Coronary Blood Flow Response Research Articles

Angiotensin II Type 1 Receptor Antagonist Protects Ventricular and Coronary Endothelial Function After 24-hour Heart Preservation

Angiotensin II type 1 (AT1) receptor antagonists may enhance the cyclic guanosine monophosphate-nitric oxide system and thereby attenuate ventricular and coronary endothelial dysfunction after heart preservation. We used an isolated rabbit heart preparation perfused with blood from a support rabbit. The rabbit heart was excised, stored for 24 hours, and then perfused with blood from a support rabbit that was treated with an AT1 receptor antagonist (telmisartan; 5 mg/kg) or solvent. We evaluated the cardiac output with the working preparation, and coronary blood flow and coronary endothelial function with the Langendorff preparation. In addition, we measured the serum nitric oxide level in the coronary effluent. The Telmisartan Group showed higher plasma angiotensin II levels (928.6 +/- 136.2 vs 271.6 +/- 81.6 pg/ml, p < 0.01), better cardiac output (116.2 +/- 5.4 vs 88.8 +/- 7.1 ml/min, p < 0.05), and higher coronary blood flow (25.0 +/- 2.2 vs 14.9 +/- 1.3 ml/min, p < 0.01). The coronary blood flow in response to acetylcholine was higher in the Telmisartan Group (47.8 +/- 3.9 vs 28.0 +/- 2.1 ml/min, p < 0.01), but there was no difference in response to sodium nitroprusside. The Telmisartan Group showed higher serum nitric oxide levels in the coronary effluent (33.9 +/- 4.6 vs 20.6 +/- 3.3 mumol/liter, p < 0.05). Treatment with the AT1 receptor antagonist improved ventricular and endothelial function after 24-hour heart preservation. These data imply that AT1 activation plays a critical role in reperfusion injury. AT1 receptor blockade may be a promising strategy for long-term heart preservation.

Aortic stiffness affects the coronary blood flow response to percutaneous coronary intervention

We examined the hypothesis that a stiff aorta is associated with reduced coronary blood flow (CBF) and CBF response to percutaneous coronary intervention (PCI). Aortic mechanical properties are thought to affect CBF, with increased stiffness associated with decreased coronary perfusion. Animal studies are conflicting, and human evidence is lacking. Even less is known about the effects of aortic stiffness on the CBF response to successful PCI. In 18 subjects undergoing elective PCI, a Doppler velocity guidewire was positioned proximal to a severe coronary stenosis to measure resting and adenosine-induced hyperemic CBF before and after PCI. Stenosis severity was assessed with Doppler velocity and pressure guidewires. Aortic mechanical indexes measured included central pulse-wave velocity (cPWV) and central pulse pressure (cPP). PCI was successful in all subjects (diameter stenosis: 88 +/- 9% to 2 +/- 7%; coronary flow velocity reserve: 1.8 +/- 0.6 to 3.0 +/- 0.8; fractional flow reserve: 0.57 +/- 0.19 to 0.92 +/- 0.06; all P < 0.001). With the adjustment for age and gender, resting and hyperemic CBF were inversely related to cPWV irrespective of the presence of stenosis (resting: before PCI, r2 = 0.452, P < 0.01; after PCI, r2 = 0.261, P = 0.043; hyperemic: before PCI r2 = 0.503, P = 0.005; after PCI r2 = 0.500, P = 0.002), whereas they were related to cPP in absence of stenosis (resting: r2 = 0.368, P = 0.022; hyperemic: r2 = 0.370, P = 0.016). Hyperemic CBF response (P = 0.005) and hyperemic CBF improvement from PCI (P = 0.025) were less marked in a stiff aorta than a compliant aorta. A stiff aorta is associated with a reduction in CBF, a lower hyperemic CBF response, and may reduce the improvement in hyperemic CBF after successful PCI.

