Cardiomyopathies — Written Clinical Reasoning

SAQ 1 — The Approach to a Newly Diagnosed Cardiomyopathy (25 marks, 35 minutes)

Prompt: A 34-year-old man presents after a witnessed collapse during exercise. He has known hypertrophic cardiomyopathy with obstruction, non-sustained VT on Holter, an abnormal blood pressure response to exercise, and a family history of sudden cardiac death. Address: (a) the phenotype-first classification of cardiomyopathies; (b) the pathophysiology of LVOT obstruction and the dynamic manoeuvres; (c) the five major SCD risk factors and the HCM Risk-SCD calculator; (d) the stepwise symptomatic management of obstructive HCM; (e) the role of mavacamten and its monitoring; and (f) the most dangerous pharmacological error in obstructive HCM. [1]

Model Answer

(a) The phenotype-first classification of cardiomyopathies (3 marks): [1]

The 2008 European Society of Cardiology position statement (Elliott) and the 2020 AHA/ACC framework classify cardiomyopathies by their dominant morphological and functional phenotype, then sub-classify each phenotype into familial (genetic) and non-familial causes [9]. The four phenotypes are:

1. Hypertrophic cardiomyopathy — thick walls, small cavity, preserved or hyperdynamic ejection fraction; the dominant cause is autosomal dominant sarcomeric mutation (MYH7, MYBPC3).
2. Dilated cardiomyopathy — dilated ventricle, thin walls, reduced ejection fraction; the causes are genetic (titin TTN, LMNA), ischaemic, toxic (alcohol, anthracycline), viral myocarditis, tachycardia-induced, peripartum, and metabolic (haemochromatosis).
3. Arrhythmogenic right ventricular cardiomyopathy — fibrofatty replacement of the right ventricular myocardium (and often the left ventricle); autosomal dominant desmosomal mutation (PKP2, DSG2, DSP).
4. Restrictive cardiomyopathy — stiff, non-compliant ventricles with bi-atrial enlargement and preserved ejection fraction; the dominant cause in the developed world is cardiac amyloidosis (AL and ATTR). [1]

The phenotype tells the clinician the management logic before the cause is even named: hypertrophic is about obstruction and SCD prevention; dilated is about GDMT and the device decision; arrhythmogenic is about sport restriction and ICD; restrictive is about finding and treating the infiltrative cause. [1]

(b) The pathophysiology of LVOT obstruction and the dynamic manoeuvres (4 marks): [1]

In hypertrophic cardiomyopathy, the asymmetrical septal hypertrophy narrows the left ventricular outflow tract. During systole, the high-velocity flow through the narrowed tract creates a Venturi effect and drag forces that pull the anterior mitral leaflet toward the septum — this is systolic anterior motion (SAM). SAM does two things simultaneously: it worsens the LVOT obstruction, and it causes mitral regurgitation (the leaflet fails to coapt). [1]

The obstruction is dynamic — it varies with loading conditions. The ejection systolic murmur at the lower left sternal edge and apex therefore changes with the dynamic manoeuvres: [1]

• Valsalva (strain phase) and standing: the murmur gets louder — the decreased preload makes the left ventricle smaller, bringing the septum and the mitral leaflet closer together, increasing the obstruction.
• Squatting: the murmur gets softer — the increased preload and afterload make the ventricle larger, separating the septum and the leaflet, reducing the obstruction.
• Handgrip: the murmur gets softer — the increased afterload enlarges the ventricle and reduces the obstruction.
• Passive leg raise: the murmur gets softer — the increased preload enlarges the ventricle. [1]

This dynamic behaviour is the PACES discriminator. It distinguishes HCM from aortic stenosis (the AS murmur gets softer with Valsalva, because the reduced preload reduces the stroke volume across the fixed stenotic valve) and from mitral valve prolapse (the MVP click-murmur moves earlier and gets longer on standing, rather than louder). [1]

(c) The five major SCD risk factors and the HCM Risk-SCD calculator (5 marks): [1]

The 2020 AHA/ACC guideline identifies five major risk factors for sudden cardiac death in HCM [1]:

1. Massive LVH — maximal wall thickness at least 30 mm.
2. Unexplained syncope — especially within the preceding 6 months, or exertional/arrhythmic in nature.
3. Family history of SCD in a first-degree relative (at least one relative under 50, or appropriate sudden death at any age).
4. Non-sustained VT on ambulatory ECG — especially in patients under 30, or runs that are frequent, prolonged, or fast.
5. Abnormal blood pressure response to exercise — a failure to rise by at least 20 mmHg systolic, or a fall in blood pressure during exercise. [1]

