Coronary Flow Response Research Articles

Association between carotid plaque progression and persistent endothelial dysfunction in an infarct-related coronary artery in STEMI survivors.

Persistent coronary endothelial dysfunction predicts future adverse events; however, performing multiple invasive endothelial function tests is difficult in actual clinical practice. This study examined the association between carotid plaque progression and persistent coronary endothelial dysfunction using serial assessments of the coronary vasomotor response to acetylcholine (ACh) in the infarct-related artery (IRA) among patients with ST-elevation acute myocardial infarction (STEMI). This study included 169 consecutive patients with a first STEMI due to the left anterior descending coronary artery (LAD) occlusion who underwent successful percutaneous coronary intervention. The vasomotor response to ACh in the LAD was measured within two weeks after acute myocardial infarction (AMI) (first test) and repeated at six months (second test) after AMI. Ultrasonography of the bilateral common carotid artery and internal carotid artery was performed during the acute phase, and the thickest intima-media thickness (IMT) of either artery was measured as the maximum IMT. After six months, the IMT at the site of maximal IMT was re-measured to determine the carotid plaque progression. Finally, 87 STEMI patients analyzed. At 6months, 25 patients (28.7%) showed carotid plaque progression. In a multivariable analysis, carotid plaque progression was identified as an independent predictor of persistent coronary endothelial dysfunction, both in terms of coronary diameter response [odd ratio (OR) 3.22, 95% confidence interval (95% CI) 1.13-9.15, p = 0.03] and coronary flow response [OR 2.65, 95% CI 1.01-7.00, p = 0.04]. Independently, carotid plaque progression is linked to persistent endothelial dysfunction in the IRA among STEMI survivors.

Effects of short-term dietary nitrate supplementation on exercise and coronary blood flow responses in patients with peripheral artery disease.

Peripheral arterial disease (PAD) is a prevalent vascular disorder characterized by atherosclerotic occlusion of peripheral arteries, resulting in reduced blood flow to the lower extremities and poor walking ability. Older patients with PAD are also at a markedly increased risk of cardiovascular events, including myocardial infarction. Recent evidence indicates that inorganic nitrate supplementation, which is abundant in certain vegetables, augments nitric oxide (NO) bioavailability and may have beneficial effects on walking, blood pressure, and vascular function in patients with PAD. We sought to determine if short-term nitrate supplementation (via beetroot juice) improves peak treadmill time and coronary hyperemic responses to plantar flexion exercise relative to placebo (nitrate-depleted juice) in older patients with PAD. The primary endpoints were peak treadmill time and the peak coronary hyperemic response to plantar flexion exercise. Eleven PAD patients (52-80 yr.; 9 men/2 women; Fontaine stage II) were randomized (double-blind) to either nitrate-rich (Beet-IT, 0.3 g inorganic nitrate twice/day; BRnitrate) or nitrate-depleted (Beet-IT, 0.04 g inorganic nitrate twice/day, BRplacebo) beetroot juice for 4 to 6 days, followed by a washout of 7 to 14 days before crossing over to the other treatment. Patients completed graded plantar flexion exercise with their most symptomatic leg to fatigue, followed by isometric handgrip until volitional fatigue at 40% of maximum on day 4 of supplementation, and a treadmill test to peak exertion 1-2 days later while continuing supplementation. Hemodynamics and exercise tolerance, and coronary blood flow velocity (CBV) responses were measured. Although peak walking time and claudication onset time during treadmill exercise did not differ significantly between BRplacebo and BRnitrate, the diastolic blood pressure response at the peak treadmill walking stage was significantly lower in the BRnitrate condition. Increases in CBV from baseline to peak plantar flexion exercise after BRplacebo and BRnitrate showed a trend for a greater increase in CBV at the peak workload of plantar flexion with BRnitrate (p = 0.06; Cohen's d = 0.56). Overall, these preliminary findings suggest that inorganic nitrate supplementation in PAD patients is safe, well-tolerated, and may improve the coronary hyperemic and blood pressure responses when their calf muscles are most predisposed to ischemia.Clinical trial registration:https://clinicaltrials.gov/, identifier NCT02553733.

Graphene Oxide Significantly Modifies Cardiac Parameters and Coronary Endothelial Reactivity in Healthy and Hypertensive Rat Hearts Ex Vivo.

