Benyu Jiang

Vascular Dysfunction and Reduced Circulating Endothelial Progenitor Cells in Young Healthy UK South Asian Men

Objectives—The objective of this study was to examine determinants of excess coronary artery disease risk in UK South Asians, more prevalent in this population than UK Caucasians, by examining differences in risk factors, vascular function, and endothelial progenitor cells (EPCs). Methods and Results—24 South Asian and 25 Caucasian healthy age-matched nonsmoking men were studied. Vascular function was assessed by flow-mediated and GTN brachial artery dilatation and blood flow responses to infusion of ACh, SNP, and L-NMMA. EPC number and function were measured by flow cytometry (CD34, CD133, and KDR positive cells), and CFU/migration assays. Traditional risk factors and anthropometric measurements were similar in the groups. South Asians had higher fasting insulin levels (6.01 versus 3.62 &mgr;U/mL; P=0.02). South Asians had lower FMD (6.9 versus 8.5%; P=0.003), L-NMMA response (0.8 versus 1.3 mL/min/100 mL; P=0.03), mean SNP response (9.5±0.6 versus 11.6±0.6; P=0.02), EPC number (0.046±0.005% versus 0.085±0.009%; P=< 0.001), and CFU ability (CFU 4.29±1.57 versus 18.86±4.00; P=0.005). EPC number was the strongest predictor of FMD. Ethnicity was the strongest predictor of EPC number. Conclusions—Healthy South Asian men are more insulin resistant, and demonstrate endothelial dysfunction and reduced EPC number and function compared with Caucasians. These abnormalities may contribute to their increased CAD risk.

Increased Wave Reflection Rather Than Central Arterial Stiffness Is the Main Determinant of Raised Pulse Pressure in Women and Relates to Mismatch in Arterial Dimensions A Twin Study

OBJECTIVESnOur aim was to examine the relative contributions of the first systolic shoulder (P1) and augmentation pressure (DeltaP(aug)) to central pulse pressure (cPP), their relation to central arterial stiffness (pulse wave velocity [PWV]) and arterial diameters, and their respective heritability estimates.nnnBACKGROUNDncPP is augmented above P1 by DeltaP(aug) due to pressure waves reflected from the periphery of the circulation.nnnMETHODSnWomen (n = 496) from the Twins UK adult twin registry (112 monozygotic, 135 dizygotic pairs) age 21 to 81 years were studied. cPP, P1, and DeltaP(aug) were estimated using the SphygmoCor system (Atcor, West Ryde, Australia) from transformed radial waveforms. Carotid-femoral PWV was measured using the same system. Aortic and femoral artery diameters were measured by ultrasonography. Heritability was estimated using structural equation modeling.nnnRESULTSnP1 and DeltaP(aug) accounted for 22% and 76%, respectively, of the variance in cPP. After adjustment for mean arterial pressure and heart rate, P1 strongly independently positively correlated with PWV (standardized regression coefficient, beta = 0.4, p < 0.0001), whereas DeltaP(aug) did not independently correlate with PWV but independently negatively correlated with the ratio of the diameter of the femoral to that of the abdominal aorta (beta = -0.12, p < 0.001). Estimates of heritability (h(2)) of cPP, PWV, P1, and DeltaP(aug) were 0.43, 0.34, 0.31, and 0.62, respectively, after adjustment for mean arterial pressure and heart rate.nnnCONCLUSIONSnThese results suggest that, in women, DeltaP(aug) is highly heritable, is associated with the ratio of distal to proximal arterial diameters, and, independent of PWV, is a major determinant of cPP.

Effects of Neuronal Nitric Oxide Synthase on Human Coronary Artery Diameter and Blood Flow In Vivo

