• 1 in 500 to 1 in 1000 individuals in the general population ^[1][2]. This makes HCM one of the most common inherited cardiac diseases — slightly less common than dilated cardiomyopathy (DCM).
• Many individuals are undiagnosed because 60–70% of patients with HCM will never experience any symptoms/presentation and live a completely normal life ^[1]. The disease is often discovered incidentally (e.g. an abnormal ECG during a routine check-up, or an echocardiogram done for another reason).

• HCM can present at any age, from infancy to the elderly. The hypertrophy typically develops during adolescence and early adulthood coinciding with the pubertal growth spurt — this is when the genetic programme for abnormal sarcomere proteins becomes phenotypically manifest.
• Male predominance in clinically diagnosed cases (roughly 2:1), though genetic prevalence is equal between sexes. The discrepancy likely reflects referral bias and the fact that women may present later with more symptomatic heart failure.
• In Hong Kong and East Asia, apical HCM accounts for 25–30% of all HCM cases (compared to only ~1–2% in Western populations) ^[3]. This is a crucial point for local exams.

• Why athletes? Exercise increases heart rate and contractility → worsens the dynamic LVOT obstruction (discussed below) → provokes ventricular arrhythmias (VT/VF) → sudden cardiac death. The disorganised myocardial architecture also creates re-entrant circuits that are arrhythmogenic.

• The LV is the thickest-walled chamber (normal wall thickness 6–11 mm in adults at end-diastole).
• The interventricular septum (IVS) separates the LV from the RV. In the most common form of HCM (asymmetric septal hypertrophy), the IVS becomes disproportionately thick (septum:free wall ratio > 1.3).

• The LVOT is the passage between the interventricular septum (anteriorly) and the anterior mitral valve leaflet (posteriorly) through which blood exits the LV into the aorta.
• This narrow corridor is the anatomical bottleneck where obstruction occurs in hypertrophic obstructive cardiomyopathy (HOCM).

• The anterior mitral valve leaflet is tethered by chordae tendineae to the papillary muscles attached to the LV wall.
• In HCM, hypertrophy displaces the papillary muscles anteriorly and inward, altering the geometry of the mitral valve apparatus, predisposing to systolic anterior motion (SAM).

• The myocardium is supplied by epicardial coronary arteries that branch into intramural arterioles.
• In HCM, these intramural vessels can be compressed by the hypertrophied muscle, and the increased muscle mass outstrips the vascular supply → demand-supply mismatch → ischaemia even without epicardial coronary artery disease.

A positive family history is defined as: ≥ 2 first- or second-degree relatives with HCM, OR one first-degree relative who has autopsy-proven HCM and sudden cardiac death < 50 years old ^[1].

LVOTO occurs in ~1/3 of HCM patients ^[3] and is a major determinant for HF symptoms and death ^[3].

LVOTO is due to two mechanisms ^[1][3]:

1. Asymmetric septal hypertrophy (ASH) — The thickened septum encroaches on the LVOT, narrowing the outflow passage.

2. Systolic anterior motion (SAM) of the anterior mitral valve leaflet — This is the more interesting mechanism:

   • The hypertrophied septum displaces the papillary muscles anteriorly
   • During systole, blood accelerating through the narrowed LVOT creates a Venturi effect (or Bernoulli's principle ^[1]) — the high-velocity flow creates a low-pressure zone that sucks the anterior mitral valve leaflet toward the septum
   • The anterior leaflet physically contacts the septum during mid-to-late systole → further obstructs the LVOT

Consequences of LVOTO ^[3]:

• ↑ Afterload → ↑ myocardial oxygen demand + ↓ cardiac output → myocardial ischaemia
• SAM → mitral regurgitation (because the mitral leaflet is pulled out of its proper coaptation position)
• Dynamic obstruction → jerky pulse (bisferiens or spike-and-dome pulse) ^[3]

Diastolic dysfunction is a contributing factor in 80% of HCM patients ^[3].

Mechanisms:

• ↓ Compliance → ↓ diastolic filling → ↑ LV end-diastolic pressure → ↑ afterload ^[3]
  • The hypertrophied, fibrotic myocardium is stiff and cannot relax properly during diastole
• Asymmetrical hypertrophy → non-uniform ventricular contraction/relaxation ^[3]
  • Different segments of the LV relax at different rates, further impairing filling
• ↓ Diastolic filling → ↑ pulmonary venous pressure → accounts for exertional dyspnoea ^[3]
  • Blood backs up into the pulmonary veins because the stiff LV cannot accommodate normal filling volumes

Why does this matter? Even without obstruction, diastolic dysfunction alone can cause significant symptoms. This is why many patients with non-obstructive HCM still have exertional dyspnoea and exercise intolerance.

Myocardial ischaemia often occurs without coronary artery disease ^[3].

Postulated mechanisms ^[3]:

• Hypertrophy → partial obliteration of intramural coronary arteries — the thickened muscle compresses the small vessels within it
• Inadequate vascular supply for the increased LV mass — the capillary density does not increase proportionally with muscle mass (demand-supply mismatch)
• Additionally: elevated LV end-diastolic pressure compresses the subendocardial vessels during diastole (when coronary flow normally occurs)

This explains why patients with HCM experience angina even with normal coronary arteries on angiography.

Cause: SAM of the mitral valve ^[3] — as the anterior leaflet is pulled toward the septum during systole, it fails to coapt properly with the posterior leaflet, creating a regurgitant jet directed posterolaterally.

