Approach

There is no curative treatment for hypertrophic cardiomyopathy (HCM). Therapies are advocated in select patient populations in order to reduce symptoms (which may occur secondary to subaortic obstruction, diastolic dysfunction, or ischaemia) and to reduce the risk of sudden cardiac death (SCD). Patient care requires the collaboration of different specialties and coordination between different levels of care; a shared care approach between cardiomyopathy specialists and general adult cardiology centres is strongly recommended.[1]

Initial assessment and approach to treatment in all patients

On initial evaluation, patients must be classified as asymptomatic or symptomatic. They must also undergo risk stratification to further define their risk of SCD.[1][2] Only patients with symptoms related to outflow tract obstruction, diastolic dysfunction, or systolic dysfunction require medical therapy. Only certain patients at high risk for SCD warrant implantable cardioverter-defibrillator (ICD) placement.

Arrhythmic risk calculators may be useful in predicting the risk of SCD and have been validated in large populations.[63][64]​ One study, however, evaluated the 2014 European Society of Cardiology SCD risk model for HCM. The prognostic score was applied retrospectively to a large independent cohort of patients with HCM and was found to be generally unreliable for prediction of future SCD; most patients who had experienced SCD or undergone appropriate ICD interventions were misclassified as low risk.[39]

Consensus recommendations have previously restricted all athletes with HCM from all competitive sports; however, US and European guidelines now advise that participation in high-intensity exercise/competitive sports may be considered for some individuals after comprehensive evaluation and shared discussion.[2][65]​ A large prospective cohort study found that among individuals with HCM, or those who are genotype positive/phenotype negative, who are treated in experienced centres, those exercising vigorously do not experience a higher rate of death or life-threatening arrhythmias than those exercising moderately or those who are sedentary.[66] 

Patients at high risk of sudden death

SCD is the most common mode of death in young people with HCM, occurring with an incidence of 1% per year.[67] The proposed mechanism of SCD is ventricular tachycardia (VT) or ventricular fibrillation (VF) secondary to ischaemia.[4] SCD typically occurs in the setting of extreme exertion. No medical or surgical treatment has been shown to lessen the risk of sudden death in large populations, thus ICD therapy is first-line therapy in those patients in whom the risk of SCD is considered significant.[2] For details of risk stratification, see Diagnostic approach.

Guidelines recommend ICD placement for patients with HCM and previous documented cardiac arrest or sustained ventricular arrhythmia causing syncope or haemodynamic compromise in the absence of reversible causes.[1][2] Routine diagnostic testing to evaluate the risk of SCD is recommended, regardless of symptom status.[2]​ European guidelines recommend comprehensive SCD risk stratification in all patients at initial presentation, then at 1-2 year intervals or whenever there is a change in clinical status.[1]

No randomised controlled trials (RCTs) studying the effect of ICD placement have been performed in patients with HCM, although there is evidence from observational studies.[2][68]

A single marker of high risk for sudden cardiac arrest may be sufficient to consider prophylactic ICD placement in selected patients.[1][2]​​[68]​ Patients in whom this would apply include those with one or more first-degree or close relatives 50 years of age or less with sudden death presumably caused by HCM, patients with a maximum LV wall thickness greater than or equal to 30 mm, patients with one or more recent episodes of syncope suspected to be arrhythmic, LV apical aneurysm, LV systolic dysfunction with ejection fraction <50%, and late gadolinium enhancement >15% on cardiac magnetic resonance imaging.[1] [2]

Complications following ICD placement have been reported to occur at a rate of 3.4% per year.[69] Contact sports should be avoided after ICD implant.[70]

Patients and carers should be fully informed and participate in decision-making regarding ICD placement.[2]​ They should be counselled on the risk of inappropriate shocks, implant complications, and the social, occupational, and driving implications of the device. Implantation of a cardioverter defibrillator is only recommended in patients who have an expectation of good-quality survival >1 year.[1]

Asymptomatic patients: not at high risk of sudden death

If the patient is not considered at high risk of SCD, ICD placement is not required. Patients in this category who are asymptomatic should be closely observed for the development of HCM. US and European guidelines now advise that for those who are genotype-positive and phenotype-negative (asymptomatic without evidence of left ventricular hypertrophy [LVH] on cardiac imaging), participation in competitive sport of any intensity is reasonable.[2][65]​ These patients should be regularly assessed for change in clinical status.