Background— Nitric oxide (NO)-mediated local regulation of vascular tone is considered to involve endothelial NO synthase (eNOS). However, we recently reported that human forearm basal microvascular tone in vivo is tonically regulated by neuronal NO synthase (nNOS), in contrast to an acetylcholine-stimulated reduction in tone, which is eNOS dependent. Here, we investigated the in vivo effects of an nNOS-selective inhibitor, S-methyl-l-thiocitrulline (SMTC), on the human coronary circulation and on flow-mediated dilatation in the forearm. Methods and Results— In patients with angiographically normal coronary arteries, intracoronary infusion of SMTC (0.625 &mgr;mol/min) reduced basal coronary blood flow by 34.1±5.2% (n=10; P<0.01) and epicardial coronary diameter by 3.6±1.2% (P=0.02) but had no effect on increases in flow evoked by intracoronary substance P (20 pmol/min). The nonselective NOS inhibitor NG-monomethyl-l-arginine (25 &mgr;mol/min) also reduced basal coronary flow (by 22.3±5.3%; n=8; P<0.01) but, in contrast to SMTC, inhibited substance P-induced increases in flow (P<0.01). In healthy volunteers, local infusion of SMTC (0.2 &mgr;mol/min) reduced radial artery blood flow by 36.0±6.4% (n=10; P=0.03) but did not affect flow-mediated dilatation (P=0.55). In contrast, NG-monomethyl-l-arginine (2 &mgr;mol/min) infusion reduced radial blood flow to a similar degree (by 39.7±11.8%; P=0.02) but also inhibited flow-mediated dilatation by ≈80% (P<0.01). Conclusions— These data indicate that local nNOS-derived NO regulates basal blood flow in the human coronary vascular bed, whereas substance P-stimulated vasodilatation is eNOS mediated. Thus, nNOS and eNOS have distinct local roles in the physiological regulation of human coronary vascular tone in vivo.

Exercise reduces arterial pressure augmentation through vasodilation of muscular arteries in humans

Exercise markedly influences pulse wave morphology, but the mechanism is unknown. We investigated whether effects of exercise on the arterial pulse result from alterations in stroke volume or pulse wave velocity (PWV)/large artery stiffness or reduction of pressure wave reflection. Healthy subjects (n = 25) performed bicycle ergometry. with workload increasing from 25 to 150 W for 12 min. Digital arterial pressure waveforms were recorded using a servo-controlled finger cuff. Radial arterial pressure waveforms and carotid-femoral PWV were determined by applanation tonometry. Stroke volume was measured by echocardiography, and brachial and femoral artery blood flows and diameters were measured by ultrasound. Digital waveforms were recorded continuously. Other measurements were made before and after exercise. Exercise markedly reduced late systolic and diastolic augmentation of the peripheral pressure pulse. At 15 min into recovery, stroke volume and PWV were similar to baseline values, but changes in pulse wave morphology persisted. Late systolic augmentation index (radial pulse) was reduced from 54 +/- 3.9% at baseline to 42 +/- 3.7% (P < 0.01), and diastolic augmentation index (radial pulse) was reduced from 37 +/- 1.8% to 25 +/- 2.9% (P < 0.001). These changes were accompanied by an increase in femoral blood flow (from 409 +/- 44 to 773 +/- 48 ml/min, P < 0.05) and an increase in femoral artery diameter (from 8.2 +/- 0.4 to 8.6 +/- 0.4 mm, P < 0.05). In conclusion, exercise dilates muscular arteries and reduces arterial pressure augmentation, an effect that will enhance ventricular-vascular coupling and reduce load on the left ventricle.

Infliximab improves vascular stiffness in patients with rheumatoid arthritis

Objectives: Patients with rheumatoid arthritis (RA) have increased cardiovascular mortality. Tumour necrosis factor α (TNFα)-blocking therapy has been shown to reduce RA disease activity measures and joint damage progression. Some observational studies suggest that TNFα blockade reduces mortality and incidence of first cardiovascular events. The mechanisms contributing to these outcomes are unclear. This study assessed the effects of infliximab treatment on vascular stiffness and structure in patients with RA. Methods: A post hoc analysis of longitudinal data from a randomised placebo controlled study evaluated the effect of infliximab on vascular assessments. 26 patients received intravenous infliximab (3 mg/kg) at weeks 0, 2, 6 and every 8 weeks thereafter to week 54. Patients were followed up to 56 weeks of infliximab therapy with assessments of RA disease activity, cardiovascular risk factors, vascular stiffness (pulse wave velocity (PWV)), carotid intima media thickness (CIMT) and carotid artery plaque (CAP). Univariate analyses of changes over time by repeated measures analysis of variance (ANOVA) were followed by multivariate time-series regression analysis (TSRA) if changes were seen. Results: PWV was significantly lower (better) after 56 weeks of treatment with infliximab (ANOVA p<0.01, TSRA p<0.01). However, CIMT (ANOVA pu200a=u200a0.50) and CAP (χ2u200a=u200a4.13, pu200a=u200a0.88) did not change over the study period. Multiple cardiovascular risk measures did not change with treatment and did not correlate with changes in measures of vascular structure. Conclusions: Arterial stiffness improves with infliximab treatment in RA. This change may help explain the improved cardiovascular disease survival in patients with RA receiving TNFα-blocking therapy.

