[Acute and chronic heart failure]. / Akute und chronische Herzinsuffizienz.

The initial therapy of chronic heart failure is still based on diuretics, angiotensin-converting enzyme (ACE) inhibitors, beta-blockers and in specific cases mineralocorticoid receptor antagonists. The new European Society of Cardiology (ESC) guidelines published in 2016 introduced angiotensin-receptor-neprilysin inhibitors, such as sacubitril/valsartan (LCZ 696) as new therapeutic agents in patients with chronic and progressive heart failure. New subgroup analyses for LCZ 696 have been published showing a beneficial effect in the context of various comorbidities, such as renal insufficiency, diabetes and hypotension. Furthermore, new data are available on intravenous iron substitution in chronic heart failure and on the indications for implantable converter defibrillators, cardiac resynchronization therapy and other cardiac devices. Medicinal therapy of acute heart failure is still limited. For patients who cannot be treated with medicinal therapy, mechanical circulatory support, such as extracorporeal membrane oxygenation (ECMO) should be recommended.

[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.

Effects of mesenchymal stromal cells on diabetic cardiomyopathy.

Diabetic cardiopathy includes a specific cardiomyopathy, which occurs in the absence of coronary heart disease under diabetes mellitus. Hallmarks of diabetic cardiomyopathy are besides others, interstitial inflammation, cardiac oxidative stress, interstitial and perivascular fibrosis, cardiac apoptosis, intramyocardial microangiopathy, endothelial dysfunction, abnormal intracellular Ca²âº-handling, cardiomyocyte hypertrophy, and impaired cardiac stem cells. Since mesenchymal stromal cells have been shown to have anti-diabetic as well as cardioprotective features, we summarize in this review how they can indirectly affect diabetic cardiomyopathy via their influence on the metabolic trigger hyperglycemia, and how they can directly influence the cardiac cellular consequences typical for diabetic cardiomyopathy via their immunomodulatory, anti-oxidative, anti-fibrotic, anti-apoptotic, pro-angiogenic, and endothelial-protective features, and their ability to activate cardiac progenitor cells. Furthermore, the dysfunctionality of (bone marrow-derived) mesenchymal stromal cells under diabetes mellitus and potential strategies to overcome this impairment in cell functionality are outlined.

The cardiovascular influence of interleukin-1 beta on the expression of bradykinin B1 and B2 receptors.

The cytokine interleukin 1ss (IL-1ss) and the bradykinin receptors 1 (B1R) and 2 (B2R) are known to be upregulated in the ischemic heart. In the present study we investigated whether or not there is a causal link between these entities. Further we investigated whether or not pharmacological inhibition of IL-1ss release affects B1R and B2R regulation as well as left ventricular (LV) function in an in vivo rat model of myocardial infarction (MI). B1R and B2R mRNA levels were determined in cultured rat cardiomyocytes, aortic smooth muscle cells and cardiac fibroblasts (n=6 per group) under basal conditions, and after incubation of IL-1ss (40, 400 and 4000 pg/ml). Also, MI was induced in male Sprague-Dawley rats by ligation of the left descending coronary artery. Rats were treated with the interleukin converting enzyme inhibitor (ICEI) pralnacasan (50 mg/kg/day), or with a placebo. Three weeks after induction of MI, LV function was assessed using a 1.4 Millar TIP-catheter. Cardiac expressions of B1R and B2R mRNA were measured using ribonuclease-protection assays. Under basal conditions, both B1R and B2R were expressed in cardiomyocytes and smooth muscle cells, but not in cardiac fibroblasts. IL-1ss cultivation led only in cardiomyocytes to a significant upregulation of B1R mRNA. To a significant upregulation of B2R mRNA, it did not. In addition, ICEI treatment led in vivo to a significant downregulation of cardiac B1R mRNA, but not of B2R mRNA expression three weeks after induction of MI. Our data suggest that a causal link exists between cardiac IL-1ss content and B1R regulation after MI.

Anti-inflammatory effects of atorvastatin improve left ventricular function in experimental diabetic cardiomyopathy.