Severity of MR is directly proportional to the degree of LVOT obstruction ^[3].

Consequence: ↑ pulmonary venous pressure → dyspnoea, orthopnoea ^[3].

Although not one of the "classic four" pathophysiological processes, the disorganised myocardial architecture (myocardial disarray + fibrosis) creates electrical heterogeneity → re-entrant circuits → substrate for ventricular tachycardia (VT) and ventricular fibrillation (VF) → sudden cardiac death.

Atrial fibrillation (AF) is also common (20–25% of HCM patients) due to left atrial enlargement from diastolic dysfunction and MR.

Treatment is required when the gradient is ≥ 50 mmHg ^[1].

LVOTO is assessed at rest and with provocation (infused epinephrine / exercise) — this is only for risk stratification and prognosis testing ^[1].

HOCM has worse survival compared to those without obstruction ^[1].

Three anatomical types of HCM ^[1][2]:

1. Asymmetric septal hypertrophy (ASH) — the most common form (~70%). The interventricular septum is disproportionately thickened compared to the free wall. This is the type most likely to cause LVOTO.

2. Symmetric (concentric) hypertrophy — uniform thickening of all LV walls. Could theoretically cause obstruction in very severe cases, but rarely seen ^[1].

3. Apical hypertrophy — hypertrophy predominantly affects the LV apex.

   • 25–30% of HCM in Japan and Hong Kong (much higher than ~1–2% elsewhere) ^[3]
   • More benign prognosis ^[3]
   • Unclear pathogenesis, likely familial inheritance ^[3]

HCM sits within the broader WHO/ISFC classification of cardiomyopathies alongside dilated (DCM), restrictive (RCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), and unclassified cardiomyopathies ^[2].

HCM may present in several ways ^[1][2]:

1. As an incidental ECG/echo finding — the most common scenario, given that 60–70% are asymptomatic
2. Heart failure symptoms
3. Angina
4. Syncope / presyncope
5. Palpitations and arrhythmias
6. Stroke and thromboembolism due to AF ^[1]
7. Sudden cardiac death ^[1]

1. During exercise → heart rate increases, contractility increases
2. Increased contractility + shorter diastolic filling time → smaller LV cavity → septum and mitral valve closer together → worsened LVOT obstruction
3. Simultaneously, exercise causes peripheral vasodilation → reduced afterload → further worsens the gradient
4. Net effect: inability to increase cardiac output during exercise + cerebral hypoperfusion → syncope

• The stiff, hypertrophied LV depends heavily on atrial contraction ("atrial kick") for 30–40% of its diastolic filling (compared to ~15–20% in a normal heart)
• AF eliminates the atrial kick → sudden drop in LV filling → severe reduction in cardiac output
• Additionally, the rapid ventricular rate in AF → shortened diastolic filling time → further worsens filling
• Also: AF + stagnant blood in the dilated LA → high risk of thromboembolism/stroke

• Chronic ischaemia + fibrosis → progressive loss of functional myocytes
• Over decades, the hypertrophied myocardium "burns out" → the LV dilates, walls thin, and EF drops below 50%
• This is clinically indistinguishable from DCM and is managed as HFrEF
• Occurs in ~5% of HCM patients ^[3]

• The single most common cause of LVH worldwide and the most important condition to exclude before diagnosing HCM.
• Hypertension causes pressure overload → concentric LVH as a compensatory mechanism ^[1].
• How to distinguish from HCM:
  • Document blood pressure: sustained hypertension ≥ 140/90 mmHg (or on antihypertensives)
  • LVH is typically concentric (uniform thickening), rarely exceeds 15 mm, and regresses with BP control (unlike HCM which does not regress)
  • No SAM, no LVOT obstruction, no myocardial disarray on MRI
  • Absence of family history of HCM/SCD
• Pitfall: Elderly patients may have both hypertension AND HCM. A wall thickness grossly disproportionate to the degree of hypertension (e.g. septum 22 mm in a patient with mild hypertension) should raise suspicion for co-existing HCM.

• Aortic stenosis causes chronic pressure overload → concentric LVH ^[1][6].
• Valvular, subvalvular, or supravalvular obstruction forces the LV to generate higher pressures → compensatory hypertrophy.
• How to distinguish from HOCM:

↓ Preload by Valsalva manoeuvre or from squatting to standing will ↑ intensity of HOCM but will ↓ intensity of AS ^[6]. This is a classic clinical pearl and favourite exam question.

• Highly trained athletes (especially endurance athletes like cyclists, rowers) develop physiological LVH as an adaptation to chronic volume and pressure loading during exercise.
• Wall thickness can reach 13–16 mm, overlapping with the "grey zone" of mild HCM.
• How to distinguish from HCM:

• This distinction is extremely important because misdiagnosing an athlete with HCM leads to unnecessary restriction from sport (and psychological harm), while missing HCM in an athlete can be fatal.

• Amyloid protein (light chain AL, or transthyretin ATTR) infiltrates the myocardium → increased wall thickness that mimics HCM.
• Low voltage ECG despite thick walls on echo → classical for amyloidosis ^[7]. This paradox is because the amyloid deposits are electrically inert and the pericardial effusion (common in amyloidosis) further dampens the voltage. In contrast, true HCM causes high voltage (more myocytes = more electrical signal).
• Other clues: biventricular thickening, "sparkling" myocardium on echo, diastolic heart failure, nephrotic syndrome (AL amyloidosis), peripheral neuropathy (ATTR), carpal tunnel syndrome (ATTR).
• Investigations: 99mTc-PYP scan for transthyretin (TTR) amyloidosis; serum protein / immunofixation electrophoresis for AL amyloidosis ^[7].

