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Biomedical subjects

Sanjay Rajagopalan

Publications and source records attributed to Sanjay Rajagopalan.

At least 37 records · Page 2Linked to original sources
PubMed2005

Quality of life in chronic kidney disease (CKD): a cross-sectional analysis in the Renal Research Institute-CKD study.

BACKGROUND: Health-related quality of life (QOL) is an important measure of how disease affects patients' lives. Dialysis patients have decreased QOL relative to healthy controls. Little is known about QOL in patients with chronic kidney disease (CKD) before renal replacement therapy. METHODS: The Medical Outcomes Study Short Form-36 (SF-36), a standard QOL instrument, was used to evaluate 634 patients (mean glomerular filtration rate [GFR], 23.6 +/- 9.6 mL/min/1.73 m2 [0.39 +/- 0.16 mL/s/1.73 m2]) enrolled in a 4-center, prospective, observational study of CKD. SF-36 scores in these patients were compared with those in a prevalent cohort of hemodialysis (HD) patients and healthy controls (both from historical data). QOL data also were analyzed for correlations with GFR and albumin and hemoglobin levels in multivariable analyses. RESULTS: Patients with CKD had higher SF-36 scores than a large cohort of HD patients (P < 0.0001 for 8 scales and 2 summary scales), but lower scores than those reported for the US adult population (P < 0.0001 for 7 of 8 scales and 1 of 2 summary scales). Patients with CKD stage 4 had lower QOL scores than patients with CKD stage 5, although differences were not significant. Hemoglobin level was associated positively with higher mental and physical QOL scores (P < 0.05) in all individual and component scales except Pain. CONCLUSION: SF-36 scores were higher in this CKD cohort compared with HD patients, but lower than in healthy controls. GFR was not significantly associated with QOL. Hemoglobin level predicted both physical and mental domains of the SF-36. Longitudinal studies are needed to define at-risk periods for decreases in QOL during progression of CKD.

Black or African American↗
PubMed2005

Acute blood pressure responses in healthy adults during controlled air pollution exposures.

Exposure to air pollution has been shown to cause arterial vasoconstriction and alter autonomic balance. Because these biologic responses may influence systemic hemodynamics, we investigated the effect of air pollution on blood pressure (BP). Responses during 2-hr exposures to concentrated ambient fine particles (particulate matter < 2.5 microm in aerodynamic diameter; PM2.5) plus ozone (CAP+O3) were compared with those of particle-free air (PFA) in 23 normotensive, nonsmoking healthy adults. Mean concentrations of PM2.5 were 147 +/- 27 versus 2 +/- 2 microg/m3, respectively, and those of O3 were 121 +/- 3 versus 8 +/- 5 ppb, respectively (p < 0.0001 for both). A significant increase in diastolic BP (DBP) was observed at 2 hr of CAP+O3 [median change, 6 mm Hg (9.3%); binomial 95% confidence interval (CI), 0 to 11; p = 0.013, Wilcoxon signed rank test] above the 0-hr value. This increase was significantly different (p = 0.017, unadjusted for basal BP) from the small 2-hr change during PFA (median change, 1 mm Hg; 95% CI, -2 to 4; p = 0.24). This prompted further investigation of the CAP+O3 response, which showed a strong association between the 2-hr change in DBP (and mean arterial pressure) and the concentration of the organic carbon fraction of PM2.5 (r = 0.53, p < 0.01; r = 0.56, p < 0.01, respectively) but not with total PM2.5 mass (r < or = 0.25, p > or = 0.27). These findings suggest that exposure to environmentally relevant concentrations of PM2.5 and O3 rapidly increases DBP. The magnitude of BP change is associated with the PM2.5 carbon content. Exposure to vehicular traffic may provide a common link between our observations and previous studies in which traffic exposure was identified as a potential risk factor for cardiovascular disease.

Adult↗
PubMed2004

Effect of carotid atherosclerosis screening on risk stratification during primary cardiovascular disease prevention.

