Role of genetic polymorphisms of ion channels in the pathophysiology of coronary microvascular dysfunction and ischemic heart disease

Fedele, Francesco; Mancone, Massimo; Chilian, William M.; Severino, Paolo; Canali, Emanuele; Logan, Suzanna; Marchis, Maria Laura De; Volterrani, Maurizio; Palmirotta, Raffaele; Guadagni, Fiorella

doi:10.1007/s00395-013-0387-4

Cited by 66 publications

(100 citation statements)

References 76 publications

(94 reference statements)

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“…37 Previously, polymorphisms in several ion channels and in eNOS, but not in Kv1.5 channels were associated with coronary microvascular disease. 38 …”

Section: Discussionmentioning

confidence: 99%

Requisite Role of Kv1.5 Channels in Coronary Metabolic Dilation

Ohanyan

Yin

Bardakjian

et al. 2015

Circulation Research

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Rationale In the working heart coronary blood flow is linked to the production of metabolites, which modulate tone of smooth muscle in a redox-dependent manner. Voltage-gated potassium channels, which play a role in controlling membrane potential in vascular smooth muscle, have certain members that are redox sensitive. Objective To determine the role of redox-sensitive Kv1.5 channels in coronary metabolic flow regulation. Methods and Results In mice (wild type [WT], Kv1.5 null [Kv1.5−/−], and Kv1.5−/− and WT with inducible, smooth muscle specific expression of Kv1.5 channels) we measured mean arterial pressure (MAP), myocardial blood flow (MBF), myocardial tissue pO2, and ejection fraction (EF) before and after inducing cardiac stress with norepinephrine (NE). Cardiac work (CW) was estimated as the product of MAP and heart rate. Isolated arteries were studied to establish if genetic alterations modified vascular reactivity. Despite higher levels of CW in the Kv1.5−/− (versus WT at baseline and all doses of NE), MBF was lower in Kv1.5−/− than in WT. At high levels of CW, tissue pO2 dropped significantly along with EF. Expression of Kv1.5 channels in smooth muscle in the null background rescued this phenotype of impaired metabolic dilation. In isolated vessels from Kv1.5−/− mice, relaxation to H2O2 was impaired, but responses to adenosine and acetylcholine were normal compared to WT. Conclusions Kv1.5 channels in vascular smooth muscle play a critical role in coupling myocardial blood flow to cardiac metabolism. Absence of these channels disassociates metabolism from flow resulting in cardiac pump dysfunction and tissue hypoxia.

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“…37 Previously, polymorphisms in several ion channels and in eNOS, but not in Kv1.5 channels were associated with coronary microvascular disease. 38 …”

Section: Discussionmentioning

confidence: 99%

Requisite Role of Kv1.5 Channels in Coronary Metabolic Dilation

Ohanyan

Yin

Bardakjian

et al. 2015

Circulation Research

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“…There is a growing body of evidence supporting K V channels as critical modulators in the local metabolic control of coronary blood flow [3, 31, 36]. Other K + channels, such as inwardly rectifying K + channels (Kir) may also be important [11], but were not studied here. Non-selective inhibition of K V channels with 4-AP dose-dependently reduces resting coronary blood flow and decreases the balance between myocardial oxygen delivery and metabolism in response to cardiac pacing, norepinephrine, and exercise [3, 36].…”

Section: Discussionmentioning

confidence: 99%

Critical contribution of KV1 channels to the regulation of coronary blood flow

et al. 2016

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Ion channels in smooth muscle control coronary vascular tone, but the mechanisms require further investigation. The purpose of this study was to evaluate the functional role of KV1 channels on porcine coronary blood flow by using the selective antagonist correolide. KV1 channel gene transcripts were found in porcine coronary arteries, with KCNA5 (encoding KV1.5) being most abundant (P<0.001). Immunohistochemical staining demonstrated KV1.5 protein in the vascular smooth muscle layer of both porcine and human coronary arteries, including microvessels. Whole-cell patch clamp experiments demonstrated significant correolide-sensitive (1–10 µM) current in coronary smooth muscle. In vivo studies included direct intracoronary infusion of vehicle or correolide into a pressure-clamped left anterior descending artery of healthy swine (n=5 in each group) with simultaneous measurement of coronary blood flow. Intracoronary correolide (~0.3–3 µM targeted plasma concentration) had no effect on heart rate or systemic pressure, but reduced coronary blood flow in a dose-dependent manner (P<0.05). Dobutamine (0.3–10 µg/kg/min) elicited coronary metabolic vasodilation and intracoronary correolide (3 µM) significantly reduced coronary blood flow at any given level of myocardial oxygen consumption (P<0.001). Coronary artery occlusions (15 s) elicited reactive hyperemia and correolide (3 µM) reduced the flow volume repayment by approximately 30% (P<0.05). Taken together, these data support a major role for KV1 channels in modulating baseline coronary vascular tone and perhaps vasodilation in response to increased metabolism and transient ischemia.

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“…SNPs for MYH15 (codes for myosin heavy chain), VEGFA, and NT5E (associated with vascular calcification) were associated with low CFR in men but not women. In a prospective study, Fedele et al 58 identified specific polymorphisms in the gene for eNOS, and for ion channels including Kir6.2 (Katp channels), and Nav1.5 (sodium channel) in patients undergoing cardiac catheterization. SNPs in eNOS and in Kir6.2 were specific for subjects with microcirculatory dysfunction.…”

Section: The Microcirculation As a Window Into Conduit Artery Diseasementioning

confidence: 99%

The Human Microcirculation

Gutterman

Chabowski

Kadlec

et al. 2016

Circulation Research

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The microcirculation is responsible for orchestrating adjustments in vascular tone to match local tissue perfusion with oxygen demand. Beyond this metabolic dilation, the microvasculature plays a critical role in modulating vascular tone by endothelial release of an unusually diverse family of compounds including nitric oxide, other reactive oxygen species, and arachidonic acid metabolites. Animal models have provided excellent insight into mechanisms of vasoregulation in health and disease. However there are unique aspects of the human microcirculation that serve as the focus of this review. The concept is put forth that vasculo-parenchymal communication is multimodal, with vascular release of nitric oxide eliciting dilation and preserving normal parenchymal function by inhibiting inflammation and proliferation. Likewise, in disease or stress, endothelial release of ROS both mediates dilation and parenchymal inflammation leading to cellular dysfunction, thrombosis, and fibrosis. Some pathways responsible for this stress-induced shift in mediator of vasodilation are proposed. This paradigm may help explain why microvascular dysfunction is such a powerful predictor of cardiovascular events, and help identify new approaches to treatment and prevention.

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Role of genetic polymorphisms of ion channels in the pathophysiology of coronary microvascular dysfunction and ischemic heart disease

Cited by 66 publications

References 76 publications

Requisite Role of Kv1.5 Channels in Coronary Metabolic Dilation

Requisite Role of Kv1.5 Channels in Coronary Metabolic Dilation

Critical contribution of KV1 channels to the regulation of coronary blood flow

The Human Microcirculation

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