[show abstract][hide abstract] ABSTRACT: AIM: The purpose of the current study was to determine if long term treatment with an endothelin-A (ET(A)) receptor antagonist attenuates the progression of coronary plaques in patients with coronary endothelial dysfunction. METHODS: Thirty-five patients with non-obstructive coronary disease and coronary endothelial dysfunction were randomized in a double blind manner to treatment with placebo or ET(A) receptor antagonist Atrasentan (10 mg) for six months. Endothelial function was assessed by the change in coronary blood flow and coronary artery diameter in response to intracoronary acetylcholine. Normalized mean total atheroma volume (TAV(MEAN)), percent atheroma volume (PAV) and changes of atheroma volume were assessed by intravascular ultrasound (IVUS) at baseline and 6-month follow-up. RESULTS: In segments with coronary endothelial dysfunction, there was a significant decrease in normalized TAV(MEAN) and PAV at six months from baseline in the Atrasentan group compared to the placebo group median (IQR) -2.00mm(3) (-7.28, 2.53.) vs 9.11mm(3) (1.23, 14.05), p=0.0024 and 0.955% (-3.43, 1.70) vs 3.85% (-0.39, 14.59) p=0.010. There was no change in normalized TAV or PAV in the segments with normal endothelial function. CONCLUSION: This study demonstrates that 6-month treatment with Atrasentan attenuates progression of coronary plaque in segments with endothelial dysfunction.
International journal of cardiology 01/2013; · 7.08 Impact Factor
[show abstract][hide abstract] ABSTRACT: Background: Vascular dysfunction is a surrogate marker of early-stage atherosclerosis. Serum leukocyte count is a non-traditional risk factor of cardiovascular (CV) disease and has predictive value for CV outcome. The aim of this study was to investigate the relationship between leukocyte count and peripheral vascular dysfunction. Methods and Results: In this cross-sectional study, 357 individuals without known CV disease and with low Framingham risk (10-year hard coronary heart disease risk <10%) were identified. Vascular function was measured by assessing reactive hyperemia-induced vasodilation (reactive hyperemia index, RHI). In 105 individuals with vascular dysfunction (29.4%), the median leukocyte count was significantly higher than in those with normal RHI (6.4×10(9)/L vs. 6.0×10(9)/L; P=0.04). The neutrophil count was the strongest predictor of impaired vascular function among leukocyte subtypes (odds ratio [OR], 2.70; 95% confidence interval [CI]: 1.58-4.60, P<0.001). In a multivariate logistic regression model, the highest quintile of neutrophil count (OR, 2.36; 95% CI: 1.35-4.12; P=0.003), body mass index (OR, 1.05; 95% CI: 1.01-1.09; P=0.009) and systolic blood pressure (OR, 0.97; 95% CI: 0.97-0.99; P<0.001) were independently predictive for vascular dysfunction. Conclusions: The highest quintile of leukocyte count is independently associated with vascular dysfunction in individuals with low CV risk. This suggests that subclinical inflammation affects vascular function. Leukocyte count may be useful for personalized risk stratification.
[show abstract][hide abstract] ABSTRACT: Context:Vascular calcification, an important feature of diabetic vasculopathy, is an active process potentially mediated by endothelial progenitor cells (EPCs) coexpressing the osteoblastic marker osteocalcin (OCN).Objective:In this study we tested the hypothesis that cells expressing these markers are associated with the presence of elevated glycated hemoglobin (HbA1c).Design, Setting, and Patients:This was a cross-sectional comparison. Patients (n = 133, aged 57.4 ± 15.7 yr) were divided into two groups according to the presence of an HbA1c in a (pre-)diabetic (>5.6) or normal range at the time of blood sampling.Methods:Using flow cytometry of peripheral blood mononuclear cells (MNCs), cells positive for OCN, the EPC markers (CD34/KDR and CD133(+)/CD34(-)/KDR(+)) and OCN(+) EPCs were counted.Results:Patients with elevated HbA1c compared with those with normal HbA1c had a significantly higher percentage of circulating OCN(+) MNCs [4.6 (interquartile range 2.68-7.81%) vs. 3.12 (0.99-7.81%), P = 0.035], higher numbers of OCN(+)/CD133(+)/CD34(-)/KDR(+) cells [20 (9-74) vs. 8 (0-19) counts per 100,000 gated events, P < 0.001] and a higher fraction of CD133(+)/CD34(-)/KDR(+) and CD34/KDR cells coexpressing OCN (23.7 ± 24.3 vs. 40.5 ± 34.6%, P = 0.002 and 37.1 ± 39.5 vs. 59.7 ± 37.7%, P = 0.002, respectively). The association between circulating OCN(+)/CD133(+)/CD34(-)/KDR(+) cells and an HbA1c in the (pre-) diabetic range remained strong, even after adjusting for differences in obesity and cardiovascular risk factors, disease, and medications in a multivariate model [odds ratio 1.72 (1.21-2.61), P =0.002].Conclusion:This study demonstrated that patients with HbA1c in the (pre-)diabetic range have a significant increase in OCN(+) MNCs, and OCN(+)/CD133(+)/CD34(-)/KDR(+) cells, in particular. Whether these cells increase vascular calcification in (pre-)diabetes warrants further studies.
