[Cardiovascular risk of androgen deprivation therapy for treatment of hormone-dependent prostate cancer : Differences between GnRH antagonists and GnRH agonists]. / Kardiovaskuläres Risiko unter Androgendeprivationstherapie zur Behandlung des hormonabhängigen Prostatakarzinoms : Unterschiede zwischen GnRH-Antagonisten gegenüber GnRH-Agonisten.

BACKGROUND: Several studies have indicated that reduction of testosterone levels in patients with prostate cancer undergoing androgen deprivation therapy (ADT) with gonadotropin-releasing hormone (GnRH) agonists can be associated with an increased risk of cardiovascular events. The GnRH antagonists have a different mode of action compared with GnRH agonists and may be preferred in ADT for patients with cardiovascular disease. OBJECTIVE: This review article discusses potential mechanisms underlying the development of cardiovascular events associated with ADT when using GnRH agonists and explains the differences in mode of action between GnRH agonists and GnRH antagonists. Additionally, relevant studies are presented and practical recommendations for the clinical practice are provided. MATERIAL AND METHODS: A literature search was performed. Full publications and abstracts published in the last 10 years up to September 2015 were considered to be eligible. RESULTS: The GnRH antagonists were associated with a decreased risk of cardiovascular events compared with GnRH agonists in prostate cancer patients undergoing ADT and particularly in patients with cardiovascular risk factors or a history of cardiovascular disease. This decrease may be due to the different mode of action of GnRH antagonists compared with GnRH agonists. CONCLUSION: Prostate cancer patients with either cardiovascular disease or an increased risk of experiencing a cardiovascular event undergoing ADT should be preferentially treated with GnRH antagonists.

[The effects of multimodal intervention for the primary prevention of cardiovascular diseases on depression, anxiety, and Type-D pattern: initial results of the randomized controlled PreFord trial]. / Effekte einer multimodalen Intervention zur Primärprävention kardiovaskulärer Krankheiten auf Depressivität, Angst und Typ-D-Muster: Erste Ergebnisse der randomisierten, kontrollierten PräFord-Studie.

Depression, anxiety, and Type-D pattern are associated with the earlier development and faster progression of cardiovascular disease (CVD). The aim of the randomized controlled PreFord trial was to improve multiple biological and psychosocial risk factors in the primary prevention of CVD. A total of 447 women and men with an ESC risk score >5% were randomly assigned to either multimodal or routine care groups. Somatic and psychosocial variables (HADS, DS-14) were assessed before and after the intervention, and annually for 2 years thereafter. The intervention showed no significant effects on the symptoms of depression, anxiety, and type D personality, either in the whole sample or in those with elevated scores at baseline. Thus, our study did not provide evidence that symptoms of depression, anxiety, or Type D personality can be effectively treated by multimodal behavioral interventions for the primary prevention of CVD.

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.

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.

Delta-glycated hemoglobin: a novel independent risk factor for cardiovascular events in patients without diabetes mellitus.

BACKGROUND: A single measurement of glycated hemoglobin (HbA1c) is a weak predictor for cardiovascular events in patients without Type 2 diabetes mellitus. We hypothesized that dynamic changes in HbA1c (Delta-HbA1c) would better predict cardiovascular outcome than a single value. METHODS: In 99 consecutive patients with stable coronary artery disease (CAD) and without diabetes mellitus who were seen twice in our outpatient clinic (4-6 months apart) in 1998, Delta-HbA1c (follow-up HbA1c--baseline HbA1c) was assessed. Between August and September 2007 (mean observation period 9.1 yr), patients and their physicians were contacted by telephone to evaluate the incidence of cardiovascular endpoints. The combined primary endpoint of our study was defined as the incidence of myocardial infarction, stroke or death from any cause. The endpoints were validated by chart review. RESULTS: Multivariate analysis demonstrated that the change of HbA1c between first and second examination in 1998 was the most powerful parameter for prediction of the combined primary endpoint in the next 9 yr. The hazard ratio was 5.03 [95% confidence interval (CI) 1.4-17.9] for any increase in HbA1c and 1.99 (95%CI 1.3-3.0) for an HbA1c increase of 0.3%. In addition, Kaplan-Meier survival analysis showed a significant association between endpoint-free survival and dynamic changes in HbA1c. CONCLUSIONS: Hence, changes in the glucometabolic milieu within 4-6 months calculated by the difference of two values of HbA1c affect the long-term prognosis of patients with CAD but without diabetes mellitus.

[Predictive value of NT-pro-BNP for the non-cardiologist. A study on 573 hospitalized patients with cardiovascular disease]. / Welchen Aussagewert hat der kardiale Funktionsmarker NT-pro-BNP für den Nicht-Kardiologen? Eine Untersuchung an 573 hospitalisierten Patienten mit kardiovaskulärer Erkrankung.