Symptomatic patients: predominantly left ventricular outflow tract obstruction (LVOTO) with preserved systolic function

In symptomatic patients with LVOTO, the aim is to improve symptoms by using drugs, surgery, or alcohol septal ablation. A symptomatic patient with resting or provocable LVOTO is initially treated with negative inotropic or chronotropic therapy. Tachyphylaxis to medication is common, and medication dosage must be adjusted over time. In the absence of many RCTs, pharmacological therapy is mostly administered on an empirical basis to improve functional capacity and reduce symptoms.[1]

Beta-blockers

  • Beta-blockers are beneficial due to their negative inotropic and chronotropic properties. Non-vasodilating beta-blockers are considered first-line therapy for symptomatic HCM due to LVOTO. In standard doses, they are usually well tolerated. Reported side effects include fatigue, impotence, sleep disturbances, and bradycardia.

  • Substantial experience suggests that beta-blockers can mitigate symptoms and reduce outflow tract obstruction in those patients with LVOTO occurring with exercise. There is little evidence to suggest a beneficial effect on resting outflow tract gradients; however, one small RCT found that metoprolol reduced LVOTO at rest and during exercise, provided symptom relief, and improved quality of life in patients with obstructive HCM. Maximum exercise capacity remained unchanged. This is the first RCT in over 50 years to address the use of beta-blockers in HCM.[71][72]

  • Beta-blocker may be of benefit in patients with HCM and symptoms suggestive of ischaemia.

Non-dihydropyridine calcium-channel blockers

  • Used for relief of symptoms, including those with a component of chest pain.[2] Verapamil and diltiazem have vasodilating properties as well as negative inotropic and chronotropic effects.[2] ​Short-term oral administration may increase exercise capacity, improve symptoms, and normalise or improve LV diastolic filling without altering systolic function.[1]

  • Verapamil can be used when beta-blockers are contraindicated or ineffective, but it is potentially harmful in patients with obstructive HCM and severe dyspnoea at rest, hypotension, and very high resting gradients (e.g., >100 mmHg), and infants <6 weeks of age.[2] Verapamil has been reported to cause death in a few HCM patients with severe LVOTO or elevated pulmonary arterial pressure as it may provoke pulmonary oedema.[1] It should therefore be used with caution in these patients.[2] As a result, some favour disopyramide as second-line therapy over calcium-channel blockers.[4]

  • Diltiazem should be considered in patients who are intolerant or have contraindications to beta-blockers and verapamil.[1]

Disopyramide

  • Negative inotrope and a type IA anti-arrhythmic agent. For patients with LVOTO and persistent severe symptoms despite therapy with beta-blockers or non-dihydropyridine calcium-channel blockers, adding disopyramide is recommended.[1][2]

  • Often disopyramide is used in combination with an agent that has atrioventricular nodal blocking properties as it may increase the ventricular rate in patients with atrial fibrillation.

  • It may be considered as monotherapy in patients who are intolerant of or have contraindications to beta-blockers and calcium-channel blockers.[1]

  • Disopyramide decreases resting LVOTO. In one multicentre study it was shown that 75% of patients with obstructive HCM who were managed with disopyramide had amelioration of symptoms in association with a 50% reduction in LV outflow gradient. This beneficial effect was sustained for the study period of 3 years.[73]

  • Dose-limiting anticholinergic side effects include dry eyes and mouth, urinary hesitancy or retention, and constipation. The ECG QT interval should be monitored for prolongation.[1]

Mavacamten

  • A myosin inhibitor approved for the treatment of adults with symptomatic New York Heart Association (NYHA) class II-III obstructive HCM to improve functional capacity and symptoms.[1][74][75] It works by inhibiting cardiac myosin adenosine triphosphatase (ATPase), thus reducing actin-myosin cross-bridge formation; this reduces contractility and improves myocardial dynamics.[1]

  • While mavacamten is approved for this indication in the US, the most recent guidelines from the American Heart Association and American College of Cardiology do not include a cardiac myosin inhibitor in the treatment cascade.[2] Mavacamten is currently available in the US through a Risk Evaluation and Mitigation Strategy (REMS) programme, designed to monitor patients periodically with echocardiograms for early detection of systolic dysfunction and to screen for drug interactions prior to each prescription.[76]

  • European and UK guidelines now recommend mavacamten as a second-line treatment for patients with HCM and LVOTO.[1][75] It should be considered when optimal medical therapy with beta-blockers, calcium-channel blockers, and/or disopyramide is ineffective or poorly tolerated. European guidelines stipulate that in the absence of evidence to the contrary, mavacamten should not be used with disopyramide, but may be coadministered with beta-blockers or calcium-channel blockers.[1] UK guidelines differ, stating that it can be added‑on to individually optimised standard care that includes beta‑blockers, calcium-channel blockers, or disopyramide, unless these are contraindicated.[75]

