Cecchi, Franco

Coronary microvascular dysfunction (CMD) is an important primary feature of hypertrophic cardiomyopathy (HCM), contributing to myocardial ischemia and ventricular remodelling, and is predictive of adverse outcome. Whether there is any association between presence/severity of CMD and HCM’s pathogenic substrate remains to be determined. To address this issue, we used positron emission tomography (PET) to assess CMD in an HCM cohort that received comprehensive genetic testing for sarcomeric/myofilament-HCM. We measured maximum (intravenous dipyridamole, 0.56 mg/kg) myocardial blood flow (Dip-MBF), using 13 N-labeled ammonia and PET in 46 HCM patients (age 38±14 years, 32 male). Genetic testing was performed by denaturing high performance liquid chromatography and automatic DNA sequencing of nine myofilament-encoding genes including both thick filament proteins (myosin binding protein C, beta-myosin heavy chain, regulatory and essential light chains); and thin filament proteins (troponin-T, troponin-I, troponin-C, alpha-tropomyosin and alpha-actin). Results . Thirty-four mutations were identified in 30/46 patients (myofilament-HCM; 65%), including 29 with thick filament and 6 with thin filament mutations, as well as 4 with complex genotype. Despite similar age and clinical features, patients with myofilament-HCM showed lower Dip-MBF values than the patients with a negative genetic test (1.6±0.7 versus 2.2±0.9 ml/min/g, respectively; p=0.03). Specifically, 13/30 (43%) patients with myofilament-HCM had a Dip-MBF below the lower tertile for the study group (≤1.38 ml/min/g), compared to 2/16 (12%) patients with a negative genetic test (p=0.034). No difference in Dip-MBF was evident with respect to the particular sarcomeric gene involved (ANOVA p=0.63). HCM due to sarcomere gene mutations is characterized by more severe impairment in microvascular function compared to myofilament negative disease, irrespective of the involved contractile protein. These findings suggest that sarcomeric mutations might be implicated in adverse remodelling of the microcirculation in patients with HCM, and account for the greater prevalence of ventricular dysfunction and failure in this subset.

Background: Identification of people with hypertrophic cardiomyopathy (HCM) who are at risk of sudden cardiac death (SCD) and require a prophylactic implantable cardioverter defibrillator is challenging. In 2014, the European Society of Cardiology proposed a new risk stratification method based on a risk prediction model (HCM Risk-SCD) that estimates the 5-year risk of SCD. The aim was to externally validate the 2014 European Society of Cardiology recommendations in a geographically diverse cohort of patients recruited from the United States, Europe, the Middle East, and Asia. Methods: This was an observational, retrospective, longitudinal cohort study. Results: The cohort consisted of 3703 patients. Seventy three (2%) patients reached the SCD end point within 5 years of follow-up (5-year incidence, 2.4% [95% confidence interval {CI}, 1.9–3.0]). The validation study revealed a calibration slope of 1.02 (95% CI, 0.93–1.12), C-index of 0.70 (95% CI, 0.68–0.72), and D-statistic of 1.17 (95% CI, 1.05–1.29). In a complete case analysis (n= 2147; 44 SCD end points at 5 years), patients with a predicted 5-year risk of <4% (n=1524; 71%) had an observed 5-year SCD incidence of 1.4% (95% CI, 0.8–2.2); patients with a predicted risk of ≥6% (n=297; 14%) had an observed SCD incidence of 8.9% (95% CI, 5.96–13.1) at 5 years. For every 13 (297/23) implantable cardioverter defibrillator implantations in patients with an estimated 5-year SCD risk ≥6%, 1 patient can potentially be saved from SCD. Conclusions: This study confirms that the HCM Risk-SCD model provides accurate prognostic information that can be used to target implantable cardioverter defibrillator therapy in patients at the highest risk of SCD.