ISSN:0009-7322    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

BackgroundAdenoviral constructs have been used for studies of injury-induced vascular hyperplasia in immunologically naive laboratory animals, but their usefulness for intra-arterial gene therapy may be limited by the prevalence of preexisting immunity to adenovirus in the patient population. Here, we explored the efficacy of adenovirus-mediated transfer of Fas ligand, a cytotoxic gene with immunomodulatory properties, in inhibiting injury-induced vascular lesion formation in both naive and immunologically primed animals.Methods and Results-Lesion formation was evaluated in balloon-injured carotid arteries of naive and adenovirus-immunized rats that were infected with adenoviral constructs expressing Fas ligand (Ad-FasL), the cyclin-dependent kinase inhibitor p21 (Ad-p21), or beta-galactosidase (Ad-beta gal). In naive rats, Ad-FasL induced apoptosis in medial vascular smooth muscle cells and inhibited intimal hyperplasia by 60% relative to Ad-beta gal-treated vessels (P<0.05), whereas the cytostatic agent Ad-p21 decreased lesion size by 58% (P<0.05). In animals preimmunized with an adenoviral vector containing no transgene, Ad-FasL significantly inhibited neointima formation (73% reduction, P<0.05), but Ad-p21 failed to inhibit neointima formation relative to controls. Immunologically primed rats displayed robust T-cell infiltration in Ad-p21- and Ad-beta gal-treated vessels, but T-cell infiltration was markedly attenuated in Ad-FasL-treated vessels.ConclusionsOur data demonstrate that adenovirus-mediated Fas ligand delivery can inhibit intimal hyperplasia in both immunologically primed and naive animals, whereas the efficacy of an adenovirus-mediated p21 delivery is limited to immunologically naive animals. This study documents, for the first time, the therapeutic efficacy of intravascular adenoviral gene transfer in animals with preexisting immunity to adenovirus. (Circulation. 1999;99:1776-1779.)

ISSN:0009-7322    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

BackgroundPlaque disruption and subsequent thrombus formation lead to acute coronary syndromes and progression of atherosclerotic disease. Tissue factor (TF) appears to mediate plaque thrombogenicity. Tissue factor pathway inhibitor (TFPI) is the major physiological inhibitor of TF. This study analyzes the role of TF on thrombogenicity of disrupted human atherosclerotic plaques and the therapeutic possibilities of its specific inhibition.Methods and Results-Human atherosclerotic and normal arterial segments were exposed to heparinized blood at flow conditions modeling medium-grade coronary stenosis in the Badimon perfusion chamber. The antithrombotic effects of the specific inhibition of plaque TF was assessed by reduction in the deposition of radiolabeled platelets and fibrin(ogen) and immunohistochemical analysis of perfused arteries. TF activity was inhibited by both recombinant TFPI and a polyclonal antibody against human TF. Human lipid-rich plaques were more thrombogenic than less advanced atherosclerotic plaques. Specific inhibition of TF activity reduced plaque thrombogenicity, inhibiting both platelet and fibrin(ogen) deposition (580 versus 194 plateletsx106/cm2; P<0.01, and 652 versus 172x1012molecules of Fg/cm2; P<0.05, respectively) and thrombosis (immunohistochemistry).ConclusionsThis study documents the key role of TF activity in acute arterial thrombosis after atherosclerotic plaque disruption and provides evidence of the benefit of blocking plaque TF activity. Therefore the inhibition of the TF pathway opens a new therapeutic strategy in the prevention of acute coronary thrombosis after plaque disruption. (Circulation. 1999;99:1780-1787.)

ISSN:0009-7322    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

BackgroundGelatinase B, a matrix metalloproteinase that has proteolytic activity against connective tissue proteins, has been suggested to be important in the connective tissue remodeling processes associated with atherogenesis and plaque rupture. This study tested the hypothesis that sequence variation in the promoter region of the gelatinase B gene influences its expression, predisposing individuals carrying certain genetic variants to more severe atherosclerosis.50% stenosis in 3 coronary arteries, whereas only 15% of C/C homozygotes had triple-vessel disease.ConclusionsThese data suggest that this functional genetic variation influences gelatinase B gene promoter activity in an allele-specific manner and has an effect on atherosclerotic phenotype. (Circulation. 1999;99:1788-1794.)