Interactions of graphene oxide (GO) with an ex vivo rat heart and its coronary vessels have not been studied yet. Moreover, the conflicting data on the "structure-properties" relationships do not allow for biomedical applications of GO. Herein, we study the impact of GO on the ex vivo isolated rat heart, normotensive and hypertensive, under the working heart and the constant-pressure perfusion (Langendorff) regimes. Four structural GO variants of the following initial morphology were used: few-layer (below 10-layer) GO1, O < 49%; predominantly single-layer GO2, O = 41-50%; 15-20-layer GO3, O < 11%; and few-layer (below 10-layer) NH4 +-functionalized GO4, O < 44%, N = 3-6%. The aqueous GO dispersions, sonicated and stabilized with bovine serum albumin in Krebs-Henseleit-like solution-uniformized in terms of the particle size-were eventually size-monodisperse as revealed by dynamic light scattering. To study the cardiotoxicity mechanisms of GO, histopathology, Raman spectroscopy, analysis of cardiac parameters (coronary and aortic flows, heart rate, aortic pressure), and nitric oxide (NO-)-dependent coronary flow response to bradykinin (blood-vessel-vasodilator) were used. GO1 (10 mg/L) exerted no effects on cardiac function and preserved an increase in coronary flow in response to bradykinin. GO2 (10 mg/L) reduced coronary flow, aortic pressure in normotensive hearts, and coronary flow in hypertensive hearts, and intensified the response to bradykinin in normal hearts. GO3 (10 mg/L) reduced all parameters in hypertensive hearts and coronary response to bradykinin in normal hearts. At higher concentrations (normotensive hearts, 30 mg/L), the coronary response to bradykinin was blocked. GO4 (10 mg/L) reduced the coronary flow in normal hearts, while for hypertensive hearts, all parameters, except the coronary flow, were reduced and the coronary response to bradykinin was blocked. The results showed that a low number of GO layers and high O-content were safer for normal and hypertensive rat hearts. Hypertensive hearts deteriorated easier upon perfusion with low-O-content GOs. Our findings support the necessity of strict control over the GO structure during organ perfusion and indicate the urgent need for personalized medicine in biomedical applications of GO.

Effect of esaxerenone on ischemia and reperfusion injury in rat hearts.

In myocardial infarction, the addition of mineralocorticoid receptor blockers (MRBs) to standard therapies, such as angiotensin-converting enzyme inhibitors or beta-blockers, reportedly reduces mortality and cardiac events. We investigated whether the non-steroidal MRB esaxerenone has cardioprotective effects and its protective mechanisms. Isolated rat hearts were Langendorff-perfused (constant pressure, 80 mmHg) with oxygenated Krebs-Henseleit bicarbonate buffer and reperfused for 60 min; afterwards, recovery of function (left ventricular pressure, measured with an intraventricular balloon) and myocardial injury were measured. In a preliminary study, we determined the optimal concentration of esaxerenone required for myocardial protection. Next, esaxerenone was administered in the pre- and post-ischemic phases to determine the optimal timing of administration. In addition, we assessed coronary flow response to acetylcholine (ACh) with and without esaxerenone. We examined whether esaxerenone-induced cardioprotection was prevented by targeting putative components in the preconditioning manner (the mitochondrial ATP-sensitive potassium (KATP) channel). Myocardial protection by esaxerenone was observed when esaxerenone was administered before ischemia but not after ischemia. The coronary flow response to ACh was significantly better in the esaxerenone group than in the control group. The cardioprotective effect of esaxerenone was eliminated by the mitochondrial KATP channel blocker, 5-hydroxy decanoate. This study confirmed the myocardial protective effect of the pre-ischemic administration of esaxerenone. Esaxerenone may contribute to coronary endothelial protection and exert pharmacological preconditioning via the mitochondrial KATP channel.

Altered autonomic control or coronary artery blood flow by the aortic body chemoreceptors in conscious normotensive and hypertensive sheep

Peripheral arterial chemoreceptors monitor the chemical composition of the blood. While, the carotid bodies located at the bifurcation of the common carotid arteries have been extensively studied. The physiological role of the aortic bodies located in the walls of the aortic arch remains relatively under-studied, and its role in hypertension is unexplored.We hypothesized that activation of the aortic bodies would increase coronary blood flow in the normotensive state and that the parasympathetic nerves to the heart would mediate this.Experiments were conducted in conscious and anesthetized ewes instrumented to record arterial pressure, coronary blood flow, and cardiac output. Two groups of animals were studied, one made hypertensive using a 2 kidney one-clip model (HTN. n=6) and a sham-clipped normotensive group (Con. n=6). Unilateral renal clipping increased resting mean arterial pressure (Con: 84±5 vs HTN 115±6 mmHg). The aortic body chemoreceptors were stimulated by a bolus infusion of potassium cyanide (KCN; 10-30 μg/kg) into the left ventricle.Activation of the aortic bodies in the normotensive and hypertensive animals resulted in a significant increase in coronary blood flow ( P&lt;0.05, 2-way ANOVA, interaction effect), which was not different between groups. In normotensive sheep, the aortic body chemoreflex-mediated coronary vasodilation was attenuated by atropine infusion. Interestingly, the coronary vasodilation in hypertensive animals was not altered by the blockade of muscarinic receptors but was attenuated after propranolol infusion ( P&lt;0.05, interaction effect). Bilateral vagotomy is not possible in conscious animals; under anesthesia, the coronary blood flow response to aortic body stimulation was significantly attenuated in normotensive sheep. Neither atropine nor propranolol affected the aortic body chemoreflex meditated changes in either group's blood pressure, heart rate, or cardiac output. This data suggests that the aortic bodies play an important role in modulating coronary blood flow and that their effector mechanism is altered in hypertension. Many patients with hypertension are on beta-blockers. Our finding indicates that the aortic bodies modulate coronary blood flow via a beta-adrenergic mechanism in hypertension, which may have important implications for regulating coronary blood flow during exertion in hypertensive patients. Work is supported by the Health Research Council (HRC) of New Zealand. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Acute Increase in Ocular Microcirculation Blood Flow Upon Cholesterol Removal. The Eyes Are the Window of the Heart

