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Piovà Massaia, Italy

Price A.,University of Texas Southwestern Medical Center | Raheja P.,University of Texas Southwestern Medical Center | Wang Z.,University of Texas Southwestern Medical Center | Arbique D.,University of Texas Southwestern Medical Center | And 5 more authors.

In young healthy humans, sympathetic vasoconstriction is markedly blunted during exercise to optimize blood flow to the metabolically active muscle. This phenomenon known as functional sympatholysis is impaired in hypertensive humans and rats by angiotensin II-dependent mechanisms, involving oxidative stress and inactivation of nitric oxide (NO). Nebivolol is a β1-adrenergic receptor blocker that has NO-dependent vasodilatory and antioxidant properties. We therefore asked whether nebivolol would restore functional sympatholysis in hypertensive humans. In 21 subjects with stage 1 hypertension, we measured muscle oxygenation and forearm blood flow responses to reflex increases in sympathetic nerve activity evoked by lower body negative pressure at rest, and during rhythmic handgrip exercise at baseline, after 12 weeks of nebivolol (5-20 mg/d) or metoprolol (100-300 mg/d), using a double-blind crossover design. We found that nebivolol had no effect on lower body negative pressure-induced decreases in oxygenation and forearm blood flow in resting forearm (from -29±5% to -30±5% and from -29±3% to -29±3%, respectively; P=NS). However, nebivolol attenuated the lower body negative pressure-induced reduction in oxygenation and forearm blood flow in exercising forearm (from -14±4% to -1±5% and from -15±2% to -6±2%, respectively; both P<0.05). This effect of nebivolol on oxygenation and forearm blood flow in exercising forearm was not observed with metoprolol in the same subjects, despite a similar reduction in blood pressure. Nebivolol had no effect on sympathetic nerve activity at rest or during handgrip, suggesting a direct effect on vascular function. Thus, our data demonstrate that nebivolol restored functional sympatholysis in hypertensive humans by a mechanism that does not involve β1-adrenergic receptors. CLINICAL TRIAL REGISTRATION - : URL: http://www.clinicaltrials.gov. Unique identifier: NCT01502787. © 2013 American Heart Association, Inc. Source

Rodriguez K.,U.S. National Institutes of Health | Kwan A.C.,U.S. National Institutes of Health | Lima J.A.C.,Cardiology Division | Vigneault D.,U.S. National Institutes of Health | And 6 more authors.

Purpose: To assess the relationship between total, calcified, and noncalcified coronary plaque burdens throughout the entire coronary vasculature at coronary computed tomographic (CT) angiography in relationship to cardiovascular risk factors in asymptomatic individuals with low-to-moderate risk. Materials and Methods: This HIPAA-compliant study had institutional review board approval, and written informed consent was obtained. Two hundred two subjects were recruited to an ongoing prospective study designed to evaluate the effect of HMG-CoA reductase inhibitors on atherosclerosis. Eligible subjects were asymptomatic individuals older than 55 years who were eligible for statin therapy. Coronary CT angiography was performed by using a 320-detector row scanner. Coronary wall thickness and plaque were evaluated in all epicardial coronary arteries greater than 2 mm in diameter. Images were analyzed by using dedicated software involving an adaptive lumen attenuation algorithm. Total plaque index (calcified plus noncalcified plaque) was defined as plaque volume divided by vessel length. Multivariable regression analysis was performed to determine the relationship between risk factors and plaque indexes. Results: The mean age of the subjects was 65.5 years 6 6.9 (standard deviation) (36% women), and the median coronary artery calcium (CAC) score was 73 (interquartile range, 1-434). The total coronary plaque index was higher in men than in women (42.06 mm2 6 9.22 vs 34.33 mm2 6 8.35; P , .001). In multivariable analysis controlling for all risk factors, total plaque index remained higher in men than in women (by 5.01 mm2; P = .03) and in those with higher simvastatin doses (by 0.44 mm2/10 mg simvastatin dose equivalent; P = .02). Noncalcified plaque index was positively correlated with systolic blood pressure (b = 0.80 mm2/10 mm Hg; P = .03), diabetes (b = 4.47 mm2; P = .03), and low-density lipoprotein (LDL) cholesterol level (b = 0.04 mm2/mg/dL; P = .02); the association with LDL cholesterol level remained significant (P = .02) after additional adjustment for the CAC score. Conclusion: LDL cholesterol level, systolic blood pressure, and diabetes were associated with noncalcified plaque burden at coronary CT angiography in asymptomatic individuals with low-to-moderate risk. © RSNA, 2015. Source

Dai X.,Cardiology Division | Dai X.,University of North Carolina at Chapel Hill | Faber J.E.,University of North Carolina at Chapel Hill
Circulation Research