• X-linked lysosomal storage disease (α-galactosidase A deficiency) → accumulation of globotriaosylceramide (Gb3) in multiple organs including the heart → progressive concentric LVH.
• Typically presents in males aged 30–50 (females may have milder, later-onset disease due to random X-inactivation).
• Clues beyond cardiac: angiokeratomas (dark red papules in "bathing trunk" distribution), corneal verticillata (whorl-like opacities on slit-lamp), acroparesthesias (burning pain in hands/feet from small fibre neuropathy), proteinuria/renal impairment, stroke in young patients.
• Why it matters: Fabry disease is treatable with enzyme replacement therapy (agalsidase alfa/beta) or oral chaperone therapy (migalastat). Missing this diagnosis means missing a treatable cause of "HCM."
• Diagnosed by α-galactosidase A enzyme activity (low in males), confirmed by genetic testing (GLA gene).

• PRKAG2 syndrome: Autosomal dominant, causes glycogen accumulation in the myocardium → LVH + pre-excitation (WPW) + progressive conduction disease. The combination of LVH + WPW on ECG should raise suspicion.
• Pompe disease (acid maltase deficiency): Autosomal recessive, infantile form presents with massive cardiomegaly and hypertrophic cardiomyopathy.
• Danon disease (LAMP2 mutation): X-linked, severe HCM in young males, often with skeletal myopathy and intellectual disability.

• Noonan syndrome is associated with hypertrophic cardiomyopathy ^[8] — this is a paediatric phenocopy.
• Noonan syndrome is caused by mutations in the RAS-MAPK signalling pathway.
• Clinical features: Turner-like appearance (short stature, webbed neck, low hairline, shield chest, hypertelorism, ptosis, downslanting palpebral fissures, low-set ears, cryptorchidism in males) ^[8].
• Associated with right-sided cardiac lesions: valvular pulmonary stenosis with thick dysplastic valve cusps, peripheral branch pulmonary artery stenosis, ASD in addition to HCM ^[8].

• Autosomal recessive neurodegenerative disorder (GAA trinucleotide repeat in FXN gene) → deficiency of frataxin → mitochondrial iron accumulation → cardiac and neurological disease.
• ~65% develop concentric LVH mimicking HCM.
• Clues: progressive cerebellar ataxia (onset in adolescence), dysarthria, absent deep tendon reflexes (peripheral neuropathy), upgoing plantars (pyramidal tract involvement), pes cavus, scoliosis, diabetes mellitus.

• RCM causes increased myocardial stiffness → abnormal LV filling → diastolic dysfunction ^[1], which overlaps with the diastolic dysfunction seen in HCM.
• However, RCM does not have to be hypertrophied ^[1] — the walls may be of normal thickness but the myocardium is stiff (e.g. from infiltration, fibrosis, or endocardial disease).
• Distinguishing features: biatrial enlargement, normal or near-normal wall thickness (unless infiltrative), Kussmaul sign (JVP rises on inspiration), may need endomyocardial biopsy.
• Key causes: amyloidosis (most common), sarcoidosis, haemochromatosis, radiation, endomyocardial fibrosis, scleroderma.

Causes of exercise-related syncope ^[9]:

• (1) LVOT obstruction: AS, HCMP
• (2) RVOT obstruction: pulmonary hypertension
• (3) Cardiomyopathy: DCMP, HCMP, ARVD
• (4) Coronary artery disease: atherosclerotic, anomalous origin of coronary arteries
• (5) Arrhythmogenic: VT, SVT, WPWS, LQTS

This list is extremely high yield. The approach to a young person with exertional syncope should systematically consider all of these.

For the specific case of exertional syncope with a family history of sudden death ^[6]:

Differential diagnosis includes: Hypertrophic obstructive cardiomyopathy, Aortic stenosis, Exercise-induced arrhythmia, Coronary artery disease ^[6].

Causes of exercise-induced syncope in HCM specifically ^[6]:

• Dynamic outflow obstruction
• Exercise-induced atrial or ventricular arrhythmia
• Reflex vasodilation

Primary cardiac causes of ischaemic heart disease without atherosclerotic coronary disease include ^[10]:

• Coronary artery anomalies
• Radiation-induced coronary disease
• Myocardial bridging
• Aortic stenosis
• Hypertrophic cardiomyopathy
• Dilated cardiomyopathy
• Tachycardia

The mechanism in HCM is demand-supply mismatch (as discussed in Part 1): increased muscle mass, compressed intramural vessels, inadequate capillary density, and elevated LVEDP reducing the coronary perfusion gradient.

This is the scenario where HCM classically comes to mind. The DDx includes:

Cardiomyopathy is listed as a primary cardiac cause of palpitations ^[12] — the hypertrophied, disorganised myocardium is a substrate for both atrial (AF, SVT) and ventricular arrhythmias (NSVT, VT, VF).

HCM (specifically HOCM) is listed as a cause of both systolic and diastolic heart failure ^[13]:

• HF due to systolic dysfunction: HOCM causes ↑ afterload ^[13]
• HF due to diastolic dysfunction: HOCM causes LVH → impaired relaxation ^[13]

The DDx of HFpEF includes hypertensive heart disease, HCM, RCM, constrictive pericarditis, and cardiac amyloidosis. All share the phenotype of dyspnoea/exercise intolerance with preserved EF but impaired diastolic filling.