Dehydroepiandrosterone Sulfate Induces Acute Vasodilation of Porcine Coronary Arteries In Vitro and In Vivo

Although an inverse relationship between dehydroepiandrosterone sulfate (DHEAS) and coronary artery disease has been demonstrated in men, the vascular effects of DHEAS are not well defined. The vasoactive effects of intracoronary DHEAS and testosterone (0.1 nM to 1 microM) were examined in vivo in 24 pigs. Epicardial cross-sectional area was measured by intravascular ultrasound, and coronary flow velocity by intravascular Doppler velocimetry. We also examined the effects of antagonism of the androgen receptor, nitric oxide synthase, and potassium channels on DHEAS-induced vasodilation in vitro in coronary rings from male and female pig hearts. DHEAS and testosterone induced increases in cross-sectional area, average peak velocity, and coronary blood flow. The maximal increase in coronary blood flow in response to testosterone was 1.26-fold (P=0.02), and in average peak velocity 1.43-fold (P=0.05), greater than that to DHEAS, whereas increases in cross-sectional area were similar. Vasodilation to both hormones was rapid, with maximal responses occurring <10 minutes after administration. In vitro, DHEAS and testosterone induced vasodilation in coronary rings, greater with testosterone. At doses of 0.1 and 1 microM, the vasodilator effects of DHEAS and testosterone were inhibited by the androgen receptor antagonist flutamide but not the estrogen receptor antagonist ICI 182,780. At 10 microM, neither DHEAS- nor testosterone-induced vasorelaxation was inhibited by flutamide, ICI 182,780, L-NAME, or deendothelialization, but both were attenuated by pretreatment with glibenclamide. No gender differences were observed in any of the responses examined. In conclusion, DHEAS is an acute coronary artery vasodilator, but less potent than testosterone. Its effect might be mediated via androgen receptors and may involve ATP-sensitive potassium channels.

Elevated C-reactive protein levels and coronary microvascular dysfunction in patients with coronary artery disease

It is still unknown whether elevated C-reactive protein levels are responsible for coronary microcirculatory dysfunction in patients with coronary artery disease (CAD). This study was aimed at evaluating the association between C-reactive protein levels and endothelium-dependent and endothelium-independent coronary blood flow (CBF) responses in non-culprit arteries of patients with CAD. We studied 28 patients (14 with normal and 14 with elevated C-reactive protein levels, >5 mg/L) with single-vessel disease and otherwise angiographically normal coronary arteries undergoing percutaneous transluminal coronary angioplasty (PTCA). CBF was measured in the non-PTCA vessel using an intracoronary Doppler guide wire and quantitative coronary angiography at baseline, after intracoronary infusion of substance P and of adenosine, and expressed as per cent change from baseline. The increases in CBF during infusion of substance P and of adenosine were lesser in patients with elevated than in those with normal C-reactive protein levels (34+/-22 vs. 61+/-34%, P=0.04 and 131+/-53 vs. 189+/-89%, P=0.03, respectively). Multivariable analysis identified elevated C-reactive protein level as the only independent predictor of reduced response to substance P (P=0.01) and adenosine (P=0.02). In patients with CAD, evidence of systemic inflammation is independently associated with endothelium-dependent and endothelium-independent coronary microvascular dysfunction, which, in turn, may be critical to precipitate myocardial ischaemia, in particular, in unstable patients.

Hormone Replacement Therapy and Coronary Endothelial Function in Postmenopausal Women