The Journal of clinical endocrinology and metabolism 09/2012; · 6.50 Impact Factor
[show abstract][hide abstract] ABSTRACT: Background: The absence of coronary artery calcium (CAC) is a marker of very low cardiovascular risk. Endothelial cells may have an effect on the initiation and propagation of arterial calcification. We aimed to identify the relationship between the absence of CAC and endothelial function in individuals without cardiovascular disease and diabetes. Methods and Results: CAC was assessed using electron-beam computed tomography and the calcium score was then computed. Endothelial function was measured by assessing reactive hyperemia-induced vasodilation and expressed by the reactive hyperemia index (RHI). Of 82 patients, 39 had non-detectable calcium (CAC score=0) and 43 had a CAC score >0. In the CAC score=0 group, the prevalence of normal endothelial function was 84.6%, compared to 48.8% in the CAC score >0 group, P=0.001. The absence of CAC was highly correlated with normal endothelial function (γ=0.704, P<0.001). On average, endothelial function was significantly better in the CAC score=0 group than in the CAC score >0 group (RHI 2.2±0.6 vs. 1.8±0.5, P=0.002). In a multivariate logistic regression model, only normal endothelial function (odds ratio [OR] 5.03, 95% confidence interval [CI] 1.55-16.27, P=0.007) and age (years) (OR 0.91, 95% CI 0.86-0.96, P=0.002) were independently associated with the absence of CAC. Conclusions: Normal functional status of the vasculature may be important for the prevention of coronary calcification and may partly account for the low cardiovascular risk of absent CAC. (Circ J 2012; 76: 2705-2710).
[show abstract][hide abstract] ABSTRACT: AimsFor the characterization of endothelial progenitor cells (EPCs), commonly the markers CD34 and KDR have been used. CD133+/CD34-/KDR+ cells may represent more immature 'early' progenitors. In patients with coronary artery disease (CAD), a large fraction of EPCs carry the osteoblastic marker osteocalcin (OCN), which may mediate vascular calcification and abnormal repair. The aim of this study was to evaluate the expression of OCN+ 'early' EPCs in patients with risk factors (RFs) and a history of stable (history of stenting/coronary artery bypass grafting) or unstable CAD (myocardial infarction).Methods and resultsMedical history and blood samples from 282 patients (age 58 ± 16 years) with CAD or at least one RF (mean 2.5 ± 1.5) were analysed. For the analysis of EPC markers (CD133, CD34, KDR) and OCN, the flow cytometry of peripheral blood mononuclear cells was performed. Circulating OCN+/CD133+/CD34-/KDR+ cells (median counts [interquartile range] per 100 000 events) were 15 [4-41] in patients with RF (n = 199), 26 [1-136] in those with a history of stable (n = 57), and 246 [105-308] in those with a history of unstable CAD (n = 26; P < 0.001). The association with unstable CAD remained highly significant even after multivariate adjusting for RFs and the different characteristics of the groups. Osteocalcin positive 'early' EPCs trend to predict further events [HR for each doubling of the cell number: 1.20 (95% CI: 1.00-1.46), P = 0.06].Conclusion
Circulating OCN+ 'early' EPCs are strongly associated with unstable CAD. Therefore, this particular subset of EPCs could mediate abnormal vascular repair and may help identifying patients with a more unstable phenotype of atherosclerosis.
European Heart Journal 07/2012; · 14.10 Impact Factor
[show abstract][hide abstract] ABSTRACT: Over the years there has been considerable improvement in the clinical outcomes of patients treated for acute coronary syndrome (ACS). Despite a significant reduction in acute mortality, a large percentage of patients post ACS continue to experience adverse cardiovascular (CV) events, with high long-term mortality rates and overall suboptimal medical management. Long-term risk prediction tools rely on traditional CV risk factors and are developed and validated in specific populations. Established CV risk factors, however, only explain half or fewer of CV events. These risk models may thus not be optimal in determining individual risk for long-term adverse outcomes or in helping to identify individual patients who do not respond to therapy. Identifying the specific plaque characteristics associated with increased likelihood for thrombotic complications and rapid progression has led to the concept of the vulnerable plaque. Recently, "vulnerable myocardium" (ie, myocardium that is prone to myocardial ischemia and fatal arrhythmia) has been shown to play an important role in outcome. Both vulnerable plaque and vulnerable myocardium are associated with functional vascular abnormalities, such as endothelial dysfunction, which are considered a key event in the initiation, progression and complications of coronary artery disease. Endothelial dysfunction may serve as an underlying unifying mechanism that would independently predict long-term outcome in patients with ACS undergoing revascularization.
