Increase In Coronary Flow Research Articles

Prolonged Administration of the KCa Channel Activator SKA‐31 Improves Cardiac Function and Blood Pressure in Type 2 Diabetic Goto‐Kakizaki Rats

Endothelial dysfunction represents an independent risk factor contributing to the onset and progression of cardiovascular complications (e.g. hypertension, cardiomyopathy, stroke) in patients with Type 2 Diabetes (T2D). It is further predicted that reduction/reversal of endothelial dysfunction will mitigate T2D‐associated cardiovascular deficits. Small‐ and intermediate‐conductance, Ca2+‐activated K+ channels (KCa2.3 and KCa3.1, respectively) are prominently expressed in the vascular endothelium, and pharmacologic activators of these channels (e.g. SKA‐31) induce robust vasodilation upon acute application to isolated resistance arteries and intact animals. However, the effects of prolonged, in vivo administration of a KCa activator on the cardiovascular system have not been examined to date. In our current study, we have hypothesized that daily administration of SKA‐31 (10 and 30 mg/kg, I.P. injection) to male, non‐obese Type 2 Diabetic Goto‐Kakizaki rats (T2D GK, 14 weeks of age) for 12 weeks would oppose the development of diabetes‐related cardiac dysfunction. Echocardiographic analyses revealed that left ventricular (LV) ejection fraction, stroke volume and fractional shortening all significantly declined over time in vehicle‐treated rats, but remained at pre‐trial levels in animals administered either 10 or 30 mg/kg SKA‐31 for 12 weeks (n = 5–6/group). Chronic blood pressure measurements over the same period via radiotelemetry further revealed that SKA‐31 treatment lowered mean arterial pressure, compared with vehicle treated animals, with effects observed on both systolic and diastolic pressures (n = 5–6/group). To determine if the observed improvements in cardiac performance may be due to direct changes in the responsiveness of the coronary vasculature, isolated hearts from vehicle and SKA‐31 treated T2D GK rats were mounted in a Langendorff perfusion system under constant pressure (n ≥ 3/group). We observed that endothelium‐dependent, agonist‐evoked increases in coronary flow were similar in hearts from vehicle and SKA‐31 treated animals, as was baseline LV developed pressure. Histological staining of isolated hearts revealed differing levels of LV collagen content in the 3 treatment groups. In summary, these results indicate that prolonged SKA‐31 administration in T2D GK rats can improve cardiac function, which likely occur via both direct and indirect effects.Support or Funding InformationThis study was supported by research funding to APB from the Canadian Institutes of Health Research (MOP‐142467) and the Natural Sciences and Engineering Research Council of Canada (RGPIN‐2017‐04116), and to HW from the National Institutes of Health (R21 NS101876).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Paradoxical arteriole constriction compromises cytosolic and mitochondrial oxygen delivery in the isolated saline-perfused heart.

The isolated saline-perfused heart is used extensively to study cardiac physiology. Previous isolated heart studies have demonstrated lower tissue oxygenation compared with in vivo hearts based on myoglobin oxygenation and the mitochondrial redox state. These data, consistent with small anoxic regions, suggest that the homeostatic balance between work and oxygen delivery is impaired. We hypothesized that these anoxic regions are caused by inadequate local perfusion due to a paradoxical arteriole constriction generated by a disrupted vasoregulatory network. We tested this hypothesis by applying two exogenous vasodilatory agents, adenosine and cromakalim, to relax vascular tone in an isolated, saline-perfused, working rabbit heart. Oxygenation was monitored using differential optical transmission spectroscopy and full spectral fitting. Increases in coronary flow over control with adenosine (27 ± 4 ml/min) or cromakalim (44 ± 4 ml/min) were associated with proportional spectral changes indicative of myoglobin oxygenation and cytochrome oxidase (COX) oxidation, consistent with a decrease in tissue anoxia. Quantitatively, adenosine decreased deoxymyoglobin optical density (OD) across the wall by 0.053 ± 0.008 OD, whereas the reduced form of COX was decreased by 0.039 ± 0.005 OD. Cromakalim was more potent, decreasing deoxymyoglobin and reducing the level of COX by 0.070 ± 0.019 OD and 0.062 ± 0.019 OD, respectively. These effects were not species specific, as Langendorff-perfused mouse hearts treated with adenosine demonstrated similar changes. These data are consistent with paradoxical arteriole constriction as a major source of regional anoxia during saline heart perfusion. We suggest that the vasoregulatory network is disrupted by the washout of interstitial vasoactive metabolites in vitro. NEW & NOTEWORTHY Regional tissue anoxia is a common finding in the ubiquitous saline-perfused heart but is not found in vivo. Noninvasive optical techniques confirmed the presence of regional anoxia under control conditions and demonstrated that anoxia is diminished using exogenous vasodilators. These data are consistent with active arteriole constriction, occurring despite regional anoxia, generated by a disrupted vasoregulatory network. Washout of interstitial vasoactive metabolites may contribute to the disruption of normal vasoregulatory processes in vitro.

