Hypertrophic Cardiomyopathy

Core Characteristics

• Hypertrophic cardiomyopathy (HCM) is a genetic myocardial disorder defined by left ventricular hypertrophy (LVH) that cannot be fully attributed to abnormal loading conditions such as hypertension or aortic stenosis.
• It is among the most common inherited cardiac diseases worldwide and a leading cause of sudden cardiac death (SCD) in young individuals, including athletes.
• The condition is frequently misdiagnosed: in younger patients, it may be confused with athlete’s heart, while in older individuals, it may be mistaken for hypertensive heart disease.
• A significant proportion of patients are asymptomatic at diagnosis, with many identified incidentally during routine evaluation or through family screening of affected relatives.

Genetic Basis

• HCM is typically inherited in an autosomal dominant pattern with variable penetrance and expression.
• The disease arises from mutations in sarcomeric protein genes, which encode components of the cardiac contractile apparatus.
• These genetic changes lead to structural and functional myocardial abnormalities that drive the disease phenotype.

Structural and Functional Cardiac Changes

• Cardiac structural hallmarks include increased LV wall thickness, most prominently in the interventricular septum.
• These changes may result in dynamic left ventricular outflow tract (LVOT) obstruction, diastolic dysfunction, mitral regurgitation, myocardial ischaemia, and arrhythmogenic substrate formation.
• Additional features may include autonomic dysfunction and microvascular impairment, further contributing to symptoms and adverse outcomes

Clinical Importance

• In the United States, HCM is recognised as the most common identifiable cause of sudden cardiac death in individuals under 35 years, particularly in otherwise healthy and well-trained athletes.

Genetic Causes

• HCM is primarily a genetic disease of the cardiac sarcomere, inherited most often in an autosomal dominant manner with variable penetrance and expression.
• Mutations in sarcomeric protein genes disrupt the contractile apparatus of the myocardium, leading to hypertrophy and myocyte disarray.
• The most commonly implicated genes are:
  • MYH7 (β-myosin heavy chain 7) – accounts for around 40–45% of mutations.
  • MYBPC3 (myosin-binding protein C3) – responsible for approximately 30–40% of cases.
• Less frequent mutations involve thin filament proteins:
  • TNNT2 (troponin T), TNNI3 (troponin I), TPM1 (α-tropomyosin), ACTC1 (actin), MYL2 and MYL3 (myosin light chains).
  • These collectively account for about 5–10% of identified mutations.
• Some patients harbour multiple pathogenic variants (double or compound heterozygosity), which may confer a more severe phenotype.
• Despite advances in genetic testing, up to 40–50% of patients do not have an identifiable pathogenic mutation, suggesting that non-sarcomeric or undiscovered mechanisms contribute to disease expression.
• More than 1500 pathogenic variants have been reported, most being unique to individual families.

Nonfamilial and Sporadic Forms

• A substantial minority of patients present with nonfamilial (sporadic) HCM, with no family history or identifiable mutation.
• These may arise from de novo mutations or reflect alternative molecular pathways yet to be fully elucidated.
• The heterogeneity in phenotypic expression, even within the same family, highlights the interplay of genotype, modifier genes, and environmental influences.

Abnormal Calcium Kinetics

• Abnormalities in myocardial calcium handling are thought to contribute to the pathogenesis.
• Increased calcium channel activity and abnormal calcium flux elevate intracellular calcium concentration, driving hypertrophy, impaired relaxation, and myocyte disarray.
• These mechanisms may be particularly relevant in patients with diastolic dysfunction, linking calcium handling defects to the hallmark impaired filling in HCM.

Other Proposed Mechanisms

Abnormal sympathetic stimulation

• Excessive catecholamine production or impaired neuronal reuptake of norepinephrine may exacerbate hypertrophic changes.

Microvascular abnormalities

• Thickened intramural coronary arteries with poor vasodilatory capacity result in microvascular ischaemia, promoting fibrosis and compensatory hypertrophy.

Subendocardial ischaemia

• Inadequate microcirculatory function impairs energy-dependent calcium sequestration during diastole, producing increased stiffness and persistent cross-bridge activity.

