Suppression of Endothelial Progenitor Cells in Human Coronary Artery Disease by the Endogenous Nitric Oxide Synthase Inhibitor Asymmetric Dimethylarginine
Thomas Thum, Dimitrios Tsikas, Sylvia Stein, ...Maximilian Schultheiss, Martin Eigenthaler, Stefan D. Anker, Philip A. Poole-Wilson, Georg Ertl, Johann Bauersachs
Endothelial progenitor cells (EPCs) play a pivotal role in regeneration of injured endothelium. Patients with reduced numbers of EPCs are at increased risk for coronary artery disease. Regulation of EPC mobilization and function is mediated in part by nitric oxide (NO). Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of the endothelial NO synthase. In patients with stable angina, plasma concentrations of ADMA were inversely correlated with EPC numbers. In vitro differentiation and function of EPCs was repressed by ADMA. This could be reversed by 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibition. We show ADMA to be an endogenous inhibitor of mobilization, differentiation, and function of EPCs.
We tested the hypothesis that asymmetric dimethylarginine (ADMA) may be an endogenous inhibitor of endothelial progenitor cells (EPCs).
Endothelial progenitor cells play a pivotal role in regeneration of injured endothelium, thereby limiting the formation of atherosclerotic lesions. Reduced numbers of EPCs may affect progression of coronary artery disease. Regulation of EPC mobilization and function is mediated in part by nitric oxide (NO). Endogenous inhibitors of NO synthases, such as ADMA, contribute to endothelial dysfunction and injury.
We used flow cytometry and in vitro assays to investigate the relationship between EPC number and function with ADMA plasma levels in patients with stable angina.
The plasma concentration of ADMA was related to the severity of coronary artery disease and correlated inversely with the number of circulating CD34+/CD133+progenitor cells (r = −0.69; p < 0.0001) and endothelial colony forming units (CFUs) (r = −0.75; p < 0.0001). Adjusting for all patient characteristics, we confirmed these findings in multivariate regression analyses. In vitro differentiation of EPCs was repressed by ADMA in a concentration-dependent manner. Compared with untreated cells, ADMA reduced EPC incorporation into endothelial tube-like structures to 27 ± 11% (p < 0.001). Asymmetric dimethylarginine repressed the formation of CFUs from cultured peripheral blood mononuclear cells to 35 ± 7% (p < 0.001). Asymmetric dimethylarginine decreased endothelial nitric oxide synthase activity in EPCs to 64 ± 6% (p < 0.05) when compared with controls. Co-incubation with the hydroxymethyl glutaryl coenzyme A reductase inhibitor rosuvastatin abolished the detrimental effects of ADMA.
Asymmetric dimethylarginine is an endogenous inhibitor of mobilization, differentiation, and function of EPCs. This contributes to the cardiovascular risk in patients with high ADMA levels and may explain low numbers and function of EPCs in patients with coronary artery disease.
The regional wall motion impairment and predisposition to arrhythmias in human ventricular hibernation may plausibly result from abnormal intercellular propagation of the depolarizing wave front. ...This study investigated the hypothesis that altered patterns of expression of connexin43, the principal gap junctional protein responsible for passive conduction of the cardiac action potential, contribute to the pathogenesis of hibernation.
Patients with poor ventricular function and severe coronary artery disease underwent thallium scanning and MRI to predict regions of normally perfused, reversibly ischemic, or hibernating myocardium. Twenty-one patients went on to coronary artery bypass graft surgery, during which biopsies representative of each of the above classes were taken. Hibernation was confirmed by improvement in segmental wall motion at reassessment 6 months after surgery. Connexin43 was studied by quantitative immunoconfocal laser scanning microscopy and PC image software. Analysis of en face projection views of intercalated disks revealed a significant reduction in relative connexin43 content per unit area in reversibly ischemic (76.7+/-34.6%, P<.001) and hibernating (67.4+/-24.3%, P<.001) tissue compared with normal (100+/-30.3%); ANOVA P<.001. The hibernating regions were further characterized by loss of the larger gap junctions normally seen at the disk periphery, reflected by a significant reduction in mean junctional plaque size in the hibernating tissues (69.5+/-20.8%) compared with reversibly ischemic (87.4+/-31.2%, P=.012) and normal (100+/-31.5%, P<.001) segments; ANOVA P<.001.
These results indicate progressive reduction and disruption of connexin43 gap junctions in reversible ischemia and hibernation. Abnormal impulse propagation resulting from such changes may contribute to the electromechanical dysfunction associated with hibernation.
OBJECTIVES
We aimed to determine whether growth hormone (GH) resistance is present in patients with chronic heart failure (CHF) and whether it may be linked to the biochemical response to GH ...treatment.
BACKGROUND
Acquired GH resistance is a feature of severe illness, in particular, cachexia. In patients with CHF, the response to GH therapy appears to be variable.
