Cardiovascular

Hypertrophic cardiomyopathy: screening, management, and family counseling

Clinical Overview and When to Suspect HCM

— Obstructive HCM (oHCM): ~70%, dynamic LVOT obstruction from septal hypertrophy + systolic anterior motion (SAM) of the mitral valve.

— Nonobstructive HCM: diastolic dysfunction predominates.

— Apical HCM (Yamaguchi): giant T-wave inversions in precordial leads; "ace-of-spades" LV cavity on imaging.

— Young patient with exertional syncope, family history of sudden death <50, or syncope during exertion (vs. vasovagal post-exertion).

— Athlete with new murmur or abnormal pre-participation ECG.

— Asymptomatic relative of a known HCM proband presenting for screening.

— Incidental LVH on echo disproportionate to BP history.

— Heart failure with preserved EF in a younger patient.

Board pearl: Any young patient with exertional syncope plus a systolic murmur that increases with Valsalva or standing is HCM until proven otherwise — order TTE before discharge from clinic.

Definition: Hypertrophic cardiomyopathy (HCM) is a primary myocardial disorder defined by unexplained LV wall thickness ≥15 mm (or ≥13 mm with family history or positive genotype) in the absence of loading conditions (HTN, aortic stenosis) sufficient to cause that degree of hypertrophy.

Genetics: Autosomal dominant, variable penetrance; >1500 mutations identified, most commonly in sarcomere genes — MYH7 (β-myosin heavy chain) and MYBPC3 (myosin-binding protein C) together account for ~70% of genotype-positive cases.

Prevalence: ~1 in 500 adults; most common inherited cardiac disorder and the leading cause of sudden cardiac death (SCD) in young athletes in the US.

Physiology spectrum:

When to suspect on Step 3:

Outpatient framing: HCM is a longitudinal, family-anchored diagnosis. The Step 3 vignette often hinges on what you do after the index diagnosis — cascade screening, activity counseling, SCD risk stratification.

Presentation Patterns and Key History

— Exertional syncope = ominous; reflects inability to augment cardiac output across a fixed/dynamic obstruction, or ventricular arrhythmia.

— Post-exertional or positional syncope is less alarming but still warrants workup.

— Sudden cardiac death at age <50 in any first-degree relative.

— Unexplained drowning, single-car MVA, "seizure" deaths.

— Known HCM, ICD placement, or septal myectomy in relatives.

— Pacemakers in young family members.

Step 3 management: In a clinic patient with exertional dyspnea + family history of SCD, the first action is TTE — do not order stress testing until obstruction is characterized, because exercise stress in undiagnosed severe oHCM can be hazardous. Counsel temporary activity restriction pending evaluation.

Symptom triad: dyspnea (most common, ~90%), chest pain (anginal pattern from supply-demand mismatch despite normal coronaries), and syncope/presyncope.

Dyspnea mechanism: elevated LV end-diastolic pressure from diastolic dysfunction + dynamic LVOT obstruction → pulmonary venous congestion. Often exertional, sometimes with orthopnea.

Chest pain: typically exertional, anginal quality. Driven by small-vessel disease, increased wall stress, and microvascular ischemia. Coronary anatomy is usually normal in young patients.

Syncope/presyncope red flags:

Palpitations: atrial fibrillation occurs in ~20% (poorly tolerated due to loss of atrial kick into a stiff LV); ventricular ectopy and NSVT are SCD markers.

Family history — must ask explicitly:

Activity history: competitive sports participation, intensity, recent escalation in training. Document prior pre-participation evaluations.

Medication history: diuretics, vasodilators (dihydropyridine CCBs, nitrates, ACEi/ARB), and PDE5 inhibitors — all worsen LVOT obstruction by reducing preload/afterload and should raise suspicion if symptoms worsened after these were started.

Triggers of obstruction: dehydration, large meals (postprandial vasodilation), hot showers, alcohol, Valsalva (straining at stool).

Physical Exam Findings and Hemodynamic Maneuvers

• Classic auscultatory finding: harsh crescendo-decrescendo systolic murmur at the left lower sternal border / apex, without radiation to the carotids (distinguishing from aortic stenosis).
• Dynamic maneuvers — the Step 3 favorite:
— ↓ Preload or ↓ afterload → louder murmur: Valsalva (strain phase), standing from squat, amyl nitrite, dehydration.
— ↑ Preload or ↑ afterload → softer murmur: squatting from standing, passive leg raise, sustained handgrip, phenylephrine.
• Mitral regurgitation murmur: holosystolic, radiates to axilla, from SAM-mediated posterior MR jet. Often coexists with the LVOT murmur.
• Pulse character: bisferiens (biphasic) carotid pulse — brisk upstroke, mid-systolic dip from obstruction, then secondary peak. Contrasts with pulsus parvus et tardus of fixed AS.
• Apical impulse: sustained, often with a palpable double or triple apical impulse (presystolic atrial kick + systolic outflow).
• Heart sounds:
— S4 common (atrial contraction into noncompliant LV).
— S3 suggests decompensation or end-stage disease.
— Paradoxical S2 split possible with severe obstruction.
• JVP: prominent a-wave from forceful RA contraction against hypertrophied/stiff RV (when RV involved).
Key distinction:
Maneuver	HCM murmur	AS murmur	MVP click/murmur
Valsalva (strain)	↑ Louder	↓ Softer	Click earlier, murmur longer
Squatting	↓ Softer	↑ Louder	Click later, murmur shorter
Handgrip	↓ Softer	↓ Softer	↑ Louder
Board pearl: A systolic murmur that gets louder with Valsalva and softer with squatting is HCM until echo proves otherwise. The bisferiens pulse + non-radiating murmur essentially clinches it before imaging. On Step 3, choose TTE next — not carotid ultrasound, not stress test, not cardiac catheterization.

