Mineralocorticoid Receptor Antagonists in the Treatment of Coronary Artery Disease, Myocardial Infarction and Heart Failure

Affecting sodium reabsorption and potassium excretion in the kidney, mineralocorticoid receptor antagonists (MRA) were originally developed as antihypertensive drugs. After several large clinical trials, the concept of MR blockade has nowadays become a main treatment paradigm in heart failure with reduced ejection fraction (HFrEF) and for patients after myocardial infarction (MI) with left ventricular (LV) dysfunction. Recent analyses also point to a beneficial effect of early MRA treatment in patients with acute MI without LV dysfunction, however, there is no clear evidence yet. Although promising data from preclinical settings suggest that MRAs mediate favorable anti-atherogenic effects, clinical studies in patients with stable coronary artery disease (CAD) have not been able to detect differences of hard clinical outcomes. The concept might still be pursued using the most recent MRA, like the non-steroidal MR antagonist finerenone, and larger clinical trials need to be performed. Here, we review the current impact of MRA in patients with CAD and focus on the conflicting evidence of preclinical and clinical data in patients with stable CAD and preserved ejection fraction and summarize the current indications for MRA in these patients according to the guidelines

Serum circular RNAs act as blood-based biomarkers for hypertrophic obstructive cardiomyopathy

Altres ajuts: Junge Akademie (MHH); ERC grant Longheart; Deutsche Forschungsgemeinschaft (TRR_267, KFO311).Hypertrophic cardiomyopathy (HCM) is one of the most common hereditary heart diseases and is associated with a high risk of sudden cardiac death. HCM is characterized by pronounced hypertrophy of cardiomyocytes, fiber disarray and development of fibrosis and can be divided into a non-obstructive (HNCM) and obstructive form (HOCM) therefore requiring personalized therapeutic therapies. In the present study, we investigated the expression patterns of several circulating circular RNAs (circRNAs) as potential biomarkers in patients with HCM. We included 64 patients with HCM and 53 healthy controls to the study and quantitatively measured the expression of a set of circRNAs already known to be associated with cardiac diseases (circDNAJC6) and/or being highly abundant in blood (circTMEM56 and circMBOAT2). Abundancy of circRNAs was then correlated to relevant clinical parameters. Serum expression levels of circRNAs DNAJC6, TMEM56 and MBOAT2 were downregulated in patients with HCM. The inverse association between circRNA levels and HCM remained unchanged even after adjusting for confounding factors. All circRNAs, evaluated separately or in combination, showed a robust discrimination capacity when comparing control subjects with HCM, HNCM or HOCM patients (AUC from 0.722 to 0.949). Two circRNAs, circTMEM56 and circDNAJC6, significantly negatively correlated with echocardiographic parameters for HOCM. Collectively, circulating circRNAs DNAJC6, TMEM56 and MBOAT2 can distinguish between healthy and HCM patients. In addition, circTMEM56 and circDNAJC6 could serve as indicators of disease severity in patients with HOCM. Thus, circRNAs emerge as novel biomarkers for HCM facilitating the clinical decision making in a personalized manner

Serum circular RNAs act as blood-based biomarkers for hypertrophic obstructive cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is one of the most common hereditary heart diseases and is associated with a high risk of sudden cardiac death. HCM is characterized by pronounced hypertrophy of cardiomyocytes, fiber disarray and development of fibrosis and can be divided into a non-obstructive (HNCM) and obstructive form (HOCM) therefore requiring personalized therapeutic therapies. In the present study, we investigated the expression patterns of several circulating circular RNAs (circRNAs) as potential biomarkers in patients with HCM. We included 64 patients with HCM and 53 healthy controls to the study and quantitatively measured the expression of a set of circRNAs already known to be associated with cardiac diseases (circDNAJC6) and/or being highly abundant in blood (circTMEM56 and circMBOAT2). Abundancy of circRNAs was then correlated to relevant clinical parameters. Serum expression levels of circRNAs DNAJC6, TMEM56 and MBOAT2 were downregulated in patients with HCM. The inverse association between circRNA levels and HCM remained unchanged even after adjusting for confounding factors. All circRNAs, evaluated separately or in combination, showed a robust discrimination capacity when comparing control subjects with HCM, HNCM or HOCM patients (AUC from 0.722 to 0.949). Two circRNAs, circTMEM56 and circDNAJC6, significantly negatively correlated with echocardiographic parameters for HOCM. Collectively, circulating circRNAs DNAJC6, TMEM56 and MBOAT2 can distinguish between healthy and HCM patients. In addition, circTMEM56 and circDNAJC6 could serve as indicators of disease severity in patients with HOCM. Thus, circRNAs emerge as novel biomarkers for HCM facilitating the clinical decision making in a personalized manner.This work was supported by Junge Akademie, MHH (to K.S.), ERC grant Longheart (to T.T.) and Deutsche Forschungsgemeinschaft, TRR_267 (to T.T.) and KFO311 (to T.T. and J.B. (D.d.G.C. was a recipient of a Juan de la Cierva-Incorporación grant from the Ministry of Science Innovation and Universities (IJCI-2016-29393). CIBER Cardiovascular (CB16/11/00403 to DdG-C) is a project from Carlos III Health Institute

C1q and Tumor Necrosis Factor Related Protein 9 Protects from Diabetic Cardiomyopathy by Alleviating Cardiac Insulin Resistance and Inflammation

