Maximal Coronary Vasodilation Research Articles

The impact of AAOCA anatomical characteristics in coronary blood supply

Abstract Background Impact of AAOCA in coronary blood flow and myocardial perfusion is an unknown field although it is well-accepted that the anomaly is one of the leading causes of sudden death during effort. The risk factors for AAOCA are the anatomical characteristics of the abnormal vessel, such as the presence of intramural (IM) segment, the ostium shape, and the take-off angle. Purpose We aim to evaluate the impact of AAOCA anatomical risk profile in the blood flow using the thermodilution technique, an accurate and reproducible method used to investigate coronary physiology. Methods This is a single-centre prospective study that included AAOCA subjects who underwent invasive thermodilution functional coronary assessment. We divided patients into two groups according to the anatomical risk profile: a) ischemic risk (IR): concomitant presence of IM segment, take-off angle<45°, and slit-like/oval shape ostium, or a IM length>10 mm; b) no-ischemic risk (no-IR): absence of IM segment, take-off angle>45°, round ostium. We obtained coronary functional measures using the thermodilution method. We measured the absolute flow, and coronary resistance at rest and maximal hyperemia. Data were reported as median and IQR and we used Wilcoxon signed-rank test for paired data in the rest vs. hyperaemia comparison. Results We included 28 AAOCA pts (22 male, 6 female, median age: 48.6 (IQR: 18.9) ) that were 20 anomalies of the right coronary and 8 of the left. Symptomatic subjects (n=16) presented with angina (n=12), syncope (n=1), presyncope (n=1), fatigue (n=1), and dyspnea associated with arrhythmia (n=1). The IR group (26 pts; R-AAOCA=24, L-AAOCA=2) has an IM segment with a median length of 10 mm (IQR: 5.5), a median take-off angle of 28° and the ostium was slit-like (n=16), oval (n=10), and round (n=1). The no-IR group consisted of 9 (R-AAOCA=3, L-AAOCA=6), median take-off angle of 69° and the ostium was oval (n=1), and round (n=8). The absolute flow and coronary resistance at rest of the IR group did not have significant differences compared to no-IR. Hyperemia determines an increment of coronary flow in both groups although the IR had a 2.9 fold increase and the no-IR as 3.5 fold increase compared to rest. In particular, the absolute flow of the IR group was significantly lower compared to the no-IR group (185 vs. 330 mL/min, p=0.012) and there was a greater coronary resistance (419 vs. 268 mmHg/(mL/min), p=0.027), as shown in Fig. 1. Conclusions Anatomical risk factors of AAOCA, such as IM take-off angle and ostium morphology, have a negative impact on the coronary blood supply that is reduced when compared to AAOCA without such anatomical features. Such impact can be revealed also at rest using the thermodilution method that induces maximal coronary vasodilatation that is the natural coronary response to physical effort. Further studies are needed to validate benefit of functional assessment in AAOCA risk stratification.

Early Hyperdynamic Sepsis Alters Coronary Blood Flow Regulation in Porcine Fecal Peritonitis.

Background: Sepsis is a common condition known to impair blood flow regulation and microcirculation, which can ultimately lead to organ dysfunction but such contribution of the coronary circulation remains to be clarified. We investigated coronary blood flow regulatory mechanisms, including autoregulation, metabolic regulation, and endothelial vasodilatory response, in an experimental porcine model of early hyperdynamic sepsis.Methods: Fourteen pigs were randomized to sham (n = 7) or fecal peritonitis-induced sepsis (n = 7) procedures. At baseline, 6 and 12 h after peritonitis induction, the animals underwent general and coronary hemodynamic evaluation, including determination of autoregulatory breakpoint pressure and adenosine-induced maximal coronary vasodilation for coronary flow reserve and hyperemic microvascular resistance calculation. Endothelial-derived vasodilatory response was assessed both in vivo and ex vivo using bradykinin. Coronary arteries were sampled for pathobiological evaluation.Results: Sepsis resulted in a right shift of the autoregulatory breakpoint pressure, decreased coronary blood flow reserve and increased hyperemic microvascular resistance from the 6th h after peritonitis induction. In vivo and ex vivo endothelial vasomotor function was preserved. Sepsis increased coronary arteries expressions of nitric oxide synthases, prostaglandin I2 receptor, and prostaglandin F2α receptor.Conclusion: Autoregulation and metabolic blood flow regulation were both impaired in the coronary circulation during experimental hyperdynamic sepsis, although endothelial vasodilatory response was preserved.

