17 Analysis of a hypertrophic cardiomyopathy cohort in a regional inherited cardiac conditions service, with a focus on eligibility for novel cardiac myosin inhibitor therapies

Abstract

<h3>Introduction</h3> 2285 patients currently attend our regional inherited cardiac conditions (ICC) service, 652 of whom are screened or managed for hypertrophic cardiomyopathy (HCM). With the anticipated arrival of novel myosin ATPase inhibitors (1) for those with symptomatic left-ventricular outflow tract obstruction (LVOTO), we analysed our HCM cohort to identify patients who may be eligible for such therapies. <h3>Methods</h3> A database was populated with demographic, diagnostic, clinical and imaging data from electronic care records and imaging archives. Presence of significant LVOTO was defined as an outflow tract gradient ≥30 mmHg at rest or ≥50 mmHg on provocation as per European Heart Society guidelines (2). Symptomatic patients reported chest pain or New York Heart Association score ≥class II breathlessness. <h3>Results</h3> A guideline based clinical HCM phenotype was seen in 259 of the 652 patients; of which 63 (24.3%) had pathogenic sarcomeric variants and 26 (10%) had variants of unknown significance (VUS). The average age was 56 years; 71.4% were male. Mean presenting septal wall thickness was 18.4 mm. 53 (20.4%) had an implantable cardioverter defibrillator. 23 (8.8%) had prior septal reduction therapy. 25 (9.6%) had an ejection fraction &lt;55%. 61 (23.6%) had significant LVOTO at presentation (mean gradient 64.4 mmHg). Emergence of significant LVOTO was seen in 9 patients who initially had no presenting gradient. LVOTO frequency was similar (~19%) across genotype categories (positive, negative, VUS or unknown) (Figure 1), not fully aligning with recent reports (3) although our sample size was small, with a number of pending genetic tests due to pandemic impacts. On either single, or combination, regimens of beta blocker, verapamil or disopyramide 20 patients now have no obstruction, and 10 have residual gradients that are no longer classified as significant (Figure 2). Therefore 40 patients would meet LVOT gradient based eligibility for enrolment into the EXPLORER trial (4), the first phase III trial to investigate a specific myosin ATPase inhibitor (Mavacamten) in HCM patients with symptomatic obstruction. However only 22 (8.5% of total or 36% of the HoCM cohort) also meet the symptomatic inclusion criteria. Initiation of myosin ATPase inhibitors paralleling EXPLORER-like trial standards of 4-weekly follow-ups, including imaging and blood tests, will effectively require an additional weekly clinic session to on-board all eligible patients at our site over a 16-week period. <h3>Conclusion</h3> We find that although most HCM patients with LVOTO can be managed with existing therapies, a significant unmet need attributable to symptomatic obstruction remains. 8.5% of our HCM cohort would be the focus of initial myosin ATPase inhibitor roll out should these therapies become available. This would come with attendant resource implications that may only be practical to deliver in larger ICC centres. <h3>References</h3> 1. Daniels MJ, <i>et al Circulation</i>. 2021;<b>144</b>(10):759–762. 2. The Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC), <i>European Heart Journal</i> (2014) <b>35</b>, 2733–2779 3. Neubauer S, <i>et al. J Am Coll Cardiol</i>. 2019;<b>74</b>(19):2333–2345. 4. Olivotto I, <i>et al Lancet</i>. 2020;<b>396</b>(10253):759–769. <h3>Conflict of Interest</h3> Dr Matthew J Daniels (last author) reports advisory board payments from Bristol Myers Squibb