PubMed Health⌕ Search

Biomedical subjects

Subodh Verma

Publications and source records attributed to Subodh Verma.

At least 19 recordsLinked to original sources
PubMed2006

Effects of folinic acid on forearm blood flow in patients with end-stage renal disease.

BACKGROUND: Abnormalities of endothelial function are likely to contribute to the accelerated atherosclerotic risk in subjects with end-stage renal disease (ESRD). While folates can improve endothelial function, their role in ESRD has not been fully studied. The objective was to determine the acute and 12 week-effect of folinic acid on endothelium-dependent vasodilation in subjects with ESRD. METHODS: Forearm blood flow (FBF) was assessed by strain gauge plethysmography at baseline and after 12 weeks in 34 ESRD patients (57 +/- 14 years). Vascular function was assessed with acetylcholine (ACh), and sodium nitroprusside (SNP). Patients were randomized to receive folinic acid (50 mg i.v. once weekly) or a matching placebo. A subset of 25 subjects also received folinic acid (500 microg/min intra-arterially) or placebo to determine the acute effect on ACh and SNP mediated dilation at the time of the baseline vascular study. RESULTS: Folinic acid acutely improved the maximum change in ACh mediated FBF (10.0 +/- 2.4 to 12.8 +/- 2.2 ml/min/100 ml, P = 0.017), but did not change SNP responses. Chronic active therapy did not change ACh or SNP-mediated increases in FBF. Folinic acid resulted in a non-significant decrease in homocysteine (21 +/- 6 vs 28 +/- 18 micromol/l, P = 0.16) and diastolic blood pressure was significantly reduced (P = 0.05). CONCLUSIONS: The present study demonstrated that folinic acid acutely improved endothelium-dependent vasodilatation in patients with ESRD suggesting a direct vascular effect. Chronic treatment with folinic acid did not show benefit in endothelial function, but did lower diastolic blood pressure. Further work is required to determine the optimal regime to protect vascular health in subjects with ESRD.

Acetylcholine↗
PubMed2006

Altered expression of disintegrin metalloproteinases and their inhibitor in human dilated cardiomyopathy.

BACKGROUND: Disintegrin metalloproteinases (ADAMs) may contribute to structural cardiac remodeling by altering cell-surface matrix receptors (integrins) and activating potent biomolecules. We compared expression of ADAMs, their endogenous inhibitor tissue inhibitor of metalloproteinases (TIMP)-3, and integrins in human heart tissue with varied patterns of structural remodeling. METHODS AND RESULTS: Myocardium was obtained from patients with dilated cardiomyopathy (n=20), hypertrophic obstructive cardiomyopathy (n=5), and nonfailing donor hearts (n=7). Paired samples (n=10) were obtained before left ventricular assist device insertion and at transplantation. The expressions of ADAM10, ADAM12, ADAM15, and ADAM17, TIMP-3, and integrin receptors beta1D and beta3 were determined by quantitative immunoblotting. Integrin shedding was assessed by the ratio of integrin cleavage products to intact protein abundance. Confocal microscopy was performed. Dilated cardiomyopathy was characterized by increased ADAM10 and ADAM15 expression and reduced TIMP-3 expression. The integrin beta1D cleavage ratio was elevated, indicating receptor shedding. ADAM10 and ADAM15 expressions correlated with the cleavage ratio. ADAM10 colocalized with integrin beta1D by confocal microscopy. ADAM10 expression correlated with clinical indices of chamber dilatation and systolic dysfunction. Hemodynamic unloading reduced ADAM10 and ADAM12 expressions and increased integrin beta1D expression. ADAM12 and integrin beta1D expressions were increased in HOCM. ADAM17 was increased in both dilated cardiomyopathy and hypertrophic obstructive cardiomyopathy. CONCLUSIONS: Disintegrin metalloproteinases are differentially expressed in human myocardium, reflecting the underlying pattern of structural remodeling. ADAM10 and ADAM15 may contribute to cardiac dilatation by reducing cell-matrix interactions via integrin shedding. Targeting disintegrin metalloproteinases, perhaps by restoring deficient TIMP-3 levels with gene or cell-based therapies, may prevent progressive chamber dilatation in human dilated cardiomyopathy.

