Coronary Endothelial Vasomotor Dysfunction Research Articles

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

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

Persistent Dysfunction of Coronary Endothelial Vasomotor Responses is Related to Atheroma Plaque Progression in the Infarct-Related Coronary Artery of AMI Survivors.

Aim: Although coronary endothelial vasomotor dysfunction predicts future coronary events, there are few human studies showing the relationship between endothelial vasomotor dysfunction and atheroma plaque progression in the same coronary artery. This study examined whether endothelial vasomotor dysfunction is related to atheroma plaque progression in the infarct-related coronary artery of ST-segment elevation myocardial infarction (STEMI) survivors using serial assessment of coronary plaque size with intravascular ultrasound (IVUS) and coronary vasomotor responses to acetylcholine (ACh).Methods: This study included 50 patients with a first acute STEMI due to occlusion of the left anterior descending coronary artery (LAD) and successful reperfusion therapy with percutaneous coronary intervention (PCI). IVUS and vasomotor response to ACh in the LAD were measured within two weeks of acute myocardial infarction (AMI) (1st test) and repeated six months (2nd test) after AMI under optimal anti-atherosclerotic therapies.Results: Percent atheroma volume (PAV) and total atheroma volume (TAV) in the LAD progressed over six months of follow-up in 18 and 14 patients, respectively. PAV and TAV progression was significantly associated with persistent impairment of epicardial coronary artery dilation and coronary blood flow increase in response to ACh at both the 1st and 2nd tests. PAV and TAV progression had no significant association with traditional risk factors, PCI-related variables, medications, and the coronary vasomotor responses to sodium nitroprusside, an endothelium-independent vasodilator.Conclusions: Persistent impairment of endothelial vasomotor function in the conduit arterial segment and the resistance arteriole was related to atheromatous plaque progression in the infarct-related coronary arteries of STEMI survivors.

Abstract 12338: Production of Plasminogen Activator Inhibitor-1 in Infarcted Lesion was Associated With Coronary Endothelial Vasomotor Dysfunction and Progressive Dysfunction of Left Ventricle in Patients With Acute Myocardial Infarction

Experimental studies showed that plasminogen activator inhibitor-1 (PAI-1) is abundantly expressed in the infarcted myocardium and that the increased PAI-1 expression causes an impairment of fibrinolysis in the coronary vascular beds and left ventricular (LV) adverse remodeling after acute myocardial infarction (AMI). However, little is known in humans. Thus, this study examined whether PAI-1 produced in the infarcted lesion may contribute to coronary endothelial dysfunction and LV dysfunction in patients with AMI. Methods: Plasma levels of PAI-1 activity and tissue-plasminogen activator (tPA) protein were measured by ELISA in plasma obtained from aortic root (AO), anterior interventricular vein (AIV), and peripheral vein (PV) in 41 patients with a first AMI due to occlusion of a proximal segment of the LAD at 6 months (M) after MI. Coronary blood flow responses in the LAD to intracoronary infusion of acetylcholine (ACh, 50 μg/min) were measured by an intracoronary flow wire technique 6M after MI. Left ventriculography was repeated twice, 2 weeks (2W) and 6M after MI. Results: The trans-myocardial gradient of PAI-1 from AO to AIV (0.14 ± 0.15 ng/mL), reflecting a production/release of PAI-1 from the infarcted lesion, had an inverse correlation with coronary blood flow response to ACh (r = -0.43 , p = 0.02). The trans-myocardial gradient of PAI-1 had an inverse correlation with the % changes in LV regional motion in the LAD territory from 2W to 6M after MI (r = -0.37, p = 0.02). PAI-1 level in the PV and the trans-myocardial gradient of tPA had no significant correlation with the coronary blood flow response to ACh and the LV regional motion. The trans-myocardial gradient in PAI-1 level was lower in patients taking than not taking angiotensin II receptor blocker (ARB) (n = 22, -0.15 ± 0.19 ng/mL vs. n = 19, 0.48 ± 0.21 ng/mL, respectively, p = 0.03). Conclusions: PAI-1 produced in the infarcted myocardium and released into the coronary circulation was associated with endothelial dysfunction in resistance vessels of the infarct-related coronary arteries and progressive dysfunction of the infarcted region of LV in AMI survivors. ARB might inhibit PAI-1 production in the infarcted myocardium in the chronic phase of MI, which may represent an additional benefit of ARB therapy.