ISSN:0009-7322    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

BackgroundImpaired vasodilatation capacity in patients with angina pectoris and a normal coronary arteriogram (syndrome X [SX]) has been reported. Most studies report on the response in epicardial vessels. This does not necessarily reflect compromised myocardial microcirculation. Lack of the NO precursor L-arginine has been suggested as a possible cause.Methods and Results-Myocardial blood flow (MBF) was measured, using PET, at rest (MBF-rest) and during intravenous dipyridamole (MBF-DIP) in 25 women (mean age 53 +/- 7 years) with SX. Thirty healthy volunteers served as controls. One group (A) consisted of 15 age-matched female volunteers (54 +/- 10 years). The other control group consisted of 15 young healthy women (B; 24 +/- 5 years). In 12 SX patients, MBF-rest and MBF during cold pressor testing were also measured after infusion of L-arginine (6.7 g/min for 45 minutes). The increase in MBF after cold pressor testing was similar in the SX group compared with controls. L-arginine did not affect MBF-rest (0.83 +/- 0.14 versus 0.89 +/- 0.13 mL [middle dot] g-1[middle dot] min-1) or MBF after cold pressor test (0.95 +/- 0.10 versus 1.03 +/- 0.17 mL [middle dot] g-1min-1). In contrast, the hyperemic response to DIP was blunted compared with the group A controls (1.68 +/- 0.49 versus 2.34 +/- 0.45 mL [middle dot] g-1[middle dot] min-1, P<0.05); this resulted in a significant reduction of the coronary flow reserve in SX patients relative to controls (2.03 +/- 0.53 versus 2.96 +/- 0.63 mL [middle dot] g-1[middle dot] min-1, P<0.01).ConclusionsIn patients with SX, the microcirculatory response to cold, reflecting the endothelium function, is normal and unaltered by intravenous L-arginine. This suggests preserved microcirculatory endothelial function. However, a markedly attenuated hyperemic flow and flow reserve after DIP suggest a dysfunction of the adenosine-mediated endothelium-independent vasodilatation at the microcirculatory level in these patients. (Circulation. 1999;99:1795-1801.)

ISSN:0009-7322    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

BackgroundAn activated endothelin (ET) system may be of pathophysiological relevance in human heart failure. We characterized the functional effects of ET-1, ET receptors, and ET-1 peptide concentration in left ventricular myocardium from 10 nonfailing hearts (NF) and 27 hearts in end-stage failure due to idiopathic dilative cardiomyopathy (DCM).Methods and Results-Inotropic effects were characterized in isolated muscle strips (1 Hz; 37[degree sign]C). ET-1 0.0001 to 0.3 [micro sign]mol/L significantly (P<0.05) increased twitch force by maximally 59 +/- 10% in NF and by 36 +/- 11% in DCM (P<0.05 versus NF). Preincubation with propranolol 1 [micro sign]mol/L and prazosin 0.1 [micro sign]mol/L did not affect the response to ET-1, but the mixed ET receptor antagonist bosentan and the ETAreceptor antagonist BQ-123 shifted the concentration-response curves for ET-1 rightward. The ETBreceptor agonist sarafotoxin S6c 0.001 to 0.3 [micro sign]mol/L had no functional effects. The inotropic response to ET-1 was not associated with increased intracellular Ca2+transients, as assessed in aequorin-loaded muscle strips. ET receptor density (Bmax; radioligand binding) was 62.5 +/- 12.5 fmol/mg protein in NF and 122.4 +/- 24.3 fmol/mg protein in DCM (P<0.05 versus NF). The increase in Bmaxin DCM resulted from an increase in ETAreceptors without change in ETBreceptors. ET-1 peptide concentration (radioimmunoassay) was higher in DCM than in NF (14 447 +/- 2232 versus 4541 +/- 1340 pg/mg protein, P<0.05).ConclusionsET-1 exerts inotropic effects in human myocardium through ETAreceptor-mediated increases in myofibrillar Ca2+responsiveness. In DCM, functional effects of ET-1 are attenuated, but ETAreceptor density and ET-1 peptide concentration are increased, indicating an activated local cardiac ET system and possibly a reduced postreceptor signaling efficiency. (Circulation. 1999;99:1802-1809.)