The HCM Risk-SCD calculator (O'Mahony, Eur Heart J 2014) integrates seven variables to estimate the 5-year risk of SCD: age at evaluation, maximal LV wall thickness, left atrial diameter, maximal LVOT gradient, family history of SCD, non-sustained VT, and unexplained syncope [2]. The risk score determines the ICD recommendation: at least 6 per cent (high risk) — ICD recommended; 4 to less than 6 per cent (intermediate) — consider ICD; below 4 per cent (low risk) — ICD not indicated. The calculator is the ESC-endorsed tool; the AHA/ACC uses the simpler major-risk-factor approach. This patient has at least three major risk factors (NSVT, abnormal BP response, family history of SCD) and a high HCM Risk-SCD score — an ICD for primary prevention is indicated.

(d) The stepwise symptomatic management of obstructive HCM (5 marks): [1]

1. First-line: a beta-blocker (bisoprolol, metoprolol, propranolol, atenolol). The mechanism is reduced heart rate and contractility — this lengthens diastole (improves filling) and reduces the dynamic LVOT gradient (less contractility means less SAM).
2. Alternative or add-on: a non-dihydropyridine calcium channel blocker (verapamil 240 to 480 mg daily, or diltiazem). Avoid verapamil in patients with resting LVOT obstruction and severe low-output symptoms, or advanced conduction disease.
3. Add disopyramide (150 to 200 mg three to four times daily) for persistent obstructive symptoms despite a beta-blocker or CCB. Disopyramide is a class Ia antiarrhythmic with a powerful negative inotropic effect that reduces the LVOT gradient. Combine with an AV nodal blocker because disopyramide can accelerate AV conduction if AF develops.
4. Cardiac myosin inhibitor (mavacamten) for NYHA class II to III obstructive HCM despite maximally tolerated medical therapy.
5. Septal reduction therapy (surgical septal myectomy or alcohol septal ablation) for refractory obstructive symptoms (NYHA III to IV) despite maximally tolerated medical therapy. [1]

(e) The role of mavacamten and its monitoring (4 marks): [1]

Mavacamten is a first-in-class allosteric inhibitor of cardiac myosin that reduces the number of myosin heads available for actin binding, decreasing contractility and the LVOT gradient. The EXPLORER-HCM trial (Olivotto, Lancet 2020) randomised 251 patients with symptomatic obstructive HCM (LVOT gradient at least 50 mmHg, NYHA II to III) to mavacamten or placebo for 30 weeks: 37 per cent of the mavacamten group met the primary composite endpoint of improved peak VO2 and at least one NYHA class improvement, versus 17 per cent of placebo (P equal to 0.0005), with significant reduction in the LVOT gradient [3].

The monitoring requirements are essential: mavacamten can cause reversible LV systolic dysfunction (LVEF below 50 per cent), so echocardiography is required before initiation, at weeks 4 and 8, and then every 12 weeks; if the LVEF falls below 50 per cent, therapy is interrupted until recovery. Mavacamten also has significant drug-drug interactions (CYP2C19 and CYP3A4 metabolism) and a long half-life of 6 to 9 days. [1]

(f) The most dangerous pharmacological error in obstructive HCM (4 marks): [1]

The most dangerous error is the administration of a drug that reduces preload or afterload — nitrates, dihydropyridine calcium channel blockers (amlodipine, nifedipine), pure vasodilators (hydralazine, minoxidil), or excessive diuresis with high-dose loop diuretics. These drugs reduce the ventricular size, bringing the hypertrophied septum and the mitral leaflet closer together, which worsens the dynamic LVOT obstruction and can precipitate acute haemodynamic collapse. A patient who presents with chest pain and an ejection systolic murmur must NOT be given sublingual glyceryl trinitrate until the diagnosis of HCM is excluded — this is the classic exam trap. The correct response to chest pain in a patient with a possible HCM murmur is to assess the murmur with the dynamic manoeuvres and obtain an echocardiogram before administering any vasodilator. [1]

SAQ 2 — The Dilated Cardiomyopathy Workup and the ICD Decision (10 marks)

Prompt: A 48-year-old woman presents with 4 months of progressive exertional dyspnoea and orthopnoea. Echocardiography shows a dilated left ventricle with an ejection fraction of 30 per cent and global hypokinesis. Coronary angiography is normal. She is in sinus rhythm with a left bundle branch block and a QRS of 140 ms. (a) Outline the systematic workup for the cause of her dilated cardiomyopathy. (b) Describe the four pillars of GDMT and the evidence for each. (c) What is the role of cardiac resynchronisation therapy, and does she qualify? (d) How did the DANISH trial change the approach to the primary prevention ICD in non-ischaemic dilated cardiomyopathy? [1]

