Ischemic heart disease is a highly heritable disorder and the leading cause of mortality worldwide. At a total cost of $475 billion/year, it is also the most costly disease in the US. Unbiased genome-wide association studies (GWAS) have identified genetic variants contributing to risk of myocardial infarction. In population-based healthy cohorts, genetic variation has been shown to contribute to gene expression level variation, also called expression quantitative trait loci (eQTL), which may contribute to complex phenotypes. Importantly, eQTLs show a high degree of tissue specificity. To date, only a handful of human tissues have been interrogated for eQTLs, with none comprising human cardiac tissue. This grant proposal builds upon our pilot data demonstrating that myocardial transcription is significantly altered upon exposure to ischemia, and that genetic variants markedly determine transcriptional response. We will rigorously test our global hypothesis that genetic variation contributes to differences in gene expression in human left ventricular myocardium, and that these variants contribute to clinically significant myocardial injury.
Aim 1 : We will characterize the effect of acute ischemia on the transcriptional profile of left ventricular myocardium by performing whole transcriptome next-generation RNA-sequencing in 1) 100 patients undergoing cardiac surgery by sampling human left ventricular tissue prior to, and after the obligate ischemic insult of CPB; 2) isolated perfused mice hearts exposed to hypoxic and ischemic conditions.
Aim 2 : We will quantify the effects of common genetic variants upon gene expression levels in human left ventricular myocardium subjected to ischemia as described in Aim 1. We will use whole genome genotyping and next generation RNA sequencing to perform independent eQTL analysis in ventricular myocardium before and after ischemic injury. This approach will provide an unbiased assessment of the genetic contribution to human cardiac gene regulation in myocardial ischemia.
Aim 3 : To determine clinical relevance of genetic variants associated with expression changes from Aim 2, we will examine these variants in a cohort of 2,400 patients who have also undergone cardiac surgery with CPB. eQTL variants will be genotyped and tested for association with perioperative myocardial injury, all-cause mortality and ventricular dysfunction in this very well phenotyped cohort. These results will define the link between genetic variation, altered expression and myocardial injury in humans, and significantly advance the biological understanding of myocardial injury. These insights may facilitate the development of new therapeutic strategies to alleviate the burden of myocardial injury in humans.
Cardiovascular disease is the leading cause of death and disability in the world, and with an aging population only expected to increase. Genetics play a significant role in the causes and outcomes of a heart attack, yet we know little about the etiology, pathways and modifiers of disease progression. We are examining genetic effects of a mild heart attack on the left ventricle of the heart in mice and humans, and confirming these findings in a much larger population of patients undergoing heart surgery.
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| Saddic, Louis A; Muehlschlegel, Jochen D (2016) Sarco""MiR"" friend or foe: a perspective on the mechanisms of doxorubicin-induced cardiomyopathy. Ann Transl Med 4:203 |
| Sigurdsson, Martin I; Saddic, Louis; Heydarpour, Mahyar et al. (2016) Allele-specific expression in the human heart and its application to postoperative atrial fibrillation and myocardial ischemia. Genome Med 8:127 |
| Saddic, Louis A; Chang, Tzuu-Wang; Sigurdsson, Martin I et al. (2015) Integrated microRNA and mRNA responses to acute human left ventricular ischemia. Physiol Genomics 47:455-62 |
| Muehlschlegel, Jochen D; Christodoulou, Danos C; McKean, David et al. (2015) Using next-generation RNA sequencing to examine ischemic changes induced by cold blood cardioplegia on the human left ventricular myocardium transcriptome. Anesthesiology 122:537-50 |
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