1,10-Phenanthroline-dithiine iridium and ruthenium complexes: synthesis, characterization and photocatalytic dihydrogen evolution.

We report the synthesis and the spectroscopic and electrochemical properties of six mononuclear iridium(iii) and ruthenium(ii) complexes bearing S,S'-extended phenanthroline ligands. Starting from 5,6-dibromide-1,10-phenanthroline, the dithiine derivatives N,N'-1,10-phenanthrolinedithiino[2,3-b]quinoxaline and N,N'-1,10-phenanthrolinedithiino[2,3-b]benzene were prepared by primary N,N'-complexation of the dibromo derivative and subsequent nucleophilic substitution at the complex. The photoluminescence of the phenanthroline-dithiine containing complexes shows distinctively increased lifetimes for all Ir(iii) and Ru(ii) complexes. The activity of the series of Ir(iii) and Ru(ii) complexes as photosensitizers in visible-light photocatalytic water reduction is demonstrated by dihydrogen evolution with a [Fe3(CO)12] catalyst and triethylamine as a sacrificial donor.

Ten-year observational follow-up of PROactive: a randomized cardiovascular outcomes trial evaluating pioglitazone in type 2 diabetes.

AIMS: To conduct a 10-year, observational follow-up of patients completing PROactive to investigate whether trends of cardiovascular benefit with pioglitazone and imbalances in specific malignancies persisted over time. METHODS: Macrovascular endpoints and malignancies were compared based on original randomization to pioglitazone or placebo and 'any' versus 'no' pioglitazone use for bladder and prostate cancer. RESULTS: Of 4873 patients completing the PROactive trial, 74% entered the follow-up. During follow-up (mean 7.8 years), there were no statistically significant differences in the primary [all-cause mortality, myocardial infarction (MI), cardiac intervention, stroke, major leg amputation, leg revascularization] or main secondary (death, MI, stroke) endpoints for subjects originally randomized to pioglitazone and placebo, except for leg amputations during follow-up [4.1% pioglitazone, 5.6% placebo; hazard ratio 0.74, 95% confidence interval (CI) 0.55-0.99; p = 0.046]. During follow-up, the incidence of total malignancies was similar between groups; bladder cancer was reported in 0.8% of patients (n = 14) in the pioglitazone versus 1.2% (n = 21) in the placebo group [relative risk (RR) 0.65, 95% CI 0.33-1.28], and prostate cancer was reported in 44 men (3.7%) in the pioglitazone versus 29 men (2.5%) in the placebo group (RR 1.47, 95% CI 0.93-2.34). CONCLUSIONS: The trends of macrovascular benefits of pioglitazone compared with placebo during PROactive did not persist in the absence of continued pioglitazone during this 10-year follow-up. Trends of decreased bladder cancer and increased prostate cancer were observed in the pioglitazone group during follow-up; however, these imbalances should be interpreted with caution because of the limitations of the observational study design.

[Wine consumption and prevention of coronary artery disease]. / Weingenuss und Prävention der koronaren Herzkrankheit.

There is a J-shaped correlation between the amount of alcohol consumed per day and overall mortality risk and an inverse correlation between the amount of alcohol consumed per day and cardiovascular mortality. The evidence is stronger for men than for women. The correlations are independent of the type of alcoholic beverage predominantly consumed. Possible mechanisms explaining the cardioprotective, antiatherosclerotic effects of moderate alcohol consumption are inhibition of platelet aggregation, increase in serum high density lipoprotein (HDL) levels and prevention of diabetes mellitus. The two latter mechanisms can also explain a delayed progression of atherosclerosis due to alcohol consumption. The beneficial effects are counteracted by detrimental effects of alcohol on the incidence of cancer diseases, liver cirrhosis, violence and accidents; therefore, alcohol consumption in general cannot be recommended for prevention of cardiovascular diseases.

Observational follow-up of the PROactive study: a 6-year update.

