Six-month quality-of-life and functional status of acute respiratory distress syndrome survivors compared to patients at risk: a population-based study.

INTRODUCTION: The long-term attributable burden related to acute respiratory distress syndrome (ARDS) is not fully investigated. The aim of this study is to evaluate the quality of life (QOL) and functional status at 6 months after hospitalization in patients at risk for ARDS who did and did not develop the syndrome. METHOD: This is a population-based prospective cohort study of adult patients from Olmsted County, Minnesota, with or at risk for ARDS hospitalized from October 2008 to July 2011. The primary outcomes were changes in QOL and functional status, measured through 12-Item Short Form Survey (SF-12) and Barthel Index (BI) respectively, from baseline to 6 months, compared between survivors who did and did not develop ARDS. RESULTS: Of 410 patients with or at risk for ARDS, 98 had baseline surveys collected and 67 responded to a 6-month survey (26 ARDS, 41 non-ARDS). Both ARDS and non-ARDS groups had lower physical component of SF-12 at baseline compared to general population (P < 0.001 for both). ARDS patients had poorer baseline functional status compared to non-ARDS (mean BI 80 ± 25 vs. 88 ± 22, P = 0.03). No significant differences were observed for the change between 6 months and baseline BI (delta 2.3 for ARDS vs. 2.0 for non-ARDS, P = 0.5), or mental (delta 2.7 vs. 2.4, P = 0.9) or physical (delta -3 vs. -3.3, P = 0.9) component of SF-12 between survivors with and without ARDS. CONCLUSION: In this population-based study, decreased QOL and functional status 6 months after hospitalization were largely explained by baseline condition, with similar recovery in survivors who did and did not develop ARDS.

Neuromuscular and neuropsychological assessments in survivors of acute respiratory distress syndrome: exploratory comparisons with an at-risk cohort.

BACKGROUND: Long-term studies of survivors of acute respiratory distress syndrome (ARDS) have reported neuromuscular, quality of life, and neuropsychological impairments. This study aims to determine if development of ARDS was associated with neuromuscular weakness and depression at 6-month following hospital discharge in a population-based cohort of patients at high risk for ARDS. METHODS: A validated lung injury prediction model prospectively identified adult patients at increased risk for ARDS admitted to Mayo Clinic between October 2008 and July 2011. Instruments for functional impairment [Overall Neuropathy Limitations Scale (ONLS)] and the presence of depressive symptoms (the Yale Single Question) were administered at baseline and at 6 months. RESULTS: Of 107 patients enrolled in the study, 98 (92 %) underwent baseline assessment. Of these, 83 (85 %) were admitted to intensive care, 41 (42 %) developed ARDS, and 67 (68 %) completed assessment at 6 months. Patients with ARDS had longer intensive care and hospital length of stay (7.9 vs. 3.1 days, p = 0.005 and 19.5 vs. 10.6 days, p = 0.004, respectively). There was no difference in reported functional impairment at 6 months from baseline in the ARDS group compared to the non-ARDS group-mean ONLS Total Score 2.95 versus 2.07 p = 0.09 and 3.0 versus 2.1 p = 027, respectively. There was also no difference in the prevalence of depression at 6 months between the ARDS and non-ARDS group (21.9 vs. 30.7 % p = 0.41). CONCLUSIONS: In this single-center population-based cohort study, survivors of ARDS in the community had similar reported functional impairment and depression prevalence compared to an at-risk cohort that did not develop ARDS.

High leukocyte count is associated with peripheral vascular dysfunction in individuals with low cardiovascular risk.

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.

Osteocalcin positive CD133+/CD34-/KDR+ progenitor cells as an independent marker for unstable atherosclerosis.

AIMS: For 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 RESULTS: Medical 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.

Novel functional risk factors for the prediction of cardiovascular events in vulnerable patients following acute coronary syndrome.

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.

Normal vascular function as a prerequisite for the absence of coronary calcification in patients free of cardiovascular disease and diabetes.

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.

Long-term administration of endothelin receptor antagonist improves coronary endothelial function in patients with early atherosclerosis.

BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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.

Effects of statins on coronary and peripheral endothelial function in humans: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: 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. BACKGROUND: Early atherosclerosis is characterized by endothelial dysfunction, a known prognostic factor for cardiovascular disease. METHODS AND RESULTS: 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. CONCLUSION: 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.