Cardiac structural variants

• Anatomical configurations, such as a catenoid-shaped septum, can predispose to abnormal stress distribution, hypertrophy, and cellular disarray.

Structural and Histological Features

• HCM results from genetic mutations that cause myocyte hypertrophy, disarray, and an abnormally thickened, disorganised collagen matrix.
• The hypertrophy often involves the interventricular septum, which may be diffuse or localised. The most classic form shows marked thickening immediately below the aortic valve.
• Apical HCM may occur with isolated hypertrophy at the apex.
• Histological features include fibrosis and disarray of myocytes, which provide an arrhythmogenic substrate.

Left Ventricular Outflow Tract Obstruction (LVOTO)

• Obstruction may occur at multiple sites:
  • Subaortic obstruction due to septal hypertrophy, often exacerbated by systolic anterior motion (SAM) of the mitral valve.
  • Mid-cavity obstruction resulting from hypertrophy of the mid-septum and papillary muscles, leading to systolic apposition without SAM.
• SAM arises when turbulent subaortic flow pulls the anterior mitral leaflet towards the LVOT, worsening obstruction.
• Obstruction is dynamic and can be provoked by tachycardia, increased contractility, reduced ventricular volume, or vasodilation.
• A gradient ≥30 mmHg is considered haemodynamically significant, while ≥50 mmHg is the threshold for intervention if symptomatic.

Mitral Regurgitation

• Mitral regurgitation in HCM commonly results from LVOTO with SAM.
• The direction of the regurgitant jet can help determine the underlying mechanism, with posteriorly directed jets usually associated with SAM.
• Structural abnormalities such as elongated mitral leaflets and anterior displacement of papillary muscles further contribute.

Diastolic Dysfunction

• Impaired relaxation is a hallmark, occurring regardless of obstruction.
• Increased stiffness due to fibrosis, myocyte disarray, and hypertrophy raises LV filling pressures and left atrial pressure.
• Abnormal calcium reuptake kinetics delay myocardial inactivation, exacerbating diastolic dysfunction.
• Diastolic impairment is often considered the primary driver of symptoms, particularly in younger patients.

Myocardial Ischaemia

• Ischaemia is common and multifactorial:
  • Mismatch of supply and demand due to hypertrophy.
  • Reduced capillary density and microvascular dysfunction.
  • Compression of septal perforators and myocardial bridging of epicardial arteries.
  • Increased vascular resistance from abnormal relaxation and elevated LV filling pressures.
• Chronic ischaemia contributes to fibrosis and arrhythmogenic substrate formation.

Autonomic Dysfunction

• Defined by an abnormal blood pressure response to exercise, such as a failure to increase systolic pressure by ≥20 mmHg or a fall of ≥20 mmHg.
• Mechanism likely involves inappropriate firing of stretch-sensitive mechanoreceptors, causing mismatched changes in systemic vascular resistance.
• Clinically, this may result in presyncope or syncope, often exertional.

Arrhythmias

• Atrial fibrillation occurs in ~25% of patients, with a four- to six-fold higher prevalence than the general population.
  • Poorly tolerated due to reliance on atrial contraction for ventricular filling (up to 35%).
  • Loss of atrial contribution can precipitate hypotension and heart failure symptoms.
• Non-sustained ventricular tachycardia (NSVT) is detected in 20–30% of patients.
  • NSVT may progress to ventricular fibrillation, the principal arrhythmic mechanism underlying sudden cardiac death (SCD).
• Arrhythmogenic triggers include fibrosis, myocyte disarray, and ischaemia.

Global Prevalence

• HCM is among the most common inherited cardiac disorders, with a reported prevalence of 0.2% (1 in 500 adults) in echocardiographic population studies.
• More recent genetic-based population studies suggest the prevalence of pathogenic sarcomeric variants may be closer to 1 in 200 individuals, indicating the true disease burden may be underestimated.
• Approximately 15–20 million people worldwide are affected, making it a major global cardiovascular disorder.
• Among patients undergoing echocardiography for clinical indications, HCM is identified in up to 0.5% of referrals.