AIMS: The PROactive study investigated pioglitazone for secondary prevention of macrovascular events in type 2 diabetes mellitus. Pioglitazone showed a 10% (non-significant) relative risk (RR) reduction for the primary composite endpoint and a significant 16% reduction for the main secondary endpoint (death, myocardial infarction, stroke) after a mean 34.5 months. There was no difference in cumulative malignancy incidence, but an imbalance in bladder malignancies (pioglitazone 14, placebo 5). We present a pre-specified 6-year interim analysis of a 10-year observational follow-up. METHODS: Any patient completing PROactive was eligible. No study treatments were provided. A Cox proportional hazard model compared non-adjudicated macrovascular events (same endpoints as PROactive excluding acute coronary syndrome) based on original randomization. Malignancies were compared using conventional RR ratios. RESULTS: Of 5238 randomized patients, 3599 (74%) entered the follow-up. For the follow-up (mean 5.8 years) or combined double-blind and follow-up periods (≤9.5 years, mean 8.7), there were no statistically significant differences in primary or main secondary endpoints. For the combined period, a similar percentage of patients had any diagnosed malignancy (RR = 1.05, 95% CI [0.89, 1.24]) or bladder malignancy (RR = 1.06, 95% CI [0.59, 1.89]) in the pioglitazone and placebo groups. There were fewer cases of bladder malignancy with pioglitazone (15 [0.6%] vs. 19 [0.7%] for placebo) for the combined period when events diagnosed in the first 365 days were excluded, and fewer cases for the follow-up period alone (10 [0.5%] vs. 17 [1.0%] for placebo). Further analyses of pioglitazone use (including use during follow-up) found no significant difference in bladder malignancies between any and no pioglitazone use for the combined period. CONCLUSIONS: These data suggest that improved macrovascular outcomes seen with pioglitazone subside without continued pioglitazone treatment. The double-blind period bladder cancer imbalance did not persist in follow-up.

[Safety of ß-blockers. Prejudices and reality]. / Sicherheit von ß-Blockern. Vorurteile und Realität.

ß-blockers clearly prolong life in patients with heart failure and after myocardial infarction in all controlled prospective trials. Nevertheless, many colleagues and even more patients fear unwanted effects like low blood pressure, bradycardia, increased bronchial resistance, or erectile dysfunction. There are a limited number of serious side effects, which have to be recognized. In spite of these, we should encourage our patients, who profit from the beneficial actions of ß-blockers, to take them regularly. Some controversial aspects of ß-blocker therapy are discussed in the light of newer studies.

Prognostic impact of electrocardiographic signs in patients with Type 2 diabetes and cardiovascular disease: results from the PROactive study.

AIMS: Although a resting electrocardiograph is broadly applied in clinical practice for evaluating patients with Type 2 diabetes and cardiovascular disease, the independent prognostic relevance of electrocardiographic signs has not thoroughly been examined. METHODS: Baseline 12-lead electrocardiographs available in 5231 of the 5238 participants of the PROactive trial were analysed for heart rate, heart rate corrected QT-interval, presence of atrial fibrillation/flutter, left axis deviation, right and left bundle branch block. The association of electrocardiographic signs with total mortality, the principal secondary composite endpoint (death, myocardial infarction and stroke) and serious adverse heart failure events was examined by Cox-regression analysis. RESULTS: Two hundred and twenty-three (4.3%) patients showed atrial fibrillation/flutter, 213 (4.1%) patients had right bundle branch block, 111 (2.1%) patients had left bundle branch block and 706 (13.5%) patients had left axis deviation. Mean cQT-interval was 418 ms (± 25 ms) and mean heart rate was 72/min (± 14/min). In multivariate adjusted analyses, heart rate and cQT-interval were significantly associated with mortality, the composite secondary endpoint and heart failure, whereas right and left bundle branch blocks were significantly associated with heart failure only. Left axis deviation was associated with heart failure and atrial fibrillation/flutter was associated with mortality and heart failure in univariate but not multivariate analyses. CONCLUSION: Easily assessable electrocardiographic signs such as heart rate, cQT-interval and bundle branch blocks were predictive for adverse outcome independently of multiple risk factor adjustment and should be considered in clinical care.

High-density lipoprotein-cholesterol and not HbA1c was directly related to cardiovascular outcome in PROactive.