Clinical implications of guiding catheter extubation during fractional flow reserve measurements

Fractional flow reserve (FFR) is defined by the maximal coronary flow ratio with and without stenosis. We hypothesized that guiding catheter intubation in coronary ostia during FFR measurements may underestimate FFR value by limiting the increase of coronary flow during maximal hyperaemia. Between June 2013 and January 2014, we prospectively included all patients with i.v. adenosine FFR measurements. FFR was measured with the guiding catheter intubated in the coronary ostia (FFRint) and extubated in the aorta (FFRext). We calculated the ratio between coronary ostium assessed by quantitative coronary angiography and guiding catheter surfaces, defined as the free ostial lumen ratio. In total, 151 lesions in 104 patients were included; 121 lesions and 88 patients were eligible for analysis. Mean±SD FFRext was significantly lower compared with FFRint; 0.82±0.08 and 0.84±0.08, respectively (P<0.001). Revascularization indication changed in 14 patients (16%). The difference induced by guiding extubation correlated significantly with the free ostial lumen ratio (R2=0.06, P=0.008). FFR value is significantly lower when the guiding catheter is extubated. The smaller the coronary ostium, the greater the difference observed between FFRext and FFRint. Guiding extubation during FFR measurements changed the revascularization indication in 16% of cases.

Regulation of myocardial oxygen delivery in response to graded reductions in hematocrit: role of K+ channels.

This study was designed to identify mechanisms responsible for coronary vasodilation in response to progressive decreases in hematocrit. Isovolemic hemodilution was produced in open-chest, anesthetized swine via concurrent removal of 500ml of arterial blood and the addition of 500ml of 37°C saline or synthetic plasma expander (Hespan, 6% hetastarch in 0.9% sodium chloride). Progressive hemodilution with Hespan resulted in an increase in coronary flow from 0.39±0.05 to 1.63±0.16ml/min/g (P<0.001) as hematocrit was reduced from 32±1 to 10±1% (P<0.001). Overall, coronary flow corresponded with the level of myocardial oxygen consumption, was dependent on arterial pressures≥~60mmHg, and occurred with little/no change in coronary venous PO2. Anemic coronary vasodilation was unaffected by the inhibition of nitric oxide synthase (L-NAME: 25mg/kg iv; P=0.92) or voltage-dependent K+ (K V) channels (4-aminopyridine: 0.3mg/kg iv; P=0.52). However, administration of the K ATP channel antagonist (glibenclamide: 3.6mg/kg iv) resulted in an~40% decrease in coronary blood flow (P<0.001) as hematocrit was reduced to~10%. These reductions in coronary blood flow corresponded with significant reductions in myocardial oxygen delivery at baseline and throughout isovolemic anemia (P<0.001). These data indicate that vasodilator factors produced in response to isovolemic hemodilution converge on vascular smooth muscle glibenclamide-sensitive (K ATP) channels to maintain myocardial oxygen delivery and that this response is not dependent on endothelial-derived nitric oxide production or pathways that mediate dilation via K V channels.

Novel Rotational Speed Modulation System Used With Venoarterial Extracorporeal Membrane Oxygenation