The diagnosis of HCM is predicated on increased left ventricular wall thickness at end-diastole that cannot be explained by abnormal loading conditions such as hypertension or aortic stenosis ^[1].

This means you must satisfy two conditions simultaneously:

1. Wall thickness exceeds the diagnostic threshold (see below)
2. No identifiable loading condition adequately explains the degree of hypertrophy

Why z-scores in children? A 6-year-old and a 16-year-old have vastly different normal wall thicknesses. Using absolute millimetres would either miss HCM in small children or over-diagnose it in large adolescents. Z-scores normalise the measurement to what is expected for that child's body surface area — a z-score of 2.5 means the wall is 2.5 standard deviations thicker than average for their body size.

A positive family history is defined as ≥ 2 first- or second-degree relatives with HCM, OR one first-degree relative who has autopsy-proven HCM and sudden cardiac death < 50 years old ^[1].

Not all HCM has obstruction, and defining obstruction has separate thresholds:

LVOTO can be assessed at rest and with provocation (infused epinephrine / exercise) ^[1]. About one-third of patients have obstruction at rest, another third have latent/provokable obstruction, and one-third are truly non-obstructive.

Why provocation? At rest, the LV is reasonably filled and the LVOT may be wide enough to avoid significant obstruction. During exercise or with catecholamines, heart rate increases, contractility increases, and preload may decrease — all of which shrink the LV cavity and worsen the dynamic obstruction. Patients with "latent obstruction" (normal at rest, obstructive with provocation) may still be very symptomatic during exercise.

The ECG is abnormal in > 90% of patients with phenotypically expressed HCM. It is the most accessible screening tool and often the first clue to the diagnosis.

ECG findings in HCM ^[1][2][14]:

Special ECG pattern — Apical HCM:

• Giant T-wave inversion in precordial leads ^[3] (V3–V5, can be > 10 mm deep)
• This is the "Yamaguchi pattern," particularly common in Japan and Hong Kong (25–30% of HCM cases) ^[3]
• The ECG may be more dramatic than the clinical picture, as apical HCM has a more benign prognosis ^[3]

The cornerstone of HCM diagnosis and the first-line imaging modality.

Echo findings in HCM ^[1][2]:

Provocative testing during echo: LVOTO is assessed at rest and with provocation (infused epinephrine / exercise) — only for risk stratification and prognosis testing ^[1]. If the resting gradient is < 30 mmHg, provocation with Valsalva, amyl nitrite, exercise, or dobutamine infusion can unmask latent obstruction. This matters because latent obstruction still carries prognostic significance and may guide management decisions.

ECHO findings summary for HCM ^[2]:

• LVH, ASH, SAM of mitral valve, LVOT

CMR is the gold standard for myocardial tissue characterisation and is superior to echo in several aspects.

Cardiac MRI findings in HCM ^[1]:

Why LGE indicates worse prognosis: Fibrosis is the end result of chronic myocyte injury (ischaemia, disarray, mechanical stress). Fibrotic tissue is electrically inert, creating areas of slow conduction and conduction block — the perfect substrate for re-entrant ventricular arrhythmias (VT/VF). More fibrosis = more arrhythmogenic substrate = higher risk of SCD.

CMR LGE pattern can sometimes help differentiate the type of cardiomyopathy ^[16]: hereditary forms show a specific mid-wall pattern at the RV insertion points, myocarditis shows subepicardial LGE, and sarcoidosis shows patchy septal LGE.

Holter findings in HCM ^[1]:

Per the 2020 AHA/ACC guidelines, greater weight should be placed on NSVT as a risk marker when runs are frequent (≥ 3), longer (≥ 10 beats), and faster (≥ 200 bpm), usually occurring over 24–48 hours of monitoring ^[5].

Choice of ambulatory monitoring device ^[9]:

ECG is only diagnostic when recorded during symptoms ^[9] — this is why choosing the right duration of monitoring matters. A 24-hour Holter will miss an arrhythmia that occurs once a month.

Exercise testing serves multiple purposes in HCM:

3-generation family history / genetic testing ^[1]:

• A detailed three-generation pedigree is essential — look for sudden cardiac death, heart failure, pacemaker/ICD implantation, and known HCM diagnoses among relatives
• Genetic testing is NOT mandatory ^[2] for the diagnosis of HCM (the diagnosis is clinical + imaging), but it is strongly recommended when:
  • The diagnosis is equivocal (grey zone thickness)
  • Cascade screening of family members is planned (genotype-positive/phenotype-negative relatives need surveillance echocardiography)
  • A phenocopy is suspected (Fabry, PRKAG2, etc.)
  • Prognostic information is desired (certain mutations, e.g. TNNT2, carry higher SCD risk even with modest hypertrophy)

Cascade screening concept: If a patient is confirmed to have HCM and their causative mutation is identified, all first-degree relatives can be tested for the same mutation. Genotype-positive relatives (even if currently phenotype-negative — no LVH yet) require regular surveillance echocardiography (typically every 1–3 years in adults, annually in children/adolescents) because the hypertrophy may develop later due to variable penetrance ^[1].