Arterial Stiffening Relates to Arterial Calcification But Not to Noncalcified Atheroma in Women A Twin Study

Objectives Our aim was to examine the relationship of arterial stiffness to measures of atherosclerosis, arterial calcification, and bone mineral density (BMD); the heritability of these measures; and the degree to which they are explained by common genetic influences. Background Arterial stiffening relates to arterial calcification, but this association could result from coexistent atherosclerosis. A reciprocal relationship between arterial stiffening/calcification and BMD could explain the association between cardiovascular morbidity and osteoporosis. Methods We examined, in 900 women from the Twins UK cohort, the relationship of carotid-femoral pulse wave velocity (cfPWV) to measures of atherosclerosis (carotid intima-media thickening; carotid/femoral plaque), calcification (calcified plaque [CP]; aortic calcification by computed tomography, performed in subsample of 40 age-matched women with low and high cfPWV), and BMD. Results The cfPWV independently correlated with CP but not with intima-media thickness or noncalcified plaque. Total aortic calcium, determined by computed tomography, was significantly greater in subjects with high cfPWV (median Agatston score 450.4 compared with 63.2 arbitrary units in subjects with low cfPWV, p = 0.001). There was no independent association between cfPWV and BMD. Adjusted heritability estimates of cfPWV and CP were 0.38 (95% confidence interval: 0.19 to 0.59) and 0.61 (95% confidence interval: 0.04 to 0.83), respectively. Shared genetic factors accounted for 92% of the observed correlation (0.38) between cfPWV and CP. Conclusions These results suggest that the association between increased arterial stiffness and the propensity of the arterial wall to calcify is explained by a common genetic etiology and is independent of noncalcified atheromatous plaque and independent of BMD.

Relationship of calcification of atherosclerotic plaque and arterial stiffness to bone mineral density and osteoprotegerin in postmenopausal women referred for osteoporosis screening.

Arterial calcification leading to increased arterial stiffness, a powerful risk factor for cardiovascular disease, may underlie the association of osteoporosis with cardiovascular disease in postmenopausal women. Osteoprotegerin (OPG), an indirect inhibitor of osteoclastogenesis, may be involved in arterial calcification. We examined relationships between calcification of subclinical atherosclerotic plaque and arterial stiffness with bone mineral density (BMD) and OPG in a group of 54 postmenopausal women referred for routine osteoporosis screening by dual-energy X-ray absorptiometric scanning of the lumbar spine and hip. Presence of calcified and noncalcified plaque in carotid and femoral arteries was examined using ultrasonography. Pulse wave velocity (PWV), a measure of arterial stiffness, was determined by sequential tonometry over the carotid and femoral region. Fifty-nine percent of osteoporotic women had calcified (echogenic) plaque at one or more sites compared with 42% and 20% for women with osteopenia and normal BMD, respectively (Pxa0=xa00.04). There was a significant negative correlation between PWV and hip BMD (rxa0=xa0−0.35, Pxa0=xa00.01), which remained significant when age, mean arterial pressure, and serum lipids were taken into account (Pxa0=xa00.05). No significant relationships were observed between serum concentrations of OPG and lumbar spine or total hip BMD or with the number of arterial sites with calcified or noncalcified plaque. However, there was a strong correlation between OPG and PWV (rxa0=xa00.44, Pxa0=xa00.001), which remained significant when adjusted for age (Pxa0=xa00.01). These findings suggest that decreased BMD is associated with arterial calcification and stiffening and raise the possibility that OPG is a marker of arterial stiffening, independent of any association with BMD.

Acute Reduction of Blood Pressure by Nitroglycerin Does Not Normalize Large Artery Stiffness in Essential Hypertension

Stiffness of large elastic arteries is elevated in subjects with hypertension, an effect that could potentially be explained by increased distending pressure. We examined effects of an acute change in blood pressure on carotid-femoral pulse wave velocity and carotid artery distensibility (inversely related to stiffness) in normotensive control subjects (n=20, mean age 42) with mean arterial pressure (MAP) 84±1.7 mm Hg (mean±SE) and subjects with essential hypertension (n=20, mean age 45, MAP 104±2.0 mm Hg). Normotensive subjects received intravenous nitroglycerin (NTG) and angiotensin II to lower/increase blood pressure. Hypertensive subjects received NTG to lower blood pressure. Pulse wave velocity was 24% (95% CI: 12% to 35%) higher and carotid distensibility 47% (95% CI: 32% to 63%) lower in hypertensive subjects compared with controls. In normotensive subjects, acute changes in blood pressure produced expected changes in stiffness. However, in hypertensive subjects, despite reducing MAP by 22 mm Hg to the same level as in normotensive subjects, there was no detectable reduction in arterial stiffness: pulse wave velocity remained 24% (95% CI: 10% to 38%) higher and carotid distensibility 48% (95% CI: 31% to 63%) lower in hypertensive compared with normotensive subjects. Because blood pressure–independent effects of NTG are, if anything, to reduce stiffness, these results indicate that elevated carotid and aortic stiffness in hypertensive subjects is not explained by elevated blood pressure but relates to structural change in the arterial wall.