Femoral venoarterial extracorporeal membrane oxygenation (VA-ECMO) is widely used to maintain blood flow in patients with cardiogenic shock. However, retrograde blood flow increases left ventricular (LV) afterload during femoral VA-ECMO. Additional support by means of an intraaortic balloon pump (IABP) alleviates LV afterload but is associated with significant adverse events. We previously developed a system for rotational speed modulation in synchrony with the native cardiac cycle, for use with implantable continuous-flow LV assist devices. Here, we aimed to evaluate whether our novel rotation speed modulation system can improve coronary artery flow and reduce LV during femoral VA-ECMO. VA-ECMO was installed by means of right atrial drainage and distal abdominal aortic perfusion in six adult goats. Cardiogenic shock was induced with β-adrenergic antagonist infusion. An IABP was placed in the descending aorta. LV stroke work, LV end-systolic pressure, and coronary arterial flow were evaluated. Data were collected under five conditions (modes): baseline, circuit-clamp (cardiogenic shock), continuous mode (constant rotational speed), counterpulse mode (increasing rotational speed during diastole), and continuous mode with IABP support. LV stroke work and LV end-systolic pressure tended to be lower in the counterpulse mode, indicating decreased LV work load and afterload in this mode. Furthermore, coronary arterial flow tended to be higher in the counterpulse mode. Our system enabled an increase in coronary arterial flow and a decrease in LV work load and afterload during VA-ECMO. The system offers the effects of VA-ECMO and an IABP in a single device.

Cardiomyopathy development protection after myocardial infarction in rats: Successful competition for major dihydropyridines' common metabolite against captopril.

During the last 25 years angiotensin-converting enzyme inhibitors spectacularly conquered the field of cardiovascular diseases therapy. Nevertheless, lack of new studies concerning side effects associated with their chronic administration seems to be rather confusing. In our previous research, we proved that the main furnidipines’ metabolite (M-2) possess multiple cardioprotective actions. Currently, we compared effects of post-infarction long-term oral treatment with M-2 and captopril on hemodynamic parameters and “ischemic cardiomyopathy” development in rats. Myocardial infarction was evoked by permanent left anterior descending coronary artery occlusion for 35 days. Surviving rats were treated with captopril (2 × 25 mg/kg) or M-2 (4 mg/kg) from 6th– 35th day. At 35th day rats’ hearts were tested on working heart setup, where following parameters were measured: heart rate, preload pressure, aortic systolic and diastolic pressures, aortic maximum rise and fall, aortic and coronary flow, myocardial oxygen consumption and oximetry in perfusate. Subsequently, heart tissue specimens were assessed during morphological estimation. Captopril caused significant heart rate increase and markedly diminished preload pressure in comparison to M-2. Both drugs evoked essential aortic pressure increase. Aortic flow was significantly decreased after M-2, whereas captopril increased this parameter in comparison to M-2. Both agents caused marked coronary flow increase. Morphologic examination in captopril revealed cardiomyopathic process in 70% of hearts, whereas in M-2 this value reached 30%. Neovascularization of post-infarcted myocardium was visible only after M-2 therapy. Concluding, M-2 presented itself as more attractive agent in long-term post-infarction treatment by preventing cardiomyopathy development, angiogenesis stimulation and preserving cardiac performance.

Angiotensin (1-7) facilitates cardioprotection of ischemic preconditioning on ischemia-reperfusion-challenged rat heart.

Ischemic preconditioning (IPC) is one of the most promising strategies used to protect the myocardium from ischemia-reperfusion injury. Ang (1-7) exhibits cardioprotective activity; however, its therapeutic potential on IPC-induced cardioprotection has not been reported in ischemia-reperfusion injury till date. Therefore, the first set of experiment was designed to evaluate the direct effect of Ang (1-7), in perfusion medium, on cardioprotective activity of IPC in rat heart challenged to ischemia-reperfusion injury. In addition, the acute and chronic effects of pretreated Ang (1-7) were investigated on cardioprotection of IPC in ischemia-reperfusion-challenged hearts in subsequent sets of experiments. The results showed that Ang (1-7) potentiated the IPC-induced increase in coronary flow and heart rate, decrease in lactate dehydrogenase and creatine kinase activity, ventricular fibrillation, and infarct size in ischemia-reperfusion-challenged animals in direct and chronic sets of experiments. Further, Ang (1-7) enhanced the IPC-induced attenuation in mitochondrial dysfunction, oxidative stress, and apoptosis in ischemia-reperfusion-challenged hearts in both sets of experiments. A-779, Mas receptor antagonist, abrogated potentiation effects of Ang (1-7) on IPC-induced cardioprotection in ischemia-reperfusion-challenged rats in the above set of experiments. These observations indicate that Ang (1-7)/Mas receptor activation could be a potential adjuvant to IPC during ischemia-reperfusion-induced cardiac injury.