Diagnostic Workup — Initial Labs, ECG, and Echocardiography

— LVH with strain pattern (deep S in V1–V2, tall R in V5–V6, lateral ST depression/T-wave inversion).

— Deep, narrow Q waves in inferior (II, III, aVF) or lateral (I, aVL, V5–V6) leads — septal depolarization abnormality, mimics old MI.

— Apical HCM: giant symmetric T-wave inversions in precordial leads (V3–V6), often >10 mm deep.

— Left atrial enlargement, atrial fibrillation, WPW pattern (especially in PRKAG2/Danon storage variants).

— Maximal LV wall thickness ≥15 mm (≥13 mm with FHx/genotype) without alternative cause.

— Asymmetric septal hypertrophy (septum-to-posterior wall ratio >1.3) classic but not required.

— LVOT gradient assessment: resting and provoked (Valsalva, post-exercise). ≥30 mmHg = obstructive; ≥50 mmHg = threshold for invasive therapy if symptomatic.

— SAM of mitral valve with posteriorly directed MR jet.

— Diastolic dysfunction (impaired relaxation, elevated E/e′).

— LA enlargement (marker of chronicity and AF risk).

CCS pearl: Order TTE, 12-lead ECG, and 48-hour ambulatory monitor on the initial outpatient visit. Advance clock 2 weeks; review results before any activity clearance or pharmacotherapy. Do not order coronary angiography reflexively in a young patient unless atypical features or age >40 with risk factors.

ECG — abnormal in >90% of HCM patients (often before echo changes):

TTE — diagnostic cornerstone:

Basic labs: BNP/NT-proBNP (elevated, prognostic), troponin (chronic mild elevation possible), BMP, TSH (rule out thyroid contributors to arrhythmia).

Exercise stress echo: indicated if resting and Valsalva gradients <50 mmHg but symptoms present — unmasks provocable obstruction. Do not perform if severe resting obstruction or unstable symptoms.

Ambulatory ECG (Holter, 24–48 hr): part of initial SCD risk assessment to screen for NSVT.

Diagnostic Workup — Advanced and Confirmatory Studies

— TTE is suboptimal or equivocal.

— Apical HCM suspected (TTE often misses; CMR is gold standard).

— Risk stratification: late gadolinium enhancement (LGE) ≥15% of LV mass is an SCD risk modifier.

— Differentiating HCM from athlete's heart, amyloid, Fabry, or hypertensive LVH.

— Measuring apical aneurysms (newer recognized SCD risk feature).

— Offer to every patient with clinical HCM diagnosis after genetic counseling.

— Primary purpose: enable cascade screening of first-degree relatives, not to confirm proband diagnosis.

— A pathogenic variant identified → targeted testing of relatives (sensitive, specific, cost-effective).

— Genotype-negative proband → relatives screened clinically only (genetics noninformative).

— Not routine for diagnosis.

— Indicated to exclude CAD in patients >40 with anginal symptoms or before septal reduction therapy.

— Can document LVOT gradient and Brockenbrough-Braunwald sign (post-PVC beat: ↑ contractility → ↑ obstruction → paradoxically decreased pulse pressure, opposite of AS).

— First-degree relatives: clinical screen with ECG + TTE.

— Children/adolescents: start at age 12–18, repeat every 1–2 years through adolescence, then every 5 years in adulthood.

— Earlier screening if competitive athletics, symptoms, or malignant family history.

— If genotype-positive but phenotype-negative ("G+/P−"): periodic surveillance, no activity restriction.

Board pearl: Apical HCM with normal TTE and giant precordial T-wave inversions → next step is cardiac MRI, not stress test. The "ace-of-spades" LV configuration is pathognomonic.

Cardiac MRI (CMR) with gadolinium — indicated when:

Genetic testing — when and why:

Cardiac catheterization:

Electrophysiology study: generally not used for risk stratification in HCM (low predictive value); reserved for documented sustained VT or unexplained syncope when noninvasive workup negative.

Cascade family screening protocol:

Risk Stratification for Sudden Cardiac Death

— Personal history of cardiac arrest or sustained VT/VF (secondary prevention — ICD indicated, full stop).

— Family history of SCD in ≥1 first-degree or close relative, particularly <50 years old.

— Unexplained syncope, especially recent (within 6 months) and exertional.

— Massive LVH: maximal wall thickness ≥30 mm.

— NSVT on ambulatory monitoring (≥3 beats, ≥120 bpm).

— LV apical aneurysm (regardless of size).

— LV systolic dysfunction (EF <50%) — uncommon but high risk ("end-stage" HCM).