AIMS/HYPOTHESIS: Emerging evidence suggests that statins exert beneficial effects beyond those predicted by their cholesterol-lowering actions. We investigated whether atorvastatin influences the development of left ventricular (LV) dysfunction, independently of cholesterol-lowering, in an experimental model of type 1 diabetes mellitus cardiomyopathy. METHODS: Streptozotocin-induced diabetic rats were treated with atorvastatin (50 mg/kg daily, orally) or with vehicle for 6 weeks. LV function was analysed using tip-catheter measurements. Cardiac stainings of TNF-alpha, IL-1beta, intercellular adhesion molecule-1, vascular cellular adhesion molecule-1, CD11a/lymphocyte-associated antigen-1, CD11b/macrophage antigen alpha, CD18/beta2-integrin, ED1/CD68, collagen I and III, and Sirius Red were assessed by digital image analysis. Ras-related C3 botulinum toxin substrate (RAC1) and ras homologue gene family, member A (RHOA) activities were determined by RAC1 glutathione-S-transferase-p21-activated kinase and rhotekin pull-down assays, respectively. Cardiac lipid peroxides were measured by a colorimetric assay. The phosphorylation state of p38 mitogen-activated protein kinase (MAPK) and endothelial nitric oxide synthase (eNOS) protein production were analysed by western blot. RESULTS: Diabetes was associated with induced cardiac stainings of TNF-alpha, IL-1beta, cellular adhesion molecules, increased leucocyte infiltration, macrophage residence and cardiac collagen content. In contrast, atorvastatin reduced both intramyocardial inflammation and myocardial fibrosis, resulting in improved LV function. This effect was paralleled with a normalisation of diabetes-induced RAC1 and RHOA activity, in the absence of LDL-cholesterol lowering. In addition, atorvastatin decreased diabetes-induced cardiac lipid peroxide levels and p38 MAPK phosphorylation by 1.3-fold (p < 0.05) and 3.2-fold (p < 0.0005), respectively, and normalised the reduced eNOS production caused by diabetes. CONCLUSIONS/INTERPRETATION: These data indicate that atorvastatin, independently of its LDL-cholesterol-lowering capacity, reduces intramyocardial inflammation and myocardial fibrosis, resulting in improved LV function in an experimental model of diabetic cardiomyopathy.

Murine models of myocardial and limb ischemia: diagnostic end-points and relevance to clinical problems.

Ischemic disease represents the new epidemic worldwide. Animal models of ischemic disease are useful because they can help us to understand the underlying pathogenetic mechanisms and develop new therapies. The present review article summarizes the results of a consensus conference on the status and future development of experimentation in the field of cardiovascular medicine using murine models of peripheral and myocardial ischemia. The starting point was to recognize the limits of the approach, which mainly derive from species- and disease-related differences in cardiovascular physiology. For instance, the mouse heart beats at a rate 10 times faster than the human heart. Furthermore, healing processes are more rapid in animals, as they rely on mechanisms that may have lost relevance in man. The main objective of the authors was to propose general guidelines, diagnostic end points and relevance to clinical problems.

Benfotiamine accelerates the healing of ischaemic diabetic limbs in mice through protein kinase B/Akt-mediated potentiation of angiogenesis and inhibition of apoptosis.

AIMS/HYPOTHESIS: Benfotiamine, a vitamin B1 analogue, reportedly prevents diabetic microangiopathy. The aim of this study was to evaluate whether benfotiamine is of benefit in reparative neovascularisation using a type I diabetes model of hindlimb ischaemia. We also investigated the involvement of protein kinase B (PKB)/Akt in the therapeutic effects of benfotiamine. METHODS: Streptozotocin-induced diabetic mice, given oral benfotiamine or vehicle, were subjected to unilateral limb ischaemia. Reparative neovascularisation was analysed by histology. The expression of Nos3 and Casp3 was evaluated by real-time PCR, and the activation state of PKB/Akt was assessed by western blot analysis and immunohistochemistry. The functional importance of PKB/Akt in benfotiamine-induced effects was investigated using a dominant-negative construct. RESULTS: Diabetic muscles showed reduced transketolase activity, which was corrected by benfotiamine. Importantly, benfotiamine prevented ischaemia-induced toe necrosis, improved hindlimb perfusion and oxygenation, and restored endothelium-dependent vasodilation. Histological studies revealed the improvement of reparative neovascularisation and the inhibition of endothelial and skeletal muscle cell apoptosis. In addition, benfotiamine prevented the vascular accumulation of advanced glycation end products and the induction of pro-apoptotic caspase-3, while restoring proper expression of Nos3 and Akt in ischaemic muscles. The benefits of benfotiamine were nullified by dominant-negative PKB/Akt. In vitro, benfotiamine stimulated the proliferation of human EPCs, while inhibiting apoptosis induced by high glucose. In diabetic mice, the number of circulating EPCs was reduced, with the deficit being corrected by benfotiamine. CONCLUSIONS/INTERPRETATION: We have demonstrated, for the first time, that benfotiamine aids the post-ischaemic healing of diabetic animals via PKB/Akt-mediated potentiation of angiogenesis and inhibition of apoptosis. In addition, benfotiamine combats the diabetes-induced deficit in endothelial progenitor cells.