METHODS
Biochemical markers of the GH-insulin-like growth factor-I (IGF-I) axis were compared in 21 cachectic patients with CHF, 51 noncachectic patients and 26 healthy control subjects. In separate studies, the predictive value of baseline biochemical variables for the IGF-I response to GH treatment was analyzed.
RESULTS
Cachectic patients showed an increase of total GH and immunologically intact GH (p ≤ 0.0002) and a decrease of GH-binding protein (BP) (p = 0.005), IGF-BP3 (p = 0.01) and IGF-I (p = 0.06), compared with noncachectic patients. Similar changes were found when the cachectic group was compared with the control group. No differences were found between noncachectic patients and control subjects. Levels of GH-BP correlated with the IGF-I/GH ratio in all subgroups (all p ≤ 0.002). Baseline GH-BP levels were related to the increase of IGF-I levels in response to GH treatment in patients with CHF after 24 h (r = 0.83, p = 0.005; n = 9; study 2), 44 days (r = 0.52, p = 0.007; n = 25; study 3) and 96 days (r = 0.54, p = 0.006; n = 24; study 3).
CONCLUSIONS
Most cachectic and some noncachectic patients with CHF show features of acquired GH resistance. The principal predictors of the biochemical features of GH resistance and of the poor biochemical response to short-term and longer-term GH treatment are GH-BP plasma levels. The presence of GH resistance is potentially a major factor determining the response to GH therapy in patients with CHF.
Oestradiol-17β causes relaxation of isolated coronary arteries and increases blood flow in several vascular beds in human beings and animals. Oestrogen replacement therapy is associated with a lower ...incidence of cardiovascular disease, but the acute effects of Oestradiol-17β on myocardial ischaemia are unknown. We have studied the acute effect of sublingual oestradiol-17β on exercise-induced myocardial ischaemia in eleven women (mean age 58 SD 8 years) with coronary artery disease. The women did two treadmill exercise tests on separate days; 40 min before the test they took sublingual oestradiol-17β (1 mg) or placebo, in random order. Plasma Oestradiol-17β concentrations were confirmed to be higher after sublingual oestradiol-17β than after placebo (2531 1192 vs 155 168 pmol/L, p<0·001). Oestradiol-17β increased both time to 1 mm ST depression (456 214 vs 579 191 s, p<0·004; difference of medians 92 95% Cl 46-254) and total exercise time (569 249 vs 658 193 s, p<0·01; difference 54 10-212). Acute administration of oestradiol-17β therefore has a beneficial effect on myocardial ischaemia in women with coronary artery disease. This effect may be due to a direct coronary-relaxing effect, to peripheral vasodilation, or to a combination of these mechanisms. Oestradiol-17β may prove to be a useful adjunct to the treatment of angina in postmenopausal women with coronary heart disease.
This study was designed to investigate the loss of well-being, in terms of life-years, overall and in patients randomized to metoprolol versus carvedilol in the Carvedilol Or Metoprolol European ...Trial (COMET).
The ultimate objectives of treating patients with heart failure are to relieve suffering and prolong life. Although the effect of treatment on mortality is usually described in trials, the effects on patient well-being throughout the trials' courses are rarely reported.
A total of 3,029 patients randomized in the COMET study were included in the analysis. "Patient journey" was calculated by adjusting days alive and out of hospital over four years using a five-point score completed by the patient every four months, adjusted according to the need for intensification of diuretic therapy. Scores ranged from 0% (dead or hospitalized) to 100% (feeling very well).
Over 48 months, 17% of all days were lost through death, 1% through hospitalization, 23% through impaired well-being, and 2% through the need for intensified therapy. Compared with metoprolol, carvedilol was associated with fewer days lost to death, with no increase in days lost due to impaired well-being or days in hospital. The "patient journey" score improved from a mean of 54.8% (SD 26.0) to 57.4% (SD 26.3%) (p < 0.0068).
Despite treatment with beta-blockers, heart failure remains associated with a marked reduction in well-being and survival. Loss of quality-adjusted life-years through death and poor well-being seemed of similar magnitude over four years, and both were much larger than the loss that could be attributed to hospitalization.