In silico analysis of the anti-hypertensive drugs impact on myocardial oxygen balance.

Hypertension is a very common pathology, and its clinical treatment largely relies on different drugs. Some of these drugs exhibit specific protective functions in addition to those resulting from blood pressure reduction. In this work, we study the impact of commonly used anti-hypertensive drugs (RAAS, [Formula: see text] and calcium channel blockers) on myocardial oxygen supply-consumption balance, which plays a crucial role in type 2 myocardial infarction. To this aim, 42 wash-out hypertensive patients were selected, a number of measured data were used to set a validated multi-scale cardiovascular model to subject-specific conditions, and the administration of different drugs was suitably simulated. Our results ascribe the well-known major cardioprotective efficiency of [Formula: see text] blockers compared to other drugs to a positive change of myocardial oxygen balance due to the concomitant: (1) reduction in aortic systolic, diastolic and pulse pressures, (2) decrease in left ventricular work, diastolic cavity pressure and oxygen consumption, (3) increase in coronary flow and (4) ejection efficiency improvement. RAAS blockers share several positive outcomes with [Formula: see text] blockers, although to a reduced extent. In contrast, calcium channel blockers seem to induce some potentially negative effects on the myocardial oxygen balance.

Prevalence and Clinical Significance of Discordant Changes in Fractional and Coronary Flow Reserve After Elective Percutaneous Coronary Intervention.

BackgroundFractional flow reserve (FFR) and coronary flow reserve (CFR) are well‐validated physiological indices; however, changes in FFR and CFR after percutaneous coronary intervention (PCI) remain elusive. We sought to evaluate these changes and to investigate whether physiological indices predict cardiac event‐free survival after PCI.Methods and ResultsPhysiological assessment of 220 stenoses from 220 patients was performed before and after PCI. The changes in FFR and CFR were studied, and factors associated with CFR change were investigated. Follow‐up data were collected to determine the predictor of cardiac events. CFR increase was found in 158 (71.8%) territories, and 62 (28.2%) presented a decrease, whereas FFR increased in all 220 (100%) territories. Pre‐ and post‐PCI percentage diameter stenoses were 57.7±11.2% and 7.48±4.79%, respectively. Post‐PCI CFR increase was associated with pre‐PCI indices including low FFR, low CFR and high microvascular resistance, and post‐PCI hyperemic coronary flow increase. Post‐PCI CFR decrease was not associated with significant post‐PCI hyperemic coronary flow increase. At a median follow‐up of 24.3 months, adverse event–free survival was significantly worse in patients with lower pre‐PCI CFR (log‐rank test λ2=7.26; P=0.007). Cox proportional hazards analysis showed that lower pre‐PCI CFR (hazard ratio 0.73; 95% CI 0.55–0.97; P=0.028) was an independent predictor of adverse cardiovascular events after PCI.Conclusions CFR decrease after PCI was not uncommon, and discordant change in FFR and CFR was associated with high pre‐PCI CFR, low pre‐PCI microvascular resistance, and no significant post‐PCI hyperemic coronary flow increase. Pre‐PCI CFR, not post‐PCI physiological indices, may help identify patients who require adjunctive management strategy after successful PCI.

Assessment of coronary flow reserve using a combination of planar first-pass angiography and myocardial SPECT: Comparison with myocardial 15O-water PET

Coronary flow reserve (CFR), defined as the ratio of maximum coronary flow increase from baseline resting blood flow, is one of the most sensitive parameters to detect early signs of coronary arteriosclerosis at the microvascular level. Myocardial perfusion PET is a well-established technology for CFR measurement, however, availability is still limited. The aim of this study is to introduce and validate myocardial flow reserve measurement by myocardial perfusion SPECT. MethodsMyocardial perfusion SPECT at rest and ATP stress (0.16mg/Kg/min) was performed in 10 patients with known coronary artery disease. Immediately after the injection of Tc-99m sestamibi (MIBI), left ventricular (LV) dynamic planar angiographic data were obtained for 90s. Coronary flow reserve index as measured by MIBI SPECT (CFRMIBI) was calculated as follows: CFRMIBI=CmsSbmb/CmbSbms, where subscripts b, s, Cm, and Sbm indicate baseline, during stress, myocardial counts with MIBI SPECT, and integral of LV counts with first pass angiography, respectively. Additionally, standard stress/rest 15O-water PET to estimate CFR was performed in all patients as standard of reference. ResultsCFRMIBI increased in conjunction with CFR, but underestimated blood flow at high flow rates. The relationship between CFRMIBI (Y) and CFRPET (X) was well fitted as follows: Y=1.40x(1-exp(1.79/x)) (r=0.84). ConclusionsThe index of CFRMIBI reflects the CFR by 15O-water PET but underestimates flow at high flows, maybe as a reflection of pharmacokinetic limitations of MIBI.