Dr Singh raises some excellent points, and we appreciate his comments. For the sake of brevity, we did not include the number of patients taking progesterone alone. Eighty-two patients took estrogen alone, and 19 took a combined estrogen plus progesterone preparation. However, we did note that concurrent administration of progesterone was not significantly associated with a change in the coronary blood flow or the coronary artery diameter response to acetylcholine or the coronary velocity reserve response to adenosine. Dr Singh's second point is an important one in that calcium channel blockers can affect vasomotor tone. For brevity, we did not include these data in our article. However, there was no significant difference in the rate of calcium channel blocker use between premenopausal and postmenopausal women (P=.52). The rates were also similar between postmenopausal women who were not receiving HRT compared with those who were (P=.17) and compared with those who had received HRT for more than 2 years (P=.20). Furthermore, there was no evidence of an interaction between calcium channel blocker use and any of the 3 comparisons (premenopausal vs post-menopausal, HRT vs no HRT, and HRT for more than 2 years vs no HRT) with regard to percent change in coronary blood flow in response to acetylcholine, percent change in coronary artery diameter in response to acetylcholine, or coronary velocity reserve response to adenosine: all interaction tests yielded P>.20. Dr Singh's final point is interesting. Age certainly could contribute to the observed differences, and it is possible that estrogen has different physiological effects in postmenopausal compared with premenopausal women. Recent animal study data from researchers at the Medical College of Georgia show that, when the activity of nitric oxide synthase that produces nitric oxide is blocked, the administration of estrogen causes not vasodilation but vasoconstriction.1White RE, HanG, Fulton D, Barman S. Dual and opposite effects of estrogen on coronary arteries mediated by type 1 (N) nitric oxide synthase via nitric oxide and superoxide. Presented at the American Heart Association Second International Conference on Women, Heart Disease, and Stroke; Orlando, Fla; February 16-19, 2005.Google Scholar Theoretically, since nitric oxide production is reduced in older women, giving postmenopausal women estrogen might, in this context, be expected to have detrimental cardiovascular effects, as seen in trials such as the Heart and Estrogen/progestin Replacement Study (HERS) and the Women's Health Initiative. Obviously, the physiology of HRT remains incompletely understood, and further study is needed to elucidate the different effects of estrogen on young vs older coronary arteries. Hormone Replacement Therapy and Coronary Endothelial Function in Postmenopausal WomenMayo Clinic ProceedingsVol. 80Issue 6PreviewTo the Editor: I read with interest the article by Halligan et al1 about the effects of long-term hormone replacement therapy (HRT) on coronary endothelial function in postmenopausal women that was published in the December 2004 issue of the Mayo Clinic Proceedings. Although the authors reached interesting conclusions, a few discrepancies should be addressed. Full-Text PDF

Coronary Blood Flow Responses are Impaired Independent of NO and Endothelial Function in Conscious Dogs with Dilated Cardiomyopathy

Background Dilated cardiomyopathy (DCM) is characterized by nitric oxide (NO) deficiency and endothelial dysfunction. Whether endothelium-independent vasodilation is preserved, particularly in the coronary circulation, remains controversial. Methods and Results We studied systemic and coronary flow responses to the endothelium-dependent agonist, acetylcholine, the cGMP-dependent NO-donor, nitroglycerin, the predominantly endothelium-independent agonist, adenosine, the β-adrenergic cAMP-dependent agonist, isoproterenol, and the calcium channel antagonist, nicardipine, in conscious dogs with pacing-induced DCM. Systemic blood flow response was impaired to acetylcholine but preserved to other vasodilators in DCM. In contrast, coronary blood flow response was significantly ( P < .05) depressed to all agonists. (Peak coronary blood flow response, control versus DCM: acetylcholine: 221 ± 14% versus 156 ± 11%; nitroglycerin: 220 ± 17% versus 138 ± 9%; adenosine: 635 ± 65% versus 376 ± 56%; nicardipine: 338 ± 59% versus 115 ± 23%; isoproterenol: 219 ± 18% versus 86 ± 20%). The attenuation was independent of systemic hemodynamic differences. Conclusion In contrast to systemic responses, coronary blood flow responses in DCM are impaired dependent or independent of NO or second messenger mechanisms, implying either distal signaling defects or structural abnormalities in the coronary vasculature.

Effect of Nifedipine on C-Reactive Protein Levels in the Coronary Sinus and on Coronary Blood Flow In Response to Acetylcholine in Patients With Stable Angina Pectoris Having Percutaneous Coronary Intervention

The effects of nifedipine on inflammation and endothelial function in the coronary circulation were studied in patients who had angina pectoris (n = 17). Long-term treatment with nifedipine (nifedipine CR, 20 mg/day for 4 months) decreased levels of C-reactive protein in the coronary sinus (from 0.35 +/- 0.09 mg/dl to 0.07 +/- 0.01 mg/dl, mean +/- SEM, p <0.05) and enhanced acetylcholine-induced increases in coronary blood flow. Thus, nifedipine is effective in decreasing inflammation and incresing endothelial function in the coronary circulation.