— Extensive LGE on CMR ≥15% LV mass.

— Left atrial diameter ≥48 mm.

— Resting LVOT gradient ≥30 mmHg (modest risk modifier).

— Class I (definite ICD): prior cardiac arrest, sustained VT/VF.

— Class IIa (reasonable): ≥1 major risk factor above.

— Class IIb (consider): isolated risk modifier in absence of major factors.

— Shared decision-making essential — discuss device complications, inappropriate shocks, lead failures, lifestyle implications.

Step 3 management: A 22-year-old with HCM, maximal wall thickness 32 mm, and one episode of NSVT on Holter — refer for ICD placement (two major risk factors). Don't get distracted by his asymptomatic status; primary prevention is the point.

SCD is the most feared complication — risk stratification drives ICD decision-making and is heavily tested.

Major (conventional) SCD risk factors (2020 AHA/ACC + 2024 update):

Risk modifiers (used when decision borderline):

ICD decision framework:

ESC HCM Risk-SCD calculator: estimates 5-year SCD risk; ≥6% favors ICD, 4–6% reasonable, <4% generally not. US guidelines favor the major-risk-factor model over the calculator.

What does NOT independently warrant ICD: isolated LVOT obstruction, exercise-induced hypotension alone, mild LVH, or genotype positivity without phenotype.

Pharmacotherapy — First-Line Regimens

— Vasodilators: dihydropyridine CCBs (amlodipine, nifedipine), ACEi/ARBs (unless for HFrEF/end-stage), nitrates, hydralazine.

— PDE5 inhibitors (sildenafil).

— Pure inotropes (digoxin, dobutamine) — worsen obstruction.

— Aggressive diuresis — reduces preload, worsens dynamic gradient.

— Nonvasodilating β-blockers: metoprolol succinate, atenolol, or propranolol. Titrate to symptom control and HR ~60. Negative inotropy and chronotropy reduce gradient and improve diastolic filling.

— Start low, uptitrate over weeks; reassess gradient and symptoms.

— Verapamil or diltiazem (non-dihydropyridine CCBs). Caution: avoid in patients with resting gradient >100 mmHg, severe dyspnea at rest, or hypotension — vasodilatory component can precipitate decompensation.

— Disopyramide (class IA antiarrhythmic with negative inotropic effect) — added to β-blocker or verapamil. QT prolongation and anticholinergic effects (urinary retention, dry mouth) limit use. Often paired with β-blocker to blunt AV nodal effects of any AF.

— Mavacamten (FDA-approved 2022) and aficamten (emerging): reduce hypercontractility, lower LVOT gradient, improve symptoms and exercise capacity (EXPLORER-HCM, SEQUOIA-HCM).

— REMS program; requires serial TTE monitoring for EF reduction.

— CYP2C19/3A4 interactions matter.

Board pearl: A patient with oHCM started on amlodipine for newly diagnosed hypertension presents with worsening syncope — stop the amlodipine. Switch to a β-blocker, which treats both HCM and HTN.

General principles: treatment targets symptoms (dyspnea, chest pain, palpitations) and obstruction physiology. No drug has been shown to prevent SCD or alter natural history — that is the ICD's role.

Avoid in all HCM patients (especially obstructive):

First-line for symptomatic obstructive HCM:

Second-line / β-blocker intolerance:

Add-on for refractory obstruction:

Cardiac myosin inhibitors — newer class:

Nonobstructive HCM with HF symptoms: β-blockers or non-DHP CCBs for diastolic dysfunction; cautious low-dose diuretic; manage AF aggressively.

Invasive Therapies — Septal Reduction and Device Management

— NYHA III–IV symptoms (or III–IV equivalent angina) despite maximal tolerated medical therapy.

— LVOT gradient ≥50 mmHg (resting or provoked).

— Performed at comprehensive HCM centers (volume-outcome relationship well established).

— Surgical septal myectomy (Morrow procedure):

· Gold standard, durable, low operative mortality (<1%) at high-volume centers.

· Preferred in younger patients (<65), those with concomitant MV pathology, anomalous papillary muscles, or significant MR not solely from SAM.

· Can address apical/midventricular obstruction with extended myectomy.

— Alcohol septal ablation (ASA):

· Catheter-based; ethanol injected into septal perforator branch to infarct the hypertrophied basal septum.

· Preferred in older patients, high surgical risk, or patient preference.

· Risks: complete heart block requiring permanent pacemaker (~10%), residual gradient, VT scar substrate.

· Avoid if septal thickness >30 mm (less effective) or unfavorable septal perforator anatomy.

— Indicated per risk stratification (chunk 6).

— Subcutaneous ICD acceptable if no pacing needed and no VT amenable to ATP.

— Rhythm control preferred (sinus rhythm critical for diastolic filling); amiodarone is mainstay; catheter ablation reasonable.

— Anticoagulation: all HCM patients with AF receive anticoagulation regardless of CHA₂DS₂-VASc — HCM itself confers high thromboembolic risk. DOACs preferred; warfarin acceptable.

CCS pearl: For NYHA III oHCM patient with gradient 80 mmHg on max β-blocker + disopyramide → refer to comprehensive HCM center for septal myectomy evaluation. Don't order routine cath first unless angina or age >40; the center will coordinate workup.