AIM: In PROactive, pioglitazone reduced the incidence of death, myocardial infarction and stroke, and significantly improved HbA1c, systolic blood pressure (SBP), triglycerides and high-density lipoprotein (HDL)-cholesterol relative to placebo. As these glycaemic and lipid parameters are major cardiovascular (CV) risk factors, we assessed their separate contribution to the reduced incidence of CV outcomes. METHODS: Patients (n = 5238) with type 2 diabetes and macrovascular disease were randomized to 45 mg pioglitazone or placebo. Relationships among treatment, outcome (time to first event of all-cause mortality, myocardial infarction and stroke) and 10 laboratory measurements and vital signs were investigated using log-linear models. Continuous variable measurements (percent changes from baseline to average of all postbaseline values prior to censoring) were made discrete by categorizing into tertiles. Log-linear models were fitted to multiway tables of discrete data and analysis of deviance used to summarize sources of variation in the data. RESULTS: Although pioglitazone treatment was associated with a decrease in HbA1c and an increase in HDL-cholesterol (HDL-C), only the change from baseline HDL-C predicted the outcome (χ(2) = 28.89, p < 0.0001). No other variables, including HbA1c, triglycerides and systolic blood pressure, showed significant direct associations with outcome. When the analysis was extended to include baseline statin use, this was associated with an improved outcome independently of HDL-C changes. CONCLUSIONS: This post hoc analysis suggests that HDL-C, but probably not HbA1c, is a driver of pioglitazone's favourable influence on CV outcome.

NT-pro-BNP predicts worsening renal function in patients with chronic systolic heart failure.

BACKGROUND: Worsening renal function (WRF) is frequently observed in patients with heart failure and is associated with worse outcome. The aim of this study was to examine the association of the cardiac serum marker N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) and WRF. METHODS: A total of 125 consecutive patients of a tertiary care outpatient clinic for heart failure prospectively underwent evaluation of renal function every 6 months. The association of baseline NT-pro-BNP with WRF was analysed during a follow up of 18 months. RESULTS: Twenty-eight (22.4%) patients developed WRF (increase in serum creatinine ≥0.3 mg/dL). Patients with WRF (2870 pg/mL, interquartile range (IQR) 1063-4765) had significantly higher baseline NT-pro-BNP values than patients without WRF (547 pg/mL, IQR 173-1454). The risk for WRF increased by 4.0 (95% CI 2.1-7.5) for each standard deviation of log NT-pro-BNP. In multivariable analysis including age, baseline renal function, ejection fraction, New York Heart Association class and diuretic dose, only NT-pro-BNP and diabetes were independent predictors of WRF. At a cut-off level of 696 pg/mL, NT-pro-BNP showed a sensitivity of 92.9% and a negative predictive value of 96.4% for WRF. CONCLUSION: NT-pro-BNP is a strong independent predictor of WRF within 18 months in patients with systolic heart failure with a high negative predictive value. Further studies are needed to evaluate reno-protective strategies in patients with elevated NT-pro-BNP.

[Heart failure update 2010 and current ESC guidelines]. / Herzinsuffizienz Update 2010 und aktuelle ESC-Leitlinien.

Chronic heart failure may be caused by systolic pump failure and/or impairment of diastolic filling of the ventricles. Standard pharmacotherapy of systolic heart failure includes an ACE inhibitor, betablocker, diuretics and in patients with severe symptoms a low-dose aldosterone antagonist. An AT(1) receptor blocker is indicated in those not tolerating ACE inhibitors. If patients remain in functional class NYHA III-IV despite optimal medication and have cardiac dyssynchrony, biventricular pacing may improve symptoms and prognosis. While evidence-based treatment significantly reduces morbidity and mortality in systolic heart failure, hardly any results of clinical trials are available for diastolic heart failure. Therefore, therapy in patients with diastolic heart failure remains symptomatic in most cases.

Cost-effectiveness of pioglitazone in patients with type 2 diabetes and a history of macrovascular disease in a Swiss setting.