Increased Ambulatory Pulse Pressure Is a Strong Risk Factor for Coronary Endothelial Vasomotor Dysfunction

This study was aimed to determine the relationship between pulse pressure (PP) and coronary vasomotor dysfunction, a predictor of coronary events. Pulse pressure is a strong risk factor for coronary artery disease (CAD). However, the mechanisms by which an increase in PP affects the pathogenesis of CAD are unclear. Ambulatory blood pressure (BP) monitoring for 24 h was performed in 103 consecutive patients with normal coronary angiograms (51 hypertensive and 52 normotensive; age 42 to 70 years). The relationship between changes in coronary arterial diameter and blood flow during an intracoronary infusion of acetylcholine (ACh) (5, 10, 50 microg/min), and BP parameters, and other traditional risk factors was evaluated using univariate and multivariate linear regression analyses. With multivariate analyses, the 24-h PP showed an inverse correlation with the epicardial coronary dilator response to ACh independently of other covariates including age, smoking, and 24-h systolic BP in normotensive as well as hypertensive patients. Furthermore, multivariate analysis showed that the 24-h PP was inversely and independently correlated with the increase in coronary blood flow in response to ACh. The dilator response of epicardial coronary arteries to nitrate was not significantly correlated with 24-h PP. Increased 24-h PP is independently associated with endothelial vasomotor dysfunction in conduit and resistance coronary arteries irrespective of the presence of hypertension. Increased ambulatory PP may have an intimate relation to coronary endothelial vasomotor dysfunction.

Effects of supplemental oxygen administration on coronary blood flow in patients undergoing cardiac catheterization

Patients with heart disease are frequently treated with supplemental oxygen. Although oxygen can exhibit vasoactive properties in many vascular beds, its effects on the coronary circulation have not been fully characterized. To examine whether supplemental oxygen administration affects coronary blood flow (CBF) in a clinical setting, we measured in 18 patients with stable coronary heart disease the effects of breathing 100% oxygen by face mask for 15 min on CBF (via coronary Doppler flow wire), conduit coronary diameter, CBF response to intracoronary infusion of the endothelium-dependent dilator ACh and to the endothelium-independent dilator adenosine, as well as arterial and coronary venous concentrations of the nitric oxide (NO) metabolites nitrotyrosine, NO(2)(-), and NO(3)(-). Relative to breathing room air, breathing of 100% oxygen increased coronary resistance by approximately 40%, decreased CBF by approximately 30%, increased the appearance of nitrotyrosine in coronary venous plasma, and significantly blunted the CBF response to ACh. Oxygen breathing elicited these changes without affecting the diameter of large-conduit coronary arteries, coronary venous concentrations of NO(2)(-) and NO(3)(-), or the coronary vasodilator response to adenosine. Administering supplemental oxygen to patients undergoing cardiac catheterization substantially increases coronary vascular resistance by a mechanism that may involve oxidative quenching of NO within the coronary microcirculation.

Provocation of Microvessel Spasm by Low-Dose Acetylcholine in Patients with Suspected Coronary Artery Disease

Endothelial dysfunction plays an important role in the pathogenesis of cardiac syndrome X, and intracoronary low-dose acetylcholine infusion is a widely used diagnostic modality for studying the coronary artery endothelial function. The authors herein report 2 cases of cardiac syndrome X with coronary artery endothelial dysfunction and microvessel spasm. The findings of non-invasive testing were positive for ischemia. Coronary angiograms appeared entirely normal in both cases. However, the intracoronary infusion of low-dose (1.5-15 microg/minute) acetylcholine demonstrated an impairment of the coronary blood flow response and consequently provoked an ST-segment elevation in an electrocardiogram. The coronary angiograms showed no spasm in the epicardial arteries. These patients are thus suggested to have cardiac syndrome X with microvessel spasms associated with coronary artery endothelial dysfunction.

Brachial Artery Flow-Mediated Vasodilation Is Correlated with Coronary Vasomotor and Fibrinolytic Responses Induced by Bradykinin

