Hypertrophic Cardiomyopathy (Braunwald, NEJM 2025)

Authors, Journal, Affiliations, Type, DOI

• Author: Eugene Braunwald, MD
• Journal: New England Journal of Medicine 2025;393(10):1004–1015 (published online August 30, 2025); CME article
• Affiliations: TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital; Department of Medicine, Harvard Medical School, Boston
• Type: Narrative state-of-the-art review
• DOI: 10.1056/NEJMra2413445

Overview

This is a comprehensive review of hypertrophic cardiomyopathy by one of the physicians who defined the field. It covers genetics, imaging, sudden cardiac death, heart failure, atrial fibrillation, and the full therapeutic ladder — beta-blockers, calcium-channel blockers, disopyramide, cardiac myosin inhibitors (mavacamten and aficamten), septal reduction therapy and transplantation — and closes with nonobstructive HCM, paediatric HCM and emerging therapies. Its central clinical message is that HCM is now a treatable disease: the combination of ICDs and proven pharmacotherapy has reduced mortality to near that of the general population. It is a synthesis rather than a systematic review, and it predates or does not incorporate the negative ODYSSEY-HCM result in nonobstructive HCM.

Keywords

Hypertrophic cardiomyopathy; Left ventricular outflow tract obstruction; Sarcomere; Sudden cardiac death; Cardiac myosin inhibitors; Septal reduction therapy; Atrial fibrillation

Key Takeaways

Definition, epidemiology and history

• HCM is a complex, heterogeneous disorder that directly affects only the heart, characterised by hypertrophy of any portion of the LV wall — most often the basal interventricular septum — not explained by abnormal loading conditions or infiltration.
• It is the most common monogenic cardiac disorder, with a prevalence of approximately 1 in 500 adults; it occurs worldwide, in both sexes, all races and all age groups.
• The LV cavity is usually small with increased contractility and a supranormal ejection fraction (often 70–75%). Histology shows enlarged myocytes in disarray, interstitial fibrosis and thick-walled intramural coronary arteries.
• Teare described the pathology in 1958 (eight patients, seven sudden deaths); LV outflow tract obstruction was reported in 1959, and this large subgroup is now called obstructive HCM.

Genetics

• Pathogenic variants in at least eight genes encoding sarcomeric proteins are considered causal; ~40% of people assessed are gene positive.
• MYBPC3 (~45%) and MYH7 (~35%) account for most gene-positive cases. Variants alter calcium sensitivity, actomyosin contraction, energy metabolism and mitochondrial function.
• Gene positive ≠ phenotype positive: penetrance and expressivity vary; gene-positive/phenotype-negative individuals require follow-up, and gene-positive/phenotype-positive individuals have earlier onset, more arrhythmia and more heart failure than gene-negative/phenotype-positive patients.
• Genetic testing with multigenic panels is recommended in confirmed or suspected HCM, with family testing — which also detects HCM mimics (Fabry disease, Danon, Andersen, glycogen-storage diseases, hereditary amyloidosis).

Imaging

• Echocardiography is widely available, inexpensive and usually decisive for diagnosis; combined with clinical assessment and ECG it is the first-line modality.
• Cardiac MRI is the non-invasive standard: better spatial resolution, no radiation, identifies mimics, detects late gadolinium enhancement and measures wall/septal thickness more accurately — useful for SCD risk assessment.
• Cardiac CT evaluates epicardial disease and myocardial bridging and provides ventricular volumes, wall thickness and fibrosis assessment when MRI is contraindicated; PET identifies ischaemia and microvascular perfusion.

Sudden cardiac death

• Before ICDs, the annual incidence of SCD in HCM was approximately 1%; ventricular fibrillation is the most common cause, and there is no clear evidence that antiarrhythmic drugs prevent it.
• Secondary prevention: prior VF, cardiac arrest or sustained VT → ICD.
• Primary prevention risk markers: family history of SCD, LV wall thickness ≥30 mm, LV apical aneurysm, unexplained syncope, multiple/prolonged NSVT, extensive LGE, LVEF <50%.
• Patients with overt HCM without risk markers should be reassessed every 1–2 years; SCD incidence falls with age and is infrequent ≥60 years, where ICD benefit may be limited.
• Maron et al. (2,094 patients): in 527 with ≥1 risk marker and a primary-prevention ICD, 15.6% had device-terminated VF/VT; only 0.3% of patients without risk markers and without ICDs died suddenly.
• AHA/ACC risk criteria are more sensitive; ESC criteria are more specific. With high-risk ICD use, SCD has fallen to <0.5% per year.