We investigated the effect that carotid plaque area (CPA) and intima media thickness (IMT) measurements have on risk stratification in 95 patients with intermediate Framingham scores (6% to 19%). The risk status of each patient was adjusted to be low, intermediate, or high based on the results of carotid ultrasound. After carotid testing, 44% (IMT) and 45% (CPA) of the intermediate-risk patients were stratified as low risk, and 22% (IMT) and 40% (CPA) were stratified as high risk. Using the threshold values derived from our laboratory, 28% (IMT) and 45% (CPA) of patients were stratified as low risk, and 35% (IMT) and 27% (CPA) were identified as high risk. These tests adjust the risk strata of >/=63% of patients deemed as having intermediate risk by Framingham scores.

Cardiovascular Diseases↗
PubMed2004

Effect of short-term weight loss on the metabolic syndrome and conduit vascular endothelial function in overweight adults.

Impaired vascular endothelial function may be an important mechanism linking obesity to increased cardiovascular risk. We investigated whether short-term weight loss improves conduit artery endothelial dysfunction in overweight adults. Forty-three otherwise healthy overweight patients with a body mass index > or =27 kg/m(2) completed an open-label 3-month trial consisting of a calorie-restricted diet and 120 mg of orlistat taken 3 times daily with meals. Endothelial function and parameters of the metabolic syndrome were measured before and after intervention. Subjects lost 6.6 +/- 3.4% of their body weight. Low-density lipoprotein cholesterol, low-density lipoprotein concentration, fasting insulin, and leptin decreased significantly (all p <0.009), and C-reactive protein decreased (p = 0.22). Conduit vascular function did not change as assessed by flow-mediated dilation (3.86 +/- 3.54 vs 3.74 +/- 3.78%, p = 0.86) and nitroglycerin-mediated dilation (17.18 +/- 5.89 vs 18.87 +/- 7.11%, p = 0.13) of the brachial artery. A moderate degree of weight reduction over 3 months improved the metabolic syndrome profile but not the vascular dysfunction associated with uncomplicated obesity.

Adolescent↗
PubMed2004

Endothelial cell apoptosis in systemic lupus erythematosus: a common pathway for abnormal vascular function and thrombosis propensity.

Women with systemic lupus erythematosus (SLE) are at risk for premature atherothrombosis independent of Framingham risk factors. We investigated whether endothelial cell (EC) apoptosis predicts abnormal vasomotor tone and contributes to circulating tissue factor (TF) levels in this disease. Brachial artery flow-mediated dilation (FMD) and nitroglycerin-mediated dilation were determined in women with SLE, healthy control subjects, and subjects with coronary artery disease (CAD) (n = 43/group). Quantification of circulating apoptotic ECs was performed by flow cytometry (CD146(+) cells that stained for Annexin V [CD146(AnnV+)]) and immunofluorescent microscopy. Plasma TF was measured by enzyme-linked immunosorbent assay (ELISA). Compared with healthy control and CAD subjects, patients with SLE had higher numbers of circulating CD146(AnnV+) cells (10 +/- 3, 18 +/- 5, and 89 +/- 32 cells/mL, respectively, mean +/- SEM; P <.01). Increased CD146(AnnV+) cells correlated strongly with abnormal vascular function (P =.037). After adjusting for known predictors of endothelial function, CD146(AnnV+) was the only variable that predicted FMD (beta = -4.5, P <.001). Increased CD146(AnnV+) was strongly associated with elevated levels of circulating TF (r =.46, P =.002). Circulating apoptotic ECs are elevated in young women with SLE and strongly correlate with markedly abnormal vascular function and elevated TF levels. Heightened endothelial apoptosis may represent an important mechanism for development of atherothrombosis in SLE.

Adult↗
PubMed2004

Eplerenone: will it have a role in the treatment of acute coronary syndromes?