Endothelium plays a key role in the regulation of not only vascular tone but also thrombosis and fibrinolysis. Brachial flow-mediated vasodilation (FMD) provides a noninvasive method of assessing coronary endothelial dysfunction. However, no data are available on the relationship between brachial FMD and coronary fibrinolytic activity. Thus, we examined the relationship between brachial FMD and coronary vasomotor and fibrinolytic function. Brachial FMD by reactive hyperemia was defined as a change in diameter relative to the baseline as measured using high-resolution ultrasound. Coronary blood flow (CBF) responses to bradykinin (BK) were analyzed using Doppler flow velocity measurement. Coronary release of tissue-type plasminogen activator (tPA) antigen was determined as the transcardiac tPA gradient x [CBF x (100 - hematocrity 100)]. In 77 patients with normal coronary arteries, BK caused dose-dependent increases in CBF, transcardiac tPA gradient, and coronary tPA release. Among them, brachial FMD, the BK-induced CBF increase, and the coronary tPA release induced by BK in 14 diabetic subjects were lower than those in 63 non-diabetic subjects (p < 0.05, respectively). Brachial FMD correlated with the CBF increase, transcardiac tPA gradient (0.2 microg/min: r = 0.25; 0.6 microg/min: r = 0.43; 2.0 microg/min: r = 0.34; p < 0.05, respectively), and coronary tPA release (0.2 microg/min: r = 0.24; 0.6 microg/min: r = 0.44; 2.0 microg/min: r = 0.32; p < 0.05, respectively) in response to BK. Brachial FMD correlated significantly with coronary endothelial function and fibrinolytic activity in response to BK. Type 2 diabetes impaired coronary and brachial endothelium-dependent vasodilation and coronary fibrinolytic activity.

Increased superoxide production causes coronary endothelial dysfunction and depressed oxygen consumption in the failing heart

This study examined whether increased superoxide (O(2)(-).) production contributes to coronary endothelial dysfunction and decreased coronary blood flow (CBF) in congestive heart failure (CHF). To test this hypothesis, the effects of the low-molecular-weight SOD mimetic M40401 on CBF and myocardial oxygen consumption (MVo(2)) were examined in dogs during normal conditions and after CHF was produced by 4 wk of rapid ventricular pacing. The development of CHF was associated with decreases of left ventricular (LV) systolic pressure, maximum first derivative of LV pressure, MVo(2), and CBF at rest and during treadmill exercise as well as endothelial dysfunction with impaired vasodilation in response to intracoronary acetylcholine. M40401 increased CBF (18 +/- 5%, P < 0.01) and MVo(2) (14 +/- 6%, P < 0.01) in CHF dogs and almost totally reversed the impaired CBF response to acetylcholine. M40401 had no effect on acetylcholine-induced coronary vasodilation, CBF, or MVo(2) in normal dogs. Western blot analysis demonstrated that extracellular SOD (EC-SOD) was significantly decreased in CHF hearts, whereas mitochondrial Mn-containing SOD was increased. Cytosolic Cu/Zn-containing SOD was unchanged. Both increased O(2)(-). production and decreased vascular O(2)(-). scavenging ability by EC-SOD could have contributed to endothelial dysfunction in the failing hearts.

Mesenteric injury after cardiopulmonary bypass: Role of poly(adenosine 5′-diphosphate-ribose) polymerase*

To investigate the effects of the ultrapotent poly(adenosine 5'-diphosphate-ribose) polymerase (PARP) inhibitor INO-1001 on cardiac and mesenteric function during reperfusion in an experimental model of cardiopulmonary bypass with cardioplegic arrest. Prospective, randomized, and blinded experimental study. Research laboratory. : Twelve anesthetized dogs underwent cardiopulmonary bypass with hypothermic cardioplegic cardiac arrest. After 60 mins of hypothermic cardiac arrest, either PARP inhibitor INO-1001 (1 mg/kg, n = 6) or vehicle (control, n = 6) was administered during reperfusion. Left ventricular hemodynamic variables were measured by combined pressure-volume-conductance catheters. Coronary and mesenteric blood flow and vasodilatory responses to acetylcholine and sodium nitroprusside as well as mesenteric lactate and creatinine phosphokinase release were also determined. The administration of INO-1001 led to a significantly improved recovery of left ventricular systolic function (p < .05) after 60 mins of reperfusion. Coronary and mesenteric blood flow were also significantly higher in the INO-1001 group (p < .05). Although the vasodilatory response to sodium nitroprusside was similar in both groups before and after cardiopulmonary bypass and similar in response to acetylcholine before cardiopulmonary bypass, PARP-inhibited dogs had lower mesenteric vascular resistance after cardiopulmonary bypass (p < .05). Mesenteric lactate and creatinine phosphokinase release was significantly lower in the PARP inhibitor treated group (p < .05). PARP inhibition with INO-1001 improves the recovery of myocardial function and prevents mesenteric vascular dysfunction and tissue injury after cardiopulmonary bypass with hypothermic cardiac arrest.

