≥50 mmHg (rest or provoked) despite optimal drug therapy. Perform at a comprehensive HCM center — operator volume drives outcomes.
| Selection factor | Favors surgical myectomy | Favors alcohol septal ablation |
|---|
| Age / surgical risk | Younger, good operative candidate | Older or high surgical risk / comorbidity. |
| Septal thickness | Very thick septum; extensive muscle to resect | Moderate thickness with suitable target. |
| Concomitant disease | Intrinsic mitral/papillary or other valve disease, anomalous structures needing repair | Isolated SAM-mediated obstruction, no structural valve repair needed. |
| Coronary anatomy | Independent of perforator anatomy | Requires a suitable septal perforator supplying the target. |
| Durability | Most durable; lowest residual/recurrent gradient | More residual/recurrent gradient, repeat-procedure need. |
| Conduction risk | AV block / PPM less common; risk of LBBB | Heart block needing PPM ~10% (pre-existing LBBB ↑ risk). |
Not an SRT candidate? Drug-refractory with unfavorable anatomy / prohibitive risk → escalate myosin inhibitor, reassess CMR, and consider advanced-HF evaluation (transplant) for end-stage disease.
Exercise — liberalized
Mild–moderate recreational exercise for nearly all. Vigorous/competitive sport via shared decision-making at an expert center.
AF → anticoagulate
Clinical AF + HCM → anticoagulate regardless of CHA₂DS₂-VASc; HCM is an independent stroke risk.
Screen the family
First-degree relatives: genetic cascade + clinical screening — sudden death can be familial.
Pregnancy
Most tolerate; risk-stratify, continue β-blocker. Stop myosin inhibitors (teratogenic).
01
Atrial Fibrillation
Common & poorly tolerated
- Why it matters loss of atrial kick into a stiff LV → abrupt symptoms, sometimes decompensation.
- Anticoagulation clinical AF → OAC irrespective of CHA₂DS₂-VASc; DOAC preferred.
- Rhythm control favored restore/maintain sinus — amiodarone, ablation; rate control with β-blocker / verapamil.
- Acute AF in HOCM can precipitate obstruction — cardiovert promptly if unstable.
- Device-detected AF >24 h → OAC. For >5 min to <24 h, consider burden, stroke risk and bleeding risk in shared decisions.
- Catheter ablation reasonable for symptomatic AF; outcomes modestly lower than non-HCM AF.
02
Exercise & Sport
2024 update
- Recreational low–moderate intensity exercise encouraged for essentially all patients.
- Vigorous/competitive athletics no longer blanket-prohibited — individualized after comprehensive evaluation & shared decision-making.
- An ICD is not an automatic disqualifier; avoid burst dehydration & extreme exertion if obstructive.
03
Family Screening & Genetics
Cascade evaluation
- Proband testing offer genetic testing + counseling; identifies a pathogenic variant to cascade.
- Genotype-positive relatives clinical surveillance even if phenotype-negative.
- Clinically unaffected relatives who test negative for a confidently causal family P/LP variant can usually leave surveillance.
- Clinical screening when genetics unavailable: echo + ECG — more frequently in adolescence, then periodically through adulthood.
04
Follow-up Cadence
What to track
- Echo periodically & with status change (gradient, EF, MR); CMR as indicated.
- Ambulatory monitor ≥24–48 h periodically for NSVT & AF.
- Re-stratify SCD risk at routine visits — risk evolves over time.
- On a CMI serial echo surveillance of LVEF/gradient per protocol.