Rationale: The collateral circulation is tissue-and life-saving in obstructive arterial disease. Disappointing outcomes in clinical trials aimed at augmenting collateral growth highlight the need for greater understanding of collateral biology. Objective: The role of endothelial nitric oxide synthase (eNOS) in forming native (preexisting) collaterals and remodeling in obstructive disease are unknown or controversial issues, respectively. Methods and results: We compared the native collateral circulation in healthy tissue and collateral remodeling after femoral artery ligation (FAL) in wild-type and eNOS-knockout (KO) mice. Perfusion after FAL fell further in adult eNOS-KOs, in association with fewer native collaterals in hindlimb (confirmed in brain). This was not attributable to impaired collateral formation in the embryo-neonate, but rather from collateral loss during growth to adulthood. Compared to wild-type, eNOS-KOs evidenced reduced collateral remodeling, angiogenesis, and flow-mediated dilation of the arterial bed supplying the collaterals, resulting in lower perfusion and greater ischemic injury at all time points over 21 days following FAL. To probe the mechanism for impaired remodeling, we performed genome-wide expression profiling of isolated, remodeling hindlimb collaterals 24 hour after FAL. Upregulation of genes encoding cytokines/chemokines, inflammatory, stress response, and cell cycle proteins was evident in wild-type mice. In contrast, expression was lower in 40 of 44 cell cycle genes in eNOS-KO mice, in association with impaired proliferation of vascular wall cells. Conclusions: Our findings suggest a novel role for eNOS in maintaining native collateral density during natural growth to adulthood and in collateral remodeling in obstructive disease, the latter through regulation of cell proliferation. © 2010 American Heart Association, Inc. Source

Bombardini T.,National Research Council Italy | Gherardi S.,M. Bufalini Hospital | Arpesella G.,University of Bologna | MacCherini M.,University of Siena | And 4 more authors.
Journal of the American Society of Echocardiography

Background: Because of the shortage of donor hearts, the criteria for acceptance have been considerably expanded. Abnormal results on pharmacologic stress echocardiography are associated with significant coronary artery disease and/or occult cardiomyopathy on verification by cardiac autopsy. The aim of this study was to establish the feasibility of an approach based on pharmacologic stress echocardiography as a gatekeeper for extended heart donor criteria. Methods: From April 2005 to April 2010, 39 "marginal" candidate donors (mean age, 56 ± 6 years; 21 men) were initially enrolled. After legal declaration of brain death, marginal donors underwent rest echocardiography, and if the results were normal, dipyridamole (0.84 mg/kg over 6 min, n = 25) or dobutamine (up to 40 μg/kg/min, n = 3) stress echocardiography. Results: A total of 19 eligible hearts were found with normal findings. Of these, three were not transplanted because of the lack of a matching recipient, and verification by cardiac autopsy showed absence of significant coronary artery disease or cardiomyopathy abnormalities. The remaining 16 eligible hearts were uneventfully transplanted in marginal emergency recipients. All showed normal (n = 14) or nearly normal (minor single-vessel disease in two) angiographic, intravascular ultrasound, hemodynamic and ventriculographic findings at 1 month. At follow-up (median, 14 months; interquartile range, 4-31 months), 14 patients survived and two had died, one at 2 months from general sepsis and one at 32 months from allograft vasculopathy in recurrent multiple myeloma. Conclusions: Pharmacologic stress echocardiography can safely be performed in candidate heart donors with brain death and shows potential for extending donor criteria in heart transplantation. © 2010 by the American Society of Echocardiography. Source

Zareba W.,Cardiology Division | Zareba W.,Heart Research | Klein H.,Cardiology Division | Cygankiewicz I.,Cardiology Division | And 16 more authors.

Background-This study aimed to determine whether QRS morphology identifies patients who benefit from cardiac resynchronization therapy with a defibrillator (CRT-D) and whether it influences the risk of primary and secondary end points in patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT) trial. Methods and Results-Baseline 12-lead ECGs were evaluated with regard to QRS morphology. Heart failure event or death was the primary end point of the trial. Death, heart failure event, ventricular tachycardia, and ventricular fibrillation were secondary end points. Among 1817 patients with available sinus rhythm ECGs at baseline, there were 1281 (70%) with left bundle-branch block (LBBB), 228 (13%) with right bundle-branch block, and 308 (17%) with nonspecific intraventricular conduction disturbances. The latter 2 groups were defined as non-LBBB groups. Hazard ratios for the primary end point for comparisons of CRT-D patients versus patients who only received an implantable cardioverter defibrillator (ICD) were significantly (P<0.001) lower in LBBB patients (0.47; P<0.001) than in non-LBBB patients (1.24; P=0.257). The risk of ventricular tachycardia, ventricular fibrillation, or death was decreased significantly in CRT-D patients with LBBB but not in non-LBBB patients. Echocardiographic parameters showed significantly (P<0.001) greater reduction in left ventricular volumes and increase in ejection fraction with CRT-D in LBBB than in non-LBBB patients. Conclusions-Heart failure patients with New York Heart Association class I or II and ejection fraction ≤30% and LBBB derive substantial clinical benefit from CRT-D: a reduction in heart failure progression and a reduction in the risk of ventricular tachyarrhythmias. No clinical benefit was observed in patients with a non-LBBB QRS pattern (right bundle-branch block or intraventricular conduction disturbances). Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00180271. © 2011 American Heart Association. All rights reserved. Source

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