Novel thresholds for all-cause mortality risk stratification in hypertrophic cardiomyopathy using cardiac magnetic resonance- late gadolinium enhancement

Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disorder with a clinically heterogenous disease course. Cardiovascular magnetic resonance (CMR) imaging with late gadolinium enhancement (LGE) enables non-invasive quantification of myocardial fibrosis; a key substrate for arrhythmias and sudden cardiac death in HCM. Despite its potential as a predictive marker of adverse outcomes it remains underrepresented in current guidelines for risk stratification.

To determine the prognostic significance of comprehensive LGE quantification as a predictor of all-cause mortality and establish novel low, medium and high-risk groups based on thresholds of LGE burden (% of left ventricular mass).

We prospectively enrolled 436 HCM patients (median age, 58 years; 72.2% men) who underwent detailed clinical, genetic and imaging assessment at baseline. LGE burden on CMR was quantified using the Full Width Half Maximum technique. Patients were followed up over a median of 11 years (Interquartile range (IQR) 9.8-12.7) after enrolment to determine all-cause mortality. In those with a quantifiable LGE burden (removing subjects with minimal/ trivial insertion point enhancement) and follow-up of >5 years without death (n = 318), a Cox proportional hazards model was fitted to predict survival as a function of LGE extent (%) and other clinical covariates. Using Receiver Operating Characteristic (ROC) analysis, with all-cause mortality within 10 years of CMR as binary outcome, we derived low, medium and high-risk groups based on LGE extent (%) thresholds. Kaplan-Meyer (KM) curves were constructed showing survivorship probabilities for these defined groups.

Overall, 381/436 (87%) had LGE present and 92/436 (21%) met the endpoint of all-cause mortality. Multivariate Cox regression analysis demonstrated that LGE extent (%) was an independent predictor of all-cause mortality (p<0.001) (Table 1). For each 1% increment in LGE extent, the mortality risk relative to a patient with no LGE increased by 5.9% (95% CI: 2.9-9%). HCM patients with 10% and 20% LGE burden had a respective 1.8- and 3.1-fold increase in mortality risk, relative to patients with no LGE on CMR imaging. Our analysis determined low-risk (≤ 3.27%), medium-risk (> 3.27% and < 11.08%), and high-risk (≥ 11.08%) groups based on LGE burden (%). Stratification of patients using our derived thresholds showed a 5-fold increase in mortality risk (HR: 5.87, 95% CI: 2.04–16.95, p = 0.001), comparing those in the high-risk and low-risk LGE groups (Figure 1).

In HCM, myocardial fibrosis assessed by CMR-LGE is an independent predictor of all-cause mortality with an incremental additive contribution to mortality risk. Novel threshold values defining low, medium and high-risk patient groups have been identified for future validation studies.