ADAM Proteins↗
PubMed2006

The vascular biology of peroxisome proliferator-activated receptors: modulation of atherosclerosis.

Accumulating evidence suggests that peroxisome proliferator-activated receptor (PPAR) agonists possess powerful antiatherosclerotic properties, by both directly affecting the vascular wall and indirectly affecting systemic inflammation and insulin sensitivity. The PPARs are ligand-activated transcription factors, which play a number of important physiological roles in lipid and glucose homeostasis. Activation of PPARgamma appears to exert a vasculoprotective effect by limiting endothelial dysfunction, impairing atherogenesis and preventing restenosis, while simultaneously and favourably modulating adipokine expression and lipid metabolism. Several experimental and clinical studies have demonstrated the potential of the PPAR agonist drug class in terms of treating atherosclerotic disease. In the present review, the vascular biology of PPARs, and how the modulation of these molecular pathways may serve as a therapeutic strategy to prevent atherosclerosis, vascular inflammation and restenosis are discussed.

Adiponectin↗
PubMed2005

Cell transplantation preserves matrix homeostasis: a novel paracrine mechanism.

OBJECTIVES: Cell transplantation prevents chamber dilatation, but the underlying molecular mechanisms remain undefined. Structural cardiac remodeling involves matrix degradation from an imbalance of matrix metalloproteinases (MMP) relative to endogenous tissue inhibitors of metalloproteinases (TIMP). We aimed to determine the capacity of cell transplantation to alter extracellular matrix in the failing heart and, in so doing, identify novel paracrine molecular mediators underlying the beneficial effects of cell transplantation on chamber dilatation. METHODS: Smooth muscle cells were transplanted to the dilating left ventricle of cardiomyopathic hamsters (CTX, n = 15) compared with age-matched media-injected cardiomyopathic (CON, n = 15) and normal hamsters (n = 7). After 5 weeks, left ventricular volume was measured by computerized planimetry. Fibrillar collagen was examined by confocal microscopy. Matrix homeostasis was quantified by measuring MMP/TIMP expression/activity relative to myocardial collagen synthesis (14C-proline uptake). RESULTS: Left ventricular dilatation was attenuated in CTX hearts (P = .02). CTX restored perimysial collagen fiber content and architecture to normal levels. TIMP-2 and TIMP-3 expression were enhanced in CTX (TIMP-2, 195% +/- 42% of CON, P = .02; TIMP-3, 118% +/- 3% of CON, P = .002), and correspondingly, gelatinase MMP-2 activity was reduced (P < .05). The TIMP:MMP ratio was increased in CTX hearts (TIMP-2 to MMP-2, 410% +/- 134% of CON, P = .04, and TIMP-3 to MMP-9, 205% +/- 47% of CON, P = .03), reflecting a reduced capacity for matrix degradation. Collagen synthesis was equivalent (CTX vs CON), suggesting that restored matrix architecture was a function of attenuated matrix degradation. CONCLUSIONS: These data provide the first evidence that cell transplantation limits ventricular dilatation in the failing heart through a paracrine-mediated mechanism that preserves extracellular matrix homeostasis.

Animals↗
PubMed2005

Relationship between carotid artery intima-media thickness and brachial artery flow-mediated dilation in middle-aged healthy men.

OBJECTIVES: We aimed to determine the relationship between carotid intima-media thickness (IMT) and brachial artery flow-mediated dilation (FMD) in healthy middle-age men. BACKGROUND: Carotid IMT and brachial artery FMD are frequently used as surrogate measures of subclinical atherosclerosis. Whereas carotid IMT identifies early structural abnormalities, brachial artery FMD, considered a bioassay of endothelial function, measures functional vascular integrity. The relationship between carotid IMT and brachial artery FMD has not been well studied. METHODS: We measured traditional risk factors, carotid IMT, and brachial artery FMD in 1,578 middle-aged men without known cardiovascular disease and analyzed the relationship between carotid IMT and brachial FMD. RESULTS: Carotid IMT correlated with age, systolic blood pressure, body mass index, fasting glucose, total and low-density lipoprotein (LDL) cholesterol, and with the overall Framingham risk score (p < 0.001 for all), whereas impaired brachial artery FMD correlated with systolic and diastolic blood pressure (p < 0.01). No relationship was observed between carotid IMT and brachial artery FMD for the entire cohort (r = -0.006, p = 0.82) and in subgroups defined by traditional risk factors or by quintiles of carotid IMT and brachial FMD. CONCLUSIONS: In middle-aged healthy men, there is no significant correlation between carotid IMT and brachial artery FMD. This finding suggests that these are unique, independent surrogates that measure different aspects and stages of early atherosclerosis. Further studies are needed to define their role in clinical research and in cardiovascular risk assessment.