  • In patients with contraindications or known sensitivity to beta-blockers, calcium-channel blockers, and disopyramide, mavacamten may be considered as monotherapy.[1]

  • Up-titration of medication to a maximum tolerated dose should be monitored in accordance with licensed recommendations using echocardiographic surveillance of LV ejection fraction.[1]

  • In the EXPLORER-HCM phase 3 trial, treatment with mavacamten improved exercise capacity, LVOTO, NYHA functional class, and health status (symptoms, physical and social function, and quality of life) compared with placebo in patients with symptomatic obstructive HCM.[77][78][79] The drug was well tolerated and has a good safety profile; only a small subset of patients developed transient LV systolic dysfunction, which resolved after temporary discontinuation of the drug.

  • A secondary analysis found favourable changes in cardiac structure and function through 30 weeks of therapy, including improvement in echocardiographic markers of LV filling pressures, LVOT gradients, and systolic anterior motion. Reductions in NT-proBNP were also seen, further supporting the benefit of mavacamten on functional improvement and favourable remodelling.[80]​ 

  • Interim data from a long-term extension study, analysed at a median follow-up of 62.3 weeks, showed that mavacamten was associated with clinically important and sustained improvements of LVOT gradients, NYHA class, and NT-proBNP levels that were consistent with those observed in the parent trial. Treatment was generally well tolerated over 315 patient-years of exposure.[76]

  • In the VALOR-HCM phase 3 trial, patients who were assigned to mavacamten, as well as those who initially received placebo for 16 weeks and then crossed over to mavacamten, had a significantly reduced need for septal reduction therapy after 56 weeks compared with placebo.[81]

  • In another randomised trial (EXPLORER-CN), Chinese patients with symptomatic obstructive HCM who received treatment with mavacamten had a significant reduction in Valsalva LV outflow tract peak gradient, compared with those treated with placebo[82]

  • Open-label, follow-up studies evaluating the long-term efficacy and safety of mavacamten in these trials, as well as real-world experience, will provide more information on the durability of improvements and the safety profile of the drug.

Surgical myectomy (septal reduction therapy)

  • If severe symptoms persist in the face of a resting or provocable outflow tract gradient of ≥50 mmHg, consideration should be given to surgical myectomy, which reduces septal mass, thereby relieving obstruction.[2]​ European guidelines specify that patients should be in New York Heart Association/Ross functional class III-IV, or be experiencing recurrent exertional syncope due to LVOTO, despite maximum tolerated medical therapy.[1]

  • Myectomy abolishes or substantially reduces LV outflow tract gradients in over 90% of cases, reduces systolic anterior motion-related mitral regurgitation, and improves exercise capacity and symptoms.

  • Long-term symptomatic benefit is achieved in >80% of patients, with a long-term survival comparable to that of the general population.

  • Preoperative determinants of a good long-term outcome are: age <50 years; left atrial size <46 mm; absence of AF; and male sex.[1] Older age and increased severity of comorbidities are predictive of poor surgical outcomes.[83]​ Data from experienced centres suggest that institutions should aim for mortality rates of <1%.[2]

  • Surgical myectomy has not been conclusively shown to affect the incidence of sudden death.

  • The rate of postoperative complications is estimated at 5.9% in most experienced centres. The most common complications are complete heart block in patients without previous conduction abnormality (3% to 10%), left bundle branch block (40% to 56%), and ventricular septal defect (1%).[83][84]

Alcohol septal ablation (ASA)

  • May be performed as an alternative to surgical myectomy.

  • Involves the delivery of alcohol into a target septal perforator branch of the left anterior descending coronary artery, for the purpose of producing a myocardial infarction and reducing septal thickness.[1]

  • Septal remodelling and relief of obstruction after ASA occurs over several months, resulting in a smaller reduction in resting gradient compared with surgical myectomy, but a similar reduction in patient symptoms.[85][86]

  • Complications include ventricular arrhythmias (2.2%), coronary dissection (1.8%), and complete heart block (>10%) necessitating permanent pacemaker placement.[87]​ There is an increased need for permanent pacemaker implantation post-procedure compared with surgical myectomy.[88]

  • Mortality from all-cause or sudden cardiac death is low after ASA.[89]

  • ASA has not been conclusively shown to affect the incidence of sudden death.