ISSN:0009-7322    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

BackgroundThe purpose of this study was to determine if atrial natriuretic peptide (ANP) exerts a relative inhibitory effect on muscle sympathetic nerve activity (MSNA) at rest and during nonhypotensive lower body negative pressure (LBNP) in heart failure, as in healthy subjects.Methods and Results-Fifteen men (age 39 +/- 2 years [mean +/- SE]) with dilated cardiomyopathy (ejection fraction 18 +/- 3%) received intravenous ANP (50 [micro sign]g bolus, then 50 ng [middle dot] kg-1[middle dot] min-1) and nitroglycerin (NTG, 8 mg/min) as a hemodynamic control. During each infusion MSNA, blood pressure (BP), central venous pressure (CVP), and heart rate (HR) were recorded before and during LBNP at -6 and -12 mm Hg. NTG and ANP caused similar and significant reductions in CVP and diastolic BP, but resting MSNA did not increase with either infusion. LBNP at -6 mm Hg lowered CVP (P<0.05), whereas LBNP at -12 mm Hg caused significant reductions in CVP, systolic BP, and diastolic BP. These effects of nonhypotensive and hypotensive LBNP on CVP and BP were similar during ANP and NTG infusions, yet MSNA was lower both before and with LBNP during ANP (P<0.02). Nonhypotensive LBNP increased MSNA during NTG (+133 +/- 68 Units; P<0.001) but not during ANP infusion (+24 +/- 23 Units; P=NS).ConclusionsThese observations are consistent with the concept that ANP exerts a sympathoinhibitory action in heart failure. This is most evident in response to reductions in atrial pressures that do not affect systemic BP. (Circulation. 1999;99:1810-1815.)

ISSN:0009-7322    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

BackgroundPrevious natural history studies in broad populations of heart failure patients have associated female gender with improved survival, particularly in patients with a nonischemic etiology of ventricular dysfunction. This study investigates whether a similar survival advantage for women would be evident among patients with advanced heart failure.Methods and Results-The study analysis is based on the Flolan International Randomized Survival Trial (FIRST) study which enrolled 471 patients (359 men and 112 women) who had evidence of end-stage heart failure with marked symptoms (60% NYHA class IV) and severe left ventricular dysfunction (left ventricular ejection fraction 18 +/- 4.9%). A Cox proportional-hazards model, adjusted for age, gender, 6-minute walk, dobutamine use at randomization, mean pulmonary artery blood pressure, and treatment assignment, showed a significant association between female gender and better survival (relative risk of death for men versus women was 2.18, 95% CI 1.39 to 3.41; P<0.001). Although formal interaction testing was negative (P=0.275), among patients with a nonischemic etiology of heart failure, the relative risk of death for men versus women was 3.08 (95% CI 1.56 to 6.09, P=0.001), whereas among those with ischemic heart disease, the relative risk of death for men versus women was 1.64 (95% CI 0.87 to 3.09, P=0.127).ConclusionsWomen with advanced heart failure appear to have better survival than men. Subgroup analysis suggests this finding is strongest among patients with a nonischemic etiology of heart failure. (Circulation. 1999;99:1816-1821.)