OBJECTIVES: To evaluate the cost-effectiveness of pioglitazone versus placebo, given in addition to existing treatment regimens, in patients with type 2 diabetes and evidence of macrovascular disease in Switzerland. METHODS: Event rates corresponding to macrovascular outcomes from the PROactive (Prospective Pioglitazone Clinical Trial in Macrovascular Events) trial of pioglitazone were used to project long-term clinical outcomes as part of a modified version of the previously validated CORE Diabetes Model. Direct medical costs associated with treatment regimens, complications and patient management were accounted in 2005 values based on Swiss-specific unit costs. Time horizon was set to lifetime (35 years). Future costs and clinical benefits were discounted at 2.5% annually in line with Swiss recommendations. One-way sensitivity analyses were performed. RESULTS: Addition of pioglitazone was associated with a reduced incidence of most diabetes-related complications, improved life expectancy (0.258 years) and improved quality-adjusted life expectancy (0.180 QALYs) compared with placebo. Pioglitazone treatment increased direct costs by CHF 10,914 per patient over a lifetime horizon. The incremental cost-effectiveness ratio (ICER) of pioglitazone versus placebo was CHF 42,274 per life-year gained and CHF 60,596 per QALY gained. ICERs were sensitive to variation in time horizon and duration of pioglitazone treatment effects. With a willingness to pay of CHF 80,000 per QALY in the Swiss setting, there was a 62.5% chance that pioglitazone would be cost-effective. CONCLUSIONS: Addition of pioglitazone to existing therapy was projected to reduce the long-term cumulative incidence of most diabetes complications and improve quality-adjusted life expectancy. Evaluation of incremental direct medical costs associated with these clinical benefits indicated that pioglitazone is likely to be a cost-effective treatment option in the Swiss setting over patient lifetimes.

An increase in HbA1c after percutaneous coronary intervention raises the risk for restenosis in patients without Type 2 diabetes mellitus.

AIMS: The influence of dynamic changes in glycated haemoglobin (HbA(1c)) on restenosis after elective percutaneous coronary intervention (PCI) in patients without diabetes has not been analysed. Therefore, the rate of restenosis was investigated after elective PCI in 101 consecutive patients without diabetes mellitus in relation to dynamic changes of HbA(1c) levels. METHODS: Follow-up angiography was performed in all patients 4-6 months after intervention. RESULTS: Multivariate analysis demonstrated that the change in HbA(1c) between first and second coronary angiography was the most powerful metabolic parameter for prediction of restenosis. The odds ratio for restenosis was 3.0 (95% CI 1.0-9.0) for any increase in HbA(1c) and 1.9 (95% CI 1.1-3.5) for an HbA(1c) increase of 0.2%. CONCLUSIONS: Hence, chronic changes in the glucometabolic environment influence the incidence of restenosis after PCI in patients without diabetes.

Regional expression of sodium pump subunits isoforms and Na+-Ca++ exchanger in the human heart.

Cardiac glycosides exert a positive inotropic effect by inhibiting sodium pump (Na,K-ATPase) activity, decreasing the driving force for Na+-Ca++ exchange, and increasing cellular content and release of Ca++ during depolarization. Since the inotropic response will be a function of the level of expression of sodium pumps, which are alpha(beta) heterodimers, and of Na+-Ca++ exchangers, this study aimed to determine the regional pattern of expression of these transporters in the heart. Immunoblot assays of homogenate from atria, ventricles, and septa of 14 nonfailing human hearts established expression of Na,K-ATPase alpha1, alpha2, alpha3, beta1, and Na+-Ca++ exchangers in all regions. Na,K-ATPase beta2 expression is negligible, indicating that the human cardiac glycoside receptors are alpha1beta1, alpha2beta1, and alpha3beta1. alpha3, beta1, sodium pump activity, and Na+-Ca++ exchanger levels were 30-50% lower in atria compared to ventricles and/or septum; differences between ventricles and septum were insignificant. Functionally, the EC50 of the sodium channel activator BDF 9148 to increase force of contraction was lower in atria than ventricle muscle strips (0.36 vs. 1.54 microM). These results define the distribution of the cardiac glycoside receptor isoforms in the human heart and they demonstrate that atria have fewer sodium pumps, fewer Na+-Ca++ exchangers, and enhanced sensitivity to inotropic stimulation compared to ventricles.

NT-pro-BNP measured at discharge predicts outcome in multimorbid diabetic inpatients with a broad spectrum of cardiovascular disease.