  • While data comparing the later outcomes of ASA and surgical myectomy are lacking, a retrospective, observational study compared long-term mortality of patients with obstructive HCM following both procedures. It concluded that ASA was associated with increased long-term all-cause mortality compared with septal myectomy. This finding remained after adjustment for confounding factors (patients undergoing ASA tend to be older with more comorbidities and reduced septal thickness, compared with patients undergoing septal myectomy), but may still be influenced by unmeasured confounders.[90]

Dual-chamber pacing

  • May be an option in select patients with medically refractory symptomatic obstruction who are not candidates for, or who do not desire, surgery or ASA. Dual-chamber pacing is not a primary line of therapy; however, as efficacy is unproven in randomised, cross-over, blinded studies.[91][92]

  • Treatment is associated with subjective improvement in symptoms without objective improvement in exercise capacity.

  • Gradient reduction is less than that achieved with surgery.[93]

Management of complications

Myocardial ischaemia

Patients may develop symptoms or signs of ischaemia. Ischaemia in HCM is multifactorial and thus not easily treated. Decreasing myocardial oxygen demand with negative inotropic and chronotropic agents may prove beneficial. Surgical unroofing of myocardial bridging (tunnelling of coronary arteries into heart muscle) has been reported to yield symptomatic improvement in select patients, but data are limited.[30][94]​​ Moreover, myocardial bridging is frequently identified in HCM and has not been conclusively linked to SCD.[95][96]​​ Therefore, the risks of the procedure need to be considered when advising surgical intervention.

Ventricular arrhythmias

Implantation of an ICD is recommended for secondary prevention in patients with HCM who have survived a cardiac arrest due to VT or VF, or who have spontaneous sustained ventricular arrhythmia causing syncope or haemodynamic compromise in the absence of reversible causes. It should also be considered in patients presenting with haemodynamically tolerated VT, in the absence of reversible causes.[1] In patients with HCM and pacing-capable ICDs, programming antitachycardia pacing is recommended to minimise risk of shocks.[2] Although data are lacking, anti-arrhythmic drugs such as beta-blockers (e.g., sotalol) and amiodarone should be considered for patients with recurrent, symptomatic ventricular arrhythmia, or recurrent ICD shocks.[1] Catheter ablation in specialised centres may be considered in select patients with recurrent, symptomatic sustained monomorphic VT (SMVT), or recurrent ICD shocks for SMVT, in whom anti-arrhythmic drugs are ineffective, contraindicated, or not tolerated.[2][97]​​

Atrial arrhythmias

Atrial arrhythmias, including atrial fibrillation (AF), are common, particulary in older patients with HCM. Prevalence of AF among patients with HCM is estimated at 17% to 39%, with an annual incidence of 2.8% to 4.8%.[1] AF is often poorly tolerated in patients with HCM.[2] As a result, an aggressive strategy for maintaining sinus rhythm is warranted. Paroxysmal or chronic AF are linked to left atrial enlargement.[4] AF is independently associated with heart-failure-related death, and occurrence of fatal and non-fatal stroke, as well as long-term progression of heart failure symptoms.[2] Management of AF is as per patients without HCM. However, digoxin is not typically used for atrial rate control if the patient has significant hypertrophy, as there is a theoretical concern that it could exacerbate LVOTO due to a positive inotropic effect.[2] In addition, traditional stroke risk scoring systems used in the general population, such as CHA2DS2-VASc (congestive heart failure or left ventricular dysfunction, hypertension, age ≥75 [doubled], diabetes, stroke [doubled]-vascular disease, aged 65-74 years, sex category [female]) are not predictive in patients with HCM, with evidence suggesting that they may perform suboptimally.[1][2]​​​[98]​​ For this reason, although there are no RCTs evaluating the role of anticoagulation in patients with HCM, given the high incidence of stroke, prophylactic anticoagulation is recommended in all patients with HCM and AF (if no contraindication).[1] A direct oral anticoagulant is recommended first-line option, and a vitamin K antagonist (e.g., warfarin) second-line option.[1][2][98]​ See New-onset atrial fibrillation (Management) and Chronic atrial fibrillation (Management)

Symptomatic sinus node dysfunction

Permanent pacemaker implantation is indicated as in other forms of heart disease. Permanent pacemaker implantation is also indicated for patients with high-grade atrioventricular (AV) block who are symptomatic, or who have arrhythmias such as AF or ventricular arrhythmias that are worsened by bradycardia or prolonged pauses.