Familial Involvement

• Morphological abnormalities consistent with HCM are found in around 25% of first-degree relatives of affected patients on echocardiography.
• Genetic testing can identify asymptomatic relatives with pathogenic variants, enabling early detection and surveillance.

Sex-Related Demographics

• Although inheritance is autosomal dominant without sex predilection, HCM is diagnosed more frequently in males.
• Proposed explanations include screening practices, hormonal influences, and genetic modifiers.
• Women often present later in life, are more symptomatic, and are more likely to have advanced New York Heart Association (NYHA) class III/IV symptoms at diagnosis.
• Female patients may therefore experience a worse prognosis, underscoring the importance of optimised diagnostic strategies in women.

Age-Related Demographics

• HCM has a bimodal distribution of onset:
  • Children: May present from newborn period (including stillbirths) through adolescence, with a peak in the second decade for inherited forms.
  • Adults: Most commonly present in the third decade, with cases spanning into the sixth decade.
• Community-based cohorts report a mean age at diagnosis of ~57 years (range 16–87).
• Sudden cardiac death (SCD) predominates in children and young adults, whereas heart failure and stroke account for mortality in middle-aged and older patients.

Ethnic Variation

• HCM affects all ethnic groups, but apical HCM shows a clear ethnic predilection.
  • Accounts for <5% of cases in non-Asian populations.
  • Represents 15–40% of cases in Asian populations, particularly in Japan and other East Asian regions.

Presenting Symptoms and Red Flags

• Many individuals are asymptomatic at diagnosis (often identified via family screening or incidental ECG/echo abnormalities), but among symptomatic patients the following are typical.

Sudden cardiac death (SCD) or resuscitated arrest

• Prior unexplained cardiac arrest or resuscitated ventricular fibrillation/ventricular tachycardia.
• Episodes clustered in preadolescents/adolescents and during or after extreme exertion.
• Ask about aborted events in relatives and unexplained accidents or drownings.

Syncope and presyncope

• Exertional syncope/presyncope or episodes without prodrome; “grey-outs” relieved by lying flat.
• History of palpitations preceding loss of consciousness (AF/SVT/VT) or situational triggers (dehydration, heat, alcohol, Valsalva/defaecation).
• Recurrent, recent, or unexplained syncope is a high-risk feature.

Dyspnoea and heart failure symptoms

• Dyspnoea on exertion (most common symptomatic complaint) with exercise intolerance or fatigue.
• Less commonly orthopnoea and paroxysmal nocturnal dyspnoea; ask about peripheral oedema to screen for advanced disease.
• Worsening breathlessness with intercurrent illness, dehydration, or after starting preload/afterload-reducing drugs.

Chest pain

• Typical or atypical angina, often with normal coronary arteries.
• Occurs with exertion or heavy meals; explore features suggesting microvascular angina (prolonged, diffuse discomfort) and history of myocardial bridging if known.

Palpitations and arrhythmia symptoms

• Paroxysmal palpitations, irregularly irregular pulse episodes, or rapid regular tachycardia.
• Symptoms compatible with atrial fibrillation (common and poorly tolerated), SVT, NSVT (20–30% on monitoring), and associated dizziness, presyncope, or syncope.
• Prior thromboembolic events (stroke/TIA) suggesting occult AF.

Dizziness and exertional intolerance

• Light-headedness or dizziness worse on exertion, with dehydration, heat exposure, alcohol, or after sauna/hot baths.
• Episodes after sudden standing or Valsalva.

Pattern, Triggers, and Modifiers

Exertional pattern and recovery

• Symptoms during high-intensity exercise or immediately post-exercise; delayed recovery.
• Functional class (NYHA), trajectory over time, and variability day-to-day.

Provoking/relieving factors

• Factors increasing dynamic LVOT obstruction: dehydration, fever, large alcohol intake, heavy meals, hot environments, and strenuous bursts.
• Medications that worsen symptoms: nitrates, diuretics, vasodilating antihypertensives; symptom relief with beta-blockers or rest.