Encephalopathy of Unclear Etiology: A Diagnostic Dilemma.

INTRODUCTION: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a potentially fatal condition caused by drug exposure resulting in hypersensitivity reaction with involvement of different organ systems. CASE PRESENTATION: We present a case of a 65-year-old man with a recent history of right total knee arthroplasty complicated by wound infection on a regimen of vancomycin who was transferred to our hospital for further management of fever, rigors, altered mental status, acute hypoxic respiratory failure, acute kidney injury, and development of an erythematous rash. DISCUSSION: DRESS syndrome was considered definite in this patient according to the European Registry of Severe Cutaneous Adverse Reaction Criteria, also known as RegiSCAR. To our knowledge, metabolic encephalopathy associated with multiorgan dysfunction resulting from vancomycin-induced DRESS syndrome has not been reported. CONCLUSION: A thorough analysis of recent medication history is essential for the prompt identification and management of this condition.

Towards the prevention of acute lung injury: a population based cohort study protocol.

BACKGROUND: 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. METHODS/DESIGN: 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. DISCUSSION: 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.

Calcium Channel Blocker Toxicity Causing Acute Respiratory Distress Syndrome: A Commonly Used Drug Triggering a Life-Threatening Condition.

INTRODUCTION: Calcium channel blockers (CCBs) are commonly used but have the potential to cause substantial toxicity. One such underreported toxicity of CCB use is the development of acute respiratory distress syndrome (ARDS). CASE PRESENTATION: 44-year-old previously healthy woman presented to the emergency department (ED) having taken 60 tablets of 125 mg extended-release verapamil and 90 tablets of 0.25 mg clonazepam with the intent to commit suicide. On presentation to the ED, she was sedated and intubated for airway protection. She received aggressive medical resuscitation and was ventilated using low tidal volume mechanical ventilation. The hospital course was complicated by worsening hypoxia and a chest x-ray demonstrating bilateral patchy geographic areas of airspace opacities consistent with ARDS. On day 5 of hospitalization, the patient's clinical status improved significantly, and she was subsequently weaned off vasopressors and extubated. DISCUSSION: CCB toxicity can result in profound hypotension, shock, bradycardia, and conduction blocks, as well as hyperglycemia, acidosis and acute kidney injury, and ARDS. It is important for clinicians to understand the signs and symptoms of CCB toxicity, as well as how to treat it.

Vascular reactivity to mental stress is associated with poor cardiovascular disease outcomes in females following acute coronary syndrome.

BACKGROUND: We aimed to test the hypothesis that peripheral endothelial dysfunction induced by mental stress may predict cardiovascular events after acute coronary syndrome beyond traditional cardiovascular disease risk factors. METHODS: This was a prospective study in which 417 patients who had acute coronary syndrome were enrolled in two sites at the US and Qatar. Cardiovascular disease risk factors such as past medical history, blood pressure, heart rate, peripheral endothelial dysfunction, and response to three different mental stress examinations (Stroop Color Word, Arithmetic, and Spiral Omnibus) as assessed by ratio of reactive hyperemia tonometry (EndoPAT) with stress over EndoPAT at rest were obtained at baseline. Major adverse cardiac events were then recorded at 1 year after the index event. RESULTS: There were no differences in baseline peripheral endothelial dysfunction or vascular response to mental stress between the US vs. Qatar patients. Women were more likely to experience major adverse cardiac events in the year following acute coronary syndrome (relative risk 2.42, 95% confidence interval 1.53-3.84, P = 0.044), and had a significantly lower mental stress ratio compared to women who did not (1.0 ± 0.17 vs. 1.20 ± 0.17, P = 0.04). In multivariate analyses stratified by sex, baseline peripheral endothelial dysfunction (EndoPAT < 1.7) (χ = 8.0, P = 0.005) and mental stress ratio (χ = 7.7, P = 0.006), were independently predictive of major adverse cardiac events in women, but not men. CONCLUSION: The current study demonstrates that in women both baseline endothelial function and vascular function in response to mental stress ratio are predictive of worse cardiovascular disease outcomes 1 year after acute coronary syndrome. The study may suggest an important mechanism for adverse clinical outcomes in women following acute coronary syndrome.