The influence of elective percutaneous coronary intervention on microvascular resistance: a serial assessment using the index of microcirculatory resistance.

This study investigates whether hyperemic microvascular resistance (MR) is influenced by elective percutaneous coronary intervention (PCI) by using the index of microcirculatory resistance (IMR). Seventy-one consecutive patients with stable angina pectoris undergoing elective PCI were prospectively studied. The IMR was measured before and after PCI and at the 10-mo follow-up. The IMR significantly decreased until follow-up; the pre-PCI, post-PCI, and follow-up IMRs had a median of 19.8 (interquartile range, 14.6-28.9), 16.2 (11.8-22.1), and 14.8 (11.8-18.7), respectively (P < 0.001). The pre-PCI IMR was significantly correlated with the change in IMR between pre- and post-PCI (r = 0.84, P < 0.001) and between pre-PCI and follow-up (r = 0.93, P < 0.001). Pre-PCI IMR values were significantly higher in territories with decreases in IMR than in those with increases in IMR [pre-PCI IMR: 25.4 (18.4-35.5) vs. 12.5 (9.4-16.8), P < 0.001]. At follow-up, IMR values in territories showing decreases in IMR were significantly lower than those with increases in IMR [IMR at follow-up: 13.9 (10.9-17.6) vs. 16.6 (14.0-21.4), P = 0.013]. The IMR decrease was significantly associated with a greater shortening of mean transit time, indicating increases in coronary flow (P < 0.001). The optimal cut-off values of pre-PCI IMR to predict a decrease in IMR after PCI and at follow-up were 16.8 and 17.0, respectively. In conclusion, elective PCI affected hyperemic MR and its change was associated with pre-PCI MR, resulting in showing a wide distribution. Overall hyperemic MR significantly decreased until follow-up. The modified hyperemic MR introduced by PCI may affect post-PCI coronary flow.

SERCA, complex I of the respiratory chain and ATP-synthase inhibition are involved in pleiotropic effects of NS1619 on endothelial cells

A large conductance potassium (BKCa) channel opener, NS1619 (1,3-dihydro-1- [2-hydroxy-5-(trifluoromethyl) phenyl]-5-(trifluoromethyl)-2H-benzimidazole-2-one), is well known for its protective effects against ischemia-reperfusion injury; however, the exact mode of its action remains unclear. The aim of this study was to characterize the effect of NS1619 on endothelial cells.The endothelial cell line EA.hy926, guinea pig hearts and submitochondrial particles isolated from the heart were used. In the isolated guinea pig hearts, which were perfused using the Langendorff technique, NS1619 caused a dose-dependent increase in coronary flow that was inhibited by L-NAME. In EA.hy926 cells, NS1619 also caused a dose-dependent increase in the intracellular calcium ion concentration [Ca2+]i, as measured using the FURA-2 fluorescent probe. Moreover, NS1619 decreased the oxygen consumption rate in EA.hy926 cells, as assessed using a Clark-type oxygen electrode. However, when NS1619 was applied in the presence of oligomycin, the oxygen consumption increased. NS1619 also decreased the mitochondrial membrane potential, as measured using a JC-1 fluorescent probe in the presence and absence of oligomycin. Additionally, the application of NS1619 to submitochondrial particles inhibited ATP synthase.In summary, NS1619 has pleiotropic actions on EA.hy926 cells and acts not only as an opener of the BKCa channel in EA.hy926 cells but also as an inhibitor of the respiratory chain component, sarcoplasmic reticulum ATPase, which leads to the release of Ca2+ from the endoplasmic reticulum. Furthermore, NS1619 has the oligomycin-like property of inhibiting mitochondrial ATP synthase.

Preprocedural fractional flow reserve and microvascular resistance predict increased hyperaemic coronary flow after elective percutaneous coronary intervention.