Natural history cues

• Previous shift from obstructive to non-obstructive symptoms (or vice-versa).
• Features of end-stage/burnt-out HCM (declining exercise capacity, possible new ankle swelling, prior echo suggesting falling EF).

Family and Personal Background

Family history

• HCM, unexplained sudden death <50 years, implantable cardioverter-defibrillator placement, AF, stroke/TIA, or unexplained syncope in first-degree relatives.
• Age at diagnosis in relatives and any known sarcomeric variants.

Genetic and demographic considerations

• Prior genetic testing results; pregnancy plans (for counselling/screening).
• Women may present later and more symptomatic; ask about delayed diagnosis and burden of limitation.
• Age at first symptoms (bimodal distribution) and ethnic background (e.g., apical HCM more frequent in some Asian populations).

Risk Context to Capture from History

Markers linked to higher risk

• Unexplained or exertional syncope, particularly recent and in younger patients.
• Documented NSVT, family history of SCD, previous sustained VT/VF, or multiple episodes of AF with haemodynamic compromise.
• History suggesting marked hypertrophy or labile/provoked gradients (exercise-related symptoms, alcohol/heat triggers).

General Inspection

• Assess overall work of breathing and exercise intolerance at rest; look for signs of congestion in advanced disease (basal crackles, peripheral oedema are uncommon early but relevant when present).
• Observe for postural triggers during the encounter (symptom provocation on standing).

Precordial Palpation

Left ventricular lift (heave)

• Diffuse, forceful apical impulse; sustained LV heave reflecting hypertrophy and reduced compliance.

Double or triple apical impulse

• Double apical impulse from forceful atrial systole against a non-compliant LV.
• Triple apical impulse may occur due to a late systolic bulge during near-isometric contraction.

Thrills

• Systolic thrill at the apex or lower left sternal border in patients with marked LVOT obstruction.

Arterial Pulse and Blood Pressure

Carotid upstroke and contour

• Brisk upstroke with bifid (“spike-and-dome”) pulse due to midsystolic obstruction and partial aortic valve closure (bisferiens carotid pulse).

Blood pressure response

• Check for exaggerated fall or inadequate rise in systolic BP on standing or with exertion (can reflect dynamic obstruction or autonomic abnormalities).

Jugular Venous Examination

Prominent “a” wave

• Reflects reduced RV compliance secondary to septal hypertrophy and impaired diastolic filling.

Cardiac Auscultation

First and second heart sounds

• S1 typically normal.
• S2 usually splits normally; paradoxical splitting can occur with severe LVOT obstruction.

Third and fourth heart sounds

• S3: common in children; in adults suggests decompensated heart failure.
• S4: frequent, due to atrial contraction into a stiff LV.

Systolic ejection murmur (LVOT obstruction)

• Harsh crescendo–decrescendo systolic murmur, starting just after S1.
• Best heard at the apex and lower left sternal border; may radiate to the axilla or base, but not usually to the neck (helps distinguish from valvular aortic stenosis).
• Often accompanied by a small LV cavity and hyperdynamic impulse on examination.

Mitral regurgitation murmur

• Mid- to late-systolic murmur at the apex from systolic anterior motion (SAM)–related leaflet malcoaptation; jet commonly posteriorly directed.
• A holosystolic apical murmur with axillary radiation suggests more primary MR; an eccentric jet may radiate towards the base and mimic LVOT murmur.

Dynamic Auscultatory Manoeuvres (bedside provocation)

Manoeuvres that increase LVOT gradient (↑ murmur intensity)

• Standing from squat/supine, Valsalva strain, post-PVC beat, nitroglycerin, diuretics, vasodilators → ↓ preload/afterload or ↑ inotropy.

Manoeuvres that decrease LVOT gradient (↓ murmur intensity)

• Squatting from standing, passive leg raise, handgrip → ↑ preload/afterload, reducing dynamic obstruction.

Differentiation from aortic stenosis

• The HCM outflow murmur typically intensifies with Valsalva and standing; the valvular aortic stenosis murmur does not increase (often decreases slightly) with Valsalva and radiates to the neck.