Aldosterone is known to have multiple adverse cardiovascular effects that are reminiscent of but independent from angiotensin II. These effects include endothelial dysfunction, heightened thrombogenicity, inflammation, and reparative fibrosis, and have been described in experimental and human models of aldosterone excess. Recently a number of clinical investigations have demonstrated that mineralocorticoid receptor (MR) antagonism, even in conditions not traditionally associated with systemic activation of the renin-angiotensin II-aldosterone pathway, may provide additional benefits above and beyond angiotensin-converting enzyme (ACE) inhibition and angiotensin receptor blockade. The Eplerenone Neurohormonal Efficacy and Survival Study (EPHESUS) with eplerenone in patients who were post-myocardial infarction underscores the additive benefit of such a strategy in post-infarction patients that typify an at-risk population for recurrent cardiovascular events. The mechanisms operative in acute coronary syndromes (ACS), including inflammation, altered hemostasis, and endothelial dysfunction, overlap significantly with those seen in the EPHESUS patient population. One may therefore hypothesize that MR antagonism with eplerenone may be beneficial in patients with ACS. Another advantage of using eplerenone is that it offers the advantages of MR antagonism without the side effects due to blockade of other nuclear receptors such as the androgen and progesterone receptors. If MR blockade is found to be beneficial in patients with ACS, the potential reduction in morbidity, mortality, and health care costs are profound.

Angina, Unstable↗
PubMed2004

Relative contributions of PM2.5 chemical constituents to acute arterial vasoconstriction in humans.

Studies have shown associations between acute ambient particulate matter (PM) levels and increases in morbidity and mortality from cardiovascular diseases. We have previously reported in 24 healthy adults that exposure to concentrated ambient particles plus ozone (CAP + O(3)) caused a mean decrease of 0.09 mm in brachial artery diameter (BAD), which was significantly larger than a mean increase of 0.01 mm among the same individuals exposed to filtered air (FA). Our current objective is to examine the relationship between total and constituent PM(2.5) mass concentrations and the acute vascular response. We have analyzed both ambient and exposure filters from the brachial artery study for major chemical constituents, allowing us to compare the strength of the associations between each constituent and an individual's arterial response. We determined gravimetric PM(2.5) mass concentration and inorganic ion content from exposure filters. Twenty-three-hour ambient PM(2.5) filters collected from the same site and on the same day were used to estimate exposure concentrations of trace elements and organic and elemental carbon. We performed linear regression analyses on the levels of measured or estimated PM constituents using each subject's FA exposure as a control. We found, from our regression analyses, a significant negative association between both the organic and elemental carbon concentrations and the difference in the postexposure change in the BAD (Delta BAD) between and CAP + O(3) and FA exposure days. An understanding of the PM constituents most responsible for adverse health outcomes is critical for efforts to develop pollution abatement strategies that maximize benefits to public health.

Adult↗
PubMed2004

Effects of concentrated fine ambient particles on rat plasma levels of asymmetric dimethylarginine.

The health effects of ambient fine particulate matter (PM(2.5)) and its potential impact on vascular endothelial function have not been thoroughly investigated. As endothelial dysfunction plays an important role in the pathogenesis of atherosclerosis and its complications, we examined the effects of concentrated fine ambient particles (CAPs) on the plasma level of asymmetric dimethylarginine (ADMA) in a pilot study. ADMA is a circulating endogenous inhibitor of nitric oxide synthase (NOS) that is associated with impaired vascular function and increased risk for cardiovascular events. A mobile air research laboratory (AirCARE 1) was used to provide "real-world" CAPs exposures for this study conducted in Detroit, MI. Fourteen Brown Norway rats were exposed to filtered air (FA) (n = 7) or CAPs (0.1-2.5 microm) (n = 7) for 3 consecutive days (8 h/day) in July 2002. Rats were exposed during these periods to average particle mass concentrations of 354 microg/m(3). Rat plasma samples were collected 24 h postexposure. Plasma concentrations of ADMA were significantly elevated in rats exposed to CAPs versus those exposed to FA (mean +/- standard deviation = 1.49 +/- 0.18 vs. 1.29 +/- 0.26 microM, p =.05 by one-tailed t-test). Analyses of meteorological data and CAPs trace element composition suggest that local particle emission sources contributed largely to overall mass of CAPs. Results of this pilot study suggest that exposure to PM(2.5) at high concentrations may trigger an acute increase in circulating ADMA level. This finding has implications for the regulation of vasomotor tone by particulate pollutants and the propensity for adverse cardiovascular events.

Air Pollutants↗
PubMed2004

Design of the Del-1 for therapeutic angiogenesis trial (DELTA-1), a phase II multicenter, double-blind, placebo-controlled trial of VLTS-589 in subjects with intermittent claudication secondary to peripheral arterial disease.