Reduced global myocardial perfusion reserve in DCM and HCM patients assessed by CMR-based velocity-encoded coronary sinus flow measurements and first-pass perfusion imaging.

Coronary microvascular dysfunction (CMD) is an independent predictor of poor prognosis in patients suffering from dilative or hypertrophic cardiomyopathy (DCM/HCM). To assess CMD, quantitative myocardial first-pass perfusion (1P) cardiovascular magnetic resonance (CMR) can be performed. Coronary sinus flow (CSF) measurements at rest and during maximal vasodilatation are an alternative and well-validated approach for the quantification of global myocardial blood flow (MBF) in CMR. Global myocardial perfusion reserve (MPR) was used to compare both methods, 1P and CSF. This measure reflects the ratio of myocardial blood flow during maximal coronary vasodilatation over rest. 1P-MPR and CSF-MPR were calculated in 17 HCM patients, 14 DCM patients and 16 controls, who underwent a stress CMR study to rule out obstructive coronary artery disease. All patients were examined on a 1.5-T system and the study protocol comprised both, first-pass myocardial perfusion imaging (MPI) and velocity-encoded (VENC) phase-contrast imaging of CSF during rest and adenosine stress. 1P-MPR was significantly decreased only in HCM patients compared to controls (1.14 vs. 1.43, p = 0.045) whereas CSF-MPR was significantly reduced in both patient groups, HCM and DCM, compared to controls (2.38 and 2.07 vs. 3.18, p = 0.041 and p = 0.032). CSF-MBF at maximal stress was significantly lower in HCM and DCM patients compared to the control group (0.11 and 1.23 vs. 1.58ml/min/g, p = 0.008 and p = 0.040). A moderate but significant correlation between CSF-MPR and 1P-MPR was observed (r = 0.39, p = 0.011). A negative correlation between LV wall thickness and CSF-MBF at rest and stress was found in the DCM group using VENC-based CSF measurements (r=- 0.64, p = 0.013 and r=- 0.69, p = 0.006)-but not using 1P-MPI. Post-proceeding analysis regarding 1P-MPR and CSF-MPR measurements required 20.1 and 6.5min, respectively (p < 0.001). The presence of microvascular disease can be non-invasively and quickly detected by VENC-based CSF-MPR measurements during routine stress perfusion CMR in both HCM and DCM patients. Compared to conventional 1P-MPI, VENC-based CSF-MPR is particularly useful in DCM patients with thinned ventricular walls.

Spare Adenosine A2a Receptors Are Associated With Positive Exercise Stress Test In Coronary Artery Disease.

During exercise, cardiac oxygen-consumption increases and the resulting low oxygen level in myocardium triggers coronary vasodilation. This response to hypoxia is controlled notably by the vasodilator adenosine and its A2A receptor (A2AR). According to the "spare receptor" pharmacological model, a strong A2AR-mediated response can occur in the context of a large number of receptors remaining unoccupied, activation of only a weak fraction of A2AR (evaluated using KD) resulting in maximal cAMP production (evaluated using EC50), and hence in maximal coronary vasodilation. In coronary artery disease (CAD), myocardial ischemia limits adaptation to exercise, which is commonly detected using the exercise stress test (EST). We hypothesized that spare A2AR are present in CAD patients to correct ischemia. Seventeen patients with angiographically-documented CAD and 17 control subjects were studied. We addressed adenosine-plasma concentration and A2AR-expression at the mononuclear cell-surface, which reflects cardiovascular expression. The presence of spare A2AR was tested using an innovative pharmacological approach based on a homemade monoclonal antibody with agonist properties. EST was positive in 82% of patients, and in none of the controls. Adenosine plasma-concentration increased by 60% at peak exercise in patients only (p<0.01). Most patients (65%), and none of the controls, had spare A2AR (identified when EC50/KD≤0.1) and a low A2AR-expression (mean: -37% vs controls; p<0.01). All patients with spare A2AR had a positive EST whereas the subjects without spare A2AR had a negative EST (p<0.05). Spare A2AR are therefore associated with positive EST in CAD patients and their detection may be used as a diagnostic marker.