Rhythm and Peripheral Signs

Irregularly irregular pulse

• Suggests atrial fibrillation; in HCM often poorly tolerated—note pulse deficit and haemodynamic impact.

Peripheral congestion (advanced disease)

• Ankle oedema, hepatomegaly, and rales are uncommon early, but document when present as indicators of progression.

Distinguishing HCM from Other Causes of LVH

• Aim to exclude acquired hypertrophy and phenocopies before confirming sarcomeric HCM.
• Use a composite approach (history, ECG, transthoracic echocardiography, exercise testing, CMR with LGE, and targeted genetics) to differentiate entities with overlapping wall thickness.

Hypertension

• Most common cause of acquired LVH in adults; typically concentric rather than asymmetric.
• Wall thickness rarely >15 mm with treated hypertension; look for long-standing BP elevation and end-organ damage (retinopathy, nephropathy).
• Echo: concentric LVH; no SAM; regression of LV mass with BP control supports diagnosis.

Valvular aortic stenosis (AS)

• Produces concentric LVH with a fixed valve lesion.
• Echo: restricted leaflet motion, valvular gradient; murmur radiates to the neck.
• Distinguish from HCM where obstruction is subvalvular, dynamic, often with SAM and without neck radiation.

Fixed subaortic (subvalvular) stenosis

• Congenital membrane in LVOT; echo shows discrete ridge/membrane with fixed gradient.
• No SAM; LV wall thickness may be normal or secondary concentric LVH if long-standing.

Athlete’s heart (physiological remodelling)

• Grey-zone wall thickness 13–15 mm may overlap HCM.
• Helpful discriminators:
  • LV cavity size: athletes often have larger LVED diameter (≈60 mm vs ≈45 mm in HCM).
  • Diastolic function: tissue Doppler Ea normal/high in athletes, reduced in HCM.
  • Deconditioning: >2 mm regression in wall thickness favours athlete’s heart.
  • CMR: absence of patchy mid-wall LGE supports athlete’s heart; LGE (especially in hypertrophied segments/junctions) supports HCM.
  • CPET: athletes have higher peak VO₂ and oxygen pulse; markedly subnormal peak VO₂ suggests HCM.

Infiltrative and storage cardiomyopathies (phenocopies)

• Consider when hypertrophy is concentric, ECG shows discordant low voltage or there are systemic features.

Fabry disease (X-linked, α-galactosidase A deficiency)

• May present with isolated concentric LVH; look for angiokeratomas, neuropathic pain, cornea verticillata, renal involvement.
• Echo/CMR: concentric LVH; CMR may show characteristic basal inferolateral LGE; low native T1 values support Fabry.
• Enzyme replacement therapy alters management—screen when LVH is unexplained.

Cardiac amyloidosis

• Red flags: bilateral carpal tunnel, neuropathy, nephrotic syndrome, autonomic dysfunction.
• ECG: low QRS voltage or pseudo-infarct patterns despite thick walls.
• Echo: sparkling myocardium, thick valves, biatrial enlargement; CMR: diffuse subendocardial/transmural LGE, abnormal nulling; bone scintigraphy aids ATTR diagnosis.

Glycogen storage / metabolic (PRKAG2, LAMP2/Danon)

• PRKAG2: LVH + pre-excitation and conduction disease.
• Danon (LAMP2): adolescent males with skeletal myopathy and intellectual disability; rapid progression.
• CMR often shows diffuse hypertrophy; genetics confirms aetiology.

Other considerations

• LEOPARD/Noonan spectrum (multiple lentigines/dysmorphisms).
• Mitochondrial and other rare metabolic disorders—consider when multi-system features are present.

Differential Diagnosis of an Increased LV–Aortic Gradient

• Not all gradients reflect sarcomeric HCM; confirm mechanism and level of obstruction.

Volume depletion / hyperdynamic small LV

• Hypovolaemia (heat, sepsis, diuretics, vasodilators) → small cavity, intracavitary gradients that resolve with fluids.