Heart failure

• With SCD reduced, heart failure has become the greater concern. An LVEF <50% in HCM represents serious dysfunction analogous to an LVEF of 35–40% in non-HCM systolic heart failure; 6–8% of HCM patients present with LVEF <50%.
• Heart failure arises in patients with marked hypercontractility (treated by relieving obstruction) or cardiac fibrosis (treated as classic heart failure, including transplantation); annual mortality with fibrosis is ~2%.
• SHaRe registry: LV dysfunction associates with more sarcomeric variants, thicker walls, larger LA, and more death, stroke and AF.
• Septal reduction therapy may improve function in obstructive HCM with heart failure; CRT may help HCM with LBBB and QRS >120 ms; transplantation for refractory NYHA III–IV; LVAD as a bridge.

Atrial fibrillation

• AF occurs in approximately one quarter of symptomatic HCM patients and is associated with poor outcomes and thromboembolism; both loss of atrial contraction and rapid rate impair filling.
• LA enlargement and fibrosis are central to its genesis. CHA₂DS₂-VASc is not helpful for identifying high death risk, and prompt anticoagulation is essential.
• After cardioversion, rhythm control with sotalol, dofetilide or amiodarone; catheter ablation if drugs fail, though relapse is frequent and repeat procedures may be needed.
• At myectomy, surgical Maze ablation or LAA ligation are options; for rate control, beta-blockers ± non-dihydropyridine calcium-channel blockers, and AV nodal ablation if needed.

First-line pharmacotherapy

• Beta-blockers remain guideline-recommended first-line therapy for obstructive HCM; metoprolol reduced heart rate, LVOT obstruction and improved global longitudinal strain at rest and exercise in a double-blind RCT.
• If beta-blockers are inadequate, verapamil or diltiazem; disopyramide may be added (negative inotrope) and reduces LVOT obstruction.
• These agents reduce symptoms but have not been shown to alter the natural history of HCM.

Cardiac myosin inhibitors

• The cause of both obstruction and impaired relaxation is an excess of actin–myosin cross-bridges, increasing contractility and energy demand.
• Mavacamten is an allosteric inhibitor of cardiac myosin ATPase that shifts myosin to an energy-sparing super-relaxed state.
  • EXPLORER-HCM (n=251, obstructive, NYHA II–III, 30 weeks): superior to placebo on peak VO₂ and NYHA class; LVOT gradients fell by 37% at rest, 36% with Valsalva and 42% after exercise; wall thickness, mass, NT-proBNP and hs-troponin fell; KCCQ-CSS improved; benefit persisted >3 years in the open-label extension; confirmed in the Chinese HCM-CN trial (n=81).
  • VALOR-HCM (n=112, referred for septal reduction): after 16 weeks, 18% vs 77% remained eligible for septal reduction therapy; benefits sustained to 128 weeks.
  • LVEF fell below 50% in 4.6% of EXPLORER-HCM patients, requiring interruption or discontinuation. FDA approval in 2022 with a Risk Evaluation and Mitigation Program (multiple visits and echocardiograms).
• Aficamten binds myosin at a different site and has a shorter half-life and fewer drug interactions. SEQUOIA-HCM (n=282): greater improvement in peak VO₂; similar improvements in wall thickness, mass, LA volume, health status and KCCQ-CSS; transient LVEF <50% in 3.5%. Under FDA review at the time of writing.
• Guidelines recommend a cardiac myosin inhibitor in adults with obstructive HCM who remain symptomatic despite first-line therapy; wider availability may reduce the need for septal reduction. Caveats: more than half of EXPLORER-HCM patients did not meet the primary endpoint criteria, and REMS burden is substantial.

Septal reduction therapy

• Indicated for obstructive HCM in NYHA III–IV despite first-line therapy and a myosin inhibitor (if available); should be performed by experienced teams.
• Transaortic septal myectomy (early 1960s) remains the reference standard; it also allows mitral valve/subvalvular repair, CABG and Maze. Apical myectomy is an option for nonobstructive HCM, apical hypertrophy or apical aneurysm.
• Alcohol septal ablation creates a septal infarct via a septal branch; generally for frail older patients or where myectomy expertise is unavailable; higher complete heart block rate but shorter recovery.
• SHaRe (10,225 patients): 18% underwent septal reduction (75% myectomy, 25% ablation); 30-day mortality 0.4%, annual mortality 0.6%, advanced heart failure 1.9%/year; repeat septal reduction more frequent after ablation.