The objective of this phase II investigation is to assess the safety and efficacy of a plasmid mediated approach to induce angiogenesis/arteriogenesis with the angiomatrix protein Del-1 (developmentally regulated endothelial locus 1), in subjects with intermittent claudication (IC) secondary to peripheral arterial disease (PAD). VLTS-589 is an investigational nonviral therapeutic comprising a plasmid-expressing Del-1 formulated with poloxamer 188 (facilitating agent). One hundred subjects with bilateral PAD and IC will be randomized after careful screening to bilateral intramuscular delivery of VLTS-589 or placebo. A total of 84 mg of plasmid or placebo will be delivered as 42 intramuscular injections (2 ml per injection, 21 injections or 42 ml in each extremity of either plasmid or placebo) in both lower extremities. The subjects in the study will be followed at regular intervals for a year after study drug administration (days 30, 90, 180, and 365) with the primary endpoint being the safety and tolerability of VLTS-589 and change in peak walking time (PWT) at day 90. The secondary endpoints include percent and absolute change in resting ankle brachial Index, claudication onset time, and quality of life measured at various time points. DELTA-1 represents the largest plasmid-based gene transfer trial designed to test the efficacy of a Del-1 as a therapeutic approach in patients with IC caused by PAD. The novel aspects of the protocol include the usage of a Del-1 plasmid-polaxamer formulation to enhance gene transfer at doses that are an order of magnitude different than other comparable trials in a unique bilateral intramuscular dosing pattern to maximize transfection/clinical efficacy and general applicability to patients with PAD.

Adult↗
PubMed2003

Effects of cilostazol in patients with Raynaud's syndrome.

Raynaud's syndrome (RS), which is characterized by recurrent episodes of vasospasm with exposure to cold, may occur alone (primary RS) or in association with connective tissue diseases or other underlying conditions (secondary RS). We investigated the effect of cilostazol on vessel wall responses in RS. Patients were diagnosed (primary or secondary RS associated with connective tissue diseases) and randomized to placebo or cilostazol 100 mg twice daily for 6 weeks in a double-blind manner. Brachial artery vasoreactivity, laser Doppler fluxmetry, and cold pressor testing (CPT) were performed at study initiation and completion. Symptoms were assessed using standardized questionnaires. Forty subjects completed the study (19 with primary RS and 21 with secondary RS). Cilostazol significantly increased the mean brachial artery diameter at 6 weeks (primary RS, p = 0.006; secondary RS, p = 0.06). There was no change in median flow-mediated dilation (FMD) with cilostazol in primary RS (25th, 75th percentiles) (4.06% [2.5, 6.1] to -0.77% [-2.4, 3.4] or secondary RS (2.2% [0.05, 6.3] to 2.95% [1.7, 7.4]). There were no changes in nitroglycerin-mediated dilation or microvascular flow indexes in either cohort. In patients with primary RS, cilostazol treatment yielded a positive change in the slope of brachial responsiveness to CPT (increase of 0.32 mm/min; p = 0.002 vs placebo). Cilostazol treatment remained significantly associated with increased brachial artery diameter when controlling for baseline values (p = 0.018). Cilostazol increased conduit vessel diameter in patients with primary and secondary RS, with a favorable impact on conduit vessel responsiveness to cold in patients with primary RS without affecting microvascular flow or symptoms.

Adult↗
PubMed2003

Regional angiogenesis with vascular endothelial growth factor in peripheral arterial disease: a phase II randomized, double-blind, controlled study of adenoviral delivery of vascular endothelial growth factor 121 in patients with disabling intermittent claudication.