Glucagon-like peptide-1 limits myocardial stunning following brief coronary occlusion and reperfusion in conscious canines.

We have recently demonstrated the benefits of glucagon-like peptide-1 (GLP-1) in enhancing regional and global myocardial function after reperfusion in the clinical setting of acute myocardial infarction. We hypothesized that GLP-1 facilitates recovery from myocardial stunning after an ischemic event. To investigate this, we administered GLP-1 (1.5 pmol/kg/min) to six dogs undergoing 10-min occlusion of the left circumflex coronary artery, followed by 24-h reperfusion. We compared the responses of coronary blood flow and regional thickening of the posterior wall with a group of eight vehicle-treated dogs undergoing the same occlusion-reperfusion protocol. Although recovery of coronary blood flow was identical, regional wall motion recovery occurred significantly ((*)p < 0.05) earlier (92 +/- 4 versus 57 +/- 5%(*) at 15 min) and was complete in the GLP-1-treated dogs, whereas residual contractile dysfunction persisted in the control group (99 +/- 4 versus 78 +/- 3%(*) at 24 h). This phenomenon was independent of changes in systemic hemodynamics or global systolic function. However, isovolumic left ventricular relaxation improved significantly in GLP-1-treated dogs. GLP-1 caused an insulinotropic effect, but no hypoglycemia. We conclude that GLP-1 enhances recovery from ischemic myocardial stunning after successful reperfusion.

Pathophysiological plasma ET-1 levels antagonize beta-adrenergic dilation of coronary resistance vessels in conscious dogs.

On the basis of in vitro experiments showing that endothelin (ET)-1 interferes with smooth muscle ATP-sensitive K(+) (K(ATP)) channel opening, which is pivotal in beta-adrenergic coronary dilation, we hypothesized that pathophysiological plasma ET-1 levels impair beta-adrenergic dilation of resistance coronary vessels. In conscious instrumented dogs, graded intravenous doses of dobutamine caused the expected inotropic responses. As myocardial O(2) consumption (MVo(2)) increased, the disproportionate rise in coronary sinus (CS) Po(2) indicates that increases in coronary blood flow (CBF) exceeded metabolic requirements, consistent with beta-adrenergic dilation. ET-1 intravenous infusions, to reach pathophysiological plasma levels, reduced slopes of the Po(2)-MVo(2) and CBF-MVo(2) relations. In contrast, the first derivative of left ventricular pressure over time responses to dobutamine were not impaired during ET-1 delivery. Clazosentan, an ET(A) receptor blocker, prevented reduction of the slope of Po(2)-MVo(2) and CBF-MVo(2) relations. After ganglionic blockade to exclude reflex influences, ET-1 still reduced slopes of Po(2)-MVo(2) and CBF-MVo(2) relations. To assess effects of ET-1 on endothelium-dependent and -independent coronary vascular responses, intracoronary ACh and nitroglycerin were given to directly target coronary vessels. CBF responses to ACh and nitroglycerin were maintained during ET-1 delivery. In contrast, responses to intracoronary K(ATP) channel-dependent dilators adenosine and lemakalim were impaired by ET-1. In conclusion, pathophysiological levels of ET-1 impaired beta-adrenergic dilation of resistance coronary vessels through an ET(A) receptor-dependent process. In contrast, left ventricular inotropic responses to dobutamine were not impaired during ET-1 delivery. Our data suggest that ET-1 may interfere with smooth muscle K(ATP) channels to impair beta-adrenergic coronary dilation.

INO-1001 a novel poly(ADP-ribose) polymerase (PARP) inhibitor improves cardiac and pulmonary function after crystalloid cardioplegia and extracorporal circulation.

