Coronary perivascular adipose tissue (PVAT) is a naturally occurring adipose tissue depot that normally surrounds the major coronary arteries on the surface of the heart. While originally thought to promote vascular health and integrity, there is a growing body of evidence to support that coronary PVAT displays a distinct phenotype relative to other adipose depots and is capable of producing local factors with the potential to augment coronary vascular tone, inflammation, and the initiation and progression of coronary artery disease. The purpose of the present review is outline previous findings regarding the cardiovascular effects of coronary PVAT and the potential mechanisms by which adipose-derived factors may influence coronary vascular function and the progression of atherogenesis.

Objective The effects of coronary perivascular adipose tissue (PVAT) on vasomotor tone are influenced by an obese phenotype and are distinct from other adipose tissue depots. The purpose of this investigation was to examine the effects of lean and obese coronary PVAT on end-effector mechanisms of coronary vasodilation and to identify potential factors involved. Approach and Results Hematoxylin and eosin staining revealed similarities in coronary perivascular adipocyte size between lean and obese Ossabaw swine. Isometric tension studies of isolated coronary arteries from Ossabaw swine revealed that factors derived from lean and obese coronary PVAT attenuated vasodilation to adenosine. Lean coronary PVAT inhibited KCa and KV7, but not KATP channel mediated dilation in lean arteries. In the absence of PVAT, vasodilation to KCa and KV7 channel activation was impaired in obese arteries relative to lean arteries. Obese PVAT had no effect on KCa or KV7 channel mediated dilation in obese arteries. In contrast, obese PVAT inhibited KATP channel mediated dilation in both lean and obese arteries. The differential effects of obese versus lean PVAT were not associated with changes in either coronary KV7 or KATP channel expression. Incubation with calpastatin attenuated coronary vasodilation to adenosine in lean but not obese arteries. Conclusions These findings indicate that lean and obese coronary PVAT attenuates vasodilation via inhibitory effects on vascular smooth muscle K+ channels and that alterations in specific factors such as calpastatin are capable of contributing to the initiation and/or progression of smooth muscle dysfunction in obesity.

This study tested the hypothesis that obesity alters the cardiac response to ischemia/reperfusion and/or glucagon like peptide-1 (GLP-1) receptor activation, and that these differences are associated with alterations in the obese cardiac proteome and microRNA (miR) transcriptome. Ossabaw swine were fed normal chow or obesogenic diet for 6 months. Cardiac function was assessed at baseline, during a 30-min coronary occlusion, and during 2 hours of reperfusion in anesthetized swine treated with saline or exendin-4 for 24 hours. Cardiac biopsies were obtained from normal and ischemia/reperfusion territories. Fat-fed animals were heavier, and exhibited hyperinsulinemia, hyperglycemia, and hypertriglyceridemia. Plasma troponin-I concentration (index of myocardial injury) was increased following ischemia/reperfusion and decreased by exendin-4 treatment in both groups. Ischemia/reperfusion produced reductions in systolic pressure and stroke volume in lean swine. These indices were higher in obese hearts at baseline and relatively maintained throughout ischemia/reperfusion. Exendin-4 administration increased systolic pressure in lean swine but did not affect blood pressure in obese swine. End-diastolic volume was reduced by exendin-4 following ischemia/reperfusion in obese swine. These divergent physiologic responses were associated with obesity-related differences in proteins related to myocardial structure/function (e.g. titin) and calcium handling (e.g. SERCA2a, histidine-rich Ca2+ binding protein). Alterations in expression of cardiac miRs in obese hearts included miR-15, miR-27, miR-130, miR-181, and let-7. Taken together, these observations validate this discovery approach and reveal novel associations that suggest previously undiscovered mechanisms contributing to the effects of obesity on the heart and contributing to the actions of GLP-1 following ischemia/reperfusion.

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.

Capsaicin alone does not cause contractions in conduit canine coronary artery; however, pre-treatment with pro-inflammatory prostaglandin-thromboxane agonists may unmask capsaicin's vasoconstrictive potential.