Coronary endothelial function testing may improve long-term quality of life in subjects with microvascular coronary endothelial dysfunction.

Aim: Angina pectoris in the absence of obstructive coronary artery disease (CAD) is common and is associated with poor quality of life (QOL). Coronary microvascular endothelial dysfunction is associated with myocardial ischaemia and is a common cause of angina. We hypothesise that evaluation of coronary endothelial function, its diagnosis and treatment will favourably impact QOL in patients with angina symptoms and non-obstructive CAD. Methods and results: Follow-up was done on 457 patients with chest pain and non-obstructive coronary arteries who had undergone coronary vascular reactivity evaluation by administration of intracoronary acetylcholine at the time of diagnostic study. After a mean follow-up of 8.4±4.7 years, QOL was assessed by administration of the SF-36 QOL survey. Patients diagnosed and treated for microvascular endothelial dysfunction had a higher (better) overall mental composite score (44.8 vs 40.9, p=0.036) and mental health score (44.2 vs 40.7, p=0.047), and a trend towards higher vitality scores (39.1 vs 35.9, p=0.053) and role emotional scores (43.6 vs 40.4, p=0.073), compared with patients with normal endothelial function. Conclusion: Among patients with chest pain and normal coronaries, diagnosis and treatment of coronary microvascular endothelial dysfunction in those with angina pectoris and non-obstructive CAD are associated with better QOL compared with patients with normal endothelial function.

Coronary endothelial dysfunction is associated with increased risk of venous thromboembolism.

BACKGROUND: Normal endothelial function is central to physiologic anticoagulation mechanisms. Endothelial dysfunction may predispose to venous thromboembolism (VTE). We aimed to investigate if coronary endothelial dysfunction (CED) predicts development of VTE in patients presenting with coronary atherosclerosis without critical stenoses. METHODS: Coronary microvascular function was evaluated in 502 patients with coronary atherosclerosis without critical stenoses by administration of intracoronary acetylcholine at the time of diagnostic study. After a median follow-up of 6.3years, patients were assessed for the development of VTE by administration of a questionnaire. Coronary microvascular endothelial dysfunction was defined as ≤50% increase in coronary blood flow from baseline in response to maximal dose of acetylcholine. RESULTS: The median age was 53years (IQR: 45, 62) 68% were female and CED occurred in 279 (56%) patients. Hypertension (40.8%), diabetes (8.4%), and hyperlipidemia (58.3%) were common risk factors. There were no differences in baseline characteristics between those with and without CED. There were 9 VTE events (6 unprovoked) among patients with CED compared to no events in the control group (P=0.01). DISCUSSION: CED was associated with the development of VTE. Endothelial injury by causing disruption of vascular hemostasis may play a role in predisposing patients to VTE.

Coronary endothelial function testing provides superior discrimination compared with standard clinical risk scoring in prediction of cardiovascular events.

BACKGROUND: Endothelial dysfunction is regarded as the early stage of atherosclerosis and is associated with cardiovascular (CV) events. This study was designed to determine whether assessment of coronary endothelial function (CEF) is safe and can reclassify risk in patients with early coronary artery disease beyond the Framingham risk score (FRS). METHODS AND RESULTS: CEF was evaluated using intracoronary acetylcholine in 470 patients who presented with chest pain and nonobstructive coronary artery disease. CV events were assessed after a median follow-up of 9.7 years. The association between CEF and CV events was examined, and the net reclassification improvement index (NRI) was used to compare the incremental contribution of CEF when added to FRS.The mean age was 53 years, and 68% of the patients were women with a median FRS of 8. Complications (coronary dissection) occurred in three (0.6%) and CV events in 61 (13%) patients. In univariate analysis, microvascular CEF [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.72-0.97, P=0.032] and epicardial CEF (HR 0.73, 95% CI 0.59-0.90, P=0.01) were found to be significant predictors of CV events, whereas FRS was not (HR 1.05, 95% CI 0.85-1.26, P=0.61). When added to FRS, microvascular CEF correctly reclassified 11.3% of patients [NRI 0.11 (95% CI 0.019-0.21)], epicardial CEF correctly reclassified 12.1% of patients [NRI 0.12 (95% CI -0.02 to 0.26)], and the combined microvascular and epicardial CEF correctly reclassified 22.8% of patients [NRI 0.23 (95% CI 0.08-0.37)]. CONCLUSION: CEF testing is safe and adds value to the FRS, with superior discrimination and risk stratification compared with FRS alone in patients presenting with chest pain or suspected ischemia.