ISSN:0009-7322    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

BackgroundThe extent to which force-frequency and relaxation-frequency relations (FFR and RFR, respectively) and exercise-induced adrenergic stimulation affect myocardial inotropic and lusitropic reserves has not been established in patients with left ventricular (LV) hypertrophy (LVH).Methods and Results-We calculated the maximum first derivative of LV pressure (LV dP/dtmax) and the LV pressure half-time (T1/2) during pacing, exercise, and isoproterenol infusion in 17 patients with hypertensive LVH and 9 control subjects to investigate the influence of increases in heart rate (HR) and adrenergic stimulation on inotropic and lusitropic reserves. Group A consisted of 10 LVH patients who showed a progressive increase in the HR-LV dP/dtmaxrelation. Group B consisted of 7 LVH patients in whom the HR-dP/dtmaxrelation at physiological pacing rates was biphasic. The LV mass index was larger and the LV ejection fraction was smaller in group B than in group A (244 +/- 72 g/m2versus 172 +/- 22 g/m2and 55 +/- 18% versus 72 +/- 6%, respectively; both P<0.05). The increase in LV dP/dt (max) was greater during exercise than pacing alone for similar increases in HR in all groups (P<0.05) (group A, 111 +/- 22% versus 25 +/- 14%; group B, 105 +/- 35% versus 14 +/- 10%; control, 111 +/- 24% versus 25 +/- 12%). T1/2was shorter (P<0.05) during exercise than with pacing alone in all groups (group A, 41 +/- 6% versus 11 +/- 3%; group B, 38 +/- 9% versus 14 +/- 4%; control, 44 +/- 6% versus 12 +/- 5%). Isoproterenol infusion caused similar increases in LV dP/dtmaxand similar decreases in T1/2in all groups.ConclusionsThe FFR was biphasic in patients with severe LVH irrespective of LV function but was preserved in patients with less severe LVH and control subjects. Importantly, the RFR and adrenergic control of both inotropic and lusitropic reserves were well preserved in all LVH patients. A biphasic FFR at physiological pacing rates may be one of the earliest markers of the transition from physiological adaptation to the pathological process in LVH patients. (Circulation. 1999;99:1822-1830.)

ISSN:0009-7322    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

BackgroundAlthough systolic blood pressure (SBP) response to exercise has been shown to predict subsequent hypertension in small samples of men, this association has not been studied in a large population-based sample of middle-aged men and women. The purpose of this study was to examine, in normotensive subjects, the relations of SBP and diastolic blood pressure (DBP) during the exercise and recovery periods of a graded treadmill test to the risk of developing new-onset hypertension.or=to90 mm Hg or the initiation of antihypertensive drug treatment, occurred in 228 men (22%) and 207 women (16%). Exaggerated SBP (Ex-SBP 2) and DBP (Ex-DBP 2) response and delayed recovery of SBP (R-SBP 3) and DBP (R-DBP 3) were defined as an age-adjusted BP greater than the 95th percentile during the second stage of exercise and third minute of recovery, respectively. After multivariable adjustment, Ex-DBP 2 was highly predictive of incident hypertension in both men (OR, 4.16; 95% CI, 2.15, 8.05) and women (OR, 2.17; CI, 1.19, 3.96). R-SBP 3 was predictive of hypertension in men in a multivariable model that included exercise duration and peak exercise BP (OR, 1.92; CI, 1.00, 3.69). Baseline resting SBP (chi squared, 23.4 in men and 34.7 in women) and DBP (chi squared, 11.3 in men and 13.1 in women) had stronger associations with new-onset hypertension than exercise DBP (chi squared, 16.4 in men and 6.1 in women) and recovery SBP (chi squared, 6.5 in men and 2.1 in women) responses.ConclusionsAn exaggerated DBP response to exercise was predictive of risk for new-onset hypertension in normotensive men and women. An elevated recovery SBP was predictive of hypertension in men. These findings may reflect subtle pathophysiological features in the preclinical stage of hypertension. (Circulation. 1999;99:1831-1836.)

ISSN:0009-7322    

出版商:OVID    

年代:1999

数据来源: OVID