Nonobstructive HCM

• About one third of overt HCM has no outflow gradient even with provocation; some authors include resting gradients up to 30 mmHg.
• Most patients are asymptomatic; long-term mortality does not differ significantly from obstructive HCM.
• Treatment is challenging: cautious diuretics; the role of beta-blockers needs definition. Mavacamten and aficamten have completed phase 2 trials (mavacamten reduced NT-proBNP and troponin I; aficamten improved KCCQ-CSS) and phase 3 trials were fully enrolled; ninerafaxstat improved LA diameter and ventilation/CO₂ ratio in phase 2; sotagliflozin is in phase 3 (SONATA-HCM).
• 5–10% have "burned-out" HCM — long-standing obstruction with extensive fibrosis, dilatation and loss of obstruction — requiring transplantation or LVAD.

Paediatric HCM

• HCM in children/adolescents can cause SCD, LV dysfunction and heart failure; SHaRe shows childhood diagnosis increases adult heart-failure risk.
• MYBPC3 and MYH7 remain the most frequent variants. Two externally validated risk scores exist: HCM Risk-Kids and PRIMACY.
• ICDs are appropriate for high-risk children, but inappropriate shocks and lead fracture are more frequent than in adults.
• Septal myectomy by experienced teams is safe, effective and durable in severe paediatric LVOT obstruction.

The future

• Open questions for myosin inhibitors: is lifetime administration necessary, in which subgroup, and do they have a role in children or in gene-positive/phenotype-positive patients at risk of SCD or dysfunction?
• Proteomic profiling (plasma and myectomy tissue) has identified dysregulated kinase and hypoxia-inducible pathways.
• Gene therapy: CRISPR correction of MYH7, siRNA silencing of mutant mRNA, and MYBPC3 replacement (phase 1b, nonobstructive HCM).
• Artificial intelligence applied to ECG and echocardiography may detect gene-positive/phenotype-negative HCM before overt disease.

Limitations of the document

• Narrative review by a single author, not a systematic review or guideline; evidence selection and emphasis are inevitably selective, and there is no formal appraisal of study quality.
• Does not incorporate ODYSSEY-HCM (NEJM 2025), the phase 3 trial showing mavacamten did not improve peak VO₂ or KCCQ-CSS in nonobstructive HCM, despite a large NT-proBNP reduction (LVEF <50% in 21.5%). The review describes phase 3 nonobstructive trials as "fully enrolled" and implies pending benefit — a material omission in a 2025 review.
• Several claims are stated without citation-level qualification (e.g. that the prognosis is "greatly improved" and that mortality approaches the general population), and the supporting trial data are summarised rather than critically appraised.
• Paediatric and pregnancy management are covered briefly; pregnancy is mentioned only in relation to myosin inhibitor contraindication and maternal mortality is not discussed.
• No discussion of genotype-specific management, polygenic risk or the disputed HCM genes, and no detail on the diagnostic criteria for gene-elusive HCM.
• Cost, access and equity are acknowledged only in passing ("when cardiac myosin inhibitors become generally available and affordable"), despite being central to their real-world impact.
• The article predates or omits recent trial results beyond ODYSSEY-HCM — including the full publication of some nonobstructive phase 3 data and contemporary septal reduction outcome comparisons.

Key Concepts Mentioned

• entities/HCM — the disease reviewed
• concepts/LVOTO — dynamic outflow obstruction; the target of myosin inhibitors and septal reduction
• concepts/Septal-Reduction-Therapy — myectomy and alcohol ablation
• concepts/HCM-Risk-SCD — primary-prevention risk markers and ICD selection
• concepts/HCM-Exercise — activity recommendations
• concepts/HCM-Atrial-Myopathy — LA enlargement/fibrosis and AF
• entities/Mavacamten, entities/Aficamten — cardiac myosin inhibitors
• entities/Atrial-Fibrillation, entities/Heart-Failure — major complications

Key Entities Mentioned

• Eugene Braunwald — author and historical figure in HCM
• Teare, Morrow, Maron — foundational contributors
• SHaRe (Sarcomeric Human Cardiomyopathy Registry) — outcome registry
• EXPLORER-HCM, VALOR-HCM, HCM-CN, SEQUOIA-HCM, ODYSSEY-HCM, SONATA-HCM — trials
• MyoKardia/Bristol Myers Squibb (mavacamten), Cytokinetics (aficamten) — manufacturers

Wiki Pages Updated

• Created: wiki/sources/HCM-NEJM-2025.md
• Updated: wiki/entities/HCM.md
• Updated: wiki/concepts/HCM-Risk-SCD.md
• Updated: wiki/concepts/Septal-Reduction-Therapy.md
• Updated: wiki/sourceindex.md
• Updated: log.md