Systolic and/or diastolic dysfunction

While patients can have LVOTO and reduced cardiac function, this is uncommon. Patients with systolic and/or diastolic dysfunction with a significant obstructive component should have their therapy tailored to prevent worsening LVOTO. These patients require individualised therapy with specialist management.

Symptomatic patients: predominantly non-obstructive with preserved systolic function

Symptoms are related to diastolic dysfunction, with impaired filling resulting in reduced output and pulmonary congestion. Patients are more symptomatic when heart rate is higher, as diastolic filling is further compromised; a negative chronotropic agent may therefore be beneficial in this setting.[4]

Non-dihydropyridine calcium-channel blockers are thought to improve symptoms, secondary to their beneficial effect on myocardial relaxation and ventricular filling. They are also negative inotropes, which may aid in relief of symptoms. Beta-blockers may be used, as they may improve diastolic filling due to their negative chronotropic effect. Disopyramide is not recommended, as it may decrease cardiac output more than the other therapies in this setting.

Oral nitrates can be used cautiously for relief of angina.[1] Ranolazine can be considered to improve symptoms in patients with angina-like chest pain and no evidence of left ventricular outflow tract obstruction, even in the absence of obstructive coronary artery disease.[1] See Stable ischaemic heart disease (Management) for further details of management of angina.

Management of heart failure with reduced ejection fraction is focused on: (1) risk stratification and management of comorbidities, including hypertension, diabetes mellitus, obesity, atrial fibrillation, coronary artery disease, chronic kidney disease, and obstructive sleep apnoea; (2) non-pharmacological management, including exercise and weight loss; and (3) pharmacological treatment, namely disease-modifying medications and medication for symptom management (e.g., relief of congestion with loop diuretics).[99]​ For further details of management of heart failure, see Heart failure with preserved ejection fraction (Management)

Management of complications

  • If the patient develops symptoms or signs of ischaemia, decreasing myocardial oxygen demand with negative inotropic and chronotropic agents may prove beneficial. Aetiology of the ischaemia should be identified (i.e., increased LV outflow tract obstruction, coronary artery disease, or myocardial bridging).

  • In addition, all patients with symptomatic ventricular arrhythmias or important asymptomatic ventricular arrhythmias should receive an ICD.[2]

  • Atrial arrhythmias (e.g., AF) should be treated (as described for patients with predominant LVOTO) to maintain sinus rhythm. The risk of systemic thromboembolism in these patients is thought to be significant, and thus the threshold for initiation of anticoagulant therapy should be low.[2] Anticoagulation is recommended for all patients with HCM and AF, with a direct oral anticoagulant first-line, and a vitamin K antagonist (e.g., warfarin) second-line.[2]

  • Permanent pacemaker implantation is indicated in patients with symptomatic sinus node dysfunction and HCM, and in patients with high-grade AV block who are symptomatic, or who have arrhythmias such as AF or ventricular arrhythmias that are worsened by bradycardia or prolonged pauses.

Symptomatic patients: end-stage heart failure with systolic dysfunction

The average duration from onset of symptoms to end-stage disease is 14 years.[100] Systolic function deteriorates, and the left ventricle remodels and becomes dilated. The mechanism of end-stage HCM is likely to be diffuse ischaemic injury. Risk factors for end-stage disease include younger age at diagnosis, more severe symptoms, larger LV cavity size, and family history of end-stage disease. Mortality is high once this complication develops, with mean time to death or cardiac transplantation of 2.7 ± 2.1 years.[100]

Medical therapy

These patients are treated with standard heart failure therapy, including initially a beta-blocker and ACE inhibitor or angiotensin-II receptor antagonist.[101]

Second-line therapies include digoxin, diuretics, or aldosterone antagonists. Diuretics should be used cautiously in these patients compared with patients with other causes of heart failure, due to possible impairment in preload. Digoxin may be used in a patient with a dilated LV with reduced function. It is not typically used in the setting of severe hypertrophy. Digoxin should not be used if the patient has ventricular pre-excitation through an accessory pathway, as its AV nodal blocking effect may promote rapid conduction of the atrial arrhythmia across the accessory pathway, precipitating a ventricular arrhythmia or haemodynamic compromise.

Heart transplantation

If patients remain refractory to medical therapy, they should be referred for consideration for heart transplant.[101] Heart transplants have been shown to improve survival and quality of life for patients with end-stage heart failure secondary to HCM.[101] Presence of comorbidities, caretaker status, and goals of care should all be taken into account when considering patient eligibility for transplant.[101]

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