Adenosine stress native T1 mapping in severe aortic stenosis: evidence for a role of the intravascular compartment on myocardial T1 values.

BackgroundMyocardial T1 relaxation times have been reported to be markedly abnormal in diverse myocardial pathologies, ascribed to interstitial changes, evaluated by T1 mapping and calculation of extracellular volume (ECV). T1 mapping is sensitive to myocardial water content of both intra- and extracellular in origin, but the effect of intravascular compartment changes on T1 has been largely neglected. We aimed to assess the role of intravascular compartment on native (pre-contrast) T1 values by studying the effect of adenosine-induced vasodilatation in patients with severe aortic stenosis (AS) before and after aortic valve replacement (AVR).Methods42 subjects (26 patients with severe AS without obstructive coronary artery disease and 16 controls) underwent cardiovascular magnetic resonance at 3 T for native T1-mapping (ShMOLLI), first-pass perfusion (myocardial perfusion reserve index-MPRI) at rest and during adenosine stress, and late gadolinium enhancement (LGE).ResultsAS patients had increased resting myocardial T1 (1196 ± 47 ms vs. 1168 ± 27 ms, p = 0.037), reduced MPRI (0.92 ± 0.31 vs. 1.74 ± 0.32, p < 0.001), and increased left ventricular mass index (LVMI) and LGE volume compared to controls. During adenosine stress, T1 in AS was similar to controls (1240 ± 51 ms vs. 1238 ± 54 ms, p = 0.88), possibly reflecting a similar level of maximal coronary vasodilatation in both groups. Conversely, the T1 response to stress was blunted in AS (ΔT1 3.7 ± 2.7% vs. 6.0 ± 4.2% in controls, p = 0.013). Seven months after AVR (n = 16) myocardial T1 and response to adenosine stress recovered towards normal. Native T1 values correlated with reduced MPRI, aortic valve area, and increased LVMI.ConclusionsOur study suggests that native myocardial T1 values are not only influenced by interstitial and intracellular water changes, but also by changes in the intravascular compartment. Performing T1 mapping during or soon after vasodilator stress may affect ECV measurements given that hyperemia alone appears to substantially alter T1 values.

Time course of coronary vasodilator response to intravenous adenosine in humans (1071.2)

Measurement of coronary flow velocity reserve (CFVR) has proven useful in assessing coronary vasodilator potential in humans. CFVR is frequently assessed by measuring coronary vasodilator responses to intravenous infusion of adenosine. Importantly, the time course of the coronary vasodilator response to intravenous adenosine infusion has not been well documented. We retrospectively studied this time course during 39 adenosine stress tests obtained in 21 adults (6 F; age range 22‐76 yrs.). Peak coronary blood velocity (CBV) in the left anterior descending artery was assessed non‐invasively in the distal left anterior descending artery using transthoracic Doppler echocardiography before (baseline) and continuously throughout a 6‐min adenosine infusion (0.14 mg/kg/min) in all subjects. CFVR was quantified as CBV peak adenosine/CBVbaseline. Overall, adenosine infusion increased CBV in all subjects (P&lt;0.001) and peak CFVR was observed during the 4th minute in the group as a whole. However, marked variability in the timing of this response was observed. On an individual basis peak CFVR occurred during the 2nd (n=11), 3rd, (n=9), 4th (n=9,) 5th (n=7) and 6th min (n=3) of adenosine infusion. These data suggest that maximal coronary vasodilator responsiveness (i.e., CFVR) occurs variably between the 2nd and 6th minute of adenosine infusion. Based on these findings, we believe the current 6 min adenosine infusion protocol is appropriate. However, we suggest that CBV be monitored during each minute of the infusion so as to capture the true peak response in all subjects.Grant Funding Source: Supported by P01 HL096570 and UL1 TR000127

Coronary microvascular dysfunction in primary cardiomyopathies

Myocardial ischaemia is usually caused by abnormalities of the epicardial coronary arteries. In the past 30 years, however, several studies have shown that abnormalities in the coronary microcirculation may also...