Indications for septal reduction therapy (SRT):

Options:

ICD placement (separate decision from SRT):

AF management in HCM:

Heart transplant: end-stage HCM with refractory HF (EF <50%, "burned-out" HCM) — referral to advanced HF center.

Special Populations — Elderly and Renal/Hepatic Impairment

— Often presents later with dyspnea on exertion and HFpEF rather than syncope.

— Sigmoid septum variant common; associated with hypertensive remodeling overlap.

— Mavacamten and disopyramide require dose adjustment; check baseline renal/hepatic function.

— Higher pacemaker dependence post-ASA in elderly (~15–20%).

— Choose β-blockers or non-DHP CCBs (treats both).

— Avoid ACEi/ARB, dihydropyridines, and α-blockers as monotherapy.

— Volume management is delicate — gentle diuresis only if congestion clearly present.

— Aspirin and statin per ASCVD guidelines.

— Nitrates contraindicated for anginal symptoms in oHCM — they worsen obstruction. Use β-blocker uptitration first.

— Revascularization for obstructive CAD per usual indications, but avoid hypotension during PCI.

— Always consider TTR amyloid in adults >65 with "HCM phenotype", especially men, with low-flow LVH, low-voltage ECG despite thick walls, bilateral carpal tunnel history, or autonomic symptoms.

— Workup: pyrophosphate (PYP) scan + serum/urine immunofixation + free light chains.

— Disopyramide dose-adjust (renally cleared, narrow therapeutic index).

— DOACs: dose per CrCl; apixaban most flexible at low GFR.

— Mavacamten: avoid with severe renal impairment; monitor closely.

— Mavacamten contraindicated in Child-Pugh C; dose adjust in A/B.

— Verapamil hepatically metabolized — start low.

— Avoid amiodarone in advanced cirrhosis when possible.

Key distinction: Don't anchor on HCM in a 72-year-old man with LVH, low ECG voltage, and bilateral carpal tunnel — rule out ATTR amyloidosis with a PYP scan. Treatment (tafamidis) and prognosis are entirely different, and mavacamten is not indicated for amyloid.

Elderly HCM phenotype:

Coexisting hypertension:

Coexisting CAD (common >age 60):

Cardiac amyloidsosis overlap (TTR):

Renal impairment:

Hepatic impairment:

Special Populations — Pregnancy, Pediatrics, and Athletes

— Most women with HCM tolerate pregnancy well (mWHO class II–III depending on severity).

— High-risk features: severe LVOT obstruction, NYHA III–IV, prior cardiac event, severe diastolic dysfunction.

— Preconception counseling: review SCD risk, medication safety, 50% offspring transmission risk.

— Medications:

· β-blockers — continue (metoprolol or labetalol preferred; atenolol avoided due to IUGR association). Monitor fetal growth and neonatal bradycardia/hypoglycemia.

· Disopyramide — limited data, use cautiously.

· Mavacamten contraindicated (teratogenic in animal studies; REMS pregnancy requirements).

· Warfarin avoided in 1st trimester; LMWH preferred for AF anticoagulation.

— Delivery: vaginal delivery preferred in most; epidural with careful preload maintenance (avoid spinal-induced hypotension). C-section for obstetric indications.

— Continuous telemetry peripartum for high-risk patients.

— Often genotype-positive familial cases; can also be syndromic (Noonan, Pompe, mitochondrial).

— Screening of at-risk children: ECG + echo starting at age 12 (earlier if symptoms, malignant family history, or competitive athletics).

— SCD risk stratification differs in children: ESC pediatric HCM Risk-Kids calculator; criteria are age-adjusted.

— Avoid disopyramide in young children; β-blockers mainstay.

— 2020 AHA/ACC and 2024 update: shared decision-making model — blanket disqualification from competitive sports has been relaxed.

— Individualized risk assessment; many patients can participate in moderate/recreational activity.

— Avoid: burst/sprint sports, intense isometric activity, dehydration-prone settings, extreme heat.

— AED accessibility at training/competition sites strongly recommended.

Board pearl: A pregnant woman with known oHCM on metoprolol who develops worsening dyspnea at 28 weeks — continue β-blocker, gentle diuresis if congested, avoid ACEi (also teratogenic), and arrange multidisciplinary cardio-obstetric care. Do not start mavacamten.

Pregnancy in HCM:

Pediatric HCM:

Athletes and HCM:

Complications and Adverse Outcomes

— Annual incidence ~0.5–1% overall; higher in high-risk subgroups.

— Mechanism: polymorphic VT/VF arising from disarrayed myocardium and fibrotic substrate.

— Often the first manifestation in undiagnosed young athletes — basis for screening debates.

— Prevalence ~20%; lifetime risk much higher.

— Poorly tolerated due to loss of atrial kick into noncompliant LV; can precipitate acute pulmonary edema or syncope.

— Stroke risk markedly elevated — anticoagulate all HCM + AF, irrespective of CHA₂DS₂-VASc.

— Predominantly HFpEF early; diastolic dysfunction drives symptoms.

— Late "end-stage" or "burned-out" HCM: LV dilation, wall thinning, EF <50% — occurs in 3–5%; behaves like HFrEF and may need transplant evaluation.