Adult↗
PubMed2005

Nocturnal hemodialysis is associated with restoration of impaired endothelial progenitor cell biology in end-stage renal disease.

Cardiovascular disease is the principal cause of death in end-stage renal disease (ESRD) patients. Endothelial progenitor cells (EPCs) play a critical role in vascular repair, and improving EPC biology represents a novel therapeutic target. Three groups of age- and gender-matched patients were studied: 1) 10 healthy control, 2) 12 conventional hemodialysis (CHD) patients, and 3) 10 nocturnal hemodialysis (NHD) patients. EPC number and migratory function were assessed. Left ventricular mass index (LVMI) was derived, and correlations between EPC biology, uremic clearance, and LVMI were made. Compared with controls, EPC number and function were markedly impaired in CHD patients [(3.48 +/- 1.2 vs. 0.86 +/- 0.20%/50,000 cells, P < 0.05) and (18.8 +/- 2.64 vs. 3.75 +/- 0.34 cells/high-power field, P < 0.05), respectively]. In contrast, EPC number and function were normal in NHD patients [(3.48 +/- 1.17 vs. 3.83 +/- 0.77%/50,000 cells) and (18.8 +/- 2.6 vs. 22.2 +/- 2.4 cells/high-power field), respectively]. Among ESRD patients, EPC number and function inversely correlated with predialysis urea concentration (r = -0.40; r = -0.57), LVMI (r = -0.41; -0.46) and systolic BP (r = -0.58; r = -0.44). We demonstrate that NHD is associated with restoration of abnormal EPC biology in ESRD. Given the increasing importance of EPCs in the repair and restoration of cardiovascular function, these data have important clinical implications for vascular risk in ESRD patients.

Blood Pressure↗
PubMed2005

The relationship between soluble CD40 ligand levels and Framingham coronary heart disease risk score in healthy volunteers.

Elevated soluble CD40 ligand (sCD40L) levels are associated with an increased risk of cardiovascular events in patients with acute coronary syndromes and in middle-aged healthy women. However, the relationship between sCD40L and global risk assessment remains unclear. The present study was designed to examine the relationship between sCD40L and Framingham Coronary Heart Disease Risk Scores (FCRS) in healthy middle-aged men. The study population consisted of 400 active and retired male firefighters, with no previous history of cardiovascular disease, as part of the Firefighters and Their Endothelium (FATE) study. FCRS correlated poorly with sCD40L levels (p=0.14). Soluble CD40L concentrations correlated only with total (r=0.105; p=0.035) and LDL cholesterol (r=0.104; p=0.039), and CRP levels (r=0.11; p=0.03). Compared with participants with sCD40L levels <4.36 ng/mL (75th percentile), participants with sCD40L levels >4.36 ng/mL had higher total (p=0.016) and LDL cholesterol (p=0.018), CRP levels (p=0.034) and FCRS (p=0.012). Multivariate analysis revealed that CRP level was the only parameter that independently correlated with the sCD40L levels (p=0.032). This is the first study to evaluate the relationship between sCD40L levels and Framingham global risk assessment in a large cohort of otherwise healthy individuals. We demonstrate that sCD40L levels poorly correlate with both the individual components and the calculated FCRS. Long-term follow-up of the FATE study will shed light on whether the predictive value of sCD40L is independent of Framingham based global risk assessment.

Adult↗
PubMed2005

Tetrahydrobiopterin deficiency exaggerates intimal hyperplasia after vascular injury.