• Used to exclude concomitant coronary artery disease in patients with angina, particularly those > 40 years old or with cardiovascular risk factors
• CT coronary angiogram can assess coronary arteries non-invasively; invasive coronary angiography reserved for those with high pre-test probability or planned septal reduction therapy
• Important because: myocardial ischaemia in HCM can be due to the disease itself (demand-supply mismatch) OR co-existing atherosclerotic CAD — the management differs

When clinical features suggest the LVH is not true sarcomeric HCM, targeted investigations include:

EPS is indicated for suspected arrhythmic aetiology in cardiomyopathy and CHF ^[9].

In HCM specifically:

• EPS has a limited role in routine SCD risk stratification (unlike in ischaemic heart disease where inducible VT is prognostic)
• May be useful for: mapping accessory pathways (if WPW co-exists), evaluating specific arrhythmias that remain undiagnosed after non-invasive testing
• NOT indicated if normal ECG, normal cardiac structure/function unless arrhythmic aetiology suspected ^[9]

• Rarely needed in HCM — the diagnosis is almost always made non-invasively
• May be considered when an infiltrative phenocopy is suspected and non-invasive tests are inconclusive (e.g. cardiac amyloidosis where 99mTc-PYP is negative but clinical suspicion remains high)
• Carries risk of cardiac perforation ^[17]

Leisure-time activities only if high risk for life-threatening arrhythmias ^[1] — this principle from the DCM lecture applies equally to HCM.

• Competitive sports: Patients with HCM (especially HOCM) have traditionally been advised to avoid competitive vigorous sports — HCM is the leading cause of SCD in young athletes. The 2024 ESC guidelines and 2020 AHA/ACC guidelines now take a more individualised approach, but the core message remains: high-intensity competitive exercise is generally discouraged in patients with high-risk features.
• Recreational exercise: Low-to-moderate intensity recreational exercise is now considered safe and even beneficial for most patients with HCM. Complete sedentarism is harmful.
• Why exercise is dangerous in HOCM: Exercise increases heart rate (shortens diastole → less filling time), increases contractility, and causes peripheral vasodilation (decreases afterload) — all three mechanisms worsen the dynamic LVOT gradient, potentially triggering VT/VF.

• Dehydration reduces preload → smaller LV cavity → worsened LVOT obstruction
• Counsel patients to maintain adequate hydration, especially in hot weather or during illness with vomiting/diarrhoea
• This is also why excessive diuretic use is dangerous in HOCM

• Genetic testing is NOT mandatory ^[2] but genetic counselling should be offered to all patients
• First-degree relatives should undergo cascade screening with ECG + echocardiography
• Genotype-positive/phenotype-negative relatives require ongoing surveillance (every 1–3 years in adults, annually in children/adolescents)

Beta-blockers are first-line monotherapy ^[18] for symptomatic HCM, whether obstructive or non-obstructive.

Mechanism of benefit in HCM (from first principles):

• Negative chronotropy (↓ heart rate) → prolongs diastole → more time for diastolic filling → larger LV cavity → less obstruction; also more time for coronary perfusion
• Negative inotropy (↓ contractility) → less vigorous systolic contraction → less dynamic narrowing of the LVOT → less SAM
• No vasodilation (non-vasodilating beta-blockers) → maintains afterload → maintains LV cavity size

Drug choice:

• Non-vasodilating beta-blockers are preferred: metoprolol, atenolol, bisoprolol, nadolol
• Carvedilol is less ideal — it has alpha-blocking (vasodilatory) properties that reduce afterload, which can worsen the gradient
• Titrate to resting heart rate ~60 bpm and maximum tolerated dose before declaring failure

Contraindications for beta-blockers ^[18]:

• AV block, sinus node dysfunction, bradycardia
• Bronchial asthma (can trigger bronchospasm — beta-2 blockade)
• Vasospasm angina, peripheral artery disease, Raynaud phenomenon
• Depression

Side effects of beta-blockers ^[18]:

• Bradycardia, syncope, hypotension
• Bronchial spasm
• Impaired glucose tolerance

Verapamil (and to a lesser extent diltiazem) is the main alternative to beta-blockers.

Mechanism of benefit:

• Negative chronotropy and inotropy — similar to beta-blockers, slows heart rate and reduces contractility
• Improves diastolic relaxation — verapamil has a specific beneficial effect on myocardial relaxation (lusitropy), making the stiff HCM ventricle more compliant during diastole
• Particularly useful for non-obstructive HCM where diastolic dysfunction is the primary problem, and for patients who cannot tolerate beta-blockers

Drug choice:

• Verapamil 120–480 mg/day in divided doses — the most studied agent in HCM
• Diltiazem — less evidence but used similarly

Contraindications for non-DHP CCBs ^[18]:

• AV block (verapamil/diltiazem slow AV conduction)
• Severe heart failure — negative inotropy can worsen systolic function in decompensated patients
• Should be used cautiously in patients with severe resting obstruction (gradient > 100 mmHg) or high resting pulmonary pressures — the vasodilatory component can occasionally worsen obstruction

Disopyramide is a class IA antiarrhythmic (sodium channel blocker) with potent negative inotropic properties.

Breaking down the name: "dis-" = apart, "pyramide" = from its chemical pyridine structure — not etymologically helpful, but remember it as the HCM-specific drug that directly reduces contractility.

