10 Mavacamten therapy in the management of symptomatic obstructive hypertrophic cardiomyopathy: a single UK centre experience

Introduction

Hypertrophic cardiomyopathy (HCM) is a genetic disorder of cardiac myocytes leading to myocardial hypercontractility and left ventricular hypertrophy. Disease-causing genetic alterations result in enhanced calcium sensitivity and myosin ATPase activity of the myofibrils leading to an increase in force generation and myocardial contractility.¹ Myocardial hypercontractility, systolic anterior motion of the mitral valve into the left ventricular outflow tract (LVOT) and the hypertrophied interventricular septum encroaching on the LVOT result in a rise in LVOT pressure gradient.² Mavacamten, a selective myosin ATPase inhibitor, reverses these processes resulting in a reduction in LVOT pressure gradient, serum N-terminal pro B-type natriuretic peptide (NT pro BNP) and symptomatic improvement.³

Methods

Patients with symptomatic LVOT obstruction refractory to first line therapy especially those with an indication for septal reduction therapy (SRT) were offered treatment. Patient's CYP2C19 phenotype is required prior to treatment initiation. Patients were reviewed in clinic at 4 weekly intervals. At each clinic appointment, patients underwent a clinical evaluation, 12-lead ECG, transthoracic echocardiogram, and blood sampling for the measurement of serum NT pro BNP levels.

Results

15 patients were started on mavacamten with 9 completing 12 weeks on treatment. The majority (46.6%) of patients were normal metabolisers with the rest divided equally between intermediate or rapid metabolisers. 4 patients previously underwent invasive SRT and 73% were considered for SRT (see table-1 below). Only 20% of patients reported NYHA class III symptoms at week-4 clinic review compared to 60% at baseline. One patient remained in NYHA class III after 12 weeks on treatment due to discontinuation of treatment at week-8 visit because of low Valsalva LVOT gradient <20 mmHg (see figure-1 below). Marked normalisation of T wave abnormalities on 12-lead ECG with treatment was observed with complete normalisation of the 12-lead ECG in three patients. None of the patients had their treatment discontinued because of a reduction in left ventricular ejection fraction (LVEF) to <50% with marked reduction in LVOT gradient (see figure-2 below). Serum NT pro BNP levels dropped from a baseline mean level of 1443 nanogram/litre (ng/L) to 219 ng/L over a 12-week period. Treatment was discontinued in a single patient because of very low Valsalva LVOT gradient (<20 mmHg. One patient developed asymptomatic atrial fibrillation.

Conclusion

Treatment with mavacamten was very well tolerated with rapid and marked improvement in NYHA class symptoms, reduction in LVOT gradient and serum NT pro-BNP level. Normalisation of T wave abnormalities was observed in a number of patients. This may be explained by the reduced oxygen demand as a result of a reduced myocardial contractility and improved tissue perfusion. A drop in LVEF to <50% was not observed in any of these patients.

References

Marian AJ. Molecular genetic basis of hypertrophic cardiomyopathy. Circ Res. 2021 May 14;128(10):1533–53. Marian AJ, Braunwald E. Hypertrophic cardiomyopathy: genetics, pathogenesis, clinical manifestations, diagnosis, and therapy. Circ Res. 2017 Sep 15;121(7):749–70. Olivotto I, Oreziak A, Barriales-Villa R, Abraham TP, Masri A, Garcia-Pavia P, et al. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2020 Sep 12;396(10253):759–69.

Conflict of Interest

None