— Pulmonary hypertension can develop secondarily.

— SAM-mediated, posteriorly directed; severity tracks with obstruction.

— Intrinsic MV pathology (elongated leaflets, anomalous papillary muscles) may require surgical repair at time of myectomy.

— Increased risk on thickened, abnormally apposed mitral valve (SAM-related contact lesions).

— No routine antibiotic prophylaxis unless prior IE or prosthetic valve (current AHA guidance).

— Worsened obstruction from vasodilators/nitrates/PDE5 inhibitors.

— Complete heart block after ASA.

Step 3 management: New-onset AF in oHCM with acute pulmonary edema → rate vs rhythm with sinus rhythm priority; if unstable, DC cardioversion with concurrent anticoagulation. Avoid digoxin (positive inotropy worsens obstruction).

Sudden cardiac death (SCD):

Atrial fibrillation:

Heart failure:

Mitral regurgitation:

Infective endocarditis:

Ventricular arrhythmias short of SCD: NSVT (risk marker), sustained VT (rare, often around apical aneurysms).

Apical aneurysm: thrombus formation → systemic embolization; arrhythmogenic substrate.

Stroke: from AF, apical thrombus, or paradoxical embolism.

Iatrogenic complications:

When to Escalate — ICU, Consult, and Inpatient Triage

— Syncope with exertional features or recurrent.

— New-onset AF with hemodynamic compromise.

— Acute decompensated HF / pulmonary edema.

— Sustained VT, aborted SCD, appropriate ICD shock.

— Suspected acute coronary syndrome in HCM patient (troponin must be interpreted carefully — chronic elevations common).

— Hemodynamic instability or cardiogenic shock physiology.

— Sustained ventricular arrhythmias.

— Post-procedure (myectomy day 0–1, ASA day 0–2 for telemetry given heart block risk).

— Refractory pulmonary edema requiring inotrope-free support (phenylephrine for afterload, β-blocker IV) — note: standard inotropes (dobutamine, milrinone) worsen oHCM obstruction; use phenylephrine + esmolol + volume for hypotensive oHCM patient.

— Initial HCM diagnosis confirmation.

— Any consideration of ICD or SRT.

— Pregnancy planning in HCM patient.

— Genotype-positive family member surveillance plan.

— ICD candidacy and implantation.

— AF rhythm control / ablation candidates.

— Sustained VT requiring mapping.

— Symptomatic oHCM eligible for septal myectomy.

— Concomitant MV repair candidates.

— Mandatory before genetic testing per AHA/ACC/HRS guidance.

— Cascade testing coordination.

— Septal reduction therapy candidates.

— Diagnostic uncertainty (athlete's heart vs HCM vs amyloid).

— High-complexity cases (pediatric, pregnant, end-stage).

CCS pearl: For an oHCM patient hypotensive in the ED with pulmonary edema, avoid dobutamine/milrinone, nitrates, and aggressive diuresis. Order IV phenylephrine (raise afterload, reduce gradient), IV β-blocker (esmolol), and judicious volume. Admit to ICU; consult cardiology. Advance clock by 6 hours and reassess gradient on TTE.

Emergency department presentations requiring admission:

ICU criteria:

Cardiology consult — always for:

Electrophysiology consult:

Cardiothoracic surgery consult:

Genetic counselor referral:

Comprehensive HCM center referral:

Key Differentials — Same-Category (Other Cardiomyopathies/LVH Causes)

— Symmetric, mild LVH (wall typically ≤13–15 mm).

— Normal/large LV cavity (LVEDD >55 mm), normal diastolic function, normal ECG or only voltage criteria.

— Regresses with 3 months of detraining — a diagnostic maneuver.

— Genetic testing negative.

— Concentric LVH, usually <15 mm, regresses with BP control.

— Symmetric, no SAM, no LVOT obstruction.

— History of long-standing uncontrolled HTN.

— Fixed outflow obstruction; murmur radiates to carotids; pulsus parvus et tardus.

— Murmur softens with Valsalva (opposite of HCM).

— TTE shows calcified, restricted aortic valve.

— Older patients, low ECG voltage despite thick walls (voltage-mass discordance), bilateral carpal tunnel, autonomic neuropathy.

— TTE: granular sparkling myocardium, biatrial enlargement, restrictive filling.

— CMR: diffuse subendocardial LGE, abnormal native T1, elevated ECV.

— Diagnosis: PYP scan (ATTR), serum/urine immunofixation, free light chains (AL).

— X-linked α-galactosidase A deficiency.

— Concentric LVH, shortened PR interval, low T1 on CMR (lipid storage), angiokeratomas, neuropathic pain, proteinuria.

— Confirm with α-Gal A activity (males) or GLA gene sequencing.

— Marked LVH with WPW pattern on ECG; often in young men.

— Pediatric or young-adult HCM-phenotype; characteristic facies, short stature, pulmonary valve stenosis (Noonan).

Key distinction: Symmetric LVH + low ECG voltage + bilateral carpal tunnel = amyloid, not HCM. Order PYP scan and light chains. Symmetric LVH + short PR + angiokeratomas = Fabry. Asymmetric septal LVH + dynamic murmur + family history of SCD = HCM.