Background: β Blocker treatment may worsen glucose metabolism. Objective: To study the development of new onset diabetes in a large cohort of patients with heart failure treated with either ...metoprolol or carvedilol. Design: Prospective and retrospective analysis of a controlled clinical trial. Setting: Multinational multicentre study. Patients: 3029 patients with chronic heart failure. Interventions: Randomly assigned treatment with carvedilol (n = 1511, target dose 50 mg daily) or metoprolol tartrate (n = 1518, target dose 100 mg daily). Results: Diabetic events (diabetic coma, peripheral gangrene, diabetic foot, decreased glucose tolerance or hyperglycaemia) and new onset diabetes (clinical diagnosis, repeated high random glucose level or glucose lowering drugs) were assessed in 2298 patients without diabetes at baseline. Diabetic events occurred in 122/1151 (10.6%) patients in the carvedilol group and 149/1147 (13.0%) patients in the metoprolol group (hazard ratio (HR) = 0.78; 95% confidence interval (CI) 0.61 to 0.99; p = 0.039). New onset diabetes was diagnosed in 119/1151 (10.3%) v 145/1147 (12.6%) cases in the carvedilol and metoprolol treatment groups (HR = 0.78, CI 0.61 to 0.997; p = 0.048), respectively. Patients with diabetes at baseline had an increased mortality compared with non-diabetic subjects (45.3% v 33.9%; HR = 1.45, CI 1.28 to 1.65). Both diabetic and non-diabetic subjects at baseline had a similar reduction in mortality with carvedilol compared with metoprolol (RR = 0.85; CI 0.69 to 1.06 and RR = 0.82; CI 0.71 to 0.94, respectively). Conclusion: A high prevalence and incidence of diabetes is found in patients with heart failure over a course of 5 years. New onset diabetes is more likely to occur during treatment with metoprolol than during treatment with carvedilol.
The recently published guidelines by the European Society of Cardiology on the diagnosis and treatment of chronic heart failure are well worth reading, include important new recommendations and are ...reviewed here
Weight loss in chronic heart failure is linked to impaired survival. We aimed to assess the frequency of weight loss in patients with this disease, whether the degree of weight loss predicts ...mortality, and whether weight loss can be prevented by angiotensin-converting-enzyme (ACE) inhibitors.
We investigated weight changes in 1929 patients from the SOLVD trial who had chronic heart failure, were free of oedema at baseline, and survived for at least 4 months after trial entry. Mean follow-up was 35 months (SD 13). We analysed the effect of weight loss at cutpoints of 5%, 7·5%, 10%, 15% (a priori), and 6% (post hoc) to identify which one best predicted outcome. To validate results, we analysed data for 619 patients in the V-HeFT II trial.
817 (42%) patients in the SOLVD trial had weight loss from baseline of 5% or more. At 8 months follow-up, all cutpoints for weight loss were significantly associated with impaired survival after adjustment for age, sex, New York Heart Association class, left ventricular ejection fraction, and treatment allocation. Weight loss of 6% or more at any time during follow-up was the strongest predictor of impaired survival (adjusted hazard ratio 2·10, 95% CI 1·77–2·49; p<0·0001). Patients on the ACE inhibitor enalapril had a lower hazard of 6% or more weight loss than did those not taking the drug (adjusted reduction 19%, p=0·0054). Results from analyses of V-HeFT II data lent support to our findings.
Weight loss occurs frequently in patients with chronic heart disease, its reversal is rare, and when present, it is independently linked to impaired survival. Weight loss of more than 6% should be used to define the presence of cachexia in patients with chronic heart failure. In chronic heart failure, treatment with an ACE inhibitor reduces the risk of weight loss.
Chronic heart failure is a state of immune activation, and endotoxin is a potential trigger for cytokine production. Our aim was to study whether immune activation and endotoxemia occur in adults ...with congenital heart disease. We prospectively measured tumor necrosis factor (TNF)-α, soluble TNF receptors (sTNFR-1, sTNFR-2), interleukin-6, interleukin-10, endotoxin, and soluble CD14 levels in 52 consecutive adults with congenital heart disease (age 34 ± 2 years mean ± SEM) and 18 healthy controls (age 31 ± 1 years). A variety of congenital heart lesions were studied: single ventricle physiology (n = 15), systemic right ventricle (n = 7), tetralogy of Fallot (n = 20), and “other” congenital heart disease (n = 10). Patients were subgrouped into asymptomatic (New York Heart Association NYHA class I, n = 11), mild (NYHA class II, n = 30), and moderate/severe (NYHA class III/IV, n = 11) categories. Patients had elevated TNF and interleukin-6 levels compared with controls (TNF 2.8 vs 2.1 pg/ml, p <0.05; interleukin-6 8.5 vs 5.7 pg/ml, p <0.001). TNF levels were higher in patients with moderate/severe symptoms compared with patients who were asymptomatic or had mild symptoms (p <0.05). Soluble TNFR-1 levels related directly to the degree of systemic ventricular impairment (p <0.05). There were no significant differences in sTNFR-1, sTNFR-2, interleukin-10, or sCD14 levels between patients and controls. Endotoxin levels were greater in patients with congenital heart disease versus controls (0.40 vs 0.26 endotoxin units/ml, p <0.0001). Thus, adults with congenital heart disease have elevated levels of inflammatory cytokines and bacterial endotoxin, which relate to functional status. Congenital heart disease in adults may be amenable to novel anti-inflammatory therapies in selected patients.
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