BackgroundLipoprotein apheresis acutely increases coronary microvascular blood flow. However, measurement techniques are time-consuming, costly, and invasive. The ocular vasculature may be an appropriate surrogate and an easily accessible window to investigate the microcirculation. Recent advances in ocular imaging techniques enable quick, noninvasive quantification of ocular microcirculation blood flow. The insights from these techniques represent a significant opportunity to study the short-term changes in optic disk blood flow after lipoprotein apheresis for inherited hypercholesterolemia. MethodsThis study was performed at the Italian Reference Center for Inherited Dyslipidemias in Tuscany. The study sample was comprised of 22 patients with inherited hypercholesterolemia who were previously studied for coronary microcirculation. Laser speckle flowgraphy (LSFG) was used to measure optic disk blood flow before and after lipoprotein apheresis. The main outcomes measures were average tissue blood flow (referred to as mean tissue) and arteriolar/venular average blood flow (referred to as mean vessel). Eyes were divided into 2 groups based on pre-lipoprotein apheresis optic disk blood flow values. P < .05 was considered statistically significant. ResultsAfter each lipoprotein apheresis treatment resulting in the reduction of plasma lipids, there was a concurrent increase in all optic disk microcirculatory parameters. The increase was statistically significant in eyes with lower pre-apheresis optic disk blood flow values (mean tissue +7.0%, P < .005; mean vessel +7.2%, P < .05). ConclusionsA single lipoprotein apheresis session resulted in a statistically significant short-term increase in optic disk blood flow. These findings together with previous coronary microcirculation data suggest a similar ocular and coronary blood flow response to lipoprotein apheresis. Ocular microcirculation may represent a versatile biomarker for evaluating systemic microcirculatory health, including coronary microcirculation. Hence, it is plausible that plasma lipoprotein levels may influence optic disk blood flow.

Red blood cell eNOS is cardioprotective in acute myocardial infarction

Red blood cells (RBCs) were shown to transport and release nitric oxide (NO) bioactivity and carry an endothelial NO synthase (eNOS). However, the pathophysiological significance of RBC eNOS for cardioprotection in vivo is unknown. Here we aimed to analyze the role of RBC eNOS in the regulation of coronary blood flow, cardiac performance, and acute myocardial infarction (AMI) in vivo. To specifically distinguish the role of RBC eNOS from the endothelial cell (EC) eNOS, we generated RBC- and EC-specific knock-out (KO) and knock-in (KI) mice by Cre-induced inactivation or reactivation of eNOS. We found that RBC eNOS KO mice had fully preserved coronary dilatory responses and LV function. Instead, EC eNOS KO mice had a decreased coronary flow response in isolated perfused hearts and an increased LV developed pressure in response to elevated arterial pressure, while stroke volume was preserved. Interestingly, RBC eNOS KO showed a significantly increased infarct size and aggravated LV dysfunction with decreased stroke volume and cardiac output. This is consistent with reduced NO bioavailability and oxygen delivery capacity in RBC eNOS KOs. Crucially, RBC eNOS KI mice had decreased infarct size and preserved LV function after AMI. In contrast, EC eNOS KO and EC eNOS KI had no differences in infarct size or LV dysfunction after AMI, as compared to the controls. These data demonstrate that EC eNOS controls coronary vasodilator function, but does not directly affect infarct size, while RBC eNOS limits infarct size in AMI. Therefore, RBC eNOS signaling may represent a novel target for interventions in ischemia/reperfusion after myocardial infarction.

Aortic Body Chemoreceptors Regulate Coronary Blood Flow in Conscious Control and Hypertensive Sheep.

Peripheral arterial chemoreceptors monitor the chemical composition of arterial blood and include both the carotid and aortic bodies (ABs). While the role of the carotid bodies has been extensively studied, the physiological role of the ABs remains relatively under-studied, and its role in hypertension is unexplored. We hypothesized that activation of the ABs would increase coronary blood flow in the normotensive state and that this would be mediated by the parasympathetic nerves to the heart. In addition, we determined whether the coronary blood flow response to stimulation of the ABs was altered in an ovine model of renovascular hypertension. Experiments were conducted in conscious and anesthetized ewes instrumented to record arterial pressure, coronary blood flow, and cardiac output. Two groups of animals were studied, one made hypertensive using a 2 kidney one clip model (n=6) and a sham-clipped normotensive group (n=6). Activation of the ABs in the normotensive animals resulted in a significant increase in coronary blood flow, mediated, in part by a cholinergic mechanism since it was attenuated by atropine infusion. Activation of the ABs in the hypertensive animals also increased coronary blood flow (P<0.05), which was not different from the normotensive group. Interestingly, the coronary vasodilation in the hypertensive animals was not altered by blockade of muscarinic receptors but was attenuated after propranolol infusion. Taken together, these data suggest that the ABs play an important role in modulating coronary blood flow and that their effector mechanism is altered in hypertension.

Coronary microvascular dysfunction and findings of heart failure with preserved ejection fraction in patients with microvascular angina.

