ISSN:0009-7322    

出版商:OVID    

年代:2000

数据来源: OVID

ISSN:0009-7322    

出版商:OVID    

年代:2000

数据来源: OVID

ISSN:0009-7322    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

BackgroundThe cyclin-dependent kinase inhibitors (CKIs) have different patterns of expression in vascular diseases. The Kip/Cip CKIs, p27Kip1and p21Cip1, are upregulated during arterial repair and negatively regulate the growth of vascular smooth muscle cells (VSMCs). In contrast, the Ink CKI, p16Ink4, is not expressed in vascular lesions. We hypothesized that a variation in the inactivation of cdk2 and cdk4 during the G1phase of the cell cycle by p27Kip1, p21Cip1, and p16Ink4leads to different effects on VSMC growth in vitro and in vivo.Methods and ResultsThe expression of p27Kip1and p21Cip1in serum-stimulated VSMCs inactivated cdk2 and cdk4, leading to G1growth arrest. p16Ink4inhibited cdk4, but not cdk2, kinase activity, producing partial inhibition of VSMC growth in vitro. In an in vivo model of vascular injury, overexpression of p27Kip1reduced intimal VSMC proliferation by 52% (P<0.01) and the intima/media area ratio by 51% (P<0.005) after vascular injury and gene transfer to pig arteries, when compared with control arteries. p16Ink4was a weak inhibitor of intimal VSMC proliferation in injured arteries (P=NS), and it did not significantly reduce intima/media area ratios (P=NS), which is consistent with its minor effects on VSMC growth in vitro.Conclusionsp27Kip1and p21Cip1are potent inhibitors of VSMC growth compared with p16Ink4because of their different molecular mechanisms of cyclin-dependent kinase inhibition in the G1phase of the cell cycle. These findings have important implications for our understanding of the pathophysiology of vascular proliferative diseases and for the development of molecular therapies.

ISSN:0009-7322    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

BackgroundLimitations of coronary thrombolysis include the time to reperfusion, patency rate, and bleeding. We evaluated the use of noninvasive transcutaneous ultrasound to augment coronary thrombolysis.Methods and ResultsIn 24 dogs, a thrombotic occlusion of the left anterior descending coronary artery was induced and documented by 12-lead ECG and coronary angiography. After ≥60 minutes of occlusion, tissue-type plasminogen activator (t-PA; 1.42 mg/kg) was given intravenously over 90 minutes. A total of 12 of the 24 dogs had concomitant transcutaneous application of low-frequency ultrasound (27 kHz) over the chest. At 90 minutes, the mean TIMI grade flow in the t-PA alone group was 0.92±1.4 compared with 2.42±1.9 in the t-PA plus ultrasound group (P=0.006). TIMI 2 to 3 flow was present in 4 of 12 cases receiving t-PA alone compared with 10 of 12 cases receiving t-PA plus ultrasound (P=0.003). At 180 minutes, mean TIMI grade flow was 0.75±1.4 in the t-PA alone group versus 2.58±0.9 in the t-PA plus ultrasound group (P=0.001). Pathological examination confirmed the angiographic patency rate and did not reveal injury secondary to ultrasound in the skin, soft tissues, heart, or lungs.ConclusionsIn vivo, the noninvasive transthoracic application of low-frequency ultrasound (1) greatly augments the efficacy of t-PA-mediated thrombolysis, (2) seems safe, and (3) has substantial potential as a noninvasive adjunct to improve coronary patency without increasing the risk of bleeding.

ISSN:0009-7322    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

BackgroundRho-associated kinase (ROCK), an effector of small GTPase Rho, regulates vascular tone via a calcium sensitization mechanism and plays a key role in the pathogenesis of hypertension. However, its role in vascular growth remains unclear.Methods and ResultsY-27632, a specific ROCK inhibitor, and the overexpression of dominant-negative ROCK suppressed the mitogen-induced DNA synthesis of cultured vascular smooth muscle cells (VSMCs), which indicates the essential role of ROCK in the control of VSMC proliferation in vitro. Y-27632 also suppressed the chemotaxis of VSMCs. Male Wistar rats were systemically given Y-27632 (35 to 70 mg · kg−1· day−1) through an intraperitoneal infusion. The neointimal formation of balloon-injured carotid arteries was significantly suppressed in Y-27632-treated rats (intima/media ratio, 0.22±0.02) compared with vehicle-treated rats (intima/media ratio, 0.92±0.21) or hydralazine-treated rats with a similar blood pressure decrease (intima/media ratio, 1.03±0.15). The phosphorylation of myosin phosphatase and myosin light chain was elevated in injured arteries in a Y-27632-sensitive manner, indicating the augmentation of ROCK activity in neointimal formation. The downregulation of the cyclin-dependent kinase inhibitor p27kip1in injured vessels was reversed by Y-27632 treatment, reflecting the antiproliferative effect of ROCK inhibition in vivo.ConclusionsWe conclude that ROCK plays a key role in the process of neointimal formation after balloon injury. Thus, the inhibition of ROCK may be a potential therapeutic strategy for treating vascular proliferative disorders and hypertension.

