Abstract 13481: South Asian-specific MYBPC3 25bp Intronic Deletion Carriers Demonstrate Hypercontractility and Impaired Diastolic Function Under Exercise Stress

Abstract

Introduction: A 25bp intronic deletion in MYBPC3 ( Δ25bp ), present in 6% of US South Asians, is a risk allele for late onset left ventricular (LV) dysfunction and hypertrophy. Hypothesis: Asymptomatic Δ25bp carriers have detectable subclinical pathology to development of LV hypercontractility and impaired relaxation. Methods: To evaluate Δ25bp carriers for changes in cardiac function with bicycle exercise stress echocardiography and continuous cardiac monitoring, 16 Δ25bp male carriers (51±2 years) and 10 age- and sex-matched non-carrier (NCs) controls (50±3 years) participated in this pilot study. Of 16 Δ25bp carriers, six carried an additional pathogenic variant D389V in MYBPC3 . Included subjects had no uncontrolled comorbidities. Regression analysis and two-way ANOVA were performed, and 95% confidence interval (CI) and p values were reported. Results: Baseline echocardiographic parameters as well as baseline and monitored exercise heart rate and blood pressure were similar in both groups. The estimated effect of exercise stress and genotype showed that Δ25bp carriers had significantly higher ejection fraction (%) (CI: 4.03±1.64; p<0.0001) and higher LV outflow tract peak velocity (m/s) (CI: 0.15±0.06; p<0.0001) in comparison to NCs. Additionally, stress-induced LV end diastolic diameter did not increase in Δ25bp carriers as compared to NCs with a significant difference between the groups (CI: 0.22±0.11; p=0.0002). E/A ratio, a marker of diastolic function, significantly decreased with exercise in Δ25bp carriers (slope: -0.002; p=0.005) but showed non-significant change in the NCs (slope: -0.0006; p=0.428). Right ventricular systolic excursion velocity s' (m/s) as a marker of right ventricle function increased similarly in both groups, although tricuspid annular plane systolic excursion (cm) increased more dramatically in carriers (slope: 0.004; p=0.0002). Sub-analysis of Δ25bp vs Δ25bp + D389V did not reveal any differences. Conclusions: LV hypercontractility under exercise stress conditions with evidence of diastolic impairment at high workloads is evident among asymptomatic carriers of MYBPC3 Δ25bp allele, suggesting MYBPC3 Δ25bp as a risk allele with sub-clinical pathology prior to late onset LV dysfunction in South Asians .