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Role of Genetic Polymorphisms of Ion Channels in the Pathophysiology of Coronary Microvascular Dysfunction and Ischemic Heart Disease

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Basic Res Cardiol (2013) 108:387 DOI 10.1007/s00395-013-0387-4 ORIGINAL CONTRIBUTION Role of genetic polymorphisms of ion channels in the pathophysiology of coronary microvascular dysfunction and ischemic heart disease Francesco Fedele • Massimo Mancone • William M. Chilian • Paolo Severino • Emanuele Canali • Suzanna Logan • Maria Laura De Marchis • Maurizio Volterrani • Raffaele Palmirotta • Fiorella Guadagni Received: 27 May 2013 / Revised: 13 August 2013 / Accepted: 11 September 2013 / Published online: 26 September 2013 Ó The Author(s) 2013. This article is published with open access at Springerlink.com Abstract Conventionally, ischemic heart disease (IHD) study was conducted, analyzing genetic polymorphisms is equated with large vessel coronary disease. However, relative to (1) NOS3 encoding for endothelial nitric oxide recent evidence has suggested a role of compromised synthase (eNOS); (2) ATP2A2 encoding for the Ca2?/H?- microvascular regulation in the etiology of IHD. Because ATPase pump (SERCA); (3) SCN5A encoding for the regulation of coronary blood flow likely involves activity voltage-dependent Na? channel (Nav1.5); (4) KCNJ8 and of specific ion channels, and key factors involved in KCNJ11 encoding for the Kir6.1 and Kir6.2 subunits of endothelium-dependent dilation, we proposed that genetic K-ATP channels, respectively; and (5) KCN5A encoding anomalies of ion channels or specific endothelial regulators for the voltage-gated K? channel (Kv1.5). No significant may underlie coronary microvascular disease. We aimed to associations between clinical IHD manifestations and evaluate the clinical impact of single-nucleotide polymor- polymorphisms for SERCA, Kir6.1, and Kv1.5 were phisms in genes encoding for ion channels expressed in the observed (p [ 0.05), whereas specific polymorphisms coronary vasculature and the possible correlation with IHD detected in eNOS, as well as in Kir6.2 and Nav1.5 were resulting from microvascular dysfunction. 242 consecutive found to be correlated with IHD and microvascular dys- patients who were candidates for coronary angiography function. Interestingly, genetic polymorphisms for ion were enrolled. A prospective, observational, single-center channels seem to have an important clinical impact influ- encing the susceptibility for microvascular dysfunction and IHD, independent of the presence of classic cardiovascular F. Fedele and M. Mancone contributed equally to this paper. risk factors. F. Fedele (&) Á M. Mancone Á P. Severino Á E. Canali Á Keywords Ion channels Á Genetic polymorphisms Á S. Logan Coronary microcirculation Á Endothelium Á Department of Cardiovascular, Respiratory, Nephrology, Anesthesiology and Geriatric Sciences, Sapienza University Atherosclerosis Á Ischemic heart disease of Rome, Umberto I Policlinic, Viale del Policlinico 155, 00161 Rome, Italy e-mail: [email protected] Introduction W. M. Chilian Á P. Severino Department of Integrative Medical Sciences, Northeastern Ohio Historically, in the interrogation of altered vascular func- Universities College of Medicine, Rootstown, OH, USA tion in patient with ischemic heart disease (IHD), scientists have focused their attention on the correlation between M. L. De Marchis Á R. Palmirotta Á F. Guadagni Department of Advanced Biotechnologies and Bioimaging, endothelial dysfunction and atherosclerosis [11, 53, 65, IRCCS San Raffaele Pisana, Rome, Italy 67]. However, the endothelium-independent dysfunction in coronary microcirculation and its possible correlations with M. Volterrani atherosclerotic disease and myocardial ischemia have not Source Cardiovascular Research Unit, Department of Medical Sciences, Centre for Clinical and Basic Research, IRCCS San been extensively investigated. In normal conditions, coro- Raffaele Pisana, Rome, Italy nary blood flow regulation (CBFR) is mediated by several 123 Page 2 of 12 Basic Res Cardiol (2013) 108:387 different systems, including endothelial, nervous, neuro- genetic analysis, and processing of personal data). The humoral, myogenic, and metabolic mechanisms [2, 10, 14, study was approved by the Institution’s Ethics Committee. 