Intracoronary nitroprusside results in faster, uniform, and uneventful maximal coronary vasodilation during fractional flow reserve measurements

Background: Previous studies have described potential antiatherogenic effects of everolimus after systemic and local stent delivery. However, direct effects of everolimus on foam cells (FC) have not been well characterized. We used an in vitro model to explore the effects of everolimus on macrophage-derived FC. Methods: FC were derived from human THP1 macrophages via incubation with acetylated LDL (100 μg/ml) for 72 h, followed by everolimus treatment (10−5–10−11 M) for 24 h (n=4). FC viability was quantified using calcein AM/DAPI staining via fluorescent microscopy. FC lysates and media supernatants were analyzed for apoptosis/necrosis using a Cell Death Detection ELISA assay (Roche, Pleasanton, CA, USA). Media supernatants were also analyzed for inflammatory cytokines (IL1β, IL8, MCP1, TNFα) using a Procarta immunoassay (Affymetrix, Santa Clara, CA, USA). Gene expression of autophagy (MAP1LC3A), apoptosis (survivin, clusterin), and matrix degradation (MMP1, MMP9) markers were evaluated by a Quantigene Plex assay (Affymetrix). Statistical significance was calculated using one-way ANOVA (Pb.05). Results: Average FC apoptosis was significantly increased (192%, Pb.01) at a high dose of everolimus (10−5 M), with no effects on necrosis at any dose tested. In contrast, everolimus did not affect endothelial (HUVEC) and smooth muscle (HCASMC) cell apoptosis/ necrosis. Calcein AM/DAPI staining showed that FC exposed to everolimus (10−5 M) had significantly decreased viability (27%, Pb.01) compared to control. Everolimus (10−5 M) increased MAP1LC3A (50%, Pb.001) and clusterin (110%, P=.10) and decreased survivin (33%, Pb.004) and MMP1 (122%, Pb.001) gene expression in FC, suggesting that everolimus reduced FC viability through autophagy/apoptosis. MCP1 cytokine expression was significantly decreased (1000%, Pb.001) by everolimus (10−5 M) in FC, suggesting an inhibitory effect on monocyte recruitment. Conclusion: Everolimus, a potent antiproliferative agent used in drug-eluting stents/bioresorbable vascular scaffolds, may inhibit atheroma progression through autophagy/apoptosis of FC and inhibition of monocyte recruitment into the lesion.

Coronary hemodynamics in the transplanted human heart

The basal features of the coronary circulation, including coronary reserve, were assessed in 12 nonrejecting heart transplant recipients and compared to similar data obtained in 10 innervated subjects. Coronary sinus blood flow (CSBF) was determined by thermodilution, and coronary reserve was measured as the increment in flow after maximal coronary vasodilatation induced by 10 mg intracoronary papaverine. Heart rate and mean aortic pressure were significantly higher in the transplanted group. Basally, transplanted patients showed lower coronary resistance (0.65 ± 0.12 vs 0.90 ± 0.24 mmHg/ml/minute,p<0.01), higher CSBF (172 ± 24 vs 116 ± 31 ml/minute,p<0.0001), similar myocardial oxygen consumption (15.3 ± 4.0 vs 13.6 ± 4.7 ml/minute, NS), and narrower myocardial arteriovenous oxygen difference (8.9 ± 2 vs 11.6 ± 2 ml/100 ml,p<0.01). After papaverine, innervated subjects had a greater increase in CSBF (148 ± 40 vs 100 ± 37%,p<0.01) and also a larger reduction in coronary resistance (59 ± 5.3 vs 48.7 ± 9%,p<0.01). Maximum levels of CSBF attained were higher in transplanted patients (340 ± 60 vs 283 ± 68 ml/minute,p<0.05), whereas minimum levels of coronary resistance were similar in both groups (0.33 ± 0.06 vs 0.36 ± 0.06 mmHg/ml/minute, NS). According to our results, nonrejecting heart transplant patients have decreased resting coronary resistance, with a subsequent increase in CSBF for a given myocardial oxygen consumption probably due to lack of adrenergic tone and increased aortic pressure. As a consequence, coronary reserve appears diminished, though maximal coronary flow attained after papaverine may be higher than in normal individuals, depending on a superior perfusion pressure.