Athlete's heart:

Hypertensive heart disease:

Aortic stenosis:

Cardiac amyloidosis (especially ATTR):

Fabry disease:

Glycogen storage cardiomyopathies (Danon, PRKAG2):

Mitochondrial cardiomyopathies and Noonan syndrome (RASopathies):

Key Differentials — Other-Category Causes of the Clinical Syndrome

— Long QT syndrome: prolonged QTc on ECG, family history of SCD/drowning, syncope with adrenergic triggers. Genetic causes (KCNQ1, KCNH2, SCN5A).

— Catecholaminergic polymorphic VT (CPVT): normal resting ECG; bidirectional VT on exercise stress.

— Brugada syndrome: RBBB-like with coved ST elevation in V1–V2; syncope often at rest or with fever.

— ARVC: RV-predominant, epsilon wave, TWI V1–V3, exercise-related VT.

— Anomalous coronary artery (AAOCA): especially left main from right sinus passing between aorta and PA — exertional syncope/SCD in athletes; CT angiography or MRI for diagnosis.

— Congenital aortic stenosis / bicuspid AV: fixed obstruction picture.

— Vasovagal syncope: postural, prodromal symptoms, non-exertional — much more common but a diagnosis of exclusion in athletes.

— Pulmonary embolism: dyspnea, tachycardia, hypoxia, risk factors.

— Aortic stenosis (fixed, radiates to carotids).

— Mitral regurgitation (holosystolic, radiates to axilla, ↑ with handgrip).

— Mitral valve prolapse (mid-systolic click, late systolic murmur, dynamic with Valsalva but click moves earlier).

— VSD (holosystolic, harsh, left sternal border, ↑ with handgrip).

— Innocent flow murmur (soft, no radiation, decreases with standing).

— Severe long-standing HTN.

— Aortic stenosis or subaortic membrane.

— Storage disease (Fabry, glycogen storage).

— Amyloid (TTR, AL).

— Athlete remodeling.

Board pearl: In a young athlete with exertional syncope and a normal echo, do not stop at "vasovagal" — pursue CT coronary angiography (anomalous coronary), exercise stress with rhythm monitoring (CPVT, exercise-induced VT), and consider ambulatory monitoring + genetic testing. Channelopathies and AAOCA hide behind normal echoes.

Differentials for exertional syncope in a young patient:

Differentials for the systolic murmur:

Differentials for unexplained LVH on imaging:

Long-Term Plan, Discharge Medications, and Secondary Prevention

— Nonvasodilating β-blocker (metoprolol succinate, atenolol, propranolol) — first-line for obstructive disease.

— Verapamil or diltiazem if β-blocker intolerant (avoid if severe resting obstruction or rest dyspnea).

— Disopyramide for refractory obstruction (specialist-initiated).

— Mavacamten via REMS pathway in eligible symptomatic oHCM patients.

— Anticoagulation (DOAC preferred) for AF — regardless of CHA₂DS₂-VASc score.

— Statin only per usual ASCVD risk indications.

— Stop / never start: ACEi/ARB (unless end-stage HFrEF), dihydropyridine CCBs, nitrates, PDE5 inhibitors, digoxin, hydralazine.

— Maintain hydration; avoid prolonged dehydration, hot tubs, saunas, large alcohol intake.

— Activity: shared decision-making; avoid burst/sprint and intense isometric exertion in high-risk patients.

— Document and review AED accessibility for athletes.

— Weight optimization (obesity worsens HFpEF physiology).

— Smoking cessation; alcohol moderation.

— Counsel proband on autosomal dominant inheritance, 50% transmission risk.

— Refer first-degree relatives for clinical screening (ECG + TTE) and, if proband genotype-positive, cascade genetic testing.

— Document family pedigree.

Step 3 management: On discharge after first oHCM diagnosis: start metoprolol succinate, anticoagulate if AF, refer for genetic counseling, schedule TTE in 4–6 weeks, and arrange screening ECG/TTE for all first-degree relatives. Document SCD risk stratification plan.

At-discharge (post–new diagnosis or admission) medication checklist:

Lifestyle counseling:

Vaccinations: annual influenza, pneumococcal per age/risk, COVID-19, RSV (age-appropriate) — all reduce decompensation triggers.

Family screening — non-negotiable:

ICD program enrollment for patients meeting criteria; remote monitoring setup.

Pregnancy planning for women of reproductive age — preconception counseling and contraception discussion.

Comprehensive HCM center linkage for complex patients.

Follow-Up, Monitoring, and Counseling Cadence

— Clinical visit + ECG: annually (more frequent if recent diagnosis, medication titration, or symptom change).

— TTE: every 1–2 years in stable adults; sooner if change in symptoms, murmur, or before/after major interventions.

— Ambulatory ECG monitoring (24–48 hr Holter): every 1–2 years for SCD risk reassessment (NSVT screen).

— Cardiac MRI: every 3–5 years or with significant clinical change (assess LGE burden, aneurysm formation).

— Exercise testing periodically if asymptomatic to monitor functional capacity and BP response.

— Children of HCM patients: ECG + TTE every 1–2 years from age 12 through adolescence; every 5 years thereafter.