Coronary microvascular endothelial dysfunction is an independent predictor of development of osteoporosis in postmenopausal women.

BACKGROUND: A growing body of evidence links coronary artery atherosclerosis and calcification to osteoporosis in women. The endothelium plays a critical role in maintaining vascular integrity and may play a role in bone metabolism. We aimed to determine whether early coronary atherosclerosis, as detected by coronary microvascular endothelial dysfunction (CMED), predicts the development of osteoporosis in postmenopausal women. METHODS: Coronary vascular reactivity was evaluated in 194 postmenopausal women greater than 50 years of age and with non-obstructive coronary arteries by administration of intracoronary acetylcholine during diagnostic angiography. CMED was defined as ≤50% increase in coronary blood flow from baseline in response to maximal dose. After a median follow-up of 7.0±0.3 years, patients were assessed by a questionnaire for development of osteoporosis. RESULTS: The average age of the cohort was 60.9±7.4 years. Women with CMED were twice as likely to develop osteoporosis compared with women without endothelial dysfunction after adjustment for potential confounders (relative risk, 2.4; 95% confidence interval [CI], 1.1, 5.6, P=0.02). Epicardial endothelial dysfunction was not associated with development of osteoporosis. DISCUSSION: Early coronary atherosclerosis with endothelial dysfunction is an independent marker for increased risk of developing osteoporosis in postmenopausal women greater than 50 years of age without obstructive coronary artery disease. The current study supports a link between coronary atherosclerosis and osteoporosis.

Microvascular endothelial dysfunction predicts the development of erectile dysfunction in men with coronary atherosclerosis without critical stenoses.

BACKGROUND: Erectile dysfunction (ED) is associated with an increased risk for cardiovascular disease, stroke, and all-cause mortality, independent of conventional cardiovascular risk factors. Coronary endothelial dysfunction is independently associated with ED in men with early coronary atherosclerosis. We aimed to investigate whether coronary microvascular dysfunction predicts development of ED in patients presenting with coronary atherosclerosis without critical stenoses. PATIENTS AND METHODS: Coronary microvascular function was evaluated in 130 men with coronary atherosclerosis without critical stenoses by administration of intracoronary acetylcholine at the time of diagnostic study. After a mean follow-up of 8.4 years, patients were assessed for the development of ED by administration of a questionnaire. RESULTS: In all, 68 (50%) men had microvascular endothelial dysfunction at baseline; 35 (51%) men with microvascular endothelial dysfunction developed ED on follow-up compared with 19 (31%) men without microvascular endothelial dysfunction. Men who developed ED had a lower coronary blood flow response (% [INCREMENT]CBF) compared with men who did not develop ED, with mean±SD of 25.4±71.3 versus 81.7±120 (P=0.003). In univariate analysis, microvascular endothelial dysfunction was a predictor for the development of ED, with relative risk of 2.4 (1.2-4.9) (P=0.016). In multivariate logistic regression adjusting for traditional cardiovascular risk factors (age, hypertension, hyperlipidemia, diabetes, vascular disease, and family history of coronary artery disease), only microvascular endothelial dysfunction (P=0.027) and age (P=0.044) remained significant predictors of development of ED. CONCLUSION: Coronary microvascular dysfunction is a predictor of the development of ED in men with coronary atherosclerosis without critical stenoses. This study underscores the systemic involvement of the endothelial function in vascular disease.

Long-term endothelin receptor antagonism attenuates coronary plaque progression in patients with early atherosclerosis.

AIM: The purpose of the current study was to determine if long term treatment with an endothelin-A (ETA) 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 ETA 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 (TAVMEAN), 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 TAVMEAN and PAV at six months from baseline in the Atrasentan group compared to the placebo group median (IQR) -2.00 mm(3) (-7.28, 2.53.) vs 9.11 mm(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.

Effect of 24-hour mandatory vs on-demand critical care specialist presence on long-term survival and quality of life of critically ill patients in the intensive care unit of a teaching hospital.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Patients with an HbA1c in the prediabetic and diabetic range have higher numbers of circulating cells with osteogenic and endothelial progenitor cell markers.

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.