The prognostic value of NT-pro-BNP has not been thoroughly evaluated in diabetic inpatients with manifest cardiovascular disease. NT-pro-BNP was measured in 156 patients with type 2 diabetes mellitus hospitalised due to cardiovascular disease. The association of NT-pro-BNP with mortality and the combined endpoint (CE) of death, heart failure decompensation, stroke and myocardial infarction was analysed during a median follow-up time of 1183 days. Patients who died (1669 IQR 788-5640 vs. 398, IQR 158-990 pg/ml) and patients with CE (1353, IQR 730-4289 vs. 304, IQR 128-784 pg/ml, both p=0.0001) had significantly elevated NT-pro-BNP compared to patients without the corresponding endpoint. Patients with supramedian NT-pro-BNP (>518 pg/ml) had significantly worse outcome regarding mortality (HR 5.5, 95%CI 2.0-14.8) and CE (HR 5.0, 95%CI 2.2-11.2) than patients with inframedian values even after adjustment for age, NYHA class and renal function. At a cut-off of 422 pg/ml, NT-pro-BNP showed a sensitivity of 89.6% and a negative predictive value of 92.8% for detection of patients with future CE. In this sample of diabetic patients with a broad spectrum of cardiovascular disease, NT-pro-BNP was a strong predictor of long-term outcome. NT-pro-BNP measured at discharge identifies high-risk patients independently of the underlying heart disease.

[Heart Murmurs--what must the family physician know?]. / Kardiale Auskultation in der Hausarztpraxis. Das Einmaleins der Herzgeräusche.

Cardiac auscultation follows a set procedure and begins on the supine patient. If necessary, certain exercises (inspiration/expiration, Valsalva manoeuvre, squats) can be performed to facilitate the aetiological classification of a heart murmur. Functional and pathological heart murmurs must be differentiated. Factors to be considered in the evaluation of murmurs are loudness, phase of the cycle (systole/diastole), localization, character and radiation of the sound and also the state of health, age and sex of the patient.

Microalbuminuria as a marker of cardiovascular risk in patients with type 2 diabetes.

Diabetes is a major risk factor for coronary artery disease and most patients with diabetes die of cardiovascular complications. Reduction of cardiovascular risk is therefore a high priority in the management of patients with diabetes. Microalbuminuria is an important predictor of cardiovascular events and forms one of the components of the insulin resistance/metabolic syndrome, which confers a particularly high risk of cardiovascular death. The currently available glucose-lowering agents vary considerably in their ability to reduce microalbuminuria. The sulfonylureas and metformin appear to have little effect on microalbuminuria expressed as urinary albumin/creatinine ratio, while the thiazolidinediones have unique effects on this risk factor, in parallel with their effects on insulin resistance. In two 1-year European multicenter, randomized, double-blind monotherapy trials (n=2444), pioglitazone produced similar reductions in urinary albumin/creatinine ratio to gliclazide and greater reductions than metformin (P<0.001). Similarly, two further 1-year European multicenter, randomized, double-blind trials assessed the effects of add-on therapy (n=1269) on urinary albumin/creatinine ratio. In the first study, urinary albumin/creatinine ratio was reduced by pioglitazone add-on to sulfonylurea (-15%), but was largely unaffected by metformin add-on to sulfonylurea (2%; P<0.05). In the second, urinary albumin/creatinine ratio was also reduced by pioglitazone add-on to metformin (-10%), but increased by gliclazide add-on to metformin (6%, P<0.05). The results of these studies indicated that compared with metformin or gliclazide, pioglitazone may provide therapeutic benefits, over and above those due to improved glycemic control. These include significant reductions in urinary albumin/creatinine ratio, a known cardiovascular risk marker.

Ouabain-receptor interactions in (Na+ + K+)-ATPase preparations. A contribution to the problem of nonlinear Scatchard plots.

Specific [3H]ouabain binding to rat and guinea pig skeletal muscle (musculus soleus) was studied using a rapid centrifugation and a filtration method. Both assays gave identical results: the incubation of the cell membranes in 50 mM imidazole/HCl buffer pH 7.25 or 7.4 MgCl2, Pi caused a time dependent loss of (Na+ +K+)-ATPase activity indicating an alteration of the membrane preparation. Ouabain binding properties were changed concomitantly. If ouabain binding was allowed to proceed until equilibrium was reached (3 min in rat and 10 min in guinea pig) at 37 degrees C the data plotted according to Scatchard followed a straight line. The dissociation constants of the ouabain-receptor-complexes of the rat cell membrane preparation as calculated from the slope of the plot (KD = 134 nM) and from the ratio of the dissociation and association rate constants (KD = 175 nM) agreed within experimental error with that determined by Clausen and Hansen [(1974) Biochim. Biophys. Acta 345, 387-404] in intact soleus muscles (KD = 210 nM). If ouabain binding was allowed to proceed for a longer period, however, nonlinear Scatchard plots resulted with an identical maximal number of binding sites but inconstant and decreased affinity for the cardiac glycoside. Experimental evidence is presented that nonlinear Scatchard plots often obtained in hormone (drug)-receptor binding experiments may (among other things) be the result of damaged cell membrane particles in vitro.