Hemodynamics and myocardial blood flow patterns after placement of a cardiac passive restraint device in a model of dilated cardiomyopathy

The present study examined a cardiac passive restraint device which applies epicardial pressure (HeartNet Implant; Paracor Medical, Inc, Sunnyvale, Calif) in a clinically relevant model of dilated cardiomyopathy to determine effects on hemodynamic and myocardial blood flow patterns. Dilated cardiomyopatht was established in 10 pigs (3 weeks of atrial pacing, 240 beats/min). Hemodynamic parameters and regional left ventricular blood flow were measured under baseline conditions and after acute placement of the HeartNet Implant. Measurements were repeated after adenosine infusion, allowing maximal coronary vasodilation and coronary flow reserve to be determined. Left ventricular dilation and systolic dysfunction occurred relative to baseline as measured by echocardiography. Left ventricular end-diastolic dimension increased and left ventricular fractional shortening decreased (3.8 ± 0.1 vs 6.1 ± 0.2 cm and 31.6% ± 0.5% vs 16.2% ± 2.1%, both P < .05, respectively), consistent with the dilated cardiomyopathy phenotype. The HeartNet Implant was successfully deployed without arrhythmias and a computed median mid-left ventricular epicardial pressure of 1.4 mm Hg was applied by the HeartNet Implant throughout the cardiac cycle. Acute HeartNet placement did not adversely affect steady state hemodynamics. With the HeartNet Implant in place, coronary reserve was significantly blunted. In a large animal model of dilated cardiomyopathy, the cardiac passive restraint device did not appear to adversely affect basal resting myocardial blood flow. However, after acute HeartNet Implant placement, left ventricular maximal coronary reserve was blunted. These unique results suggest that cardiac passive restraint devices that apply epicardial transmural pressure can alter myocardial blood flow patterns in a model of dilated cardiomyopathy. Whether this blunting of coronary reserve holds clinical relevance with chronic passive restraint device placement remains unestablished.

Direct effect of mild hypothermia on the coronary vasodilation induced by an ATP-sensitive K channel opener, a nitric oxide donor and isoflurane in isolated rat hearts

Deliberate mild hypothermia (MHT) is applied for cerebroprotection after cardiopulmonary resuscitation and during cardiac surgery. MHT has been shown to alter both contractility and relaxation of blood vessels in the brain. However, the effects of MHT on drug-induced vasodilation are not fully understood. The aim of this study was to clarify the effects of MHT on the coronary vasodilation induced by cromakalim (an ATP-sensitive K channel opener), S-nitroso acetyl-penicillamine (SNAP; a nitric oxide donor), and isoflurane in isolated rat hearts. Male SD rat hearts were isolated and perfused with Krebs-Henseleit buffer. Coronary flow was measured with the coronary perfusion pressure kept at 60 mmHg, and coronary vascular resistance (CVR) was calculated. After cardiac arrest was induced by tetrodotoxin, the hearts were allocated to one of three temperature groups: 37, 34, and 31 degrees C (n = 7 for each). All groups received 0.01, 0.1, and 1.0 microM of either cromakalim or SNAP or were exposed to isoflurane at 1MAC and 2MAC. Finally, 50 mM of adenosine was administered to obtain maximal coronary vasodilation. CVR significantly increased after cardiac arrest, but did not change after the application of each temperature. Cromakalim, SNAP and isoflurane significantly decreased CVR in each temperature group. There were no significant differences in CVR among the three temperature groups with any of the test drugs. These results indicate that cromakalim-, SNAP-, and isoflurane-induced coronary vasodilation are not affected by MHT.

Measurement of coronary flow reserve by noninvasive cardiac imaging

Myocardial blood flow (MBF) must respond to changes in metabolic conditions and oxygen requests to meet the needs of myocytes, and autoregulation plays a mayor role in the control of the coronary circulation [1–3]. It has been demonstrated that as the coronary artery progressively narrows, resting flow does not change at first, but maximal flow resulting from injection of a vasodilator decreases progressively [4, 5]. Coronary flow reserve (CFR) indicates the amount of additional blood flow that can be supplied to the heart over baseline blood flow. The absence of CFR implies maximal vasodilatation of the resistance vessels at rest and an inability to further increase MBF. Different terms are used to describe CFR. Absolute flow reserve is the ratio of blood flow during maximal hyperaemia in a stenotic artery to blood flow in the same artery at rest [6, 7]. The invasive, Doppler-based technique that measures coronary blood velocity at rest and during hyperaemia is a good example of absolute CFR measurement. Relative flow reserve is the ratio of hyperaemic flow in a stenotic artery to hyperaemic flow in a normal artery [8, 9]. Fractional flow reserve is the ratio of the maximum achievable flow in the presence of a stenosis to the theoretical maximum flow in the same artery if the artery were normal [10, 11]. This is the basis of the pressure-derived method that is the invasive method of choice to determine the significance of a coronary stenosis [12]. Several factors influence CFR measurement, such as the ability to achieve maximal coronary vasodilatation, heart rate and myocardial contractility, right atrial pressure, serial coronary stenosis, coronary resistance, and coronary collateral circulation [13]. Each of these factors has a different impact according to the method used for CFR evaluation, and therefore the various techniques are not interchangeable. While problems with each of these techniques may explain the difference, the choice of technique used is often governed by the availability of local resources, and the important practical issue may not be which method is best, but that the techniques do not provide comparable results.