Decreased levels of tetrahydrobiopterin (BH4), an absolute cofactor for nitric oxide synthase (NOS), lead to uncoupling of NOS into a superoxide v. nitric oxide producing enzyme, and it is this uncoupling that links it to the development of vascular disease. However, the effects of in vivo deficiency of BH4 on neointimal formation after vascular injury have not been previously investigated. Hph-1 mice, which display 90% deficiency in guanine triphosphate cyclohydrolase I, the rate limiting enzyme in BH4 synthesis, were used. Hph-1 and wild-type mice, treated with either vehicle or BH4 (n = 15 per group), were subjected to wire-induced femoral artery injury, and NOS expression and activity, inflammation, cell proliferation, superoxide production, and neointimal formation were assessed. The major form of NOS expressed over vessel wall after vascular injury was endothelial NOS. Hph-1 mice exhibited lower NOS activity (2.8 +/- 0.3 vs. 4.5 +/- 0.4 pmol/min/mg protein, P < 0.01), and higher aortic superoxide content (5.2 +/- 2.0 x 10(5) cpm vs. 1.6 +/- 0.7 x 10(5) cpm, P < 0.01) compared with wild-type controls, indicating uncoupling of NOS. Treatment of hph-1 mice with BH4 significantly increased NOS activity (from 2.8 +/- 0.3 to 4.1 +/- 0.4 pmol.min(-1).mg protein(-1), P < 0.05), and attenuated superoxide production (from 5.2 +/- 2.0 x 10(5) cpm to 0.8 +/- 0.7 x 10(5) cpm, P < 0.05). Hph-1 mice also had higher inflammatory reactions and more cell proliferation after vascular injury. Furthermore, hph-1 mice responded by a marked increase in neointimal formation at 4 wk after vascular injury, compared with wild-type controls (intima:media ratio: 4.5 +/- 0.5 vs. wild-type 0.7 +/- 0.1, P < 0.001). Treatment of hph-1 mice with BH4 prevented vascular injury-induced increase in neointimal formation (intima:media ratio: 1.4 +/- 0.1 vs. hph-1, P < 0.001). Treatment had no effect on wild-type controls. In summary, we describe, for the first time, that in vivo BH4 deficiency facilitates neointimal formation after vascular injury. Modulation of BH4 bioavailability is an important therapeutic target for restenosis.

Animals↗
PubMed2005

Antiatherogenic potential of red wine: clinician update.

Complications of atherosclerosis remain the leading cause of morbidity and mortality in industrialized countries. Epidemiological studies have repeatedly demonstrated that moderate alcohol intake has a beneficial effect on cardiovascular disease. The purpose of this review is to examine the epidemiological and biological evidence supporting the intake of red wine as a means of reducing atherosclerosis. On the basis of epidemiological studies, moderate intake of alcoholic beverages, including red wine, reduces the risk of cardiovascular, cerebrovascular, and peripheral vascular disease in populations. In addition to the favorable biological effects of alcohol on the lipid profile, on hemostatic factors, and in reducing insulin resistance, the phenolic compounds in red wine appear to interfere with the molecular processes underlying the initiation, progression, and rupture of atherosclerotic plaques. Whether red wine is more beneficial than other types of alcohol remains unclear. Definitive data from a large-scale, randomized clinical end-point trial of red wine intake would be required before physicians can advise patients to use wine as part of preventative or medical therapies.

Alcohol Drinking↗
PubMed2005

Adipokines: molecular links between obesity and atheroslcerosis.

Atherosclerotic disease remains the leading cause of death in industrialized nations despite major advances in its diagnosis, treatment, and prevention. The increasing epidemic of obesity, insulin resistance, and diabetes will likely add to this burden. Increasingly, it is becoming apparent that adipose tissue is an active endocrine and paracrine organ that releases several bioactive mediators that influence not only body weight homeostasis but also inflammation, coagulation, fibrinolysis, insulin resistance, diabetes, and atherosclerosis. The cellular mechanisms linking obesity and atherosclerosis are complex and have not been fully elucidated. This review summarizes the experimental and clinical evidence on how excess body fat influences cardiovascular health through multiple yet converging pathways. The role of adipose tissue in the development of obesity-linked insulin resistance, metabolic syndrome, and diabetes will be reviewed, including an examination of the molecular links between obesity and atherosclerosis, namely, the effects of fat-derived adipokines. Finally, we will discuss how these new insights may provide us with innovative therapeutic strategies to improve cardiovascular health.

Adipose Tissue↗