Coronary microvascular dysfunction (CMD) may cause symptoms of myocardial ischemia (microvascular angina [MVA]), but recent studies suggested that it might also contribute to the syndrome of heart failure with preserved ejection fraction (HFpEF). In this study we assessed the relation of CMD with findings of HFpEF in MVA patients. We enrolled 36 consecutive patients with MVA, in whom we assessed: 1) coronary blood flow (CBF) response to adenosine and cold pressor test (CPT) by color-Doppler echocardiography of the left anterior descending coronary artery; 2) complete echocardiographic examination; 3) N-terminal-pro-B-natriuretic peptide (NT-proBNP); 4) grade of dyspnea by the modified Medical Research Scale. Among patients, 15 had definite HFpEF findings (group 1), 12 had equivocal HFpEF findings (group 2) and 9 had no evidence of HFpEF findings (group 3). Group 1 patients were older, had more cardiovascular risk factors and higher NT-proBNP levels (P=0.018), and showed a higher prevalence of diastolic dysfunction. Left ventricle dimensions and systolic function, however, did not differ among groups. Dyspnea was also not significantly different among groups (P=0.19). CBF to adenosine was 1.85±0.47, 1.78±0.40 1.49±0.32 in group 1, 2 and 3, respectively (P=0.13). Similarly, CBF response to CPT was 1.57±0.4, 1.49±0.2 and 1.45±0.3 in the 3 groups, respectively (P=0.74). Both CBF response to adenosine and CPT showed no relation with the severity of dyspnea symptoms. Our data suggest that in patients with MVA there is no relation between the grade of impairment of coronary microvascular dilatation and findings of HFpEF.

Cold pressor testing and sympathetic nervous system contribution to ischemia with no obstructive coronary artery disease: Results from the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction Project

Study objectiveCold pressor testing (CPT) is a known stimulus of the sympathetic nervous system (SNS). To better understand sympathetic contribution to coronary blood flow regulation in women with suspected ischemia and no obstructive coronary arteries (INOCA), we compared myocardial perfusion reserve during CPT stress cardiac magnetic resonance (CMR) imaging between women with suspected INOCA and reference subjects. DesignProspective cohort. SettingAcademic hospital. Participants107 women with suspected INOCA and 21-age-matched reference women. InterventionsCPT stress CMR was performed with measurement of myocardial perfusion reserve index (MPRI), adjusted for rate pressure product (MPRIRPP). Invasive coronary function testing in a subset of INOCA women (n = 42) evaluated for endothelial dysfunction in response to acetylcholine, including impaired coronary diameter response ≤0% and coronary blood flow response (ΔCBF) <50%. Main outcome measureMPRIRPP. ResultsCompared to reference women, the INOCA group demonstrated higher resting RPP (p = 0.005) and CPT MPRIRPP (1.09 ± 0.36 vs 0.83 ± 0.18, p = 0.002). Furthermore, INOCA women with impaired ΔCBF (n = 23) had higher CPT MPRIRPP (p = 0.044) compared to reference women despite lower left ventricular ejection fraction (64 ± 7% vs 69 ± 2%, p = 0.005) and higher mass-to-volume ratio (0.79 ± 0.15 vs 0.62 ± 0.09, p < 0.0001). These differences in CPT MPRIRPP did not persist after adjusting for age, body mass index, and history of hypertension. CPT MPRIRPP among INOCA women did not differ based on defined acetylcholine responses. ConclusionsMyocardial perfusion reserve to CPT stress is greater among women with INOCA compared to reference subjects. This CPT response was also noted in women with coronary endothelial dysfunction, suggesting a greater contribution of the SNS to coronary flow than endothelial dysfunction. Therapies to modulate sympathetic activity should be studied in this population.

Platelet Count Applicability in Predicting the Degree of ST-Segment Depression and Coronary Flow Rate in Acute Myocardial Infarction Patients

Introduction: It is still unclear whether platelet count can predict the outcomes of acute myocardial infarction. In this study, we assessed the relationship between the initial platelet count on the degree of ST-segment depression and coronary flow rate among patients with MI who underwent percutaneous coronary intervention (PCI). Methods: In this study, a total of 218 patients suffering from MI, who underwent primary PCI during 2016-2017 (Seyed-Shohada hospital, Urmia, Iran) were selected by consensus method. Demographic information and past medical history such as diabetes mellitus (DM), cigarette smoking, using Integrilin, and door-to-balloon (DTB) time were recorded. All patients were investigated in terms of cell blood count. Serial electrocardiogram (ECG) was also performed and the degree of ST-segment elevation was measured. Results: The mean (SD) age of participants was 58.67 (11.44) years. The initial platelet count was similar between patients with and without improvement in the ST-segment (P = 0.275). There was no significant difference regarding thrombolysis in myocardial infarction (TIMI) between patients with and without improved ST-segment (P = 0.380). Conclusion: According to our results, the initial platelet count in patients who underwent angioplasty was not associated with coronary flow and echocardiographic responses to treatment.

Activation of the carotid body increases directly recorded cardiac sympathetic nerve activity and coronary blood flow in conscious sheep.