ISSN:0009-7322    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

BackgroundIncreased research attention is being paid to the negative impact of anger on coronary heart disease (CHD).Methods and ResultsThis study examined prospectively the association between trait anger and the risk of combined CHD (acute myocardial infarction [MI]/fatal CHD, silent MI, or cardiac revascularization procedures) and of “hard” events (acute MI/fatal CHD). Participants were 12 986 black and white men and women enrolled in the Atherosclerosis Risk In Communities study. In the entire cohort, individuals with high trait anger, compared with their low anger counterparts, were at increased risk of CHD in both event categories. The multivariate-adjusted hazard ratio (HR) (95% CI) was 1.54 (95% CI 1.10 to 2.16) for combined CHD and 1.75 (95% CI 1.17 to 2.64) for “hard” events. Heterogeneity of effect was observed by hypertensive status. Among normotensive individuals, the risk of combined CHD and of “hard” events increased monotonically with increasing levels of trait anger. The multivariate-adjusted HR of CHD for high versus low anger was 2.20 (95% CI 1.36 to 3.55) and for moderate versus low anger was 1.32 (95% CI 0.94 to 1.84). For “hard” events, the multivariate-adjusted HRs were 2.69 (95% CI 1.48 to 4.90) and 1.35 (95% CI 0.87 to 2.10), respectively. No statistically significant association between trait anger and incident CHD risk was observed among hypertensive individuals.ConclusionsProneness to anger places normotensive middle-aged men and women at significant risk for CHD morbidity and death independent of the established biological risk factors.

ISSN:0009-7322    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

BackgroundObesity is a more potent cardiovascular risk factor (CVRF) in men than in women. Because traditional CVRFs cannot fully account for this sex difference, we tested the hypothesis that compared with men, women exhibit more robust endothelial function independent of obesity and that this sex difference is abrogated by diabetes.Methods and ResultsWe studied leg blood flow (LBF) responses to graded intrafemoral artery infusions of the endothelium-dependent vasodilator methacholine chloride (Mch) and the endothelium-independent vasodilator sodium nitroprusside (SNP) in groups of lean, obese (OB), and type II diabetic (DM) premenopausal women and age- and body mass index-matched men. LBF response to intrafemoral administration of L-NMMA, an inhibitor of nitric oxide synthase, was also assessed in normal men and women. Maximum LBF increments in response to Mch were 347±57% versus 231±22% in lean women versus men (P<0.05) and 203±25% versus 111±17% in OB women versus men (P<0.01), respectively. In DM, maximum LBF increments in response to Mch were 104±24% and 138±33% in women and men, respectively, (P=NS). LBF decrements in response to L-NMMA were 34.9±4.1% and 17.1±4.2% in women and men, respectively (P<0.01). The response to SNP was not different between sexes and groups.ConclusionsPremenopausal nondiabetic women exhibit more robust endothelium-dependent vasodilation owing to higher rates of nitric oxide release than men. Given the protective vascular action of nitric oxide, this difference may partially explain the lower incidence of macrovascular disease in women. In premenopausal women, DM causes impairment of endothelial function beyond that observed with obesity alone and leads to endothelial dysfunction similar to that observed in DM men. These findings may help explain the similar rates of coronary artery disease and mortality in diabetic men and women.

ISSN:0009-7322    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

BackgroundAlthough medical textbooks usually classify fasting plasma glucose <70 or 80 mg/dL (<3.89 or 4.44 mmol/L) as abnormal, the prognosis for patients with low fasting plasma glucose is unclear.Methods and ResultsWe conducted prospective cohort studies among 40 069 men and women to investigate the association between fasting plasma glucose levels and cardiovascular disease and all-cause mortality. We documented a U-shaped relation between fasting plasma glucose and mortality. In addition to diabetes and impaired fasting glucose levels, low fasting plasma glucose levels were also associated with high mortality. After multivariate adjustment for age, sex, study population, ethnicity, current smoking status, high blood pressure, total cholesterol, body mass index, triglycerides, history of cardiovascular disease and cancer, and a family history of cardiovascular disease, patients with fasting plasma glucose <70 mg/dL (<3.89 mmol/L) had a 3.3-fold increased risk of cardiovascular disease mortality, and patients with fasting plasma glucose 70 to 79 mg/dL (3.89 to 4.43 mmol/L) had a 2.4-fold increased risk compared with the risk in patients with fasting plasma glucose 80 to 109 mg/dL (4.44 to 6.05 mmol/L) (tests for trendP<0.0001). Participants with low fasting plasma glucose levels also had increased risk of all-cause mortality (test for trendP<0.0001).ConclusionsParticipants with low fasting plasma glucose levels had a high risk of cardiovascular disease and all-cause mortality.

ISSN:0009-7322    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

BackgroundWe studied the cardiac sympathetic response to selective unloading of cardiopulmonary baroreceptors in subjects with normal left ventricular (LV) function and congestive heart failure (CHF).Methods and ResultsEight patients with normal LV function (age 57±5 years, ejection fraction 58±2%) and 8 patients with CHF (age 60±2 years; ejection fraction 19±2%) were studied. Instrumentation consisted of an arterial line, a pulmonary artery catheter, and a coronary sinus thermodilution catheter. The radiotracer technique was used for measurement of cardiac norepinephrine spillover (CANESP) and total-body norepinephrine spillover. Lower-body negative pressure (LBNP) was applied at 2 levels: nonhypotensive and hypotensive LBNP. Nonhypotensive LBNP reduced filling pressures significantly in both groups. Arterial pressure did not change. This reduction in filling pressures caused a significant reduction in CANESP in the CHF group (from 167±53 to 125±37 pmol/min,P<0.05) but no change in the normal LV function group. Hypotensive LBNP caused a significant increase in CANESP in the normal group (73±13 vs 122±27 pmol/min,P<0.05) but no significant change in those with CHF.ConclusionsWe conclude that selective reduction in filling pressures lowers cardiac norepinephrine spillover in patients with CHF. These findings suggest that a goal of CHF management should be to reduce cardiac filling pressures while avoiding systemic hypotension.

ISSN:0009-7322    

出版商:OVID    

年代:2000

数据来源: OVID