BACKGROUND: "Therapeutic angiogenesis" seeks to improve perfusion by the growth of new blood vessels. The Regional Angiogenesis with Vascular Endothelial growth factor (RAVE) trial is the first major randomized study of adenoviral vascular endothelial growth factor (VEGF) gene transfer for the treatment of peripheral artery disease (PAD). METHODS AND RESULTS: This phase 2, double-blind, placebo-controlled study was designed to test the efficacy and safety of intramuscular delivery of AdVEGF121, a replication-deficient adenovirus encoding the 121-amino-acid isoform of vascular endothelial growth factor, to the lower extremities of subjects with unilateral PAD. In all, 105 subjects with unilateral exercise-limiting intermittent claudication during 2 qualifying treadmill tests, with peak walking time (PWT) between 1 to 10 minutes, were stratified on the basis of diabetic status and randomized to low-dose (4x10(9) PU) AdVEGF121, high-dose (4x10(10) PU) AdVEGF121, or placebo, administered as 20 intramuscular injections to the index leg in a single session. The primary efficacy end point, change in PWT (DeltaPWT) at 12 weeks, did not differ between the placebo (1.8+/-3.2 minutes), low-dose (1.6+/-1.9 minutes), and high-dose (1.5+/-3.1 minutes) groups. Secondary measures, including DeltaPWT, ankle-brachial index, claudication onset time, and quality-of-life measures (SF-36 and Walking Impairment Questionnaire), were also similar among groups at 12 and 26 weeks. AdVEGF121 administration was associated with increased peripheral edema. CONCLUSIONS: A single unilateral intramuscular administration of AdVEGF121 was not associated with improved exercise performance or quality of life in this study. This study does not support local delivery of single-dose VEGF121 as a treatment strategy in patients with unilateral PAD.

Adenoviridae↗
PubMed2003

Chronic iron administration increases vascular oxidative stress and accelerates arterial thrombosis.

BACKGROUND: Iron overload has been implicated in the pathogenesis of ischemic cardiovascular events. However, the effects of iron excess on vascular function and the thrombotic response to vascular injury are not well understood. METHODS AND RESULTS: We examined the effects of chronic iron dextran administration (15 mg over 6 weeks) on thrombosis, systemic and vascular oxidative stress, and endothelium-dependent vascular reactivity in mice. Thrombus generation after photochemical carotid artery injury was accelerated in iron-loaded mice (mean time to occlusive thrombosis, 20.4+/-8.5 minutes; n=10) compared with control mice (54.5+/-35.5 minutes, n=10, P=0.009). Iron loading had no effect on plasma clotting, vessel wall tissue factor activity, or ADP-induced platelet aggregation. Acute administration of dl-cysteine, a reactive oxygen species scavenger, completely abrogated the effects of iron loading on thrombus formation, suggesting that iron accelerated thrombosis through a pro-oxidant mechanism. Iron loading enhanced both systemic and vascular reactive oxygen species production. Endothelium-dependent vasorelaxation was impaired in iron-loaded mice, indicating reduced NO bioavailability. CONCLUSIONS: Moderate iron loading markedly accelerates thrombus formation after arterial injury, increases vascular oxidative stress, and impairs vasoreactivity. Iron-induced vascular dysfunction may contribute to the increased incidence of ischemic cardiovascular events that have been associated with chronic iron overload.

Adenosine Diphosphate↗
PubMed2003

Increased asymmetric dimethylarginine and endothelin 1 levels in secondary Raynaud's phenomenon: implications for vascular dysfunction and progression of disease.

OBJECTIVE: To compare microvascular and macrovascular functions in a cohort of patients with primary and secondary Raynaud's phenomenon (RP) who were matched for demographic, risk factor, and severity profiles. METHODS: Forty patients with primary or secondary RP matched for vascular risk factors and severity scores underwent testing of endothelial function and cold pressor responsiveness of the brachial artery. Microvascular perfusion of the digital vasculature was assessed using laser Doppler fluxmetry in response to reactive hyperemia. Plasma was assayed for endothelin 1 (ET-1), asymmetric dimethylarginine (ADMA), intercellular adhesion molecule 1, vascular cell adhesion molecule 1 (VCAM-1), and monocyte chemoattractant protein 1 (MCP-1). RESULTS: Patients with RP had abnormal vasoconstrictor responses to cold pressor tests (CPT) that were similar in primary and secondary RP. There were no differences in median flow-mediated and nitroglycerin-mediated dilation or CPT of the brachial artery in the 2 populations. Patients with secondary RP were characterized by abnormalities in microvascular responses to reactive hyperemia, with a reduction in area under the curve adjusted for baseline perfusion, but not in time to peak response or peak perfusion ratio. Plasma ET-1, ADMA, VCAM-1, and MCP-1 levels were significantly elevated in secondary RP compared with primary RP. There was a significant negative correlation between ET-1 and ADMA values and measures of microvascular perfusion but not macrovascular endothelial function. CONCLUSION: Secondary RP is characterized by elevations in plasma ET-1 and ADMA levels that may contribute to alterations in cutaneous microvascular function.