Epicardial focal coronary artery stenosis, diffuse coronary disease, and microvascular resistance (MR) may limit coronary flow. The purpose of percutaneous coronary intervention (PCI) is to increase coronary flow by targeting epicardial lesions. After PCI, MR might change and affect coronary flow. We investigated whether PCI influences MR using the index of microcirculatory resistance (IMR) and if pre-PCI fractional flow reserve (FFR) or MR predicts the post-PCI change in hyperaemic coronary flow. This prospective study included 245 vessels from 229 patients with stable angina pectoris undergoing elective PCI. FFR and IMR were measured before and after PCI. Post-PCI increase in hyperaemic coronary flow was assessed using the change in thermodilution-derived transit time (pre-PCI Tmn - post-PCI Tmn ). IMR significantly decreased after PCI (median 1.9; interquartile range, -4.9 to 10.1) and was significantly associated with pre-PCI IMR (r = 0.70, P < 0.001). Increased coronary flow was significantly correlated with pre-PCI IMR (r = 0.62, P < 0.001) and pre-PCI FFR (r = 0.51, P < 0.001). In multivariate analysis, factors significantly associated with decreased post-PCI IMR were pre-PCI IMR (odds ratio [OR], 1.13; 95% confidence interval [CI], 1.08-1.19; P < 0.001) and angiographic reference diameter (OR, 2.44; 95% CI; 1.09-5.48; P = 0.03). Factors significantly associated with increased coronary flow post-PCI were pre-PCI IMR (OR, 1.15; 95% CI, 1.08-1.23; P < 0.001) and pre-PCI FFR (OR, <0.001; 95% CI, 0.000-0.003; P < 0.001). PCI affected MR. Pre-PCI FFR and MR were independent predictors of post-PCI changes in hyperaemic coronary flow. © 2016 Wiley Periodicals, Inc.

Enhanced A2A adenosine receptor-mediated increase in coronary flow in type I diabetic mice

Adenosine A2A receptor (A2AAR) activation plays a major role in the regulation of coronary flow (CF). Recent studies from our laboratory and others have suggested that A2AAR expression and/or signaling is altered in disease conditions. However, the coronary response to AR activation, in particular A2AAR, in diabetes is not fully understood. In this study, we use an STZ mouse model of type 1 diabetes (T1D) to look at CF responses to the nonspecific AR agonist NECA and the A2AAR specific agonist CGS 21680 in-vivo and ex-vivo. Using immunofluorescence, we also explored the effect of diabetes on A2AAR expression in coronary arteries. NECA mediated increase in CF was significantly increased in hearts isolated from STZ-induced diabetic mice. In addition, both in in-vivo and ex-vivo responses to A2AAR activation using CGS 21680 were significantly higher in diabetic mice when compared to their controls. Immunohistochemistry showed an upregulation of A2AAR in both coronary smooth muscle and endothelial cells (~160% and ~140%, respectively). Our data suggest that diabetes resulted in an increased A2AAR expression in coronary arteries which resulted in enhanced A2AAR-mediated increase in CF observed in diabetic hearts. This is the first report implying that A2AAR has a role in the regulation of CF in diabetes, supporting recent studies suggesting that the use of adenosine and its A2A selective agonist (regadenoson, Lexiscan®) may not be appropriate for the detection of coronary artery diseases in T1D and the estimation of coronary reserve.

Effects of Epicardial and Endocardial Cardiac Resynchronization Therapy on Coronary Flow: Insights From Wave Intensity Analysis

BackgroundThe increase in global coronary flow seen with conventional biventricular pacing is mediated by an increase in the dominant backward expansion wave (BEW). Little is known about the determinants of flow in the left‐sided epicardial coronary arteries beyond this or the effect of endocardial pacing stimulation on coronary physiology.Methods and ResultsEleven patients with a chronically implanted biventricular pacemaker underwent an acute hemodynamic and electrophysiological study. Five of 11 patients also took part in a left ventricular endocardial pacing protocol at the same time. Conventional biventricular pacing, delivered epicardially from the coronary sinus, resulted in a 9% increase in flow (average peak velocity) in the left anterior descending artery (LAD), mediated by a 13% increase in the area under the BEW (P=0.004). Endocardial pacing resulted in a 27% increase in LAD flow, mediated by a 112% increase in the area under the forward compression wave (FCW) and a 43% increase in the area under the BEW (P=0.048 and P=0.036, respectively). There were no significant changes in circumflex parameters. Conventional biventricular pacing resulted in homogenization of timing of coronary flow compared with baseline (mean difference in time to peak in the LAD versus circumflex artery: FCW 39 ms [baseline] versus 3 ms [conventional biventricular pacing], P=0.008; BEW 47 ms [baseline] versus 8 ms [conventional biventricular pacing], P=0.004).ConclusionsEpicardial and endocardial pacing result in increased coronary flow in the left anterior descending artery and homogenization of the timing of waves that determine flow in the LAD and the circumflex artery. The increase in both the FCW and the BEW with endocardial pacing may be the result of a more physiological activation pattern than that of epicardial pacing, which resulted in an increase of only the BEW.