BACKGROUND: B-type natriuretic peptides are excellent markers of cardiac function and are strong prognostic parameters in patients with coronary heart disease and heart failure. We examined the diagnostic and prognostic value of natriuretic peptides in a heterogeneous group of patients of a cardiological university hospital. METHODS: NT-pro-BNP was assessed in 573 inpatients (66 % male, median age 66 years) and association with demographic and cardiological parameters, in-hospital course as well as the combined endpoint of death, heart failure hospitalization and stroke was analyzed during a median follow-up time of 1117 days. RESULTS: NT-pro-BNP was significantly associated with age, diastolic blood pressure, renal function, previous myocardial infarction, arterial occlusive disease, atrial fibrillation, NYHA class and left-ventricular dysfunction. Differentiation of distinct cardiac diseases by NT-pro-BNP was not possible. NT-pro-BNP identified patients with a length of hospital stay of more than 12 days with a sensitivity of 88,2 % and a negative predictive value of 97 %. Supramedian NT-pro-BNP values (> 300 pg/ml) indicated a relative risk for the combined endpoint of 7,5 (95 % CI 4,1 - 13,8) compared to inframedian NT-pro-BNP values. Prognostic value of NT-pro-BNP was independent of and stronger than demographic and cardiological risk markers. CONCLUSION: NT-pro-BNP is a strong and independent predictor of in-hospital course and long-term outcome in inpatients with cardiovascular disease. NT-pro-BNP assessment allows a risk-adapted patient management for non-cardiologists.

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.

Activation of the calcineurin/NFAT signalling cascade starts early in human hypertrophic myocardium.

Cardiac hypertrophy is an independent risk factor for heart failure. Recent studies on gene regulation of proteins have involved intracellular Ca2+ homeostasis. The Ca2+-sensitive phosphatase, calcineurin, is one potential regulator of the hypertrophic response, so we aimed to investigate the calcineurin-dependent signal pathway at different stages of hypertrophy in human myocardium. We found the calcineurin pathway to be significantly activated in hypertrophic compared with non-hypertrophic myocardium as demonstrated by increased calcineurin activity and expression of calcineurin A-beta and B, and GATA-4, and a shift of phosphorylated cytoplasmic NFAT-3 into the nucleus as dephosphorylated nuclear NFAT-3. There was a tendency for these changes to be more pronounced in the decompensated compared with the compensated hypertrophic myocardium. The present study provides evidence for significant activation of the Ca2+-triggered calcineurin pathway in hypertrophic humans. Already present in compensated hypertrophy it showed a tendency to a further increase following transition to decompensated hypertrophy.

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.

[Hyperglycemia and cardiovascular events]. / Hyperglykämie und kardiovaskuläre Erkrankungen.

Besides classical, modifiable risk factors (hypercholesterolemia, hypertension, smoking) abnormalities of the glucose metabolism (diabetes mellitus, impaired glucose tolerance) are strong emerging cardiovascular risk factors. Epidemiological data indicate that 8 % of the population and up to 60 % of patients with coronary artery disease have abnormalities of glucose metabolism. The prevalence of these abnormalities will increase as the population ages and the mean body weight increases. An abnormal glucose concentration damages the endothelium in several ways: increased oxidative stress, inflammatory processes and an activation of procoagulant factors all impair endothelial function. A blood glucose normalising therapy is thought to decrease the incidence of cardiovascular events in these patients. In patients with an acute myocardial infarction and diabetes mellitus an early intensive insulin therapy improves the outcome of these patients. In summary, the early detection and treatment of abnormalities of glucose metabolism reduces cardiac events.

Natriuretic peptides BNP and NT-pro-BNP: established laboratory markers in clinical practice or just perspectives?

A growing body of literature describes diagnostic and prognostic value of B-type natriuretic peptides (BNP) in cardiac diseases since it was first described in 1988. As BNP is mainly secreted in the left ventricular (LV) myocardium, BNP was found to reflect LV function much better than any other neurohumoral factor. Thus, BNP is recommended as the first noninvasive blood test for determination of cardiac function by some authors. The introduction of fully automated, rapid bioassays for measurement of BNP and the aminoterminal part of its pro-hormone (NT-pro-BNP) made it possible to use the test even in emergency care settings. Here we review the literature with special focus on assessment of BNP and NT-pro-BNP in the following clinical settings: community screening for LV dysfunction, primary diagnosis of heart failure in general practice and emergency department (ED) and risk stratification in cardiac dysfunction and acute coronary syndromes. In addition, we discuss which applications can be recommended for daily clinical use from the cardiologist's point of view.

[Secondary prevention of cardiovascular diseases]. / Sekundärprävention bei kardiovaskulären Erkrankungen.

Secondary prevention includes all measures to lower the risk of a relapse of a specific disease. For secondary prevention of cardiovascular diseases general measures and specific drug therapy are employed, according to the individual risk pattern. Among the general measures cessation of smoking is most important. In addition, an increase in daily exercise, a normalization of body weight and a healthy diet all lower the cardiovascular risk. For most cases secondary prevention includes also specific drug therapies. Aspirin, statins and beta-blockers are the cornerstones of this drug therapy. After myocardial infarction most patients will also benefit from an ACE-inhibitor therapy.