Poly(ADP-ribose) polymerase (PARP) activation plays a key role in free radical-induced injury in the context of systemic inflammation and ischemia/reperfusion. In the present preclinical study, we investigated the effects of INO-1001, a novel PARP inhibitor, on cardiac and pulmonary function during reperfusion in an experimental model of cardioplegic arrest and extracorporal circulation. Twelve anesthetized dogs underwent hypothermic cardiopulmonary bypass. After 60 min of hypothermic cardiac arrest, reperfusion was started after application of either saline vehicle (control, n = 6), or INO-1001 (1 mg/kg), a potent PARP inhibitor (n = 6). Biventricular hemodynamic variables were measured by combined pressure-volume-conductance catheters. Coronary and pulmonary blood flow and vasodilative responses to acetylcholine and sodium nitroprusside as well as pulmonary gas exchange were also determined. The administration of INO-1001 led to a significantly better recovery of left and right ventricular systolic function (P < 0.05) after 60 min of reperfusion. Coronary blood flow was also significantly higher in the INO-1001 group (P < 0.05). Although the vasodilative response to sodium nitroprusside was similar in both groups, acetylcholine resulted in a significantly greater increase in coronary and pulmonary blood flow in the INO-1001 group (P < 0.05). Pulmonary function in terms of alveolar arterial oxygen difference was better preserved in the INO-1001-treated group (P < 0.05). Thus, PARP inhibition improves the recovery of myocardial and endothelial function after hypothermic cardiac arrest and reduces pulmonary injury associated with extracorporal circulation.

Rapid Effect of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibition on Coronary Endothelial Function

Treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) decreases cardiovascular event rates in hypercholesterolemic patients. Whether statins exert effects within 24 hours on the coronary vasculature in patients with endothelial dysfunction has not been elucidated. Twenty-seven patients with stable angina pectoris and average low-density lipoprotein cholesterol concentrations of 138+/-9 mg/dL at baseline were allocated to treatment with placebo (14 patients) or 40 mg/d pravastatin (13 patients) in a randomized, double-blind, prospective trial. Coronary endothelial function was assessed before and 24 hours after single treatment by quantitative coronary angiography during intracoronary infusion of nitroglycerin or increasing concentrations of acetylcholine (0.01, 0.1, and 1 micromol/L). Coronary blood flow reserve was measured by Doppler velocimetry during adenosine infusion. Intracoronary acetylcholine infusion induced abnormal vasoconstriction in both groups before treatment, indicating coronary endothelial dysfunction. Treatment with a single oral 40-mg dose of pravastatin significantly attenuated acetylcholine-mediated vasoconstriction after 24 hours (mean+/-SE decrease in luminal diameter before and after treatment: 0.01 micromol/L, 6.1+/-2.2% versus 3.0+/-1.2%; 0.1 micromol/L, 15.6+/-2.6% versus 7.4+/-1.8%; P<0.05; 1 micromol/L, 22.9+/-2.9% versus 13.2+/-2.6%; P<0.05). There was no significant difference in the response to acetylcholine in the placebo group (8.1+/-2.4% versus 9.7+/-2.4%, 16.1+/-2.9% versus 16.8+/-3.2%, and 21.4+/-3.9% versus 23.3+/-4.2%). The response to nitroglycerin infusion was not altered in both groups. Increase in coronary blood flow in response to adenosine and coronary flow reserve remained unchanged during placebo and statin treatment. Serum concentrations of blood lipids and high-sensitive C-reactive protein were not significantly altered after 24 hours in response to placebo or pravastatin therapy. Statin treatment improves endothelium-dependent coronary vasomotion within 24 hours in the absence of significant cholesterol reduction. The full text of this article is available online at http://www.circresaha.org.

Abnormal coronary microvascular endothelial function in humans with asymptomatic left ventricular dysfunction

Background Coronary endothelial dysfunction may potentially lead to myocardial ischemia and to the progression of heart failure. Though endothelial dysfunction is associated with advanced heart failure in humans, relatively little is known regarding their temporal relationship. Thus, the current study was designed to test the hypothesis that coronary endothelial dysfunction is present in patients with asymptomatic left ventricular dysfunction. Methods and results Three hundred patients without symptoms of heart failure, with normal or mildly diseased coronary arteries at angiography underwent coronary vascular reactivity evaluation using intracoronary adenosine, acetylcholine (ACH) and nitroglycerin. Patients were divided into 2 groups based on the left ventricular ejection fraction (EF): patients with asymptomatic left ventricular dysfunction (ALVD), EF <45% (n = 11); and patients with EF ≥45% (n = 289, controls). Except for a lower high-density lipoprotein level in patients with ALVD, there were no significant differences between the groups in regards to conventional cardiovascular risk factors. There was no difference in the change (mean ± SE) in epicardial diameter in response to ACH (−21.7% ± 7.2% vs −13.8% ± 1.5%, P = .3). The change in coronary blood flow in response to ACH was significantly attenuated in the patients with ALVD when compared to the controls (−18.5% ± 14.9% vs 74.0% ± 7.2%, P < .013). By multivariate analysis, EF was an independent predictor of coronary microvascular dilation with ACH ( P < .001). Conclusion The current study demonstrates that coronary microvascular endothelial dysfunction is present in ALVD. Thus, coronary endothelial dysfunction may be an early event in the pathophysiology of heart failure.

