A 68-year-old male with hypertrophic obstructive cardiomyopathy (HOCM) was referred to our cardiomyopathy clinic for treatment with a cardiac myosin inhibitor. Symptomatic HOCM had been diagnosed three years earlier and treated with beta-blockers. The patient reported progressive exertional dyspnea (NYHA III) and dizziness. Examination revealed a harsh, mid-systolic murmur at the left lower sternal border, increasing with Valsalva maneuver. ECG showed sinus rhythm without conduction or repolarization abnormalities and normal QRS-Voltages. Laboratory tests revealed elevated NT-proBNP (1158pg/ml) and high-sensitive troponin T (29pg/ml). Echocardiography demonstrated severe asymmetric left ventricular hypertrophy (septal thickness 27mm), preserved LVEF (55%), reduced global longitudinal strain (-10%) and severe diastolic dysfunction, grade III. Mild-to-moderate mitral regurgitation with SAM was observed. LVOT gradient measured 6mmHg at rest and 51mmHg with Valsalva. Sudden cardiac death with no indication for ICD.
As the patient was on maximally tolerated beta-blocker therapy, mavacamten 5mg o.d. was initiated after CYP2C19 genotyping (normal metabolizer). After four weeks, LVEF remained preserved, and the LVOT gradient decreased to 8mmHg, accompanied by marked symptomatic improvement (NYHA II). Mavacamten was reduced to 2.5mg according to prescription recommendations. At eight weeks, LVEF declined to 48% while the gradient remained <10mmHg, prompting temporary cessation of therapy. Four weeks later, LVEF normalized, and LVOT gradient was 15mmHg with Valsalva. At this time, a history of bilateral carpal tunnel release prompted evaluation for amyloidosis. DPD scintigraphy demonstrated intense cardiac tracer uptake (Perugini grade 3). AL amyloidosis was excluded by normal serum free light chains and negative immunofixation, confirming cardiac ATTR amyloidosis (NAC stage 1). TTR-sequencing revealed no pathogenic variants. Treatment with the transthyretin stabilizer acoramidis and supportive heart failure treatment (eplerenone, dapagliflozin) were initiated and well tolerated. Exercise capacity remained stable.
This case underscores the importance of screening for ATTR amyloidosis and other HCM phenocopies in older patients presenting with symptomatic LVOT obstruction, as delayed diagnosis leads to adverse outcomes. The safety of myosin inhibitors in concomitant ATTR amyloidosis remains unknown, since these patients were excluded from trials. Modulating contractility with mavacamten may exacerbate systolic LV dysfunction in the presence of amyloid infiltration. Its effects in severe diastolic function, as seen in ATTR amyloidosis, are intriguing yet unexplored. The ODYSSEY-HCM trial, reported that mavacamten did not significantly improve peak oxygen uptake or symptoms compared with placebo in nonobstructive HCM and LVEF <50% occurred in 21.5% vs. 1.7%, respectively.(1) It is possible that some patients could benefit from concurrent treatment strategies, targeting this dual pathology (ATTR-HOCM), however, this remains unknown. LVOT obstruction has been reported in both ATTR and AL amyloidosis(2), but management of cardiac amyloidosis with LVOT obstruction remains challenging and requires an individualized approach. Close follow-up after mavacamten initiation and a high index of suspicion for phenocopies are essential in older patients presenting with LVOT obstruction.
(1) Desai MY et al. N Engl J Med. 2025.
(2) Gupta V et al. JACC Case Rep. 2025.
