CMR phenotypes and clinical outcomes in NYHA class I versus II-IV hypertrophic cardiomyopathy: identifying high-risk asymptomatic patients

Abstract Background Cardiac myosin inhibition therapy can deliver symptomatic benefit for NYHA class≥II patients with obstructive hypertrophic cardiomyopathy (HCM) and is being actively explored for non-obstructive phenotypes. However, expanding interest in clinical outcome reduction supports growing need to identify high risk cohorts across both symptomatic and asymptomatic cohorts. We aimed to examine phenotypic characteristics of NYHA-I versus NYHA≥II patients with HCM and their association with future outcomes. Methods 727 patients with HCM from the CIROC Registry who completed simultaneous CMR and patient health assessments, inclusive of NYHA evaluation and quality of life surveys, were studied. Baseline clinical and CMR characteristics were compared between NYHA-I and NYHA≥II cohorts, followed by risk modelling for the prediction of major adverse cardiovascular events (MACE), defined as: all-cause mortality, heart failure hospitalization, ventricular arrhythmia, new onset atrial fibrillation, or stroke. Cox models were constructed to identify independent predictors of MACE. Results Of the 727 patients, 546 (75%) reported NYHA-I and 181 (25%) NYHA≥II symptoms. Baseline characteristics are shown in Table 1. Compared to NYHA≥II, NYHA-I patients were younger, more likely male, and had a lower prevalence of diabetes and hypertension. No meaningful differences in CMR chamber volumes, function, left ventricular (LV) mass, or fibrosis burden were observed. Over a median follow up of 3.7 years, 109 patients (15%) experienced MACE: 12% in NYHA-I and 23% in NYHA≥II sub-groups (p<0.001). Baseline LV mass z-scores (determined from sex-matched, BSA-indexed SCMR healthy reference values) were independently associated with MACE by multivariable Cox modelling. An optimal LV mass z-score threshold of 3.9 for prediction of MACE was identified and combined with NYHA status to stratify patients into 4 categories. Kaplan-Meier curves showed patients with LV Mass z-scores >3.9 experienced worse event-free survival in both NYHA sub-groups (Figure 1a). Cox modelling in the overall cohort (Figure 1b) showed NYHA-I patients with LV Mass z-scores >3.9 experienced a 2.2-fold increased risk (p=0.007) of MACE, this exceeding the risk of NYHA ≥II patients below this threshold. Separate NYHA I and ≥II sub-group multivariable models showed LV Mass z-score >3.9 to remain a strong and independent predictor of MACE, providing respective hazards of 2.6 and 4.7 (p=0.001 and <0.001). Conclusions NYHA-I patients with HCM experience significantly lower rates of MACE versus NYHA≥II. However, LV mass z-scoring permits powerful sub-stratification of these sub-groups, identifying NYHA-I patients with higher LV mass who will experience worse outcomes versus NYHA≥II patients with lower LV mass. This simple yet powerful stratification offers unique potential to identify asymptomatic patients with HCM who may benefit from targeted therapeutics to reduce future MACE.