Ischemic heart disease (IHD) is classically associated with coronary artery disease (CAD) and cardiovascular risk factors. Recent evidences give importance to the correlation between coronary microvascular dysfunction (CMD) and IHD, in absence of CAD, underlying the importance of coronary blood flow regulation mechanisms and their pathophysiology. Ion channels, expressed by coronary microvasculature represent the end effector of these mechanisms. We proposed a correlation between ion channels genetic variants and IHD. Recently, we reported the correlation between some single nucleotide polymorphisms (SNPs) of ion channels and IHD, independently from cardiovascular risk factors. The first goal of this prospective, observational, single-center study is to evaluate genetic and molecular aspects of regulators of coronary blood flow in patients with ischemic heart disease, including coroanry artery disease (stenosis >50%), coronary microvascular dysfunction and control group. The second goal is to investigate the stability of the proteins upon mutation, both thermodynamically and structurally. We will perform in 400 patients with ischemic heart disease a genetic analysis of regulators of coronary blood flow. Moreover, we will extend this analysis on other 600 extracted DNA previously obtained from ischemic patients. Furthermore, functional effect of protein coding variants identified in genes included in the panel will be analyzed through in silico structural analyses.
Dissecting the genetic component underlying cardiovascular disease is a challenging task, as it is a complex disease, with both genetic and environmental factors exerting a role. Next Generation Sequencing technologies provide information on a genomic scale, with a single base resolution, in a rapid and cost effective way and changed the way to study genetic bases of complex traits leading to identification of molecular bases of human disease at an accelerating rate. These approaches provide the opportunity to perform parallel analysis of a great number of genes in an unbiased approach contributing to advance our knowledge regarding the pathology of complex diseases such as CVD. And potentially, to establishing a risk profile for the pathology process of these diseases.
In the study team, Unit A, identified as the UOC Malattie Cardiovascolari of the Department of Cardiovascular, Respiratory, Nephrology, Anesthesiology and Geriatric Sciences of Sapienza University, admit almost 1000 patient per year with suspected myocardial ischemia and with an indication to undergo coronary angiography. By this numerosity, we are confident we can reach the sample size within two year. Moreover, our research group in the previous published studies has already enrolled more than 600 patients with indication to undergo coronary angiography for suspected myocardial ischemia. In this population, we compared the prevalence of SNPs in genes encoding coronary ion channels between patients with CAD or CMD and those with both anatomically and functionally normal coronary arteries suggested the possibility of associations between SNPs and IHD. Moreover, patients were comparable regarding cardiovascular risk factors, while a moderate deviation from the HW equilibrium in the genotypic distribution were observed. In addition, a genotype for a subunit KATP channels (i.e. rs5215_GG for Kir6.2 subunit) appeared to be an independent protective factor in the development of CAD, illustrating a potentially important implication of genetic polymorphisms in the susceptibility to IHD.