Sex Difference in Coronary Endothelial Dysfunction in Apolipoprotein E Knockout Mouse: Role of NO and A2A Adenosine Receptor.

Sex plays an important role in the pathophysiology of cardiovascular diseases. This study aims to investigate how sex impacts on the coronary flow regulation during atherosclerosis. ApoE KO mouse fed with western diet were used for atherosclerosis model. Coronary RH and flow response were measured using Langendorff-perfused isolated hearts. Coronary RH and A23187-induced NO-dependent flow increases were significantly reduced in female (by ~28% and 48%, respectively), but not in male atherosclerotic mice. However, SNP-induced coronary vasodilation remains intact in both sexes of ApoE KO mice. L-NAME (NOS inhibitor) reduced baseline flow and RH to a lesser extent in ApoE KO (by ~19% and 31%) vs. WT (~30% and 59%, respectively), and abolished the sex difference in RH. In contrast, SCH58261 (a selective A2A AR antagonist) reduced the baseline flow and RH to a greater extent in atherosclerotic mice, but did not affect the sex difference. Immunofluorescent staining of coronary arteries showed a similar A2A AR upregulation in both sexes of ApoE KO mice. Our results suggest that during atherosclerosis, female mice are more susceptible to NO-dependent endothelial dysfunction and the upregulation of A2A AR may serve as a compensatory mechanism to counteract the compromised endothelial function.

5-hydroxytryptamine has an endothelium-derived hyperpolarizing factor-like effect on coronary flow in isolated rat hearts

Background5-hydroxytryptamine (5-HT)-induced coronary artery responses have both vasoconstriction and vasorelaxation components. The vasoconstrictive effects of 5-HT have been well studied while the mechanism(s) of how 5-HT causes relaxation of coronary arteries has been less investigated. In isolated rat hearts, 5-HT-induced coronary flow increases are partially resistant to the nitric oxide synthase inhibitor Nω-Nitro-L-arginine methyl ester (L-NAME) and are blocked by 5-HT7 receptor antagonists. In the present study, we investigated the role of 5-HT7 receptor in 5-HT-induced coronary flow increases in isolated rat hearts in the absence of L-NAME, and we also evaluated the involvement of endothelium-derived hyperpolarizing factor (EDHF) in 5-HT-induced coronary flow increases in L-NAME-treated hearts with the inhibitors of arachidonic acid metabolism and the blockers of Ca2+-activated K+ channels.ResultsIn isolated rat hearts, 5-HT and the 5-HT7 receptor agonist 5-carboxamidotryptamine induced coronary flow increases, and both of these effects were blocked by the selective 5-HT7 receptor antagonist SB269970; in SB269970-treated hearts, 5-HT induced coronary flow decreases, which effect was blocked by the 5-HT2A receptor blocker R96544. In L-NAME-treated hearts, 5-HT-induced coronary flow increases were blocked by the phospholipase A2 inhibitor quinacrine and the cytochrome P450 inhibitor SKF525A, but were not inhibited by the cyclooxygenase inhibitor indomethacin. As to the effects of the Ca2+-activated K+ channel blockers, 5-HT-induced coronary flow increases in L-NAME-treated hearts were inhibited by TRAM-34 (intermediate-conductance Ca2+-activated K+ channel blocker) and UCL1684 (small-conductance Ca2+-activated K+ channel blocker), but effects of the large-conductance Ca2+-activated K+ channel blockers on 5-HT-induced coronary flow increases were various: penitrem A and paxilline did not significantly affect 5-HT-induced coronary flow responses while tetraethylammonium suppressed the coronary flow increases elicited by 5-HT.ConclusionIn the present study, we found that 5-HT-induced coronary flow increases are mediated by the activation of 5-HT7 receptor in rat hearts in the absence of L-NAME. Metabolites of cytochrome P450s, small-conductance Ca2+-activated K+ channel, and intermediate-conductance Ca2+-activated K+ channel are involved in 5-HT-induced coronary flow increases in L-NAME-treated hearts, which resemble the mechanisms of EDHF-induced vasorelaxation. The role of large-conductance Ca2+-activated K+ channel in 5-HT-induced coronary flow increases in L-NAME-treated hearts needs further investigation.

