Hypertrophic cardiomyopathy (HCM) is an inherited disease of the cardiac sarcomere that results in left ventricular hypertrophy, hyperdynamic function, microvascular dysfunction, impaired relaxation, and myocardial fibrosis.¹ Clinical hallmarks include left ventricular outflow tract obstruction (LVOTO), arrhythmias, and heart failure.^2,3 To date, no disease-modifying therapies have been identified, although clinical trials of novel therapeutics are in progress.^4,5 This analysis focuses on HCM management strategies fundamental to the care of patients with HCM: LVOTO, sudden cardiac death (SCD), atrial fibrillation, exercise restriction, and heart failure.

Medical Therapy

A significant proportion of HCM patients suffer from LVOTO; therefore, investigating obstruction with both resting echo (with Valsalva) and stress echo if the gradient is below 50mmHg on rest interrogation should be performed. Treatment of obstruction is indicated for symptomatic patients (NYHA Class > II) and medical therapy is the first-line approach.⁶ Importantly, patients may become accustomed to their reduced functional capacity and minimize symptoms,⁷ making objective confirmation of functional capacity with cardiopulmonary exercise testing a useful adjunct to history-taking for assessment of exertional intolerance.^8,9 Medical therapies include beta-blockade and verapamil alone or in combination, though verapamil may increase LVOTO-associated symptoms in some individuals due to its vasodilatory effect.¹⁰ Disopyramide may be added for patients with symptoms refractory to the use of beta-blocker or calcium channel blocker therapy.¹⁰

Invasive Therapy

Septal reduction therapy (SRT) is indicated when medical therapy fails to control NYHA Class III symptoms or following LVOTO-associated syncope or near syncope refractory to medical therapy. There are two forms of SRT: surgical myomectomy^11,12 and alcohol septal ablation. Surgical myectomy provides definitive therapy for symptomatic LVOTO and is associated with low post-operative mortality and morbidity when carried out by experienced operators in expert centers, although no significant long-term mortality benefit has been demonstrated.² Given this, pre-operative counseling should emphasize that the benefit is currently limited to symptom improvement.

With refinement of the techniques and greater experience, post-procedural outcomes following alcohol septal ablation are comparable to surgical myectomy in appropriately selected patients at expert centers.⁷ Selecting the right approach to SRT is challenging and should include not only the assessment of provider and center expertise, but also factors such as patient age, comorbid disease, and patient preference.² Despite excellent intermediate and long-term results, some patients remain symptomatic or develop heart failure after SRT.¹³

Sudden Death

Patients with HCM are at increased risk for SCD, and risk stratification for implantable cardioverter defibrillator (ICD) implantation is critical in this population. Primary prevention with an ICD is reasonable for patients with severe hypertrophy (>30mm), family history of sudden death in a first degree relative, recent unexplained syncope, or "burnt-out" HCM (LVEF < 50%).^2,6,7 The presence of non-sustained ventricular tachycardia on 24-hour Holter or abnormal blood pressure response to exercise, when added to other risk factors, also supports primary prevention ICD.¹⁴ Other risk factors that may influence the decision to place an ICD for primary prevention include marked late-gadolinium enhancement on magnetic resonance imaging (MRI) (>15%), the presence of an apical aneurysm, and some genetic mutations present in families with high prevalence of sudden cardiac death.^3,6,7,15-17 Secondary prevention with ICD placement in those surviving SCD or with sustained ventricular tachycardia (VT) is universally recommended.⁶ In the case of syncope, a thorough evaluation for provoked obstruction is first required to avoid ICD implantation for syncope related to LVOTO rather than ventricular arrhythmias.⁷ Periodic reassessment of risk factors is recommended as part of ongoing follow up, with more frequent testing reserved for younger patients and those with borderline risk factors.

Atrial Fibrillation

Atrial fibrillation can worsen exertional symptoms and increase stroke risk in patients with HCM.² The role for catheter ablation has not been specifically studied in HCM cohorts but remains an option for patients with symptoms refractory to medical therapy.¹⁸ As refractory symptomatic atrial fibrillation often marks progressive disease with restrictive physiology, these patients also warrant evaluation for advanced heart failure therapies such as heart transplantation.¹⁹ Due to the increased risk for thromboembolism in HCM patients who develop atrial fibrillation or flutter, oral anticoagulation is recommended as primary stroke prophylaxis regardless of CHA2DS2-VASc score.⁶

Exercise

Balancing the overall benefits of exercise in the general population with the potential risk of SCD in the HCM population is a challenge. Strenuous exercise has been routinely discouraged,⁶ though there is an increasing appreciation for how the health benefits of exercise should be balanced with the potential risks.²⁰ Studies to better define the risk of high-intensity exercise in HCM are ongoing (LIVE-HCM/LQT), and thoughtful discussion with shared decision making is a widely accepted strategy for application of exercise restrictions in this population.