Mechanism of benefit:

• Strong negative inotropy → reduces the vigour of systolic contraction → reduces LVOT gradient and SAM
• Antiarrhythmic properties may help prevent AF and ventricular arrhythmias

How it is used:

• Added to beta-blocker or verapamil when monotherapy fails
• Dose: 100–200 mg TDS (controlled-release formulation preferred for compliance)

Side effects: Significant anticholinergic effects — dry mouth, urinary retention, constipation, blurred vision. Because of its anticholinergic properties, it can paradoxically increase heart rate (by blocking vagal tone), which is why it should always be combined with a beta-blocker or verapamil (to counteract the tachycardia).

Contraindications:

• QT prolongation (disopyramide prolongs QT → risk of torsades de pointes)
• Glaucoma, prostatic hypertrophy (anticholinergic effects)
• Severe HF with reduced EF

Mavacamten (brand name: Camzyos) is a first-in-class cardiac myosin inhibitor approved by the FDA in 2022 and increasingly available globally. This represents the first disease-specific targeted therapy for HCM.

Breaking down the name: "mava-" = from the drug development programme, "-camten" = cardiac myosin targeted agent.

Mechanism of action:

• Mavacamten is a selective allosteric inhibitor of cardiac myosin ATPase
• It reduces the number of myosin heads that can interact with actin during each cardiac cycle → directly reduces the hypercontractility that drives LVOT obstruction and SAM
• Essentially, it treats the fundamental sarcomeric abnormality — excess cross-bridge formation — rather than just blocking downstream compensatory mechanisms

Clinical evidence:

• The EXPLORER-HCM trial (2020) showed significant reduction in LVOT gradient, improvement in functional capacity (peak VO2), and symptom relief in obstructive HCM
• The VALOR-HCM trial (2022) showed mavacamten reduced the need for septal reduction therapy

Indications:

• Symptomatic obstructive HCM (NYHA II–III) with resting or provokable LVOT gradient ≥ 50 mmHg, despite or intolerant of beta-blocker/verapamil therapy
• Increasingly considered before invasive septal reduction therapy

Risks and monitoring:

• Excessive reduction in LVEF — mavacamten can over-suppress contractility, potentially causing systolic heart failure (LVEF < 50%). Requires regular echocardiographic monitoring (every 12 weeks initially)
• Drug interactions: metabolised by CYP2C19 and CYP3A4 — significant interactions with strong inhibitors (e.g. fluconazole, clarithromycin)
• Available through a restricted prescribing programme (REMS) in the US due to the LVEF risk

This is one of the most commonly examined topics. Understanding why each drug is contraindicated requires thinking about its haemodynamic effect on the dynamic gradient.

How to remember what's safe vs. dangerous in HOCM:

• Safe: Anything that makes the LV bigger (↑ preload, ↑ afterload) or less contractile (↓ inotropy, ↓ chronotropy)
• Dangerous: Anything that makes the LV smaller (↓ preload, ↓ afterload) or more contractile (↑ inotropy, ↑ chronotropy)

Management of HFpEF ^[22]:

• Treat underlying causes: BP control, body weight, therapy for CAD
• Treat precipitating factors: e.g. AF
• Relieve symptoms: cautious use of diuretics
• Slowing of HR to increase time for diastolic filling: beta-blocker, verapamil, diltiazem
• Regression of LVH: BP control

In non-obstructive HCM, the dominant pathophysiology is diastolic dysfunction. The management mirrors HFpEF principles — there are no disease-modifying drugs proven to reduce mortality, so the focus is on symptom relief and treating comorbidities.

• AF occurs in 20–25% of HCM patients and carries a high thromboembolic risk
• All HCM patients with AF should receive anticoagulation regardless of CHA₂DS₂-VASc score — the stroke risk is considered high enough to warrant anticoagulation in all cases (HCM itself counts as a risk factor)
• Drug choice: Direct oral anticoagulants (DOACs) (apixaban, rivarelbocaban, edoxaban, dabigatran) are now preferred over warfarin in non-valvular AF; warfarin is used if mechanical valve or mitral stenosis co-exists
• Rate control: beta-blockers or non-DHP CCBs (verapamil/diltiazem) are first-line for ventricular rate control
• Rhythm control: amiodarone is the preferred antiarrhythmic for maintaining sinus rhythm in HCM with AF (other antiarrhythmics like flecainide are generally avoided in structural heart disease)

• Historically, HOCM was considered an indication for endocarditis prophylaxis before dental procedures
• Current guidelines (2023 ESC, 2021 AHA) have narrowed the indications for prophylaxis — HOCM alone is no longer a standard indication unless there is a prosthetic valve, prior IE, or certain congenital heart conditions
• However, some centres still recommend prophylaxis in HOCM with significant obstruction — be aware of local practice

The ICD is the only proven intervention to prevent sudden cardiac death in HCM. It does not treat the underlying disease but provides a lifeline by detecting and terminating VT/VF with an electrical shock.

ICD indications in HCM:

The ESC approach uses the HCM Risk-SCD calculator — a validated model that estimates the 5-year risk of SCD based on age, maximal wall thickness, LA diameter, LVOT gradient, family history, syncope, and NSVT:

• ≥ 6% 5-year risk → ICD recommended (Class IIa)
• 4–6% → ICD may be considered (Class IIb)
• < 4% → ICD generally not indicated (Class III)

The AHA/ACC approach is more qualitative — based on the presence of individual risk factors with clinical judgement, rather than a numerical score.