Adenosine and maximum coronary vasodilation in humans: myth and misconceptions in the assessment of coronary reserve

receptors, adenylate cyclase and calcium-activated potas-sium channels in vascular smooth muscle cells [52]. Also,indirect effects contribute to the role of adenosine in cor-onary blood flow: adenosine inhibits presynaptic release ofnorepinephrine from sympathetic nerves [43], inhibitsplatelet aggregation [35] and inhibits leukocyte adherenceto the vascular wall [59]. A

Changes in Coronary Flow Reserve following Stent Implantation in the Swine Descending Thoracic Aorta

To evaluate coronary flow reserve (CFR) changes following stent implantation in the descending thoracic aorta (DTA) of a porcine model. Six pigs (3 males; 40 to 44 kg) were anesthetized and kept on mechanical ventilation. A 6-F guiding right Judkins catheter was advanced under fluoroscopy to the right coronary artery, and a pressure wire with a temperature sensor was placed within the vessel lumen at a distance of 4 cm from the ostium. CFR was estimated by the thermodilution method before and after maximal coronary vasodilation with 20 mg of intracoronary papaverine. Aortography was also performed to measure aortic diameter. Subsequently, a self-expanding vascular stent was deployed into the DTA just below the left subclavian artery (LSA), and CFR was measured again. All animals were maintained for 3 weeks; at the end of this period, a further CFR was calculated using the same procedure. The mean aortic diameter below the LSA was 12.15+/-0.15 mm. Following stent deployment, the mean aortic diameter measured at the stented segment was 12.58+/-0.11 (p=0.001 versus baseline). The mean CFR value was 4.70+/-2.00 before stent implantation, 2.68+/-0.86 immediately after, and 4.05+/-1.15 at 3 weeks after stenting. Accordingly, CFR values were significantly depressed immediately after stent placement compared with baseline (p=0.027). However, CFR values obtained 3 weeks following stent deployment were similar to the initial values (p=0.59). Stent deployment in the normal swine DTA produces a significant immediate decrease in CFR, which is attenuated 3 weeks later. The clinical impact of CFR changes following DTA endografting remain to be elucidated.

Role of A1 adenosine receptor in the regulation of coronary flow

To determine whether A1 adenosine receptors (AR) participate in adenosine-induced changes of coronary flow, isolated hearts from A1AR(-/-) and A1AR(+/+) mice were perfused under constant pressure, and the effects of nonselective and selective agonists were examined. Adenosine, 5'-N-ethylcarboxamidoadenosine (NECA, nonselective), and the selective A2AAR agonist 2-2-carboxyethylphenethylamino-5'-N-ethylcarboxamidoadenosine (CGS-21680) augmented maximal coronary vasodilation in A1AR(-/-) hearts compared with A1AR(+/+) hearts. Basal coronary flow was increased (P < 0.05) in A1AR(-/-) hearts compared with A1AR(+/+) hearts: 2.548 +/- 0.1 vs. 2.059 +/- 0.17 ml/min. In addition, selective activation of A1AR with 2-chloro-N6-cyclopentyladenosine (CCPA) at nanomolar concentrations (1-100 nM) did not significantly change coronary flow; at higher concentrations, CCPA increased coronary flow in A1AR(-/-) and A1AR(+/+) hearts. Because deletion of A1AR increased basal coronary flow, it is speculated that this effect is due to removal of an inhibitory influence associated with A1AR. Adenosine and NECA at approximately EC50 (100 and 50 nM, respectively) increased coronary flow in A1AR(+/+) hearts to 177.86 +/- 8.75 and 172.72 +/- 17% of baseline, respectively. In the presence of the selective A1AR antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 50 nM), the adenosine- and NECA-induced increase in coronary flow in A1AR(+/+) hearts was significantly augmented to 216.106 +/- 8.35 and 201.61 +/- 21.89% of normalized baseline values, respectively. The adenosine- and NECA-induced increase in coronary flow in A1AR(-/-) hearts was not altered by DPCPX. These data indicate that A1AR may inhibit or negatively modulate coronary flow mediated by other AR subtypes (A2A and A2B).