Activation of the carotid body (CB) using intracarotid potassium cyanide (KCN) injection increases coronary blood flow (CoBF). This increase in CoBF is considered to be mediated by co-activation of both the sympathetic and parasympathetic nerves to the heart. However, whether cardiac sympathetic nerve activity (cardiac SNA) actually increases during CB activation has not been determined previously. We hypothesized that activation of the CB would increase directly recorded cardiac SNA, which would cause coronary vasodilatation. Experiments were conducted in conscious sheep implanted with electrodes to record cardiac SNA and diaphragmatic electromyography (dEMG), flow probes to record CoBF and cardiac output, and a catheter to record arterial pressure. Intracarotid KCN injection was used to activate the CB. To eliminate the contribution of metabolic demand on coronary flow, the heart was paced at a constant rate during CB chemoreflex stimulation. Intracarotid KCN injection resulted in a significant increase in directly recorded cardiac SNA frequency (from 24 ± 2 to 40 ± 4 bursts/min; P < 0.05) as well as a dose-dependent increase in mean arterial pressure (79 ± 15 to 88 ± 14 mmHg; P < 0.01) and CoBF (75 ± 37 vs. 86 ± 42 mL/min; P < 0.05). The increase in CoBF and coronary vascular conductance to intracarotid KCN injection was abolished after propranolol infusion, suggesting that the increased cardiac SNA mediates coronary vasodilatation. The pressor response to activation of the CB was abolished by pretreatment with intravenous atropine, but there was no change in the coronary flow response. Our results indicate that CB activation increases directly recorded cardiac SNA, which mediates vasodilatation of the coronary vasculature.

Abstract 260: Aortic Pulse Wave Characteristics and Coronary Blood Flow Responses to Plantar Flexion in Peripheral Arterial Diseases Patients

Peripheral arterial diseases (PAD) is an atherosclerotic occlusive disease in the periphery affecting 8-12 million U.S.adults. It has been reported that the PAD patients have attenuated coronary blood flow response to stress, however how the diseases influence aortic arterial pulse wave properties during exercise, and its relationship with coronary perfusion in this patient population is unknown. Accordingly, the primary aim of this study was to examine myocardial supply and demand relationship by investigating aortic pulse wave properties and their relationship with coronary perfusion during exercise in PAD. Methods: 13 PADpatients and 13 healthy (age, sex, BMI-matched) control subjects performed rhythmic plantar flexion for 14 minutes or until fatigue (30 contractions per minute). The workload started at 2 kg and increased by 1 kg every minute up to12 kg. Brachial (oscillometric cuff) and aortic (SphygmoCor, utilizing transfer function and brachial blood pressures) blood pressures were measured during supine rest and plantar flexion exercise as well as aortic pulse wave properties from derived-aortic pulse waveforms. On a separate visit, coronary blood flow velocity was measured non-invasively during rest and exercise. Results: Due to earlier arrival of reflected wave (140.9± 2.3 vs. 150.5± 3.4 ms; P =0.0289), baseline augmented pressure (15.9± 2.4 vs. 9.3± 1.7 mmHg; AP, P =0.0380), augmentation index (27.2± 2.7 vs. 19.1± 2.2 %; AI, P =0.0263), and cardiac wasted energy (4625± 590 vs. 2875± 491 s· dyne· cm 2 ; E w , P =0.0321) were greater compared to healthy control. During exercise, changes in aortic mean arterial pressure(21.90± 5.04 vs. 9.36± 2.20 mmHg; ΔaMAP, P =0.0041), end-systolic pressure (133.38± 4.85 vs. 111.46± 4.97 mmHg; ΔESP, P =0.0043), and the tension time index (1027± 216 vs. 504± 117 mmHg· S -1 · min -1 ; ΔTTI, P =0.0035) were significantly greater in PAD while ΔAI was not different. Intriguingly, despite the augmented TTI, the first and second peaks of CBV during exercise were not different between the groups leading to significantly attenuated subendocardial viability ratio responses to exercise (-34.66± 4.19 vs. -23.03± 3.37 %; ΔSEVR, P =0.0164). Conclusions: At this peak workload for PAD patients, the patients had a greater myocardial demand compared to healthy control. However, despite the increase in the myocardial demand and the accompanying increase in initial coronary perfusion pressure (ESP), CBV of PAD patients was not different from that seen in healthy control indicating limited myocardial supply during exercise in PAD. Consequently, PAD exhibited a greater mismatch of myocardial demand and supply at the peak workload. This suggests that, in PAD patients, there are mechanisms aside from changes in coronary perfusion pressure that limit myocardial supply during exercise (i.e. a greater coronary vascular tone and diastolic dysfunction).

Enhanced coronary vasodilation in isolated Langendorff‐perfused hearts of asthmatic mice