[show abstract][hide abstract] ABSTRACT: Mandatory compared with on-demand intensivist presence improves processes of care and decreases intensive care unit (ICU) complication rate and hospital length of stay. The effect of continuous mandatory intensivist coverage on long-term patient mortality and quality of life (QOL) is not known.
We compared the long-term survival before (year 2005) and after (year 2006) the intervention when the staffing model changed from on-demand presence to mandatory 24-hour staff-critical care specialist presence in the medical ICU. Baseline and 6-month QOL surveys (SF-36 [short form 36 health survey]) were compared in subgroups of patients admitted before and after the staffing change. Cox proportional hazard and paired statistical analyses were used for survival and QOL comparisons.
The baseline characteristics did not differ significantly between the 2 groups except for race and Acute Physiology and Chronic Health Evaluation III score (median, 30 vs 37; P < .001 before and after the staffing model change). Long-term survival was not significantly different before and after the staffing change-adjusted hazard ratio, 1.05; 95% confidence interval, 0.95 to 1.16; P = .3. In a subset of ICU survivors, SF-36 physical component score improved significantly at 6 months compared with baseline after the staffing model change-Δ mean (SD) 8 (14) vs 2 (11), P = .03. However, there was no difference in the Δ mean mental component score of the SF-36 between the 2 groups (P = .77).
Introduction of an additional night shift to provide mandatory as opposed to on-demand 24-hour staff critical care specialist coverage did not affect long-term survival of medical ICU patients.
Journal of critical care 12/2011; 27(4):421.e1-7. · 2.13 Impact Factor
[show abstract][hide abstract] ABSTRACT: The purpose of this study was to quantify the effect of statins on peripheral and coronary endothelial function in patients with and without established cardiovascular disease.
Early atherosclerosis is characterized by endothelial dysfunction, a known prognostic factor for cardiovascular disease.
The search included MEDLINE, Cochrane Library, Scopus, and EMBASE to identify studies up to 1 December 2009. Eligible studies were randomized controlled trials on the effects of statins compared with placebo on endothelial function. Two reviewers extracted data on study characteristics, methods, and outcomes. Forty-six eligible trials enrolled a total of 2706 patients: 866 (32%) were women and 432 (16%) had established cardiovascular disease. Meta-analysis using random-effects models showed treatment with statins significantly improved endothelial function [standardized mean difference (SMD) 0.66, 95% CI 0.46-0.85, p < 0.001]. Subgroup analyses demonstrated statistically significant improvement in endothelial function assessed both peripherally by flow-mediated dilatation (SMD 0.68, 95% CI 0.46-0.90, p < 0.001) and venous occlusion plethysmography (SMD 0.59, 95% CI 0.06-1.13, p = 0.03) and centrally in the coronary circulation by infusion of acetylcholine (SMD 1.58, 95% CI 0.31-2.84, p = 0.01). Significant heterogeneity observed across studies was explained in part by the type of endothelial function measurement, statin type and dose, and study population differences. Exclusion of outlier studies did not significantly alter the results.
Statin therapy is associated with significant improvement in both peripheral and coronary endothelial function. The current study supports a role for statin therapy in patients with endothelial dysfunction.
European journal of cardiovascular prevention and rehabilitation: official journal of the European Society of Cardiology, Working Groups on Epidemiology & Prevention and Cardiac Rehabilitation and Exercise Physiology 03/2011; 18(5):704-16. · 2.51 Impact Factor
[show abstract][hide abstract] ABSTRACT: Endothelin (ET-1) is one of the most potent vasoconstrictors and plays a seminal role in the pathogenesis of atherosclerosis. The present study was designed to test the hypothesis that long-term treatment with an endothelin-A (ET(A)) receptor antagonist improves coronary endothelial function in patients with early coronary atherosclerosis.
Forty-seven patients with multiple cardiovascular risk factors, nonobstructive coronary artery disease, and coronary endothelial dysfunction were randomized in a double-blind manner to either the ET(A) receptor antagonist atrasentan (10 mg) or placebo for 6 months. Coronary endothelium-dependent vasodilation was examined by infusing acetylcholine (10(-6) to 10(-4) mol/L) in the left anterior descending coronary artery. N(G)-monomethyl-l-arginine was administered to a subgroup of patients. Endothelium-independent coronary flow reserve was examined by use of intracoronary adenosine and nitroglycerin. Baseline characteristics and incidence of adverse effects were similar between the 2 groups. There was a significant improvement in percent change of coronary blood flow in response to acetylcholine at 6 months from baseline in the atrasentan group compared with the placebo group (39.67%, 95% confidence interval 23.23% to 68.21%, versus -2.22%, 95% confidence interval -27.37% to 15.28%; P<0.001). No significant difference in the percent change of coronary artery diameter or change in coronary flow reserve was demonstrated. Coronary blood flow, coronary artery diameter, and the effect of N(G)-monomethyl-l-arginine were similar between the groups at baseline and at 6 months.