Heart Failure

Some patients with HCM develop clinical heart failure, ranging from heart failure with preserved ejection fraction, to severe restrictive cardiomyopathy, to 'burnt-out' dilated hypertrophic cardiomyopathy.² Patients diagnosed with HCM prior to age 40 have more than a 60% chance of experiencing clinical heart failure by age 70, and those diagnosed between ages 40 and 60 have greater than a 40% chance to experience heart failure by that age. However, only 5% of HCM patients will progress to require advanced heart failure therapies during their lifetime.²¹

Given the predominant restrictive physiology with fixed stroke volume and small left ventricular cavity, patients often do not respond to inotropic support or benefit from implantation of a durable left ventricular assist device (LVAD). This is reflected in the 2018 United Network for Organ Sharing (UNOS) allocation guidelines for heart transplantation, which affords HCM patients higher outpatient priority listing at Status 4 than other outpatient transplant candidates with ischemic or dilated cardiomyopathy, who are Status 6.²²

What's on the Horizon?

There are currently no medical interventions that alter the natural course of HCM, but cardiac myosin inhibitors have shown potential promise.^4,5 Trials investigating the effect of cardiac myosin inhibitors such as mavacamten (EXPLORER-HCM and MAVERICK-HCM) and CK-274 (REDWOOD-HCM) on LVOTO and HCM associated diastolic heart failure are underway. Finally, gene-silencing with CRISPR/Cas9 gene-editing technology may someday play a role in the prevention of disease development before the appearance of clinical manifestations.²³

In summary, patients with HCM may suffer from LVOTO obstruction, atrial arrhythmias, SCD, and advanced heart failure. Current therapies focus on the disease manifestations, but future therapies may offer hope to effectively address the pathophysiology of HCM. Until then, recognition of the role of medical, interventional, device, and surgical therapies, and the use of shared decision making in areas of exercise prescription, are essential to improve the quality of life and survival of patients with HCM.