05
Pregnancy & the cascade — practical specifics
Most pregnancies tolerated with planning
| Domain | Do | Avoid / watch |
|---|
| Pre-conception | Counsel + risk-stratify; review meds; 50% inheritance per child counseling | Stop myosin inhibitors & disopyramide before conception (teratogenic / fetal risk). |
| Medications | Continue β-blocker if needed (monitor fetal growth/HR); prefer metoprolol | Avoid atenolol where possible; avoid vasodilators in obstruction. |
| Labor & delivery | Vaginal delivery usually feasible; maintain preload; epidural with care | Treat hypotension with volume + phenylephrine; avoid aggressive diuresis & abrupt vasodilation. |
| Anticoagulation | If AF: anticoagulate per pregnancy-safe regimen | Warfarin/DOAC cautions in pregnancy — use guideline-directed alternatives. |
| Cascade screening | 1st-degree relatives: genetic test if proband variant known; otherwise echo + ECG | Discharge only if clinically unaffected and negative for a confidently causal family P/LP variant. |
| Screening interval | More frequent in adolescence/early adulthood; then periodically lifelong | Don't discharge variant-positive phenotype-negative relatives. |
| Fetal & postpartum | Fetal echo if syndromic phenocopy suspected; monitor mother through peripartum volume shifts | Decompensation risk peaks at delivery & early postpartum — continue surveillance. |
| Variant interpretation | Use ACMG criteria; P/LP variants are actionable for cascade | VUS does not drive cascade decisions — screen relatives clinically instead. |
SUMMARY
Diagnose, stratify SCD risk, relieve obstruction, and protect the family. Reduce obstruction and avoid drugs that aggravate it. Consider myosin inhibitors and septal reduction for refractory cases; anticoagulate clinical AF and assess device-detected AF by episode duration. Screen relatives and individualize exercise counseling. Re-stratify risk at every visit — HCM is a lifelong, evolving disease.
Select the drug before selecting the algorithm. Reducing sarcomere force can relieve obstruction and can impair systolic function. An echo result, symptom change or new interacting medicine must be interpreted using the prescription for that agent.
A
Two approved agents, distinct instructions
| Decision | Mavacamten · CAMZYOS | Aficamten · MYQORZO |
|---|
| US indication | Symptomatic obstructive HCM in adults and children weighing ≥30 kg. September 2026 label. | Adults with symptomatic obstructive HCM. Approved December 2025. |
| Starting dose | Adults: 5 mg daily. Children 30–<45 kg: 2.5 mg. Children ≥45 kg: 5 mg. Interactions can alter the starting dose. | 5 mg daily. Titrate in 5-mg increments every 2–8 weeks, maximum 20 mg. |
| Starting / increasing | Not recommended when LVEF <55%. Both require their own REMS and serial LVEF/LVOT-gradient assessment. |
| LVEF falls | Interrupt if <50%, or with HF symptoms or worsening clinical status. | 40–<50%: reduce 5 mg, or interrupt if already at 5 mg. <40% or clinical HF: interrupt. Restart only under the label algorithm. |
| Echo timing | Use the current initiation, maintenance and interruption figures. Dose changes and clinical deterioration need earlier review. | 2–8 weeks after starting/changing dose. Maintenance every 6 months, or 3 months with LVEF 50–<55%. |
| Interaction gate | Strong CYP2C19 inhibitors and moderate/strong CYP2C19 or CYP3A4 inducers are contraindicated. Other inhibitors require label-specific dose/echo adjustment. | Check the MYQORZO interaction table. Do not transfer the mavacamten rules. |
B
Before each prescription
Symptoms · echo · medicines
- Confirm the phenotype. Symptoms must be attributable to obstructive HCM. A high gradient without symptoms is a different decision.
- Review the actual medication list. Include OTC acid suppressants, supplements, recent antibiotics and changes to rate-slowing medicines. Check starts and stops.
- Check current function. New dyspnea, edema, arrhythmia, infection or hypotension can signal systolic deterioration. Arrange assessment before routine titration.
- Plan reproduction and follow-up. Discuss pregnancy precautions, effective contraception and the specific post-treatment interval in the label. Confirm the next echo and REMS requirements.
COMPARETrial benefit is population-specific. EXPLORER-HCM compared mavacamten with placebo. SEQUOIA-HCM compared aficamten with placebo. MAPLE-HCM compared aficamten with metoprolol. None of these is a head-to-head comparison of the two myosin inhibitors.