At the Beginning of Stiffening

Brachial cuff blood pressure (BP) continues to guide almost every decision related to the clinical management of the hypertensive patient. However, the BP within the central aorta (ie, aortic pressure) is receiving growing attention for 2 main reasons. First, brachial BP does not necessarily predict aortic pressure, and subjects with equal values of brachial cuff pressure may differ markedly in their aortic pressure.1 Second, aortic pressure may be superior to brachial BP for the prediction of several vascular complications, including the degree of carotid atherosclerosis,2 the extent of coronary artery disease,3 the likelihood of reocclusion after angioplasty,4 and, more important, the risk of major cardiovascular events.1,5 Aortic BP may be estimated noninvasively from analysis of peripheral radial artery waveforms with applanation tonometry. Although the reliability of derived aortic BP is crucially dependent on the validity of the transfer function used to generate the central aortic waveforms, the correspondence between estimated central aortic and intra-arterial systolic BP and pulse pressure (PP) seems to be quite close.6 In addition to central PP, pulse …

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.

Association of polymorphism in glutamate-cysteine ligase catalytic subunit gene with coronary vasomotor dysfunction and myocardial infarction

ObjectivesThe purpose of this study was to test the hypothesis that polymorphisms in the promoter region of the glutamate-cysteine ligase catalytic subunit (GCLC)gene may be associated with coronary endothelial vasomotor dysfunction and myocardial infarction (MI). BackgroundGlutamate-cysteine ligase is a rate-limiting enzyme for synthesis of glutathione (GSH) that plays a crucial role in the intracellular antioxidant defense systems. Oxidants transcriptionally upregulate the GCLCgene for GSH synthesis, providing a protective mechanism against oxidant-induced endothelial dysfunction or activation, which plays a pathogenetic role in cardiovascular diseases. MethodsThe association of the possible polymorphisms with coronary arterial diameter responses to acetylcholine was determined in 62 male subjects. The frequency of polymorphisms was compared between 255 male patients with MI and 179 male control subjects. ResultsWe found a polymorphism (−129C/T) in which the T allele showed lower promoter activity (50% to 60% of the activity of the C allele) in response to H2O2in human endothelial cells. Endothelium-dependent dilation of coronary arteries was impaired in subjects with the −129T allele (n = 31), as compared with the age-matched subjects without the −129T allele (n = 31). The T allele was highly frequent in patients with MI as compared with control subjects, and it was a significant risk factor for MI, independent of traditional coronary risk factors (odds ratio [OR] 1.81, 95% confidence interval [CI] 1.08 to 3.03; p = 0.03). ConclusionsThe −129T polymorphism of the GCLCgene may suppress the GCLCgene induction response to an oxidant, and it is implicated in coronary endothelial vasomotor dysfunction and MI.

Blockade of angiotensin II type 1 receptors suppressed free radical production and preserved coronary endothelial function in the rabbit heart after myocardial infarction.

The hypothesis that blockade of angiotensin II type 1 (AT1) receptors after myocardial infarction prevents coronary endothelial vasomotor dysfunction by suppressing oxygen free radical production was examined. Rabbits underwent coronary ligation or a sham operation with or without infusion of valsartan, an AT 1 receptor blocker. Two weeks after the operation, the heart was isolated from each rabbit and perfused with buffer in the Langendorff mode, and coronary flow responses to acetylcholine and sodium nitroprusside were assessed. The ratio of heart weight to body weight and the lipid peroxide level in the myocardium were increased by 30 and 50%, respectively, 2 weeks after infarction. The coronary flow response to acetylcholine (10(-8) to 10(-5) M) was reduced by 50% in the hearts with infarction compared with the sham controls, although coronary flow responses to sodium nitroprusside were similar. The coronary flow response to acetylcholine in the hearts with infarction was restored by concurrent infusion of N -2-mercaptopropionyl-glycine, a free radical scavenger. Valsartan (10 mg/kg/d) infused after infarction prevented both ventricular remodeling and elevation of the tissue lipid peroxide level and preserved coronary flow response to acetylcholine. In conclusion, long-term AT1 receptor blockade after infarction protects the coronary arteries from endothelial vasomotor dysfunction through suppression of free radical production.