Use of NT-proBNP in routine testing and comparison to BNP.

OBJECTIVES: B-type natriuretic peptide (BNP) is a strong diagnostic predictor of left-ventricular (LV)-dysfunction. Recently, the aminoterminal portion of pro-BNP (NT-proBNP) has been introduced, which could be even more sensitive because of its longer half-life. The aim of this study was to evaluate the new marker NT-proBNP within a large, heterogeneous population of patients with suspected cardiovascular disease at risk of cardiovascular dysfunction and to compare it with the established diagnostic parameter BNP. SUBJECTS AND METHODS: NT-proBNP and BNP were measured in 339 hospitalised patients undergoing diagnostic angiography (median age 66 years, 244 male vs. 95 female). RESULTS: Median values of NT-proBNP increased with worsening LV-dysfunction and higher NYHA class. The area under the receiver operator characteristics curve (AUC) of NT-proBNP for detecting severe systolic dysfunction or for detecting any systolic LV-dysfunction was 0.83 and 0.77, respectively. The latter improved (AUC=0.81) when patients with clinically relevant heart disease like valvular dysfunction were included, independent of the haemodynamic values. Compared to BNP, NT-proBNP tended to be more accurate in identifying lesser degrees of LV-dysfunction. CONCLUSIONS: Even after optimisation of target criteria, there was still a substantial overlap of NT-proBNP values between patients with and without relevant heart disease. Therefore, NT-proBNP is not suitable as a screening test for LV-dysfunction in the community. Nevertheless, because of its good negative predictive value, NT-proBNP could be an easy and effective tool to rule out severe systolic LV-dysfunction in high risk patients. No clinically significant advantage of BNP testing could be found.

[The PreFord Study. A prospective cohort study to evaluate the risk of a cardiovascular event (overall-collective) as well as a prospective, randomized, controlled, multicentre clinical intervention study (high-risk-collective) on primary prevention of cardiovascular diseases in the Ford Motor Company employees in Germany]. / Die PräFord-Studie. Prospektive Kohortenstudie zur Bewertung des Risikos für ein kardiovaskuläres Akutereignis (Gesamtkollektiv) sowie eine prospektive, randomisierte, kontrollierte, multizentrische klinische Interventionsstudie (Hochrisikoteilkollektiv) in der Primärprävention von Herz-Kreislauferkrankungen bei Mitarbeitern der Firma Ford in Deutschland.

The PreFord Study is a multicenter prospective cohort study to evaluate guideline based risk management on primary prevention of cardiovascular diseases. Furthermore a randomised controlled trial (RCT) will be designed to analyse the effect of a special intervention program. 40,000 employees of the Ford Motor Company, Visteon Company and Deutz Company in Germany will be included, monitored for ten years and the following primary endpoints will be investigated: 1. evaluation and comparison of established and newly developed risk-scores, 2. the relative impact of single and combined cardiovascular risk factors on cardiovascular diseases, 3. the influence of a novel occupationally integrated ambulant rehabilitation program in combination with a guideline oriented optimal drug therapy within a high risk group on the primary endpoint: risk reduction by, 4. the influence of this intervention on secondary endpoints: death, myocardial infarction and stroke, combined appearance of angina pectoris and hospitalisation, occurrence of cerebral circulatory disorder and hospitalisation, occurrence of peripheral occlusive arterial disease and hospitalisation and single cardiovascular risk factors and cost-benefit-analysis. Beginning with an cross sectional study there will be a systemic screening of cardiovascular risk profiles, of anthropometric data and different lifestyle-factors. Based on these data participants will be differentiated into three risk-groups according to the risk score of the European Society of Cardiology (risk of a lethal primary acute cardiovascular event: I < or = 1%; II > 1-< 5% and III > or = 5%). In the following longitudinal study different strategies will be applied: Group I: low risk (< 0.5% per year): repetition of the investigation after five and ten years. Group II: middle risk, (0.6% to 1.4% per year), repetition of the investigation every two years, instruction of the patients general practitioner (GP) with respect to a risk factor oriented and evidence based treatment. Group III: high risk, (> 1.5% per year or >15% within the next 10 years) will be randomised into two interventional groups. The first one, the intervention-group "PreFord" will perform an occupational integrated rehabilitation program (2,5-3 hours twice a week, for 15 weeks according to the BAR guidelines) with a following engagement in heart-groups and an annual repetition of the check-ups. The second group, the "classic" intervention-group will be treated evidence based in cooperation with their GP. As a result of this long term interventional study efficient, area wide implementable and economically feasible prevention concepts with special regards to operational healthcare will be developed and evaluated. Core elements will be exercise- and lifestyle-oriented concepts as well as guideline-based pharmacotherapy.