This study demonstrates that 6-month treatment with atrasentan improves coronary microvascular endothelial function and supports the role of the endogenous endothelin system in the regulation of endothelial function in early atherosclerosis in humans. Clinical Trial Registration Information- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00271492.
[show abstract][hide abstract] ABSTRACT: Traditional cardiovascular risk (CV) factors based on the Framingham study have been used to estimate the risk of CV events and determine target cholesterol levels for primary prevention. Recently published systematic reviews have, however, demonstrated that the Framingham risk score is limited in certain cohorts and requires adjustment. Indeed, traditional CV risk factors fail to predict the development of coronary heart disease in 25-50% of cases. This underscores the complex interplay between traditional CV risk factors, genetic predisposition and other atheroprotective factors present in individuals of different populations in predicting CV events. Endothelial dysfunction, a functional expression of the inherent atherosclerotic risk representing an integrated index of both the overall CV risk-factor burden and the sum of all vasculoprotective factors in an individual, may serve as the missing link between CV risk factors and atherosclerotic disease. Endothelial function measurements may aid in future prediction of CV events and help identify high-risk patients for targeted therapy as well as provide a primary therapeutic end point for clinical follow-up of these patients. Recently introduced reactive hyperemia peripheral arterial tonometry is emerging as a promising tool in endothelial function measurement and CV risk stratification.
Biomarkers in Medicine 06/2010; 4(3):351-60. · 3.22 Impact Factor
[show abstract][hide abstract] ABSTRACT: Acute lung injury (ALI) is an example of a critical care syndrome with limited treatment options once the condition is fully established. Despite improved understanding of pathophysiology of ALI, the clinical impact has been limited to improvements in supportive treatment. On the other hand, little has been done on the prevention of ALI. Olmsted County, MN, geographically isolated from other urban areas offers the opportunity to study clinical pathogenesis of ALI in a search for potential prevention targets.
In this population-based observational cohort study, the investigators identify patients at high risk of ALI using the prediction model applied within the first six hours of hospital admission. Using a validated system-wide electronic surveillance, Olmsted County patients at risk are followed until ALI, death or hospital discharge. Detailed in-hospital (second hit) exposures and meaningful short and long term outcomes (quality-adjusted survival) are compared between ALI cases and high risk controls matched by age, gender and probability of developing ALI. Time sensitive biospecimens are collected for collaborative research studies. Nested case control comparison of 500 patients who developed ALI with 500 matched controls will provide an adequate power to determine significant differences in common hospital exposures and outcomes between the two groups.
This population-based observational cohort study will identify patients at high risk early in the course of disease, the burden of ALI in the community, and the potential targets for future prevention trials.
[show abstract][hide abstract] ABSTRACT: Transfusion-related acute lung injury (TRALI) and transfusion-associated circulatory overload (TACO) commonly complicate transfusion in critically ill patients. Prior outcome studies of TACO and TRALI have focused on short-term morbidity and mortality, but the long-term survival and quality of life (QOL) of these patients remain unknown.
In a nested case-control study, we compared survival and QOL between critically ill medical patients who developed pulmonary edema after transfusion (TRALI or TACO) and medical critically ill transfused controls, matched by age, gender, and admission diagnostic group. QOL in survivors was assessed with a 36-item short form health survey 1 year after initial hospitalization.
Hospital, 1-year, and 2-year mortality among the 74 TRALI cases and 74 matched controls were 43.2% vs 24.3% (P = .020), 63.8% vs 46.4% (P = .037) and 74.3% vs 54.3% (P = .031), whereas among the 51 TACO cases and 51 matched controls these values were 7.8% vs 11.8% (P = .727), 38.0% vs 28.0% (P = .371), and 44.9% vs 38.8% (P = .512). When adjusted for age and baseline severity of illness in a Cox proportional hazard analysis, the development of TRALI remained associated with decreased survival (hazard ratio 1.86; 95% CI, 1.19-2.93; P = .006). Both TRALI (P = .006, P = .03) and TACO (P = .03, P = .049) were associated with prolonged ICU and hospital lengths of stay.
In critically ill medical patients, development of TRALI, but not TACO, is independently associated with decreased long-term survival.