Reversibility of coronary endothelial vasomotor dysfunction in idiopathic dilated cardiomyopathy: acute effects of vitamin C

In patients with idiopathic dilated cardiomyopathy, endothelium vasomotor function is disturbed. Increased oxidative stress and the consecutive formation of oxygen free radicals have been implicated as one possibility for this observation, suggesting that nitric oxide (NO) is inactivated by oxygen free radicals. We tested the hypothesis that the antioxidant, vitamin C, may improve endothelial function in idiopathic dilated cardiomyopathy. In 11 patients, the endothelium-dependent vasomotor response of the left anterior descending coronary artery to intracoronary acetylcholine (ACh) infusion (1/2 × 10 −6 mol/L, 1/4 × 10 −5 mol/L; respectively) was determined before and immediately after intravenous infusion of 3 g of vitamin C. Coronary cross-sectional diameter was obtained by quantitative coronary angiography, average peak velocity was measured by an intracoronary Doppler flow wire, and coronary blood flow (CBF) was calculated. Maximum cross-sectional diameter was determined after administration of nitroglycerin. Dose-dependent ACh showed a decrease in cross-sectional diameter (−5% to −7%, p <0.05) and an increase in average peak velocity (+16% to +25%, p <0.05); the CBF was unchanged (+1% to −2%, p = NS). After vitamin C infusion, the cross-sectional diameter increased in a dose-dependent manner from +11% to +15%, the average peak velocity increased from +20% to + 41% (p <0.05), and the CBF increased from +38% to + 82% (p <0.01, p <0.001, respectively). Thus, patients with idiopathic dilated cardiomyopathy had endothelial dysfunction, and administration of vitamin C reversed endothelium-dependent dysfunction.

Endothelin in coronary endothelial dysfunction early after human heart transplantation

Background Cytokines and growth factors released as part of the immune response to alloantigenic stimuli are capable of regulating endothelin-1 expression in the allograft. Endothelin plays a significant role as a modulator of coronary vascular reactivity in the early stages of atherosclerosis and may be important as a participant in and marker for cardiac allograft vasculopathy. Methods We characterized a possible relationship between morphological and functional coronary changes, transcardiac plasma endothelin level and myocardial endothelin–mRNA expression in 33 cardiac transplant recipients in the early, stable phase 5 ± 3 months after orthotopic heart transplantation. Coronary microvascular function was determined as endothelium-dependent with acetylcholine and endothelium-independent with adenosine using intracoronary Doppler-FloWire. The percentage of the epicardial diameter changes was measured using quantitative coronary angiography. Intravascular ultrasound was performed to quantify intimal hyperplasia. Cardiac endothelin uptake or release was determined by measuring plasma endothelin levels in the coronary sinus and aorta. Myocardial endothelin-gene expression was determined using semiquantitative RT-PCR. Results The aortic endothelin levels were significantly increased in transplant recipients compared to nontransplanted patients (11.8 ± 2.2 vs 7.2 ± 0.9 fmol/mL; P < 0.001). Endothelin uptake was noticed in the majority of patients, and the amount of endothelin uptake was correlated to microvascular ( r = 0.37; P < 0.05) and epicardial ( r = 0.41; P < 0.03) endothelium-dependent vasodilatation. High mRNA signal intensity was associated with significantly reduced coronary flow response to acetylcholine compared to patients with low myocardial gene expression (coronary flow reserve 2.4 ± 0.9 vs 3.4 ± 0.8, respectively; P < 0.005). Morphological coronary changes early after transplantation were not correlated to endothelin plasma levels or myocardial gene expression. Conclusion Coronary endothelial vasomotor dysfunction after cardiac transplantation is associated with an increased myocardial endothelin mRNA expression and decreased endothelin-uptake by the heart. We postulate that early activation in the endothelin system may have a pivotal role in the acceleration of the atherosclerotic process in transplant patients.