Dynamic LVOT obstruction in non-HCM contexts

• Occurs with basal septal bulge in older hypertensive patients or post-AVR; often provoked and load-dependent.

Valvular and subvalvular lesions

• Valvular AS: fixed valvular gradient; neck radiation.
• Subaortic membrane: fixed subvalvular gradient; membrane seen on echo; no SAM.

Ancillary Tools That Help Separate Diagnoses

ECG clues

• HCM: large voltages with repolarisation changes, pathological Q waves, LA enlargement.
• Amyloid: low voltage with thick walls.
• PRKAG2: pre-excitation/WPW pattern.

Echocardiography

• Pattern (asymmetric septal vs concentric), presence of SAM/MR, and provoked gradients (exercise/Valsalva).
• Regression with BP control or deconditioning supports non-HCM causes.

CMR with LGE and mapping

• Patchy mid-wall/junctional LGE → HCM;
• Diffuse subendocardial/transmural LGE → amyloid;
• Basal inferolateral LGE + low native T1 → Fabry;
• No LGE, larger LV volumes → athlete’s heart.

CPET (cardiopulmonary exercise testing)

• High peak VO₂/O₂-pulse in athlete’s heart vs reduced in HCM.

Genetics and targeted biochemical testing

• Sarcomeric panels when HCM likely; GLA enzyme/genetics for Fabry; PRKAG2/LAMP2 if pre-excitation or syndromic features.
• Use cascade testing to guide family screening when a causal variant is found.

General Measures

• Hydration and volume status: Patients should be counselled to maintain adequate hydration, particularly during exercise, febrile illness, or diarrhoeal episodes, as reduced preload worsens LVOT obstruction.
• Therapies to avoid: Agents that reduce preload/afterload or increase contractility should generally be avoided, including dihydropyridine calcium channel blockers (nifedipine, amlodipine), nitrates, ACE inhibitors, ARBs, digoxin, and loop diuretics (except cautiously in volume-overloaded patients).

Approach to Therapy

Asymptomatic Patients

• Those with obstructive HCM but NYHA class I symptoms do not require medical or septal reduction therapy.
• Management consists of clinical surveillance and periodic echocardiography.

Initial Medical Therapy for Symptomatic Patients

• First-line: Non-vasodilating beta blockers (e.g., metoprolol succinate, nadolol). Dose titrated to symptom control.
• Alternative: Nondihydropyridine calcium channel blockers (verapamil, diltiazem) when beta blockers are contraindicated or not tolerated.
  • Caution with verapamil in patients with hypotension or volume overload, as its vasodilatory effect may worsen haemodynamics.
• Evidence largely based on retrospective studies and guideline consensus; small trials show reduction in LVOT gradient and symptomatic benefit.

Therapies for Refractory Symptoms

Disopyramide

• Mechanism: Potent negative inotrope with class IA antiarrhythmic effects.
• Use: In combination with a beta blocker or verapamil in patients with persistent symptoms.
• Cautions:
  • Must be co-administered with AV nodal blocker to prevent rapid AF conduction.
  • Risks: QTc prolongation (torsades), proarrhythmia if combined with other class I agents, anticholinergic side effects (urinary retention, glaucoma).
• Efficacy: Observational cohorts show significant reduction in LVOT gradients and improvement in functional status, delaying or avoiding septal reduction in many cases.

Myosin Inhibitors (Mavacamten, Aficamten)

• Mechanism: Inhibit cardiac myosin ATPase, reducing hypercontractility and LVOT obstruction.
• Benefits: Improved symptoms, exercise capacity, and LVOT gradient reduction demonstrated in trials (EXPLORER-HCM, SEQUOIA-HCM).
• Cautions:
  • Risk of reversible systolic dysfunction; require frequent echocardiographic monitoring of LVEF.
  • Contraindicated in pregnancy; teratogenic.
  • CYP450 interactions; not suitable for all patients.
• Role: An emerging therapy for patients not controlled with first-line agents; may reduce the need for septal reduction procedures.