(1) Background: Diabetic cardiomyopathy is a major health problem worldwide. CTRP9, a secreted glycoprotein, is mainly expressed in cardiac endothelial cells and becomes downregulated in mouse models of diabetes mellitus; (2) Methods: In this study, we investigated the impact of CTRP9 on early stages of diabetic cardiomyopathy induced by 12 weeks of high-fat diet; (3) Results: While the lack of CTRP9 in knock-out mice aggravated insulin resistance and triggered diastolic left ventricular dysfunction, AAV9-mediated cardiac CTRP9 overexpression ameliorated cardiomyopathy under these conditions. At this early disease state upon high-fat diet, no fibrosis, no oxidative damage and no lipid deposition were identified in the myocardium of any of the experimental groups. Mechanistically, we found that CTRP9 is required for insulin-dependent signaling, cardiac glucose uptake in vivo and oxidative energy production in cardiomyocytes. Extensive RNA sequencing from myocardial tissue of CTRP9-overexpressing and knock-out as well as respective control mice revealed that CTRP9 acts as an anti-inflammatory mediator in the myocardium. Hence, CTRP9 knock-out exerted more, while CTRP9-overexpressing mice showed less leukocytes accumulation in the heart during high-fat diet; (4) Conclusions: In summary, endothelial-derived CTRP9 plays a prominent paracrine role to protect against diabetic cardiomyopathy and might constitute a therapeutic target

C1q and Tumor Necrosis Factor Related Protein 9 Protects from Diabetic Cardiomyopathy by Alleviating Cardiac Insulin Resistance and Inflammation

(1) Background: Diabetic cardiomyopathy is a major health problem worldwide. CTRP9, a secreted glycoprotein, is mainly expressed in cardiac endothelial cells and becomes downregulated in mouse models of diabetes mellitus; (2) Methods: In this study, we investigated the impact of CTRP9 on early stages of diabetic cardiomyopathy induced by 12 weeks of high-fat diet; (3) Results: While the lack of CTRP9 in knock-out mice aggravated insulin resistance and triggered diastolic left ventricular dysfunction, AAV9-mediated cardiac CTRP9 overexpression ameliorated cardiomyopathy under these conditions. At this early disease state upon high-fat diet, no fibrosis, no oxidative damage and no lipid deposition were identified in the myocardium of any of the experimental groups. Mechanistically, we found that CTRP9 is required for insulin-dependent signaling, cardiac glucose uptake in vivo and oxidative energy production in cardiomyocytes. Extensive RNA sequencing from myocardial tissue of CTRP9-overexpressing and knock-out as well as respective control mice revealed that CTRP9 acts as an anti-inflammatory mediator in the myocardium. Hence, CTRP9 knock-out exerted more, while CTRP9-overexpressing mice showed less leukocytes accumulation in the heart during high-fat diet; (4) Conclusions: In summary, endothelial-derived CTRP9 plays a prominent paracrine role to protect against diabetic cardiomyopathy and might constitute a therapeutic target

Bromocriptine treatment in patients with peripartum cardiomyopathy and right ventricular dysfunction

BackgroundRight ventricular (RV) dysfunction predicts adverse outcome in peripartum cardiomyopathy (PPCM). We recently demonstrated beneficial effects associated with the prolactin release inhibitor bromocriptine at different doses when added to standard heart failure therapy in PPCM. Here, we evaluated for the first time the therapeutic potential of bromocriptine particularly in PPCM patients with RV involvement.MethodsIn this study, 40 patients with PPCM were included, of whom 24 patients had reduced RV ejection fraction (RVEF<45%). We examined the effect of short-term (1W: bromocriptine, 2.5mg, 7days, n=10) compared with long-term bromocriptine treatment (8W: 5mg for 2weeks followed by 2.5mg for another 6weeks, n=14) in addition to guideline-based heart failure therapy in patients with an initial RVEF<45% on the following outcomes: (1) change from baseline ( delta) in RVEF, (2) change from baseline in left ventricular EF (LVEF), and (3) rate of patients with full LV recovery (LVEF50%) and (4) rate of patients with full RV recovery (RVEF55%) at 6-month follow-up as assessed by cardiac magnetic resonance imaging.ResultsReduced RVEF at initial presentation was associated with a lower rate of full cardiac recovery at 6-month follow-up (patients with RV dysfunction: 58% vs. patients with normal RV function: 81%; p=0.027). RVEF increased from 387 to 53 +/- 11% with a delta-RVEF of +15 +/- 12% in the 1W group, and from 35 +/- 9 to 58 +/- 7% with a RVEF of +23 +/- 10% in the 8W group ( RVEF 1W vs 8W: p=0.118). LVEF increased from 25 +/- 8 to 46 +/- 12% with a LVEF of +21 +/- 11% in the 1W group, and from 22 +/- 6 to 49 +/- 10% with a LVEF of +27 +/- 9% in the 8W group ( LVEF 1W vs 8W: p=0.211). Full LV recovery was present in 50% of the 1W group and in 64% of the 8W group (p=0.678). Full RV recovery was observed in 40% of the 1W group and in 79% of the 8W group (p=0.092).ConclusionsDespite overall worse outcome in patients with RV dysfunction at baseline, bromocriptine treatment in PPCM patients with RV involvement was associated with a high rate of full RV and LV recovery, although no significant differences were observed between the short-term and long-term bromocriptine treatment regime. These findings suggest that bromocriptine in addition to standard heart failure therapy may be also effective in PPCM patients with biventricular impairment