Adult↗
PubMed2003

Air pollution: the "Heart" of the problem.

Air pollution exposure is associated with an increased risk of acute and chronic cardiovascular mortality. Recent observations have implicated fine particulate matter (PM(2.5)) as one of the most important pollutants. Inhalation of PM(2.5) causes acute pulmonary inflammation and oxidative stress. The subsequent generation of a systemic inflammatory response could link air pollution exposure with the development of cardiovascular disease. Human experiments have demonstrated pro-arrhythmic alterations in cardiac autonomic tone, increased blood pressure, higher serum C-reactive protein levels, and alterations in blood rheology favoring coagulation following controlled pollution exposures or in relation to elevated ambient PM(2.5) levels. Recent studies have also uncovered several harmful impacts on the systemic vasculature, including the triggering of acute vasoconstriction and the enhanced development of atherosclerosis. Many questions, however, remain unanswered and future studies will be required to clarify the relevant biologic mechanisms and to identify the specific constituents responsible for mediating the adverse health impacts.

Air Pollutants↗
PubMed2003

Regional Angiogenesis with Vascular Endothelial Growth Factor (VEGF) in peripheral arterial disease: Design of the RAVE trial.

BACKGROUND: Patients with intermittent claudication caused by infrainguinal atherosclerosis have limited pharmacologic options "Therapeutic angiogenesis" is a novel treatment approach that seeks to improve perfusion of ischemic limbs by the induction of collateral vessel formation. This trial is a phase 2 randomized double-blind placebo-controlled proof of concept trial that will use an intramuscular adenoviral gene transfer approach of vascular endothelial growth factor, 121 isoform (Ad(GV)VEGF(121.10)) to patients with severe IC caused by infrainguinal disease. METHODS: This is a phase 2, double-blind, randomized, placebo-controlled, dose-finding, multicenter study. Patients with severe intermittent claudication caused by infrainguinal atherosclerosis predominantly involving the superficial femoral artery confirmed with imaging studies that meet inclusion criteria will be stratified on the basis of the presence or absence of diabetes mellitus and randomized in a 1:1:1 fashion to low dose (4 x 10(9) particle units), high dose (4 x 10(10) particle units), or placebo arms (35-36 patients per group). Subjects are required to have exercise-limiting IC in the index extremity during 2 qualifying exercise treadmill tests, with peak walking times between 1 and 10 minutes. A single dose of Ad(GV)VEGF(121.10) will be administered as 20 intramuscular injections throughout the area of the lower limb requiring collateralization. RESULTS: The primary efficacy parameter for the Regional Angiogenesis With Vascular Endothelial Growth Factor (RAVE) trial is the change in peak walking time at 12 weeks compared with baseline. The sample size is expected to provide an 80% power to detect a difference of 1.5 minutes between any of the 2 treatment groups and the placebo group. Secondary efficacy parameters include claudication onset time, hemodynamic effects of therapy assessed with ankle-brachial index, assessment of physical impairment, and health-related quality of life as measured with the Walking Impairment Questionnaire and SF-36 Health Survey. All randomized patients will also be evaluated for safety.

Adenoviridae↗
PubMed2003

Aldosterone as a target in congestive heart failure.

Based upon the results of the RALES trial and accumulating evidence about the role of aldosterone and aldosterone receptor antagonism in various disease states, the authors anticipate that aldosterone receptor antagonists will become standard therapy, along with ACE inhibitors and beta-adrenergic receptor blocking agents, in patients with heart failure that is caused by systolic left ventricular dysfunction. Furthermore, the prospect of the use of these agents in other disease states that have implicated an activated rennin-angiotensin-aldosterone cascade, such as diastolic dysfunction, aging, and atherosclerosis, remains to be tested. Until further data from well-designed, prospective, randomized trials are available, the use of aldosterone receptor antagonists should be restricted to patients with severe or progressive heart failure caused by systolic left ventricular dysfunction in whom serum creatinine level is < or = 2.0 mg/dL and serum potassium levels are < 5.0 meq/L at baseline.

Aldosterone↗