Involvement of NADPH oxidase in A2A adenosine receptor-mediated increase in coronary flow in isolated mouse hearts.

Adenosine increases coronary flow mainly through the activation of A2A and A2B adenosine receptors (ARs). However, the mechanisms for the regulation of coronary flow are not fully understood. We previously demonstrated that adenosine-induced increase in coronary flow is in part through NADPH oxidase (Nox) activation, which is independent of activation of either A1 or A3ARs. In this study, we hypothesize that adenosine-mediated increase in coronary flow through Nox activation depends on A2A but not A2BARs. Functional studies were conducted using isolated Langendorff-perfused mouse hearts. Hydrogen peroxide (H2O2) production was measured in isolated coronary arteries from WT, A2AAR knockout (KO), and A2BAR KO mice using dichlorofluorescein immunofluorescence. Adenosine-induced concentration-dependent increase in coronary flow was attenuated by the specific Nox2 inhibitor gp91 ds-tat or reactive oxygen species (ROS) scavenger EUK134 in both WT and A2B but not A2AAR KO isolated hearts. Similarly, the A2AAR selective agonist CGS-21680-induced increase in coronary flow was significantly blunted by Nox2 inhibition in both WT and A2BAR KO, while the A2BAR selective agonist BAY 60-6583-induced increase in coronary flow was not affected by Nox2 inhibition in WT. In intact isolated coronary arteries, adenosine-induced (10μM) increase in H2O2 formation in both WT and A2BAR KO mice was attenuated by Nox2 inhibition, whereas adenosine failed to increase H2O2 production in A2AAR KO mice. In conclusion, adenosine-induced increase in coronary flow is partially mediated by Nox2-derived H2O2, which critically depends upon the presence of A2AAR.

Involvement of NADPH oxidase in A2A adenosine receptor-mediated increase in coronary flow in isolated mouse hearts

Involvement of NADPH oxidase in A2A adenosine receptor-mediated increase in coronary flow in isolated mouse hearts

Longitudinal Myocardial Blood Flow Gradient and CAD Detection

Conventional myocardial perfusion scintigraphy with SPECT/CT or with PET/CT has been established as pivotal clinical imaging modality for the identification of hemodynamically obstructive coronary artery disease (CAD) and risk stratification of patients with suspected or known CAD. While the assessment of the relative distribution of radiotracer uptake in the left-ventricular (LV) myocardium during vasomotor stress identifies the "culprit" or most severe CAD lesion in multivessel disease, flow-limiting effects of remaining but less severe epicardial lesions may be missed. This limitation principally may be overcome by the possibility of PET/CT with radiotracer-kinetic modeling to concurrently assess left-ventricular (LV) myocardial blood flow (MBF) in ml/g/min at rest and during vasomotor stress and the resulting myocardial flow reserve (MFR). While a stress-induced regional reduction in radiotracer uptake or perfusion identifies the most advanced epicardial lesion, flow-limiting effects of the other epicardial lesions may principally be identified by regional reductions in MFR. Conversely, reductions in MFR in CAD may be appreciated as suboptimal as they reflect not only the consequences of flow-limiting effects of epicardial stenosis but also of microvascular dysfunction. The relatively low specificity of a reduced therefore MFR may hamper a clear identification of the downstream hemodynamic effects of an epicardial lesion on hyperemic coronary flow increases. In this scenario, there is increasing evidence that the PET assessment of an abnormal decrease in MBF from the base to the apex of the LV during hyperemic flows, a so-called longitudinal flow gradient, is primarily related to fluid dynamic consequences of CAD-induced diffuse luminal and/or focal narrowing of the epicardial artery. The combined evaluation of the MFR and corresponding longitudinal MBF gradient could emerge as new a novel analytic concept to further optimize the identification and characterization of hemodynamic CAD burden in multivessel disease, which, however, warrants further clinical validation.