Clinical studies have shown that asthma is associated with high risk of cardiovascular diseases. We previously demonstrated that asthmatic mice have impaired vascular reactivity and endothelial function in aorta. However, little is known regarding coronary vascular reactivity in asthmatic mice. This study aims to examine the coronary flow response to vasodilators and to short period of ischemia in isolated hearts of asthmatic mice. Asthmatic mice were induced by I.P. injection of ovalbumin (OVA, 0.2 μg) on days 1 and 6, followed by 5% OVA aerosol challenges on days 11–13. Hearts were isolated and perfused on day 14 to examine the coronary flow (CF) response. CF was measured using Langendorff system. Baseline CF was comparable between normal and sensitized mice. However, peak CF and repayment/debt ratio following a 15‐s occlusion were significantly higher (~1.14 and 1. 55 folds increase, respectively, p&lt;0.05) in sensitized versus control mice. In lines with the enhanced reactive hyperemic response, acetylcholine (ACH, 10−9‐105.5M) induced an augmented flow increase (Emax=2.8 ± 0.16 and 2.4 ± 0.14 times the baseline in sensitized versus control mice, respectively, p&lt;0.05) which was not affected by L‐NAME (nitric oxide synthase inhibitor). Additionally, sodium nitroprusside (SNP, 10−5 M) induced a ~25% more coronary flow increase (p&lt;0.05) in sensitized mice. Our data suggest that during early stage of sensitized asthmatic mouse model, the coronary circulation demonstrates an enhanced flow reserve though the baseline flow is unchanged. The changes in coronary flow reserve in asthmatic mice indicate one of the potential protective mechanisms against hypoxia/ischemia–induced heart injury in asthmatic patients. Supported by HL 027339 (SJM) and WVCTSI Pilot Grant NIH/NIGMS U54GM104942 (DSP)

Regulation of Coronary Blood Flow by the Carotid Body Chemoreceptors in Ovine Heart Failure

BackgroundThe carotid body (CB) is an arterial chemoreceptor organ located in the carotid bifurcation, which carries out essential functions in cardiorespiratory control. In response to hypoxia, carotid chemosensory discharge produces respiratory, autonomic, and cardiovascular adjustments critical for body homeostasis. Previous studies have shown that chemoreflex sensitivity is augmented animal models of heart failure (HF). However, the role of the chemoreflex in modulating coronary blood flow during HF is not clear. We hypothesized that carotid chemoreceptor stimulation would increase coronary blood flow in both normal sheep and sheep with HF.MethodsHeart failure was induced by the microembolization technique and instrumentation was performed when ejection fraction was below 40%. Both groups of sheep were implanted with a coronary artery flow probe and an arterial pressure catheter. The responses of mean arterial pressure (MAP) and coronary blood flow (CoBF) were determined in conscious sheep following CB stimulation with intracarotid potassium cyanide (KCN; 30μg/kg). To determine the cardiac vagal contribution to the CoBF response, CB activation was repeated following atropine infusion (8 mg bolus followed by 24 mg/h infusion for 30 minutes).ResultsIn control animals, activation of the CB increased MAP (114±1%) and CoBF (116±4%) but coronary vascular conductance (CVC) was unaltered. In the HF group, CB stimulation increased MAP (108±1%), CoBF (126±3%), and CVC (114±2%). The MAP increase was significantly attenuated after atropine infusion in both animal groups, however, the CoBF and CVC responses to KCN were unchanged. These responses persisted when the heart was paced at a constant rate to eliminate the role of altered metabolic demand.DiscussionOur data indicate that in an ovine model of HF, carotid body mediated increases in MAP are attenuated compared to control animals. There was a significant increase in coronary vascular conductance in the HF animals following CB activation which was absent in the normal animals. Overall, our data suggest that the hyperactive carotid body chemoreflex may serve to increase coronary blood flow in the HF condition.Support or Funding InformationHealth Research Council of New Zealand, National Heart Foundation of New Zealand

Important Roles of Endothelium-Dependent Hyperpolarization in Coronary Microcirculation and Cardiac Diastolic Function in Mice.

Endothelium-dependent hyperpolarization (EDH) factor is one of endothelium-derived relaxing factors and plays important roles especially in microvessels. We have previously demonstrated that endothelium-derived hydrogen peroxide (H2O2) is an EDH factor produced by all types of nitric oxide synthases (NOSs), including endothelial NOS (eNOS), neuronal NOS (nNOS), and inducible NOS. Recent studies have suggested the association between coronary microvascular dysfunction and cardiac diastolic dysfunction. However, the role of EDH in this issue remains to be fully elucidated. We thus examined whether EDH plays an important role in coronary microcirculation and if so, whether endothelial dysfunction, especially impaired EDH, is involved in the pathogenesis of cardiac diastolic dysfunction in mice. Using a Langendorff-perfused heart experiment, we examined the increase in coronary flow in response to bradykinin in the presence of indomethacin and N-nitro-L-arginine (EDH condition) in wild-type, eNOS-knockout (KO), and nNOS/eNOS-double-KO mice. Compared with wild-type mice, EDH-mediated relaxations were increased in eNOS-KO mice but were significantly reduced in n/eNOS-KO mice. Catalase, a specific H2O2 scavenger, markedly inhibited EDH-mediated relaxations in all 3 genotypes, indicating compensatory roles of nNOS-derived H2O2 as an EDH factor in coronary microcirculation. Although both eNOS-KO and n/eNOS-KO mice exhibited similar extents of cardiac morphological changes, only n/eNOS-KO mice exhibited cardiac diastolic dysfunction. The expression of oxidized protein kinase G I-α (PKGIα) in the heart was significantly increased in eNOS-KO mice compared with n/eNOS-KO mice. These results indicate that EDH/H2O2 plays important roles in maintaining coronary microcirculation and cardiac diastolic function through oxidative PKGIα activation.