Effects of vanadate in cultured rat heart muscle cells. Vanadate transport, intracellular binding and vanadate-induced changes in beating and in active cation flux.

Cultured rat heart muscle cells have been used to study uptake and intracellular binding of Na483VO4 (vanadate), as well as the influence of vanadate on beating and 86Rb+ uptake of these cells. 1. Vanadate is taken up into cultured rat heart muscle cells in an energy-independent manner by a saturable transport system (Km approximately 60 microM, V approximately 200 pmol per mg protein per min at 37 degrees C). Analysis of intracellular binding of vanadate reveals a curved Scatchard plot indicating more than one binding site. Maximal binding amounts to 3 . 10(9) molecules of vanadate per cell. 2. Vanadate exerts a positive chronotropic and inotropic effect and increases automaticity. First effects can be seen at 1 . 10(-7) M Na3VO4. Concentrations higher than 1. 10(-3) M induce toxic effects (arrhythmias, fibrillation and stand-still of the cell). 3. Vanadate-induced alterations of beating is paralleled by a vanadate-induced stimulation of (86Rb+ + K+) uptake into the cells of up to 75%. Maximal stimulation is obtained at concentrations of 1 . 10(-4)--1 . 10(-3) M vanadate. The stimulation is thought to be due to an increased activity of (Na+ + K+)-ATPase, since it can be inhibited by ouabain. This result is in contrast to in vitro experiments with purified membrane preparations of (Na+ + K+)-ATPase of different organs, where an inhibition of (Na+ + K+)-ATPase by vanadate has been found. 4. The results indicate a possible role of vanadate as an endogenous regulator of active cation flux in heart tissue.

Stimulatory (insulin-mimetic) and inhibitory (ouabain-like) action of vanadate on potassium uptake and cellular sodium and potassium in heart cells in culture.

(1) The influence of vanadate (Na3VO4) on sodium and potassium uptake as well as on cellular ion contents of sodium and potassium has been studied in heart muscle and non-muscle cells obtained from various species. An ouabain-like inhibition of potassium uptake (up to 50%), combined with a decrease of cellular potassium (up to 20%) has been observed by vanadate (10(-4)-10(-3) M) in heart non-muscle cells obtained from neonatal guinea pigs and chick embryos. In heart muscle and non-muscle cells prepared from neonatal rats, as well as in Girardi human heart cells, a vanadate-induced stimulation of potassium uptake (up to 100%), combined with a rise in cellular potassium (up to 20%) and without significant alteration of cellular sodium, has been found. A slight increase of 22Na+ influx can be measured in rat heart muscle cells and in Girardi human heart cells in the presence of vanadate (10(-4)--10(-3) M). (2) In beating rat heart muscle cells in culture, detrimental effects of serum deprivation--concerning beating properties, potassium uptake and cellular potassium--can at least in part be overcome by addition of vanadate. Furthermore, this compound prevents ouabain-induced signs of toxicity (contractures) in these cells. (3) The stimulatory effects of vanadate on potassium can be mimicked by insulin (1-10 mU/ml). Furthermore, vanadate produces an insulin-like stimulation of 2-deoxy-D-glucose uptake in rat heart muscle and non-muscle cells as well as in Girardi human heart cells. (4) The experimental data demonstrate an ouabain-like inhibition as well as an insulin-mimetic stimulation of potassium-uptake in various heart cells. The reason for this antagonistic mode of action may be due to the different capabilities of the heart cell types to reduce vanadium in the V-valence state of vanadium in the IV-valence state, thereby favouring either ouabain-like inhibition (vanadium V) or insulin-mimetic stimulation (vanadium IV) of potassium transport.