Upregulation of bradykinin B1-receptor expression after myocardial infarction.

To determine the influence of the myocardial infarction (MI) on bradykinin B1-receptor (B1R) regulation, we studied its expression in the left ventricle (LV) after MI. Rats were submitted to a permanent occlusion of the left coronary artery. Six hours, 24 h and 6 days after MI or after sham operation, left ventricular pressure (LVP) and dP/dt(max) were measured. LV-total RNA was extracted and B1R expression was analysed by a RNase-protection assay (each group n = 6). LVP and dP/dt(max) were impaired at all time points after MI. Basal B1R expression was not detectable in controls. Six hours after MI, the B1R expression was upregulated and reached a maximum 24 h after MI (4 fold vs. 6 h). Six days post-MI, B1R expression returned to levels found 6 h after MI. These data are the first demonstration for an induced myocardial B1R expression in an in vivo model of MI.

Myocardial bradykinin B2-receptor expression at different time points after induction of myocardial infarction.

OBJECTIVE: To characterize the regulation of the myocardial bradykinin B2 receptor after induction of myocardial infarction (MI), we studied its expression at different time points in the left ventricle (LV), right ventricle (RV) and interventricular septum (S) of the heart. DESIGN: Male Sprague-Dawley rats were submitted to permanent occlusion of the left descending coronary artery. Six hours, 24 h or 6 days after MI induction or a sham operation, a Millar-tip catheter was placed in the LV. Left ventricular pressure (LVP) and contractility [(dP/dt)max] were measured. The LV, RV and S of all animals were isolated, and total RNA was extracted. B2-receptor expression was analysed by an RNase-protection assay. In addition, Western blot analysis was used to determine protein levels of the B2 receptor in the infarcted area of the LV. RESULTS: We observed a decrease in LVP and contractility at all time points after MI in comparison with sham-operated animals. Basal B2-receptor expression was detected in the LV and RV, but not in the S of sham-operated rats. In the LV of infarcted hearts, we found a time-dependent up-regulation of the B2-receptor expression, which was increased twofold and fivefold, respectively, 6 h and 24 h after induction of MI compared with controls. This increase was maintained for at least 6 days. Similarly, we also found an up-regulation of the B2-receptor expression in the RV and S. Both reached a peak 24 h after induction of MI. The protein level of the receptor gradually increased up to day 6. CONCLUSION: We conclude that myocardial ischaemia triggers B2-receptor up-regulation in both the infarcted and non-infarcted areas of the heart.

Upregulation of the cardiac bradykinin B2 receptors after myocardial infarction.

An increase in myocardial bradykinin (BK) might be a mechanism to protect the heart during acute myocardial infarction (MI). To characterize the regulation of the myocardial B2 receptor during MI, we studied the expression of this BK receptor in the right ventricle (RV), left ventricle (LV) and myocardial septum (S) 24 h after left coronary ligation. Experiments were performed in male Wistar Kyoto rats (n = 10) and compared with sham operated animals (n = 6). After total RNA extraction, the myocardial B2-receptor expression was analyzed by a RNase protection assay (n = 6), using a specific probe from the coding region of the receptor gene. After 24 h, rats with MI were normotensive and showed an impaired left ventricular function. The B2-receptor expression of the LV of these rats was significantly elevated (2.3-fold) compared to sham operated rats. Furthermore, we found a dramatic upregulation of the B2 receptor in the RV (7.8-fold) and a dramatic expression of B2 receptor mRNA in S of infarcted hearts, whereas in the S of sham operated rats no B2 receptor expression could be detected. Our data show clearly that the described increase in BK during myocardial ischemia is accompanied by an elevated B2-receptor expression in the infarcted and non-infarcted parts of cardiac ventricles.