— Earlier and more frequent screening if competitive athlete, symptoms, or malignant family pedigree.

— Genotype-positive/phenotype-negative ("G+/P−") adults: serial imaging every 3–5 years lifelong; no activity restriction.

— Mavacamten: TTE for EF at weeks 4, 8, 12, 24, then every 12 weeks. Hold if EF <50%. Review CYP interactions at every visit.

— Disopyramide: baseline and periodic ECG (QTc), monitor for anticholinergic side effects.

— β-blockers / non-DHP CCBs: HR, BP, symptom check.

— Amiodarone (if AF): PFTs, LFTs, TFTs every 6 months; ophthalmologic exam annually.

— DOACs: annual renal function, bleeding history, medication reconciliation.

— Update family history.

— Review red-flag symptoms (syncope, palpitations, worsening dyspnea).

— Reinforce hydration, medication adherence, contraception/pregnancy plans.

Board pearl: A G+/P− 14-year-old with HCM mutation but normal echo — no activity restriction, surveillance ECG + TTE annually through adolescence, then every 5 years. Do not start medications. Reassure family about uncertainty of phenotypic expression.

Routine surveillance for stable HCM patients:

Family cascade screening cadence (clinical):

Medication-specific monitoring:

ICD interrogation: in-clinic every 6–12 months plus remote monitoring; battery and lead status, shock review.

Counseling at every visit:

Ethical, Legal, and Patient Safety Considerations

— Must be preceded by formal genetic counseling — informed consent covers implications for insurance, employment, family relationships, and psychological impact.

— GINA (Genetic Information Nondiscrimination Act) protects against health insurance and employment discrimination based on genetic information — but does NOT protect life, disability, or long-term care insurance. Patients must understand this before testing.

— Variants of uncertain significance (VUS) are common and should not drive clinical decisions; reclassification over time is expected.

— Patient is encouraged but not legally obligated (in most US jurisdictions) to inform at-risk relatives. The clinician's "duty to warn" third parties for genetic disease is jurisdiction-dependent and ethically debated.

— Provide the proband with a family letter summarizing the diagnosis and screening recommendations to facilitate disclosure.

— Generally restricted to actionable findings; many guidelines defer predictive testing in asymptomatic minors until they can consent — except in HCM, where clinical screening from age 12 is supported because of SCD risk and actionability (activity counseling, ICD candidacy).

— Documented informed-consent conversation about residual risk is essential when supporting continued participation. Coaches and athletic trainers should know the diagnosis with patient consent; AED access must be ensured.

— Primary prevention ICD: typically 1-week restriction on driving private vehicles; secondary prevention: 6 months (varies by state). Commercial driving restrictions are stricter (DOT regulations) — many ICD recipients are permanently disqualified from interstate commercial driving.

— Pediatric-to-adult cardiology handoff is a known dropout point — ensure scheduled adult HCM clinic appointment before discharge from pediatric care.

— At hospital discharge, explicitly document the "do-not-use" medication list (nitrates, dihydropyridines, PDE5 inhibitors) to prevent inadvertent prescription by other clinicians.

Step 3 management: A 17-year-old patient transitioning to adult care with newly diagnosed HCM — obtain consent for genetic counseling referral, discuss GINA limits on disability insurance, schedule adult HCM clinic before pediatric discharge, and confirm AED access at school.

Genetic testing ethics:

Disclosure to relatives:

Pediatric genetic testing:

Athletic clearance and shared decision-making:

Driving and ICD shocks:

Transition-of-care risk:

High-Yield Associations and Rapid-Fire Facts

— Valsalva strain, standing, amyl nitrite → louder.

— Squat, leg raise, handgrip, phenylephrine → softer.

Board pearl: Pair the dynamic murmur maneuvers, the ≥30 mm wall thickness SCD threshold, the "avoid vasodilators" rule, and the AF anticoagulate-always rule — these four facts cover ~70% of Step 3 HCM questions.

Most common cause of SCD in young US athletes: HCM (in some registries, coronary anomalies edge ahead — both are tested).

Most common genes: MYH7 and MYBPC3 (~70% of genotype-positive cases). Sarcomere protein mutations.

Inheritance: autosomal dominant, variable penetrance, age-dependent expression.

Diagnostic threshold: LV wall thickness ≥15 mm unexplained, or ≥13 mm with FHx/genotype.

Massive hypertrophy threshold for SCD risk: ≥30 mm.

LVOT gradient cutoffs: ≥30 mmHg = obstructive; ≥50 mmHg + NYHA III–IV despite meds = SRT candidate.

Murmur dynamics — the classic test pattern:

Brockenbrough-Braunwald sign: post-PVC ↓ pulse pressure (paradoxical) — pathognomonic for dynamic obstruction.

Bisferiens carotid pulse: biphasic; HCM hallmark (also seen in mixed AS/AR).

Apical HCM (Yamaguchi): giant precordial T-wave inversions; "ace-of-spades" LV on imaging; CMR for diagnosis.

AF in HCM: anticoagulate regardless of CHA₂DS₂-VASc.

Avoid in oHCM: dihydropyridines, ACEi/ARBs, nitrates, PDE5 inhibitors, digoxin, dobutamine/milrinone, aggressive diuresis.