Model Answer

(a) The systematic workup for the cause (3 marks): [1]

The workup has three goals: confirm the phenotype, exclude ischaemia, and find the cause. The echocardiogram confirms the dilated phenotype. The normal coronary angiography excludes ischaemic cardiomyopathy. The remaining workup searches for the treatable causes: [1]

• Bloods: full blood count (anaemia), U and E (renal function for dose adjustment), LFTs, TSH (thyroid), iron studies (haemochromatosis), BNP/NT-proBNP, HbA1c, lipid profile, HIV, troponin. Consider ANA and autoimmune screen, viral serology, and serum/urine electrophoresis with free light chains (amyloid AL even in a DCM phenotype).
• Cardiac MRI with late gadolinium enhancement: the single most useful test for differentiating causes. Mid-wall septal LGE suggests a non-ischaemic (genetic or myocarditis-recovered) cause; patchy multifocal LGE suggests myocarditis or sarcoidosis; subendocardial or transmural LGE in a coronary distribution suggests missed ischaemia. LGE extent also predicts arrhythmia risk and recovery.
• Holter monitoring: for PVC burden (tachycardia-induced cardiomyopathy if over 10 to 15 per cent) and NSVT for risk stratification.
• Genetic testing: a gene panel, especially if there is a family history, conduction disease (raising LMNA), or young onset. LMNA mutation is the high-yield gene — it carries a high arrhythmia risk disproportionate to the EF, and ICD consideration may be earlier than for other non-ischaemic DCM.
• Endomyocardial biopsy: reserved for suspected giant cell myocarditis, sarcoidosis, or amyloidosis when non-invasive testing is equivocal. [1]

(b) The four pillars of GDMT and the evidence (4 marks): [1]

1. ARNI (sacubitril/valsartan): the PARADIGM-HF trial (McMurray, NEJM 2014) established ARNI superiority over enalapril — the primary composite of cardiovascular death or heart failure hospitalisation was reduced by 20 per cent (HR 0.80, 95 per cent CI 0.73 to 0.87) and all-cause mortality was reduced (HR 0.84) [7].
2. Beta-blocker (bisoprolol, carvedilol, metoprolol succinate, or nebivolol): each independently reduces mortality.
3. MRA (spironolactone or eplerenone): reduces mortality and hospitalisation.
4. SGLT2 inhibitor (dapagliflozin or empagliflozin): the DAPA-HF trial (McMurray, NEJM 2019) showed dapagliflozin reduced the primary composite of worsening heart failure or cardiovascular death by 26 per cent (HR 0.74) regardless of diabetes status [8].

These four should be initiated promptly and titrated to target. A loop diuretic is added for symptom control (it does not reduce mortality). [1]

(c) The role of CRT and her qualification (1 mark): [1]

Cardiac resynchronisation therapy (CRT) improves symptoms, reduces heart failure hospitalisation, and reduces mortality in patients with a left bundle branch block, a QRS duration of at least 150 ms, and an ejection fraction of at most 35 per cent despite at least 3 months of optimal GDMT. This patient does NOT yet qualify for CRT because: (i) her QRS is 140 ms (the threshold is at least 150 ms for a class I indication), and (ii) she has not yet had 3 months of optimal GDMT. The correct sequence is to optimise the GDMT first, then reassess the QRS and EF — if the LBBB persists with a QRS at least 150 ms and the EF remains at most 35 per cent, CRT is indicated. [1]

(d) The DANISH trial and the primary prevention ICD (2 marks): [1]

The DANISH trial (Kober, NEJM 2016) randomised 556 patients with non-ischaemic systolic heart failure to a prophylactic ICD versus usual clinical care (which could include CRT). The primary outcome of all-cause mortality was NOT significantly reduced by the ICD (HR 0.87, 95 per cent CI 0.68 to 1.12, P equal to 0.28), although the ICD did halve the risk of sudden cardiac death (HR 0.50) [6]. The trial challenged the reflexive ICD for all non-ischaemic DCM. The contemporary approach is to consider a primary prevention ICD only if the ejection fraction remains at most 35 per cent despite at least 3 months of optimal GDMT, with careful consideration of life expectancy (over 1 year) and comorbidity. The ICD decision is individualised — the DANISH trial showed that the mortality benefit is not automatic, even though the SCD reduction is real. For this patient, the immediate priority is to complete the four pillars of GDMT, reassess the EF and QRS at 3 to 6 months, and then revisit the device decision.