Obesity decreases the contribution of Kv channels to hypoxic coronary vasodilation

Background and Hypothesis: Our group previously demonstrated that reductions in the functional expression of voltage-dependent K+ (Kv) channels contribute to impaired metabolic control of coronary blood flow in the setting of obesity. This study tested the hypothesis that obesity diminishes the contribution of Kv channels to coronary vasodilation in response to hypoxemia.&#x0D; Experimental Design or Project Methods: Control lean (n = 7) and obese (n = 5) swine were anesthetized and the heart exposed via left lateral thoracotomy. Coronary blood flow was measured in response to hypoxemia, before and after inhibition of Kv channels by 4-aminopyridine (4-AP; 0.3 mg/kg, iv), by a flow probe placed about the left anterior descending coronary artery. Hypoxemia was induced by progressive increases in the amount of nitrogen introduced into the ventilator. Arterial blood samples were obtained at each reduction in arterial oxygenation via a catheter placed in the femoral artery.&#x0D; Results: Blood pressure decreased from ~88 ± 5 mmHg to ~68 ± 6 mmHg (P = 0.01) as arterial PO2 was reduced below 50 mmHg in both lean and obese swine (P = 0.51). In lean swine, coronary flow progressively increased from ~0.6 to &gt;3.0 ml/min/g as arterial PO2 was reduced. This response was decreased by ~40% in obese swine and by ~30% in lean swine treated with 4-AP. Administration of 4AP had no effect on coronary flow in obese swine.&#x0D; Conclusion and Potential Impact: These data support that Kv channels contribute to increases in coronary flow in response to hypoxemia in lean swine and that reductions in Kv channel function contribute to impaired hypoxic coronary vasodilation in obese swine. We propose that therapeutic targeting of obesity associated pathways (angiotensin-aldosterone system) known to influence K+ channel expression could improve coronary microvascular function and cardiovascular outcomes in subjects with obesity. Supported by R01 HL136386; T35 HL 110854.

P2706Persistent impairment of coronary endothelial vasomotor responses is related to atheroma plaque progression in the infarct-related coronary artery of AMI survivors

Abstract Background Although coronary endothelial vasomotor dysfunction predicts future coronary events, there are few human studies showing the relationship between endothelial vasomotor dysfunction and atheroma plaque progression in the same coronary artery. Purpose This study examined whether endothelial vasomotor dysfunction is related with atheroma plaque progression in the infarct-related coronary artery of ST-segment elevation myocardial infarction (STEMI) survivors using serial assessment of coronary plaque size with intravascular ultrasound (IVUS) and coronary vasomotor responses to acetylcholine (ACh). Methods This study included 50 patients with a first acute STEMI due to occlusion of left anterior descending coronary artery (LAD) and successful reperfusion therapy with percutaneous coronary intervention (PCI). IVUS and vasomotor response to ACh in the LAD were measured within 2 weeks after AMI (1st test) and repeated 6 months (2nd test) after AMI under optimal anti-atherosclerotic therapies. The impairment of vasomotor response to ACh was defined as &lt;10% of the responses to ACh in 25 control subjects. Results Percent atheroma volume (PAV) and total atheroma volume (TAV) in the LAD progressed over 6 months of follow-up in 18 and 14 patients, respectively. Epicardial coronary artery dilation and coronary blood flow increase in response to ACh were persistently impaired at both the 1st and 2nd tests in 18 and 19 patients. In logistic regression analysis, the progression of PAV and TAV was significantly associated with patients with the persistent impairment of epicardial coronary diameter and blood flow response to ACh (PAV, OR, 6.2 [95% CI, 1.4–28], P=0.02 and 4.3 [1.2–16], P=0.03, respectively. TAV, 6.0 [1.4–26], P=0.02 and 5.5 [1.4–21], P=0.01, respectively). The progression of PAV and TAV had no significant association with the coronary vasomotor responses to ACh at the 1st test, traditional risk factors, PCI-related variables, medications, and the coronary vasomotor responses to sodium nitroprusside, an endothelium-independent vasodilator. Conclusions Persistent impairment of endothelial vasomotor function in the conduit arterial segment and the resistance arteriole was related to atheromatous plaque progression in the infarct-related coronary arteries of STEMI survivors despite optimized anti-atherosclerotic therapies. Acknowledgement/Funding None

Sustained endothelial dysfunction in the infarct-related coronary artery is associated with left ventricular adverse remodeling in survivors of ST-segment elevation myocardial infarction

BackgroundIschemia-reperfusion causes endothelial injury and dysfunction in the infarct-related coronary artery (IRA). Using serial assessment of coronary endothelial vasomotor function and left ventriculography (LVG), this study prospectively investigated the clinical impact of endothelial vasomotor dysfunction in the patent IRA on left ventricular (LV) remodeling in survivors of ST-elevation myocardial infarction (STEMI). MethodsThis study included 78 patients with STEMI due to occlusion of the left anterior descending coronary artery (LAD) and successful reperfusion therapy with percutaneous coronary intervention. All of them had LV ejection fraction (LVEF) <55%. LVG and the vasomotor responses to acetylcholine (ACh) in the LAD were examined within 2 weeks (1st test) and 6 months (2nd test) after MI. Cut-off values for coronary vasomotor dysfunction in response to ACh were based on the lower 10% of the distribution of coronary vasomotor responses to ACh in 20 control subjects. ResultsLV adverse remodeling, defined as a >10% increase in either LV end-diastolic volume index (LVEDVI) and/or end-systolic volume index (LVESVI) from the 1st to the 2nd test, occurred in 21 (70%) of 30 patients with sustained impairment of the coronary flow response to ACh at both the 1st and 2nd tests and 14 (29%) of 48 in the other coronary flow response group (p < 0.01). In multivariate logistic regression analysis, a >10% increase in LVEDVI and LVESVI was respectively associated with sustained impairment of the coronary diameter and flow responses to ACh (OR 4.9 and 3.5, 95% CI 1.7–14.1 and 1.1–10.9, p < 0.01 and p = 0.03, respectively), that was independent of hypertension, peak creatine phosphokinase, and the baseline coronary flow response to ACh at the 1st test. ConclusionsSustained endothelial vasomotor dysfunction in the IRA was associated with LV adverse remodeling in STEMI survivors with successful reperfusion therapy.

