Dataset Information

Genetic Reduction in Left Ventricular Protein Kinase C-? and Adverse Ventricular Remodeling in Human Subjects.

ABSTRACT: BACKGROUND:Inhibition of PKC-? (protein kinase C-?) enhances contractility and cardioprotection in animal models, but effects in humans are unknown. Genotypes at rs9912468 strongly associate with PRKCA expression in the left ventricle, enabling genetic approaches to measure effects of reduced PKC-? in human populations. METHODS AND RESULTS:We analyzed the cis expression quantitative trait locus for PRKCA marked by rs9912468 using 313 left ventricular specimens from European Ancestry patients. The forward strand minor allele (G) at rs9912468 is associated with reduced PKC-? transcript abundance (1.7-fold reduction in minor allele homozygotes, P=1×10-41). This association was cardiac specific in expression quantitative trait locus data sets that span 16 human tissues. Cardiac epigenomic data revealed a predicted enhancer in complete (R2=1.0) linkage disequilibrium with rs9912468 within intron 2 of PRKCA. We cloned this region and used reporter constructs to verify cardiac-specific enhancer activity in vitro in cardiac and noncardiac cells and in vivo in zebrafish. The PRKCA enhancer contains 2 common genetic variants and 4 haplotypes; the haplotype correlated with the rs9912468 PKC-?-lowering allele (G) showed lowest activity. In contrast to previous reports in animal models, the PKC-?-lowering allele is associated with adverse left ventricular remodeling (higher mass, larger diastolic dimension), reduced fractional shortening, and higher risk of dilated cardiomyopathy in human populations. CONCLUSIONS:These findings support PKC-? as a regulator of the human heart but suggest that PKC-? inhibition may adversely affect the left ventricle depending on timing and duration. Pharmacological studies in human subjects are required to discern potential benefits and harms of PKC-? inhibitors as an approach to treat heart disease.

SUBMITTER: Hu R

PROVIDER: S-EPMC5858599 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Genetic Reduction in Left Ventricular Protein Kinase C-α and Adverse Ventricular Remodeling in Human Subjects.

Hu Ray R Morley Michael P MP Brandimarto Jeffrey J Tucker Nathan R NR Parsons Victoria A VA Zhao Sihai D SD Meder Benjamin B Katus Hugo A HA Rühle Frank F Stoll Monika M Villard Eric E Cambien François F Lin Honghuang H Smith Nicholas L NL Felix Janine F JF Vasan Ramachandran S RS van der Harst Pim P Newton-Cheh Christopher C Li Jin J Kim Cecilia E CE Hakonarson Hakon H Hannenhalli Sridhar S Ashley Euan A EA Moravec Christine S CS Tang W H Wilson WHW Maillet Marjorie M Molkentin Jeffery D JD Ellinor Patrick T PT Margulies Kenneth B KB Cappola Thomas P TP

Circulation. Genomic and precision medicine 20180301 3

<h4>Background</h4>Inhibition of PKC-α (protein kinase C-α) enhances contractility and cardioprotection in animal models, but effects in humans are unknown. Genotypes at rs9912468 strongly associate with <i>PRKCA</i> expression in the left ventricle, enabling genetic approaches to measure effects of reduced PKC-α in human populations.<h4>Methods and results</h4>We analyzed the <i>cis</i> expression quantitative trait locus for <i>PRKCA</i> marked by rs9912468 using 313 left ventricular specimens ...[more]

PMID: 29540468

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Project description:To evaluate age-related left ventricular (LV) remodeling during longitudinal observation of a large cohort of asymptomatic individuals who were free of clinical cardiovascular disease at baseline.The applicable institutional review boards approved this study, and all participants gave informed consent. Cardiac magnetic resonance (MR) imaging was used to identify longitudinal changes in LV structure and function in 2935 participants who underwent baseline and follow-up cardiac MR imaging in the Multi-Ethnic Study of Atherosclerosis. Participants were free of clinical cardiovascular disease at baseline. Participants who experienced an incident coronary heart disease event were excluded. Data were analyzed with multivariable mixed-effects regression models in which the outcome was cardiac MR imaging measurement, and the covariates included follow-up time and cardiac risk factors.Participants were aged 54-94 years at follow-up, and 53% of the participants were women. Median time between baseline and follow-up cardiac MR imaging was 9.4 years. Over this period, LV mass increased in men and decreased slightly in women (8.0 and -1.6 g per decade, respectively; P < .001). In both men and women, LV end-diastolic volume decreased (-9.8 and -13.3 mL per decade, respectively; P < .001), stroke volume decreased (-8.8 and -8.6 mL per decade, respectively; P < .001), and mass-to-volume ratio increased (0.14 and 0.11 g/mL per decade, respectively; P < .001). Change in LV mass was positively associated with systolic blood pressure and body mass index and negatively associated with treated hypertension and high-density lipoprotein cholesterol level. In men, the longitudinal LV mass increase was in contrast to a cross-sectional pattern of LV mass decrease.As patients age, the LV responds differently in its mass and volume between men and women, although both men and women experience increased concentric LV remodeling with age. In men, the opposition of longitudinal and cross-sectional changes in LV mass highlights the importance of longitudinal study.

Dataset Information

Genetic Reduction in Left Ventricular Protein Kinase C-? and Adverse Ventricular Remodeling in Human Subjects.

Publications

Genetic Reduction in Left Ventricular Protein Kinase C-α and Adverse Ventricular Remodeling in Human Subjects.

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