Septal Reduction Therapy

Surgical Myectomy

• Procedure: Resection of hypertrophied septal myocardium via transaortic approach; may include papillary muscle or mitral repair.
• Indications: Severe symptomatic obstructive HCM refractory to medical therapy; particularly suited if concomitant mitral repair, papillary muscle anomalies, or other cardiac surgery (CABG, valve surgery) is planned.
• Outcomes: Symptomatic improvement in ~95%; perioperative mortality ~1% in high-volume centres; low reintervention rate.

Alcohol Septal Ablation

• Procedure: Catheter-based ethanol injection into septal perforator to create targeted infarction and reduce obstruction.
• Outcomes: Symptomatic improvement in ~90%; 1% peri-procedural mortality; ~10% require repeat procedures.
• Risks: Higher pacemaker implantation rate (10%); risk of septal perforation or coronary injury.
• Indications: Suitable for patients not surgical candidates or declining surgery.

Choice Between Myectomy and Ablation

• Determined by patient preference, anatomy, comorbidity, and centre expertise.
• Both procedures reduce gradients and improve survival; long-term outcomes are similar.

Therapies of Limited or Selective Use

• Dual therapy with beta blocker + calcium channel blocker: Not recommended due to bradycardia risk.
• Dual-chamber pacing: Limited evidence; may be considered in older patients (>65 years) or those needing pacing for another reason.
• Isolated mitral valve surgery: Not recommended unless concurrent pathology; usually combined with septal myectomy.
• Transcatheter mitral valve repair: Considered in non-surgical candidates with refractory symptoms, but septal reduction is preferred.

Special Circumstances

Midcavitary Obstruction

• Managed initially with beta blockers or nondihydropyridine calcium channel blockers.
• Surgical myectomy or papillary muscle intervention considered for refractory symptoms.

Apical Hypertrophy

• Rare form with reduced LV cavity size and low stroke volume.
• In refractory patients, transapical myectomy may be considered in specialised centres.

Pregnancy

• Generally well tolerated; most women adapt to pregnancy haemodynamics.
• Preconception counselling (including genetics) is essential.
• Beta blockers preferred for symptom control; verapamil as second-line. Doses should be minimised to reduce risks of foetal bradycardia and growth restriction.
• Care during delivery: Avoid sudden preload/afterload changes; manage under experienced anaesthesia and obstetric teams.

Acute Shock

• Management principles:
  • Increase preload (IV fluids, leg elevation).
  • Increase afterload (phenylephrine).
  • Use negative inotropes (IV beta blockers, IV disopyramide).
  • Avoid positive inotropes (dobutamine, dopamine, adrenaline).
• Severe cases may require mechanical circulatory support or urgent septal reduction.

Overall outlook

• With contemporary care, annual all-cause mortality is low (≈0.5–1%/year), markedly improved from historical estimates (1–4%). 
• Many patients remain asymptomatic long term, and systolic function is generally preserved until late disease.

First presentation may be sudden

• Despite the overall favourable course, sudden cardiac death (SCD) can be the first manifestation, particularly in the young and during or soon after exertion. 
• Vigilant risk stratification is essential even in minimally symptomatic or asymptomatic individuals.

Symptom status at diagnosis

• Prognosis is better in asymptomatic patients at presentation (lower annual mortality and SCD rates) than in those who are symptomatic. 
• Those with mild–moderate symptoms often experience slow progression with age.

Age at diagnosis

• Childhood-onset HCM carries higher annual mortality than the general paediatric population, reflecting more malignant phenotypes and greater hypertrophy.
• Adult-onset HCM has mortality similar to age-matched populations in many series when managed in experienced centres.

Structural and imaging markers

• Left atrial (LA) enlargement (e.g., transverse dimension >48 mm or volume ≥118 mL) correlates with higher risk of AF, heart failure (HF), and death.
• Maximal wall thickness (particularly ≥30 mm) and extensive late gadolinium enhancement (LGE) on CMR (≈≥15% LV mass) are associated with increased arrhythmic risk and adverse outcomes.
• LVOT gradients (resting or provocable) relate to symptoms and HF risk; gradients may evolve with time.

