Improvements in LVOT gradient, cardiac symptoms and QoL with a cardiac myosin inhibitor in a patient with oHCM

Initial echocardiography in early 2024 revealed normal left ventric­ular ejection fraction (LVEF) of >60 percent and increased basal sep­tal wall thickness of 21 mm. There was systolic anterior motion (SAM) of mitral valve leaflet, with moderate posteriorly directed mitral regurgita­tion. The left ventricular outflow tract (LVOT) gradient was 110 mm Hg at rest, which increased to 150 mm Hg when provoked by the Valsalva ma­noeuvre, indicating significant LVOT obstruction. N-terminal pro- B-type natriuretic peptide (NT-proBNP) lev­el was significantly elevated at 1,365 pg/mL. During the 6-minute walk test, the patient was able to walk only 120 m and experienced dyspnoea. Her heart failure symptoms were classi­fied as New York Heart Association (NYHA) class II–III.

Treatment with metoprolol 25 mg twice daily was initiated and was es­calated to 50 mg twice daily on follow up visit. However, the patient experi­enced no improvement in symptoms despite beta-blocker therapy. Since her blood pressure was borderline, further dose escalation of metoprolol was not feasible.

Treatment with mavacamten
Mavacamten 2.5 mg once daily was started in November 2024 and gradu­ally up-titrated to 5 mg. Follow-up (F/U) visits were conducted at weeks 4, 8, 12; the most recent F/U was at week 28. Overall, treatment with mavacam­ten resulted in sustained improvements in 6-minute walk distance (6MWD), NT-proBNP levels, and LVOT gradients at rest and with provocation, while LVEF remained within normal range through­out the F/U period. (Table)

The patient tolerated mavacamten well. She also reported continued im­provement in symptoms and overall quality of life (QoL), including resolu­tion of dyspnoea. Her current NYHA class is I–II.

Discussion
HCM is an inherited heart disease characterized by left ventricular hy­pertrophy (LVH), which can result in dynamic LVOT obstruction, diastolic dysfunction, heart failure, and sudden cardiac death. LVOT obstruction in HCM can cause dyspnoea and chest pain, leading to impaired QoL. Symp­tomatic HCM patients generally have a worse prognosis compared with as­ymptomatic patients.^1,2

The estimated global prevalence of HCM is 0.2–0.5 percent.³ In Hong Kong, oHCM is underdiagnosed largely due to limited awareness among healthcare professionals, misdiagnoses and insuf­ficient resources.

A screening electrocardiogram revealing LVH without an obvious sec­ondary cause should raise suspicion for HCM. In such cases, further inves­tigation with echocardiography and/ or CMR is recommended to confirm or rule out HCM. Sometimes, HCM may present as a heart murmur during physical examination, which could be due to LVOT obstruction and/or SAM-associated mitral regurgitation. Genetic testing may also play an important role in diagnosis, prognosis, and risk as­sessment of HCM, and may help identi­fy family members at risk.^3-5

Proper provocation, through techniques such as the Valsalva ma­noeuvre, is crucial for assessing the presence and severity of LVOT ob­struction in HCM. Diagnosis of oHCM is typically based on a maximal end-diastolic LV wall thickness of ≥15 mm in the absence of secondary caus­es, in addition to a peak resting LVOT gradient of ≥30 mm Hg and/or pro­voked LVOT gradient of ≥50 mmHg.^3,5

In oHCM, conventional first-line treatments such as beta-blockers and non-dihydropyridine calcium channel blockers, as well as second-line diso­pyramide, primarily focus on managing symptoms rather than addressing the underlying structural abnormality of the heart muscle.^5,6

Mavacamten is a first-in-class car­diac myosin inhibitor that targets the pathophysiological mechanism of oHCM. It inhibits actin–myosin interac­tion, thereby decreasing cardiac con­tractility and reducing LVOT obstruc­tion.⁶ Mavacamten is recommended as a second-line treatment option for oHCM by guidelines from the American Heart Association/American College of Cardiology (Class 1) and the European Society of Cardiology (Class IIa).^4,5

Our patient experienced sustained improvements in resting and provoked LVOT gradients over the 28 weeks of mavacamten therapy, whilst maintain­ing LVEF within the normal range. In the phase III randomized EXPLORER-HCM trial of 251 symptomatic oHCM patients, 30 weeks of mavacamten treatment re­sulted in remarkable reductions in LVOT gradients from baseline vs placebo (resting, -37.6 vs -5.2 mm Hg; Valsalva, -47.6 vs -11.2 mm Hg). Mavacamten treatment was also associated with im­provements in NT-proBNP level, exer­cise capacity, NYHA functional class, and patient-reported health status.⁷

In EXPLORER-HCM, the mean re­duction in LVEF from baseline was -3.9 vs -0.01 percent with mavacamten vs placebo.⁷ So far, our patients have re­sponded well to mavacamten (≤5 mg daily), and we have not observed drops in LVEF to <50 percent threshold in any of our patients. Nevertheless, mavaca­mten treatment should be interrupted if a patient’s LVEF falls to <50 percent.⁸

The 180-week analysis of the ongo­ing MAVA-LTE study, a long-term ex­tension of the EXPLORER-HCM cohort of patients (n=231) who continued to re­ceive mavacamten, showed sustained reductions in LVOT gradients (resting, -40.3 mm Hg; Valsalva, -55.3 mm Hg) vs baseline values at the start of MA­VA-LTE. Notably, 91 percent of patients had achieved a Valsalva LVOT gradient of ≤30 mm Hg.^1,9

Septal reduction therapy (SRT) is recommended for patients with symp­tomatic oHCM who are refractory to medical treatment.⁶ The phase III VAL­OR-HCM trial evaluated mavacamten’s efficacy in reducing the need for SRT in patients with symptomatic oHCM. A total of 112 patients were randomized to receive mavacamten or placebo, and patients in the placebo arm crossed over to the mavacamten arm after week 16. At week 56, only 5.6 percent of pa­tients receiving mavacamten underwent SRT, while 89 percent remained in the long-term extension phase, suggesting that mavacamten can reduce the need for SRT.¹⁰

As mavacamten is primarily me­tabolized by CYP2C19 and to a less­er extent by CYP3A4, genotyping for CYP2C19 is advisable, in particular if up-titration to dosage >5 mg is con­sidered.⁸

In summary, HCM is underdiag­nosed in Hong Kong, and proper provocation is crucial for diagnosis. Mavacamten is a disease-modifying treatment that targets the underlying pathophysiology of oHCM. Our pa­tient’s experience with mavacamten is consistent with clinical trial findings, demonstrating durable improvements in LVOT gradients, symptom burden and physical functioning, while pre­serving LVEF.