ICD for primary prevention in HF ^[23]:

• Prophylactic ICD placement should be considered in patients with NYHA II–III (LVEF < 30%), may be considered in LVEF 31–35%
• In HCM specifically, the threshold for ICD is different from ischaemic cardiomyopathy — it is driven by the SCD risk factors above, not solely by LVEF

• Transvenous ICD: Standard device with lead(s) placed through the subclavian vein into the RV (± RA). Most established and effective.
• Subcutaneous ICD (S-ICD): Entire system placed subcutaneously without transvenous leads. Increasingly used in young HCM patients (avoids complications of long-term transvenous leads in young people). Cannot provide anti-tachycardia pacing (ATP) but can defibrillate.

This is the gold standard septal reduction procedure.

Procedure: Open-heart surgery via median sternotomy with cardiopulmonary bypass. The surgeon excises a portion of the hypertrophied basal septum through the aortic valve, widening the LVOT.

Advantages:

• Most extensive experience (> 50 years)
• Excellent long-term outcomes: > 90% symptom relief, < 1% operative mortality in experienced centres
• Can address concomitant pathology (e.g. mitral valve repair if intrinsic mitral valve abnormalities contribute to MR, coronary bypass if concomitant CAD)
• Reduces LVOT gradient immediately and permanently
• Also reduces SAM and MR (by widening the LVOT, the Venturi effect is diminished)

Disadvantages:

• Requires open-heart surgery and cardiopulmonary bypass
• Risk of iatrogenic VSD (< 1%), complete heart block requiring permanent pacemaker (2–5%), and aortic valve injury (rare)

Important principle: Myectomy should be performed at experienced centres (high-volume centres with dedicated HCM programmes). Outcomes are strongly volume-dependent.

Procedure: Percutaneous catheter-based procedure. A catheter is advanced into the first septal perforator branch of the LAD coronary artery. After confirming the correct territory by myocardial contrast echocardiography (injecting echo contrast into the septal branch to verify it perfuses the relevant septum), 1–3 mL of absolute ethanol is injected. This creates a controlled infarction of the basal septum → the infarcted tissue thins and scars → the LVOT widens.

Advantages:

• Less invasive than open surgery (percutaneous, no sternotomy)
• Shorter recovery time
• Suitable for patients who are poor surgical candidates (elderly, significant comorbidities)

Disadvantages:

• Higher rate of complete heart block requiring permanent pacemaker (10–20% — higher than myectomy) — the conduction system runs through the septum and is damaged by the infarction
• Unpredictable extent of septal necrosis
• Cannot address concomitant mitral valve or coronary pathology
• Less experience and fewer long-term outcome data compared to myectomy
• Creates a myocardial scar that may itself be arrhythmogenic (theoretical concern for VT substrate)

Choosing between myectomy and ASA:

The hypertrophied, disorganised myocardium (myocardial disarray) with interspersed fibrosis creates regions of differing conduction velocities and refractory periods. This electrical heterogeneity provides the perfect substrate for re-entrant ventricular arrhythmias — a wavefront of depolarisation circles around a zone of slow conduction or block, perpetually re-exciting the tissue:

1. Trigger: A premature ventricular complex (PVC) — often provoked by exercise (catecholamine surge) or ischaemia
2. Substrate: Myocardial disarray + fibrosis → slow conduction + unidirectional block → re-entrant circuit
3. Result: Non-sustained VT → sustained VT → ventricular fibrillation → cardiac arrest

The mechanism of sudden cardiac death is primarily ventricular tachycardia (VT) and ventricular fibrillation (VF) ^[24].

SCD typically occurs during or after vigorous physical activity ^[3] — this is why exercise restriction and pre-participation screening are so important in young athletes.

Risk factors for sudden cardiac death in HOCM ^[2][5]:

• History of syncope
• Family history of SCD
• Abnormal BP response to exercise
• Non-sustained VT
• Severe LVH with thickness > 30 mm

The full 2020 AHA/ACC criteria (discussed in detail in Part 1) also include: EF < 50%, LV apical aneurysm, and extensive LGE ≥ 15% of LV mass ^[5].

The ICD is the only proven intervention that prevents SCD. Beta-blockers reduce symptoms and may reduce arrhythmic triggers but have not been proven to prevent SCD in HCM. Amiodarone has some antiarrhythmic effect but is inferior to ICD for preventing death.

1. Diastolic dysfunction → elevated LV filling pressures → chronically elevated LA pressure → LA dilatation
2. Mitral regurgitation → volume overload of the LA → further dilatation
3. A dilated, stretched LA has altered electrophysiology — shortened refractory periods, fibrosis of atrial tissue, and heterogeneous conduction → substrate for AF

• Loss of atrial kick: The stiff, hypertrophied LV relies on atrial contraction for 30–40% of its diastolic filling (vs ~15–20% in normal hearts). AF eliminates this contribution → acute drop in cardiac output → can precipitate acute heart failure, syncope, or even cardiogenic shock
• Rapid ventricular rate: Tachycardia shortens diastolic filling time → further reduces filling of the stiff LV → worsens symptoms. In HOCM, tachycardia also increases contractility and worsens LVOT obstruction
• Thromboembolic risk: Stagnant blood in the dilated LA (especially the LA appendage) → thrombus formation → systemic embolisation (most commonly stroke)

• Rate control: Beta-blockers or verapamil/diltiazem (first-line). Digoxin only as add-on if rate control inadequate (remember digoxin is a positive inotrope — use cautiously in HOCM)
• Rhythm control: Amiodarone is the preferred antiarrhythmic; catheter ablation (pulmonary vein isolation) is increasingly used for drug-refractory AF
• Anticoagulation: All HCM patients with AF should be anticoagulated regardless of CHA₂DS₂-VASc score — HCM itself is considered a high-risk condition for thromboembolism. DOACs are preferred over warfarin in the absence of mechanical valves or mitral stenosis

Diastolic heart failure results from pressure overload due to LVOT obstruction ^[2] and intrinsic myocardial stiffness.