Morphologic subtypes and complications

• Midventricular obstruction is linked to apical aneurysm formation, more symptoms, and higher HCM-related mortality, approximating risks seen with classic LVOT obstruction.
• Apical aneurysm increases risks of ventricular arrhythmia, thromboembolism, and HF progression.

Arrhythmias

• Atrial fibrillation (AF) occurs in ≈25% over time, is often poorly tolerated, and increases stroke and HF risk.
• Ventricular arrhythmias (including non-sustained VT) signal higher SCD risk and inform decisions regarding ICD therapy.

Heart failure and “end-stage” disease

• End-stage HCM (LV remodelling with LVEF <50% and cavity dilation) develops in ~2–15% and carries a poor prognosis once symptomatic 
• HF emerges (average time to death or transplant ≈2–3 years in advanced cohorts). 
• Risk factors include younger age at diagnosis, greater symptom burden, larger LV cavity size, and family history of end-stage disease. Diffuse ischaemic injury and fibrosis are implicated.

Complications to anticipate

• HF (usually diastolic early, systolic late)
• Ventricular and supraventricular arrhythmias
• SCD
• AF-related thromboembolism (mural thrombus risk heightened with apical aneurysm)
• Infective endocarditis (mitral involvement in obstructive forms)

Ventricular Arrhythmias and Sudden Cardiac Death

• Sudden cardiac death (SCD) is the leading cause of mortality in young individuals with HCM, with an estimated incidence of ~1% per year. 
• It frequently occurs during or following exertion, and is usually due to ventricular tachyarrhythmia triggered by myocardial ischaemia or scarring.
• Risk factors for SCD include:
  • Age <30 years
  • Non-sustained ventricular tachycardia on ambulatory monitoring
  • Abnormal blood pressure response to exercise
  • Massive LV hypertrophy (wall thickness ≥30 mm)
  • Severe LVOT obstruction
  • Family history of SCD
  • Unexplained syncope
  • Previous cardiac arrest or sustained VT
  • LV systolic dysfunction (EF <50%)
  • Left atrial enlargement
  • Apical aneurysm
  • Extensive late gadolinium enhancement (LGE) on CMR
• Patients who have survived cardiac arrest remain at high risk, with mortality of up to 33% at 7 years despite conventional therapy.

Atrial Fibrillation and Embolic Events

• Atrial fibrillation (AF) is common in HCM and is associated with poor tolerance due to the dependence of LV filling on atrial contraction.
• AF is a major risk factor for systemic thromboembolism and ischaemic stroke.
• Anticoagulation is indicated in all HCM patients with AF, irrespective of CHA₂DS₂-VASc score. 
• Direct oral anticoagulants (DOACs) are recommended first-line; vitamin K antagonists are a second-line option.

Heart Failure

• Diastolic dysfunction due to hypertrophy, fibrosis, and reduced LV compliance is the predominant cause of heart failure symptoms.
• In advanced disease, end-stage HCM develops in 2–15% with LV dilatation and systolic impairment (EF <50%).
• Symptomatic HF progression in this context carries a poor prognosis, with average survival 2–3 years without transplantation.

Infective Endocarditis

• Infective endocarditis (IE) may complicate HCM, typically involving the thickened anterior mitral leaflet in obstructive disease.
• Routine antibiotic prophylaxis is no longer recommended except in patients with prosthetic valves or a history of IE.
• Vigilance is needed in symptomatic patients, particularly those with systolic anterior motion of the mitral valve and significant LVOT obstruction.

Stroke and Systemic Embolism

• Stroke in HCM is predominantly a consequence of AF-related embolisation.
• Anticoagulation substantially reduces this risk and should be maintained lifelong in patients with HCM and AF.

Pregnancy-Related Complications

• Pregnancy is generally well tolerated in women with HCM, particularly if asymptomatic and without significant LVOT obstruction.
• Those with symptomatic disease or severe obstruction (>50 mmHg) are at higher risk of deterioration due to haemodynamic shifts during pregnancy and delivery.
• Management requires multidisciplinary care with cardiology and high-risk obstetrics involvement, and adjustment of medical therapy to minimise foetal risks.

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