15, 63, 64, 69]. Moreover, physiologic CBFR depends also All clinical and instrumental characteristics were collected on several ion channels, such as ATP-sensitive potassium in a dedicated database. (KATP) channels, voltage-gated potassium (Kv) channels, voltage-gated sodium (Nav) channels, and others. Ion Study design channels regulate the concentration of calcium in both coronary smooth muscle and endothelial cells, which in (a) Standard therapies were administered, according to turn modulates the degree of contractile tone in vascular current guidelines [36, 68]. muscle and the amount of nitric oxide that is produced by (b) In all patients, an echocardiography evaluation before the endothelium, respectively. In this context, ion channels and after coronary angiography was performed. play a primary role in the rapid response of both the (c) According to standard clinical practice, coronary endothelium and vascular smooth muscle cells of coronary angiography was performed using radial artery or arterioles to the perpetually fluctuating demands of the femoral artery Judkins approach via sheath insertion. myocardium for blood flow [5, 6, 13, 18, 33, 45, 46, 51, 52, (d) In patients showing normal epicardial arteries, intra- 61, 73, 75]. coronary functional tests were performed through Despite this knowledge, there still exists an important Doppler flow wire to evaluate both endothelium- gap about the clinical relevance and causes of microvas- dependent microvascular function [via intracoronary cular dysfunction in IHD. By altering the overall regulation (IC) infusion of acetylcholine (2.5–10 lg)] and non- of blood flow in the coronary system, microvascular dys- endothelium-dependent microvascular function [via function could alter the normal distribution of shear forces IC infusion of adenosine (5 lg)] [31]. in large coronary arteries, thus promoting atherosclerosis. (e) In all enrolled patients, a peripheral blood sample for On the other hand, proximal coronary artery stenosis could genetic analysis was taken. contribute to microvascular dysfunction [29, 60]. Because On the basis of the coronary angiography and the intra- ion channels play such a critical role in microvascular coronary functional tests, the 242 patients were divided endothelial and smooth muscle function, we hypothesized into three groups (see also Fig. 1). that alterations of coronary ion channels could be the pri- mum movens in a chain of events leading to microvascular • Group 1: 155 patients with anatomic coronary alter- dysfunction and myocardial ischemia, independent of the ation (comprising patients with acute coronary syn- presence of atherosclerosis. Therefore, the objective of our drome and chronic stable angina). study was to evaluate the possible correlation between IHD and single-nucleotide polymorphisms (SNPs) for genes encoding several regulators involved in CBFR, including ion channels acting in vascular smooth muscle and/or endothelial cells of coronary arteries. Methods In this prospective, observational, single-center study, 242 consecutive patients admitted to our department with the indication to undergo coronary angiography were enrolled. All patients matched inclusion (age [18; suspected or documented diagnosis of acute coronary syndrome or sta- ble angina with indication(s) for coronary angiography, in accordance with current guidelines [36, 68], and the same Fig. 1 Study design: 242 consecutive not randomized patients ethno-geographic Caucasian origin) and exclusion criteria matching inclusion and exclusion criteria were enrolled. In all (previous allergic reaction to iodine contrast, renal failure, patients, coronary angiography was performed, according to current simultaneous genetic disease, cardiogenic shock, non- ESC/ACC/AHA guidelines. In patients with angiographically normal ischemic cardiomyopathy). All patients signed an informed coronary artery, intracoronary functional tests were performed. In 242 patients (155 with coronary artery disease, 46 patients with micro- consent document prior to participation in the study, which vascular dysfunction, endothelium and/or non-endothelium depen- included acknowledgement of the testing procedures to be dent, and 41 patients with anatomically and functionally normal performed (i.e., coronary angiography; intracoronary tests; coronary arteries) genetic analysis was performed 123 Basic Res Cardiol (2013) 108:387 Page 3 of 12 • Group 2: 46 patients with functional coronary alteration sequences are listed in Table 1. In order to exclude pre- [normal coronary arteries as assessed by angiography, analytical and analytical errors, all direct sequencing and microvascular dysfunction defined as coronary flow analyses were carried out on both strands using Big Dye reserve (CFR) \ 2.5 after IC infusion of acetylcholine Terminator v3.1 Cycle Sequencing kit (Applied Biosys- and adenosine]. tems), run on an ABI 3130 Genetic Analyzer (Applied • Group 3: 41 patients with anatomically and functionally Biosystems), and repeated on PCR products obtained from normal coronary arteries as assessed by angiography new nucleic acid extractions. All data analyses were per- and with normal functional tests (CFR C 2.5 after formed in a blind fashion. intracoronary infusion of acetylcholine and adenosine) (Fig. 1). Statistical analysis This report, intended as pilot study, is the first to compare Genetic analysis the prevalence of SNPs in genes
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