First-line meds: nonvasodilating β-blockers; second-line verapamil/diltiazem; refractory adds disopyramide or mavacamten.

Mavacamten: cardiac myosin inhibitor; REMS; serial TTE for EF monitoring.

Septal reduction: myectomy (younger, surgical candidates) vs alcohol ablation (older, higher-risk surgical candidates; ~10% pacer rate).

Cascade screening: first-degree relatives, ECG + TTE every 1–2 yr ages 12–21, every 5 yr thereafter; targeted genetic testing if proband variant known.

GINA: protects health insurance/employment; not life, disability, long-term care.

End-stage HCM (3–5%): dilated, EF <50% — transplant pathway.

Septal myectomy = Morrow procedure.

Board Question Stem Patterns

Step 3 management: Recognize the dynamic murmur stem and the "which drug worsens this" stem instantly — they account for a disproportionate share of HCM questions.

Stem 1 — The young athlete: 18-year-old basketball player collapses during practice; family history of an uncle who died suddenly at 35. Exam: systolic murmur at LLSB that increases with Valsalva. → Next step: TTE. Diagnosis: HCM. Management: activity restriction pending workup, refer for risk stratification.

Stem 2 — Iatrogenic worsening: Known HCM patient develops worsening syncope after starting amlodipine for newly diagnosed hypertension. → Stop amlodipine, switch to metoprolol succinate (treats both HTN and HCM).

Stem 3 — The ED hypotensive oHCM patient: Patient with oHCM presents with pulmonary edema and BP 80/50. → Phenylephrine + IV β-blocker (esmolol) + cautious volume; avoid dobutamine, nitrates, aggressive diuresis.

Stem 4 — Family screening: 35-year-old newly diagnosed with HCM; wants to know what to tell relatives. → Autosomal dominant, 50% transmission risk; first-degree relatives need ECG + TTE; refer to genetic counselor; consider cascade genetic testing if proband variant identified.

Stem 5 — Apical HCM: Middle-aged patient with chest pain, "old MI pattern" on ECG with deep T-wave inversions in V3–V6, but normal TTE. → Cardiac MRI reveals apical HCM ("ace-of-spades"). Not ACS, not Wellens (closely tested distinction).

Stem 6 — SCD risk stratification: Asymptomatic HCM patient with maximal wall thickness 32 mm and NSVT on Holter. → ICD for primary prevention (massive LVH + NSVT = two major risk factors).

Stem 7 — Refractory oHCM: NYHA III oHCM patient on max β-blocker + disopyramide with gradient 80 mmHg. → Septal reduction therapy (myectomy preferred if younger, ASA if older/high surgical risk).

Stem 8 — Pregnant HCM patient: Pregnant with HCM, on metoprolol. → Continue metoprolol or switch to labetalol; avoid atenolol; do NOT start mavacamten; multidisciplinary care.

Stem 9 — AF in HCM: New AF in HCM patient, CHA₂DS₂-VASc = 1. → Anticoagulate regardless of score — HCM + AF mandates anticoagulation.

Stem 10 — Differential trap: 72-year-old man with LVH, low ECG voltage, bilateral carpal tunnel history. → Not HCM — TTR amyloidosis; order PYP scan and light chains.

One-Line Recap

HCM is an autosomal dominant sarcomeric cardiomyopathy in which symptomatic management hinges on relieving dynamic obstruction with negative inotropes (β-blockers → verapamil → disopyramide or mavacamten → septal reduction), while parallel SCD risk stratification drives ICD decisions, AF mandates anticoagulation regardless of CHA₂DS₂-VASc, and lifelong cascade screening of first-degree relatives is non-negotiable.

Board pearl: If you remember only one thing — HCM gets louder with anything that empties the ventricle (Valsalva, standing) and softer with anything that fills it (squat, handgrip) — and the corollary that every drug that drops preload or afterload makes HCM worse. That single physiologic principle resolves the majority of Step 3 HCM vignettes.

Diagnosis: Unexplained LV wall thickness ≥15 mm (≥13 mm with family history or pathogenic variant); dynamic murmur that louder with Valsalva/standing, softer with squat/handgrip; bisferiens pulse; ECG abnormal in >90%; TTE first, CMR for apical or equivocal cases.

Management ladder: Nonvasodilating β-blocker → non-DHP CCB → add disopyramide or mavacamten (with REMS-mandated EF monitoring) → septal myectomy or alcohol ablation for NYHA III–IV despite maximal medical therapy with gradient ≥50 mmHg. Avoid dihydropyridine CCBs, ACEi/ARBs, nitrates, PDE5 inhibitors, digoxin, and standard inotropes.

SCD prevention: ICD for prior arrest/sustained VT, family history of SCD, unexplained syncope, wall thickness ≥30 mm, NSVT, EF <50%, or apical aneurysm; LGE ≥15% of LV mass and LA ≥48 mm are risk modifiers.

Family and longitudinal care: Genetic counseling before testing (GINA caveats), cascade ECG/TTE screening of first-degree relatives every 1–2 years through adolescence and every 5 years thereafter; document do-not-use medication list at every transition; arrange comprehensive HCM center linkage for SRT, pregnancy, pediatrics, or end-stage disease.