LEFT VENTRICULAR SYSTOLIC FUNCTION IN RELATION TO GENETIC VARIATION IN THE CYCLIC GMP-DEPENDENT PROTEIN KINASE: 6B.04

Abstract

Background: Cyclic GMP–dependent protein kinase type I (PRKG1) is a major mediator of cGMP signalling in the cardiovascular system. Recent studies on cardiac-specific PRKG1 knockout mice demonstrated that PRKG1 mediates the negative inotropic effect of cGMP in the myocardium. Objectives: We investigated the association between left ventricular (LV) function and two common polymorphisms in the PRKG1 gene in a general population. Methods: In 456 participants randomly selected from a general population (50.5% women; mean age, 50.5 years; 37.2% hypertensive) without overt cardiac diseases, we performed echocardiography, and collected blood for DNA extraction and genotyping. On the basis of color Doppler myocardial motion data, we calculated end-systolic longitudinal and radial deformation (strain) of the LV inferolateral wall. Results: The genotypic frequencies did not depart from Hardy-Weinberg proportions (P > 0.36). The two PRKG1 intronic SNPs were in linkage disequilibrium (D' = 0.87; P < 0.0001). The PRKG1 haplotypes were AT (46.3%), CC (43.7%), AC (7.0%) and CT (3%). In multivariable-adjusted analyses accounting for sex, age, body mass index, systolic blood pressure, and use of antihypertensive drugs, LV radial strain (mean, 58%) was significantly lower in PRKG1 CC homozygotes than in A-allele carriers (effect size, −4.99%; P = 0.0001). No significant associations were observed between LV longitudinal strain or ejection fraction and the CC haplotype (P > 0.71). Conclusion: The present findings suggest that PRKG1 polymorphisms influence LV radial function. Pending experimental studies on the functional relevance of the CC haplotype and pending replication of our findings in other populations, our results suggest that interference with cGMP-PRKG1 signalling by modification of PRKG1 function might be a way to protect cardiac function.