A calcium channel blocker amlodipine increases coronary blood flow via both adenosine- and NO-dependent mechanisms in ischemic hearts

Amlodipine reduces oxidative stress that decreases NO and adenosine release. This study was undertaken to examine whether amlodipine mediates coronary vasodilation and improves myocardial metabolism and contractility in ischemic hearts via either adenosine- or NO-dependent mechanisms. In open-chest dogs, amlodipine (2 μg kg per min) was infused at the minimum dose that caused maximal coronary vasodilation. The perfusion pressure was reduced in the left anterior descending coronary artery so that coronary blood flow (CBF) decreased by 50%. Amlodipine increased the difference of the adenosine level (VAD (Ado): 119 ± 14 to 281 ± 46 nM) and the nitrate + nitrite level (VAD (NOx): 7.8 ± 1.3 to 16.1 ± 1.1 μM) between coronary venous and coronary arterial blood, and also increased CBF (50 ± 3 to 69 ± 6 ml/100 g/min). These changes were partially reversed by either 8-sulfophenyeltheophylline (8SPT) or l ω-nitro arginine methyl ester ( l-NAME), and were completely blocked by both 8SPT and l-NAME. The reduction of CBF increased VAD (8-iso-prostaglandin F 2α), and this increase was reduced by amlodipine (10.8 ± 1.1 to 5.0 ± 0.5 pg/ml). In addition, pretreatment with superoxide dismutase mimicked the coronary effects of amlodipine and blunted the response to amlodipine administration. Amlodipine-induced coronary vasodilation via both adenosine- and NO-dependent mechanisms. Adenosine and NO may interact in ischemic hearts to mediate coronary vasodilation by amlodipine.

Coronary flow characteristics after a Bentall procedure with or without sinuses of Valsalva.

The sinuses of Valsalva are known to contribute to the normal function of the aortic valve. Little is known about their role in promoting coronary artery blood flow. The aim of this study was to compare coronary artery flow characteristics among patients undergoing a Bentall operation by means of a conventional cylindrical Dacron conduit or with a new conduit with pseudosinuses of Valsalva or in patients retaining their natural sinuses of Valsalva after aortic valve and supracoronary ascending aorta replacement. One year after a Bentall procedure with a standard cylindrical Dacron conduit (7 patients, group A) or with the new conduit (7 patients, group B), or after aortic valve and ascending aortic replacement (control group, 7 patients, group C) coronary flow velocity reserve and diastolic to systolic time integral ratio at baseline and after maximal hyperemia (with 40 microg of adenosine) were assessed by using a 0.014-in. Doppler guidewire positioned in the middle portion of the left anterior descending coronary artery. All patients were in NYHA class I, sinus rhythm and free of coronary disease. Arterial blood pressures and heart rate were comparable among groups. Intracoronary Doppler measurements did not show any significant difference in coronary vascular reserve between the three groups (3.6+/-0.4 vs 3.1+/-0.7 vs 3.7+/-0.5, P = 0.2). A greater diastolic component at baseline was present in group B patients (5.5+/-1.9 vs 3.5+/-0.9 in group A and 3.7+/-0.9 in group C, P = 0.024). After maximal hyperemia the diastolic component increased slightly in group A patients (8%) while both in groups B and C significantly decreased (-15 and -20%, respectively) (P = 0.017). The presence of pseudosinuses of Valsalva does not influence coronary flow reserve. After maximal coronary vasodilation the increase in the systolic component of coronary flow is more evident in the presence of sinuses or pseudosinuses of Valsalva, thus suggesting that coronary flow pattern may be affected by the presence of sinuses.

Exaggerated coronary reactivity to endothelin-1 in diabetes: reversal with bosentan.