Asymmetric Dimethylarginine and Reduced Nitric Oxide Bioavailability in Young Black African Men

Black Africans have a higher incidence of cardiovascular disease than white Europeans. We explored potential mechanisms of this excess risk by assessing endothelium function, inflammatory status (C-reactive protein), oxidative stress (isoprostane-F2&agr;), and plasma asymmetrical dimethyl arginine (ADMA; an endogenous competitive inhibitor of NO synthase) in each ethnic group. Thirty healthy black Africans and 28 well-matched white European male subjects were studied (mean age±SE: 32.2±0.9 and 29.2±1.2 years, respectively; P=0.07). High-resolution ultrasound was used to assess vascular function in the brachial artery by measuring flow mediated dilatation ([percentage of change]; endothelium-dependent function) and glyceryltrinitrate dilatation ([percentage of change]; endothelium-independent function). Blood pressure, fasting lipids, glucose, and estimated glomerular filtration rate levels were similar in both groups. There was no difference in C-reactive protein (black Africans: 0.8±0.1 mg/L; white Europeans: 0.6±0.1 mg/L; P=0.22), isoprostane-F2&agr; (black Africans: 42.9±1.5 pg/mL; white Europeans: 39.2±1.5 pg/mL; P=0.23), and leptin (black Africans: 64.1±10.2 ng/mL; white Europeans: 47.8±9.8 ng/mL; P=0.37) levels between the 2 ethnic groups. However, compared with white Europeans, plasma ADMA levels were significantly higher in black Africans (0.34±0.02 &mgr;mol/L and 0.25±0.03 &mgr;mol/L; P=0.03). There was no difference in the percentage of glyceryltrinitrate dilatation (P=0.7), but the percentage of flow-mediated dilatation was significantly lower in black Africans (black Africans: 5.2±0.3; white Europeans: 6.3±0.4; P=0.02). In a stepwise multiple regression model, ADMA level was the only independent determinant of flow-mediated dilatation (P=0.02). In turn, race was the only independent determinant of ADMA levels (P=0.03). Our findings indicate that circulating ADMA levels are significantly higher in healthy black African males than in white European males. This may contribute to the lower NO bioavailability and higher incidence of cardiovascular disease seen in black Africans.

Progression of Central Pulse Pressure Over 1 Decade of Aging and its Reversal by Nitroglycerin : A Twin Study

OBJECTIVESnThe goal of this study was to examine the progression of central arterial pulse pressure (cPP) in women and the degree to which this can be reversed by nitrovasodilation.nnnBACKGROUNDncPP can be partitioned into height of the first systolic shoulder (P1), generated by a forward pressure wave and related to arterial stiffness, and augmentation pressure (AP), thought to be influenced by pressure wave reflection from muscular arteries and/or aortic reservoir.nnnMETHODSnUsing a longitudinal cohort design, cPP, P1, and AP were estimated (using the SphygmoCor System [AtCor Medical Pty Ltd., West Ryde, Australia]) in 411 female twins over a mean follow-up of 10.8 years. In a subsample (n = 42), cPP, arterial stiffness (using pulse wave velocity [PWV]) and arterial diameters (using ultrasonography) were measured before and after nitroglycerin administration (400 μg s/l).nnnRESULTSncPP increased more than peripheral pulse pressure (10.3 and 9.2 mm Hg, respectively; p < 0.0001). In women <60 years of age at follow-up, AP contributed more to the increase in cPP than did P1 (increases of 6.5 ± 6.4 mm Hg and 4.2 ± 7.8 mm Hg, respectively). P1 was significantly positively correlated to PWV (p < 0.0001); AP was correlated to aorto-femoral tapering (p < 0.0001) but not PWV. Nitroglycerin reduced cPP by 10.0 ± 6.0 mm Hg (p < 0.0001), equivalent to a decade of aging. The reduction in cPP was entirely explained by a decrease in AP, with no significant change in P1 or PWV but an increase in large artery diameters of 4% to 18% (p < 0.0001).nnnCONCLUSIONSnAge-related widening of cPP is driven in large part by an increase in AP, which can be reversed by selective dilation of muscular arteries, independent of PWV.