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This study examined the cardiovascular effects of GLP-1 (7–36) or (9–36) on myocardial oxygen consumption, function and systemic hemodynamics in vivo during normal perfusion and during acute, regional myocardial ischemia. Lean Ossabaw swine received systemic infusions of saline vehicle or GLP-1 (7–36 or 9–36) at 1.5, 3.0, and 10.0 pmol/kg/min in sequence for 30 min at each dose, followed by ligation of the left circumflex artery during continued infusion at 10.0 pmol/kg/min. Systemic GLP-1 (9–36) had no effect on coronary flow, blood pressure, heart rate or indices of cardiac function before or during regional myocardial ischemia. Systemic GLP-1 (7–36) exerted no cardiometabolic or hemodynamic effects prior to ischemia. During ischemia, GLP-1 (7–36) increased cardiac output by approximately 2 L/min relative to vehicle-controls (p=0.003). This response was not diminished by treatment with the non-depolarizing ganglionic blocker hexamethonium. Left ventricular pressure-volume loops measured during steady state conditions with graded occlusion of the inferior vena cava to assess load-independent contractility revealed that GLP-1 (7–36) produced marked increases in end diastolic volume (74 ± 1 to 92 ± 5 mL; p=0.03) and volume axis intercept (8 ± 2 to 26 ± 8; p=0.05), without any change in the slope of the end systolic pressure volume relationship vs. vehicle during regional ischemia. GLP-1 (9–36) produced no changes in any of these parameters compared to vehicle. These findings indicate that short-term systemic treatment with GLP-1 (7–36) but not GLP-1 (9–36) significantly augments cardiac output during regional myocardial ischemia, via increases in ventricular preload without changes in cardiac inotropy.

Goodwill AG, Fu L, Noblet JN, Casalini ED, Sassoon D, Berwick ZC, Kassab GS, Tune JD, Dick GM. K V7 channels contribute to paracrine, but not metabolic or ischemic, regulation of coronary vascular reactivity in swine. Am J Physiol Heart Circ Physiol 310: H693-H704, 2016. First published January 29, 2016 doi:10.1152 doi:10. /ajpheart.00688.2015 and voltage-dependent K ϩ (KV) channels play key roles in regulating coronary blood flow in response to metabolic, ischemic, and paracrine stimuli. The K V channels responsible have not been identified, but K V7 channels are possible candidates. Existing data regarding KV7 channel function in the coronary circulation (limited to ex vivo assessments) are mixed. Thus we examined the hypothesis that K V7 channels are present in cells of the coronary vascular wall and regulate vasodilation in swine. We performed a variety of molecular, biochemical, and functional (in vivo and ex vivo) studies. Coronary arteries expressed KCNQ genes (quantitative PCR) and K V7.4 protein (Western blot). Immunostaining demonstrated K V7.4 expression in conduit and resistance vessels, perhaps most prominently in the endothelial and adventitial layers. Flupirtine, a K V7 opener, relaxed coronary artery rings, and this was attenuated by linopirdine, a K V7 blocker. Endothelial denudation inhibited the flupirtine-induced and linopirdine-sensitive relaxation of coronary artery rings. Moreover, linopirdine diminished bradykinin-induced endothelial-dependent relaxation of coronary artery rings. There was no effect of intracoronary flupirtine or linopirdine on coronary blood flow at the resting heart rate in vivo. Linopirdine had no effect on coronary vasodilation in vivo elicited by ischemia, H 2O2, or tachycardia. However, bradykinin increased coronary blood flow in vivo, and this was attenuated by linopirdine. These data indicate that K V7 channels are expressed in some coronary cell type(s) and influence endothelial function. Other physiological functions of coronary vascular K V7 channels remain unclear, but they do appear to contribute to endothelium-dependent responses to paracrine stimuli. (3,14). Recent evidence suggests that myocardial production of hydrogen peroxide (H 2 O 2 ) may be a signal responsible for the near lockstep increases of coronary blood flow that accompany intensified metabolic demand (21,40,47). H 2 O 2 is generated in a variety of cellular processes and may be the primary transmitter of physiological redox signals (9, 45). For example, in coronary microvessels, H 2 O 2 is an endogenous hyperpolarizing factor released by mechanical and paracrine stimulation of the endothelium (31, 46). The specific redox-sensitive targets mediating H 2 O 2 -induced vasodilation of coronary vascular smooth have not been firmly established. Our previous findings suggest that voltage-dependent K ϩ (K V ) channels may play an important role, but the identities of individual K V channels involved remain elusive (4,5,12,38,39). K V 7 channels are expressed in a variety of vascular smooth muscle ...