Mechanism:

• Hypertrophied, fibrotic myocardium → impaired relaxation during diastole → ↓ LV compliance → ↑ LV end-diastolic pressure → transmitted back to the LA and pulmonary veins → pulmonary congestion → exertional dyspnoea, orthopnoea, PND
• In HOCM, the dynamic obstruction further raises afterload, increasing LV wall stress and oxygen demand

This is the most common form of HF in HCM and occurs while the LVEF is still preserved (typically 50–70%). Symptoms include progressive exertional dyspnoea, exercise intolerance, and fatigue.

End-stage HF with ↓ LVEF due to adverse remodelling occurs in ~5% of HCM patients ^[3].

Mechanism:

• Chronic ischaemia (from demand-supply mismatch) + ongoing fibrosis → progressive loss of viable myocytes → replacement with scar tissue → the hypertrophied walls eventually thin → the LV dilates → LVEF drops below 50%
• At this stage, the disease phenotypically resembles dilated cardiomyopathy
• The LVOT obstruction typically resolves (because the septum has thinned and the cavity has enlarged)

Management: Transitions to the standard HFrEF algorithm — the four pillars (ARNI/ACEi, beta-blocker, MRA, SGLT2i), loop diuretics, ICD, CRT if dyssynchronous, and ultimately LVAD/heart transplant if refractory.

This is a high-mortality phase — these patients often need heart transplant listing.

HCM causes myocardial ischaemia through demand-supply mismatch without epicardial coronary artery disease ^[3][10]:

HCM is listed as a primary cardiac cause of ischaemic heart disease ^[10] — it produces angina through increased demand (not reduced supply from atherosclerosis).

• Recurrent episodes of ischaemia → myocyte necrosis and replacement fibrosis → contributes to progression to end-stage HCM
• Ischaemia also promotes ventricular arrhythmias — ischaemic myocytes release potassium, creating zones of altered repolarisation that can trigger VT/VF
• Results in life-threatening arrhythmia ^[24] — this links ischaemia directly to the risk of SCD

Systolic anterior motion (SAM) of mitral valve → mitral-septal contact → secondary MR ^[2]:

• During systole, the Venturi effect drags the anterior mitral valve leaflet toward the septum
• This pulls the leaflet out of its coaptation plane with the posterior leaflet → creates a regurgitant orifice
• The MR jet is characteristically posteriorly directed (because the anterior leaflet is displaced forward)
• Severity of MR is directly proportional to the degree of LVOT obstruction

Additionally, some HCM patients have intrinsic mitral valve abnormalities (elongated leaflets, anomalous papillary muscle insertion) independent of SAM → anterior-directed MR jet.

• Volume overload of LA → LA dilatation → predisposes to AF
• ↑ Pulmonary venous pressure → worsens dyspnoea, orthopnoea, PND
• Chronic MR → further LV remodelling and eventual LV dysfunction

• Reducing LVOT obstruction (with beta-blockers, disopyramide, mavacamten, or septal reduction therapy) usually reduces the SAM-mediated MR proportionally
• Surgical myectomy can address both the LVOT obstruction and MR (concomitant MV repair if needed)
• Isolated mitral valve surgery is occasionally needed if intrinsic MV disease is the primary driver

1. AF → loss of organised atrial contraction → blood stasis in the LA (especially the LA appendage) → thrombus formation → embolisation to the cerebral circulation → ischaemic stroke
2. Even in sinus rhythm, severe LA dilatation and diastolic dysfunction can create conditions of relative blood stasis → risk of spontaneous echo contrast ("smoke") on echo → thrombus
3. In HOCM with LV apical aneurysm, thrombus can form within the dyskinetic aneurysm → systemic embolisation

• Anticoagulation for all HCM patients with AF (as discussed above)
• Consider anticoagulation in patients with LV apical aneurysm even in sinus rhythm (high thromboembolic potential of a dyskinetic pouch)

• The turbulent flow across the LVOT (due to the narrowed outflow tract and SAM) creates high-velocity jets that impact the aortic valve leaflets, the anterior mitral valve leaflet, and the septal endocardium
• This mechanical trauma damages the endothelium → platelet-fibrin deposition → non-bacterial thrombotic endocarditis (NBTE) — a nidus on which circulating bacteria can adhere during transient bacteraemia
• Additionally, the MR jet from SAM traumatises the LA endocardium

• Aortic valve (from the LVOT turbulent jet impacting the ventricular surface of the aortic cusps)
• Mitral valve (from SAM-related endothelial damage)
• Contact lesions on the septal endocardium (the "jet lesion" where the high-velocity outflow impacts the septum)

• IE in HOCM is uncommon but when it occurs, it can be devastating — vegetations can worsen MR, cause embolic events, or form paravalvular abscesses
• Current guidelines (2023 ESC) do not routinely recommend antibiotic prophylaxis for HOCM alone, but good dental hygiene should be emphasised