References

1. Marian AJ, Braunwald E. Hypertrophic Cardiomyopathy: genetics, pathogenesis, clinical manifestations, diagnosis, and therapy. Circ Res 2017;121:749-70.
2. Maron BJ, Ommen SR, Semsarian C, Spirito P, Olivotto I, Maron MS. Hypertrophic cardiomyopathy: present and future, with translation into contemporary cardiovascular medicine. J Am Coll Cardiol 2014;64:83-99.
3. Semsarian C, Ingles J, Maron MS, Maron BJ. New perspectives on the prevalence of hypertrophic cardiomyopathy. J Am Coll Cardiol 2015;65:1249-54.
4. Heitner SB, Jacoby D, Lester SJ, et al. Mavacamten treatment for obstructive hypertrophic cardiomyopathy: a clinical trial. Ann Intern Med 2019;170:741-48.
5. Robertson LA, Armas DR, Robbie E, et al. A first in human study of the selective cardiac myosin inhibitor, CK-3773274. J Card Fail 2019;25:79-80.
6. Gersh BJ, Maron BJ, Bonow RO, et al. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2011;58:e212-e60.
7. Sen-Chowdhry S, Jacoby D, Moon JC, McKenna WJ. Update on hypertrophic cardiomyopathy and a guide to the guidelines. Nat Rev Cardiol 2016;13:651-75.
8. Shah JS, Esteban MT, Thaman R, et al. Prevalence of exercise-induced left ventricular outflow tract obstruction in symptomatic patients with non-obstructive hypertrophic cardiomyopathy. Heart 2008;94:1288-94.
9. Jacoby D, McKenna WJ. Support for routine use of metabolic stress testing in hypertrophic cardiomyopathy. Am J Cardiol 2012;109:1534-35.
10. Jacoby DL, DePasquale EC, McKenna WJ. Hypertrophic cardiomyopathy: diagnosis, risk stratification and treatment. CMAJ 2013;185:127-134.
11. Hang D, Nguyen A, Schaff HV. Surgical treatment for hypertrophic cardiomyopathy: a historical perspective. Ann Cardiothorac Surg 2017;6:318-28.
12. Maron BJ, Rowin EJ, Casey SA, et al. Risk stratification and outcome of patients with hypertrophic cardiomyopathy ≥60 years of age. Circulation 2013;127:585-93.
13. Wu JJ, Seco M, Medi C, et al. Surgery for hypertrophic cardiomyopathy. Biophys Rev 2015;7117-25.
14. Adabag AS, Casey SA, Kuskowski MA, Zenovich AG, Maron BJ. Spectrum and prognostic significance of arrhythmias on ambulatory Holter electrocardiogram in hypertrophic cardiomyopathy. J Am Coll Cardiol 2005;45:697-704.
15. Trivedi A, Knight BP. ICD therapy for primary prevention in hypertrophic cardiomyopathy. Arrhythm Electrophysiol Rev 2016;5:188-96.
16. Rowin EJ, Maron BJ, Haas TS, et al. Hypertrophic cardiomyopathy with left ventricular apical aneurysm: implications for risk stratification and management. J Am Coll Cardiol 2017;69:761-773.
17. Green JJ, Berger JS, Kramer CM, Salerno M. Prognostic value of late gadolinium enhancement in clinical outcomes for hypertrophic cardiomyopathy. JACC Cardiovasc Imaging 2012;5:370-77.
18. Providencia R, Elliott P, Patel K, et al. Catheter ablation for atrial fibrillation in hypertrophic cardiomyopathy: a systematic review and meta-Analysis. Heart 2016;102:1533-43.
19. Siontis KC, Geske JB, Ong K, Nishimura RA, Ommen SR, Gersh BJ. Atrial fibrillation in hypertrophic cardiomyopathy: prevalence, clinical correlations, and mortality in a large high-risk population. J Am Heart Assoc 2014;3:1-8.
20. Papoutsidakis N, Heitner S, Ingles J, et al. Participation in thrill-seeking activities by patients with hypertrophic cardiomyopathy: individual preferences, adverse events and physician attitude. Am Heart J 2019;214:28-35.
21. Ho CY, Day SM, Ashley EA, et al. Genotype and lifetime burden of disease in hypertrophic cardiomyopathy: insights from the sarcomeric human cardiomyopathy registry (SHaRe). Circulation 2018;138:1387-98.
22. Shah KS, Kittleson MM, Kobashigawa JA. Updates on Heart Transplantation. Curr Heart Fail Rep 2019;16:150-56.
23. Repetti GG, Toepfer CN, Seidman JG, Seidman CE. Novel Therapies for Prevention and Early Treatment of Cardiomyopathies. Circ Res 2019;124:1536-50.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Cardiac Surgery, Cardiovascular Care Team, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Prevention, Anticoagulation Management and Atrial Fibrillation, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Aortic Surgery, Cardiac Surgery and Arrhythmias, Cardiac Surgery and Heart Failure, Statins, Acute Heart Failure, Chronic Heart Failure, Heart Transplant, Mechanical Circulatory Support, Interventions and Imaging, Interventions and Structural Heart Disease, Interventions and Vascular Medicine, Magnetic Resonance Imaging

Keywords: Atrial Fibrillation, Disopyramide, Stroke Volume, Hypertrophy, Left Ventricular, Cardiac Myosins, Contrast Media, Calcium Channel Blockers, Cardiomyopathy, Dilated, Cardiomyopathy, Restrictive, Sarcomeres, Heart Failure, Diastolic, Gadolinium, Secondary Prevention, Risk Factors, Quality of Life, Verapamil, Patient Preference, Heart-Assist Devices, Outpatients, Prevalence, Follow-Up Studies, Blood Pressure, Defibrillators, Implantable, Cardiomyopathy, Hypertrophic, Death, Sudden, Cardiac, Benzylamines, Heart Failure, Uracil, Syncope, Heart Transplantation, Tachycardia, Ventricular, Catheter Ablation, Stroke, Thromboembolism, Primary Prevention, Aneurysm, Magnetic Resonance Imaging, Fibrosis, Counseling, Medical History Taking, Mutation, Risk Assessment, Anticoagulants, Longitudinal Studies, ACCGrantHypertrophicCardiomyopathy

< Back to Listings