Reactive oxygen species modulate coronary wall shear stress and endothelial function during hyperglycemia.

Hyperglycemia is associated with generation of reactive oxygen species (ROS), and this action may contribute to accelerated atherogenesis. We tested the hypothesis that hyperglycemia produces alterations in left anterior descending coronary artery (LAD) wall shear stress concomitant with endothelial dysfunction and ROS production in dogs (n = 12) instrumented for measurement of LAD blood flow, velocity, and diameter. Dogs were randomly assigned to receive vehicle (0.9% saline) or the superoxide dismutase mimetic 4- hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (tempol) and were administered intravenous infusions of d-glucose to achieve target blood glucose concentrations of 350 and 600 mg/dl (moderate and severe hyperglycemia, respectively). Endothelial function and ROS generation were assessed by coronary blood flow responses to acetylcholine (10, 30, and 100 ng/kg) and dihydroethidium fluorescence of myocardial biopsies, respectively. Indexes of wall shear stress were calculated with conventional fluid dynamics theory. Hyperglycemia produced dose-related endothelial dysfunction, increases in ROS production, and reductions in oscillatory shear stress that were normalized by tempol. The results suggest a direct association between hyperglycemia-induced ROS production, endothelial dysfunction, and decreases in oscillatory shear stress in vivo.

Poly-ADP-ribose polymerase-inhibition protects against myocardial and endothelial reperfusion injury after heart transplantation

Free radical production and related cytotoxicity during ischemia/reperfusion may lead to DNA strand-breakage which activates the nuclear enzyme poly-ADP-ribose polymerase (PARP) and initiates an energy consuming, inefficient repair cycle with transfer of the ADP-ribosyl moiety of NAD+ to protein acceptors. We investigated the effects of PARP inhibition on ischemia/reperfusion injury in a rat heart transplantation model. Intraabdominal heterotopic transplantation was performed in Lewis rats. After one hour of ischemic preservation, reperfusion was started after application of either saline vehicle (control, n=12), or AIQ5 (2 mg/kg) a selective PARP-inhibitor (n=12). Coronary blood flow (CBF), left ventricular pressure (LVP), dP/dt, end-diastolic pressure (LVEDP), endothelium-dependent vasodilatation to acetylcholine (ACH) and endothelium-independent vasodilatation to sodium nitroprusside (SNP) were measured after one and 24 hours of reperfusion. Myocardial ATP content, the expression of the adhesion molecules P-Selectine and ICAM-1 were determined. After one hour, CBF (4.01±0.55 vs. 2.86±0.35, ml/min/g, p<0.05), LVP (96±3 vs. 83±4 mmHg, p<0.05) and dP/dt (2692±322 vs. 1740±116 mmHg/s, p<0.05) were significantly higher in AIQ5 group in comparison to control. Vasodilatatory response to SNP was similar in both groups. ACH resulted in a significantly higher increase in CBF in the AIQ5 group (91±8% vs. 51±9%, p<0.05). ATP content was significantly higher (8.2±0.62 vs. 2.44±0.26 μmol/g, p<0.05) and the expression of P-Selectine and ICAM-1 were significantly reduced after treatment with AIQ5. After 24 hours, there was no difference between the groups in basal CBF, LVP, dP/dt, LVEDP and the response of CBF to SNP. However, ACH led to a still significantly higher response in the AIQ5 group (128±13% vs. 88±7%, p<0.05). Thus, PARP inhibition reduces reperfusion injury by restoring the energy stores and inhibiting adhesion molecule expression.