Effects of β2 Adrenergic Receptor on Coronary Blood Flow and Cardiovascular Responses during Exercise and Metaboreflex in Men and Women

Redundant mechanisms modulate coronary blood flow (CBF) matched to the metabolic demand.However, the possible sex differences in the mechanisms of CBF control are not fully understood. In addition, the effect of skeletal muscle metaboreflex on CBF in humans is unclear. Thus, 9 men (26 ± 4 yr; 23 ± 2 kg/m2) and 7 women (24 ± 4 yr; 24 ± 3 kg/m2) had their heart rate (HR) and blood pressure recorded. Mean arterial pressure (MAP), cardiac index (CI), total vascular resistance index (TVRI), femoral blood flow (FBF) and myocardial oxygen consumption (MVO2) were estimated. CBF was calculated as average of maximal blood flow velocity on the diastolic phase of ten cardiac cycles. The protocol consisted in 3 minutes rest, 3 minutes of handgrip exercise at 40% of the maximal voluntary force, 3 minutes of peripheral circulatory occlusion (metaboreflex) and recovery, before and after β2‐AR blockade (propranolol). Effects were statistically tested by two‐way ANOVA in men and women, followed by multiple comparisons with Bonferroni correction. HR increased during exercise in men and women (MΔ24 ± 22 BPM; WΔ23 ± 10 BPM; mean ± SD), and the β2‐AR blockade blunted the increase (MΔ 10 ± 6 BPM; WΔ 13 ± 5 BPM). MAP increased during exercise (MΔ36 ± 5 mmHg; WΔ36 ± 11 mmHg); the β2‐AR blockade reduced MAP in men, with no effect on the response during exercise (MΔ36 ± 5 mmHg; WΔ36 ± 11 mmHg). MAP decreased during metaboreflex activation compared to exercise, but was increased compared to rest (M Δ26 ± 9 mmHg; W Δ22 ± 8 mmHg), and β2‐AR blockade did not change this effect. CI increased during exercise in men and women (MΔ0.96 ± 1.2 L.min.m2; WΔ1.5 ± 0.6 L.min.m2), which was blunted by β2‐AR blockade (MΔ0.5 ± 0.6 L.min.m2; WΔ0.8 ± 0.6 L.min.m2). Compared to rest, metaboreflex increased CI only in women (MΔ −0.01 ± 0.7 L.min.m2; WΔ0.88 ± 0.6 L.min.m2), the β2‐AR blockade did not change the CI. TVRI increased during exercise (MΔ0.96 ± 1.6 mmHg/11·min/m2; WΔ −0.18 ± 0.9 mmHg/11·min/m2) and metaboreflex activation (MΔ2.0 ± 1.5 mmHg/11·min/m2; WΔ −0.13 ± 0.8 mmHg/11·min/m2) only in men. With β2‐AR blockade TVRI increased in women during exercise (MΔ1.95 ± 1.4 mmHg/11·min/m2; WΔ1.26 ± 1.9 mmHg/11·min/m2) and metaboreflex (MΔ2.2 ± 1.5 mmHg/11·min/m2; WΔ0.5 ± 0.8 mmHg/11·min/m2). FBF increased during exercise (MΔ564 ± 706 ml/min1; WΔ 573 ± 438 ml/min1) and metaboreflex activation (MΔ74 ± 253 ml/min1; WΔ 280 ± 487 ml/min1) and β2‐AR blockade prevented the increase in both groups. CBF increased during exercise (MΔ11 ± 8 cm/s1; WΔ 6 ± 8 cm/s1) and metaboreflex activation (MΔ0.3 ± 2 cm/s1; WΔ −0.8 ± 3 cm/s1) in men; after β2‐AR blockade CBF did not change in either groups in both conditions. MVO2 increased during exercise (MΔ6.5 ± 3.6; WΔ 5.0 ± 2.0) and metaboreflex activation (MΔ3.2 ± 1.0; WΔ 3.0 ± 1.2) in men and women and β2‐AR blockade blunted the increase. β2‐AR seems to play an import role to the lower TVR observed in women in response to exercise and metaboreflex activation. The increase of CBF during exercise and metaboreflex was higher in men and the β2‐AR blockade prevented the increase.Support or Funding InformationCAPES, CNPQ, FAPERJ, National Institute for Science &amp; Technology ‐ INCT (In)activity &amp; ExerciseThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.