We previously demonstrated that chronic endothelin receptor blockade (with bosentan) improved functional cardiac performance in streptozotocin-diabetic rats, suggesting a novel role of endothelin-1 (ET-1) in modulating diabetic heart dysfunction. To gain insight into the mechanism(s) underlying this effect, we examined the coronary vascular responses to ET-1 in hearts from diabetic and control rats treated with or without bosentan. Rats were divided into control, control-treated, diabetic, and diabetic-treated groups. The control-treated and diabetic-treated groups received bosentan (100 mg x kg(-1) x d(-1)) for 8 weeks. Following treatment, hearts were isolated and perfused, and coronary reactivity to ET-1 was assessed by measuring the changes in coronary perfusion pressure in response to ET-1 (50 and 100 pM). Additionally, maximal coronary blood flow (assessed with 10(-5) M adenosine) was measured in isolated perfused hearts. The key observation is that coronary reactivity to ET-1 was significantly higher in the diabetic than the control rats. This effect was normalized in diabetic rats chronically receiving bosentan. Maximal coronary vasodilation did not differ between the four groups. In conclusion, the reactivity of ET-1 is altered in the isolated perfused coronary vascular bed from diabetic rats, and chronic ET receptor blockade restores this reactivity to control values. These observations provide a possible mechanism for the improvement in diabetic heart function observed after chronic bosentan treatment.

Cardiovascular phenotypes of kinin B2 receptor- and tissue kallikrein-deficient mice.

To clarify the role of the kallikrein-kinin system in cardiovascular homeostasis, the systemic and regional hemodynamics of kinin B2 receptor-deficient (B2-/-) and tissue kallikrein-deficient (TK-/-) mice were compared with their wild-type (WT) littermates on a pure C57BL/6 genetic background. B2-/-, TK-/-, and WT adult mice were normotensive and displayed normal hemodynamic (left ventricular [LV] pressure, cardiac output, total peripheral resistance, dP/dt(max)) and echocardiographic (septum and LV posterior wall thickness, LV diameter, LV mass, and LV fractional shortening) parameters. However, heart rate was lower in B2-/- mice compared with TK-/- and WT mice. In addition, B2-/- mice, but not TK-/- mice, exhibited lower coronary and renal blood flows and greater corresponding vascular resistances than did WT mice, indicating a tonic physiological vasodilating effect of bradykinin in these vascular beds. However, maximal coronary vasodilatation capacity, estimated after dipyridamole infusion, was similar in the 3 groups of mice. B2-/- mice were significantly more sensitive than were TK-/- mice to the vasoconstrictor effects of angiotensin II and norepinephrine. Finally, renin mRNA levels were significantly greater in B2-/- mice and smaller in TK-/- mice compared with WT mice. Taken together, these results indicate that under basal conditions, the kinin B2 receptor is not an important determinant of blood pressure in mice but is involved in the control of regional vascular tone in the coronaries and the kidneys. The phenotypic differences observed between TK-/- and B2-/- mice could be underlain by tissue kallikrein kinin-independent effect and/or kinin B1 receptor activation.

Targeted deletion of adenosine A(3) receptors augments adenosine-induced coronary flow in isolated mouse heart.

To determine whether adenosine A(3) receptors participate in adenosine-induced changes in coronary flow, isolated hearts from wild-type (WT) and A(3) receptor knockout (A(3)KO) mice were perfused under constant pressure and effects of nonselective and selective agonists were examined. Adenosine and the selective A(2A) agonist 2-[p-(2-carboxyethyl)]phenylethylamino-5'-N-ethylcarboxamidoadenosine (CGS-21680) produced augmented maximal coronary vasodilation in A(3)KO hearts compared with WT hearts. Selective activation of A(3) receptors with 2-chloro-N(6)-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (Cl-IB-MECA) at nanomolar concentrations did not effect coronary flow, but at higher concentrations it produced coronary vasodilation both in WT and A(3)KO hearts. Cl-IB-MECA-induced increases in coronary flow were susceptible to both pharmacological blockade and genetic deletion of A(2A) receptors. Because deletion or blockade of adenosine A(3) receptors augmented coronary flow induced by nonselective adenosine and the selective A(2A) receptor agonist CGS-21680, we speculate that this is due to removal of an inhibitory influence associated with the A(3) receptor subtype. These data indicate that the presence of adenosine A(3) receptors may either inhibit or negatively modulate coronary flow mediated by other adenosine receptor subtypes.