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Abstract Aims This meta‐analysis investigated the dose–response relationship between circulating galectin‐3 levels and adverse outcomes in patients with heart failure (HF). Methods and results PubMed and Embase were screened for studies on galectin‐3 and HF. The outcomes of interest were all‐cause mortality (ACM), and all‐cause mortality or HF‐related rehospitalization (ACM/HFR), with a follow‐up time of more than 6 months. For categorical variables, comparisons between groups with the highest and lowest galectin‐3 levels were pooled. For continuous variables, the risks of ACM and ACM/HFR increase per 1‐standard deviation (SD) and 1‐unit after logarithmic transformation galectin‐3 levels were pooled. A random‐effects model was employed to calculate the pooled results, and all pooled results were expressed as hazard ratios (HRs) and 95% confidence intervals (CIs). Besides, a dose–response analysis was performed. Twenty‐four cohort studies were included. In HF patients, higher circulating galectin‐3 levels were significantly associated with a higher risk of long‐term ACM (HR, 1.65; 95% CI 1.28–2.13; I2 = 66%), and 1 ng/mL increase in galectin‐3 was associated with a 4% (HR, 1.04; 95% CI 1.02–1.06; P = 0.002) increase in hazard. Similarly, higher circulating galectin‐3 levels were significantly associated with a higher risk of long‐term ACM/HFR (HR, 1.52; 95% CI, 1.15 to 2.00; I2 = 76%), and 1 ng/mL increase in galectin‐3 was associated with a 3% (HR, 1.03; 95% CI 1.02–1.04; P

Abstract Aim Heart failure with preserved ejection fraction (HFpEF) is associated with left ventricular stiffness, impaired diastolic relaxation, and severe exercise intolerance. Decreased homoarginine (hArg) levels are an independent predictor of mortality in cardiovascular disease and correlate with impaired exercise performance. We recently reported alterations in arginine, hArg, and related amino acids in obese ZSF1 rats (O‐ZSF1), with a HFpEF phenotype. Although low hArg is associated with diastolic dysfunction in humans, potential effects of hArg supplementation were not tested yet. Methods and results At an age of 6 weeks, 12 O‐ZSF1 were randomized into two groups: (1) O‐ZSF1 rats supplemented with hArg in their drinking water (sO‐ZSF1) or (2) O‐ZSF1 rats receiving no hArg supplementation (O‐ZSF1). At an age of 32 weeks, effects of primary prevention by hArg supplementation on echocardiographic, histological, and functional parameters of heart and skeletal muscle were determined. Lean ZSF1 rats (L‐ZSF1) served as controls. hArg supplementation did not prevent impairment of diastolic relaxation (E/e′: O‐ZSF1 21 ± 3 vs. sO‐ZSF1 22 ± 3, P = 0.954, L‐ZSF1 18 ± 5) but resulted in more cardiac fibrosis (histological collagen staining: +57% in sO‐ZSF1 vs. O‐ZSF1, P = 0.027) and increased collagen gene expression (Col1a1: +48% in sO‐ZSF1 vs. O‐ZSF1, P = 0.026). In contrary, right ventricular function was preserved by hArg supplementation (TAPSE (mm): O‐ZSF1 1.2 ± 0.3 vs. sO‐ZSF1 1.7 ± 0.3, P = 0.020, L‐ZSF1 1.8 ± 0.4). Musculus soleus maximal specific muscle force (N/cm2) in O‐ZSF1 (30.4 ± 0.8) and sO‐ZSF1 (31.9 ± 0.9) was comparable but significantly reduced compared with L‐ZSF1 (36.4 ± 0.7; both P 0.05) and cross‐sectional fibre area (arbitrary units) (O‐ZSF1: 1697 ± 57, sO‐ZSF1: 1965 ± 121, L‐ZSF1: 1691 ± 104, all P > 0.05) were not altered. Conclusions Preservation of physiological hArg level in HFpEF may not be suited to prevent alterations in left ventricular and skeletal muscle function and structure. However, hArg supplementation may be beneficial for right ventricular function especially in pulmonary hypertension in HFpEF. We may speculate that clinically observed decreased hArg level are not the cause but the consequence of a yet unrecognized pathomechanism that underpins HFpEF.

Abstract Aims Establishing a diagnosis of inflammatory cardiomyopathy (iCMP) by non‐invasive means remains challenging despite advances in cardiac magnetic resonance imaging. Previous studies suggested the involvement of microRNAs in the pathogenesis of iCMP. We examined the association of a predefined set of circulatory microRNAs with clinical characteristics of iCMP and evaluated their diagnostic performance in suspected iCMP. Methods and results Eighty‐nine patients with clinical suspicion of iCMP were included in the analysis. All patients underwent cardiac catheterization with left ventricular endomyocardial biopsy, echocardiography, and cardiac magnetic resonance imaging applying the Lake Louise criteria (LLC). Plasma levels of miR‐21, miR‐126, miR‐133a, miR‐146b, miR‐155, and miR‐206 were determined using real‐time polymerase chain reaction. Based on immunohistological findings on endomyocardial biopsy, iCMP was diagnosed in 67% of study participants (n = 60). Plasma levels of miR‐155 and miR‐206 were significantly increased in patients with iCMP as compared with patients with dilated cardiomyopathy (P = 0.008 and P = 0.009, respectively). In receiver operating characteristic curve analysis, miR‐155 and miR‐206 demonstrated superior diagnostic performance for iCMP (0.68 and 0.67, respectively) compared with LLC [area under the curve (AUC) 0.60], Troponin T (AUC 0.51), and N‐terminal pro‐brain natriuretic peptide (AUC 0.51). While baseline miR‐155 and miR‐206 plasma levels were predictive for biopsy‐proven iCMP (odds ratio = 2.61, 95% confidence interval = 1.28–5.31, P = 0.008 and odds ratio = 2.65, 95% confidence interval = 1.27–5.52, P = 0.009) on univariate logistic regression analysis, the presence of positive LLC, high baseline C‐reactive protein, or presence of clinical symptoms and signs of viral infection failed to predict iCMP (P > 0.05, respectively). Conclusions The present data suggest that plasma levels of miR‐206 and miR‐155 are potential novel biomarkers for confirming the diagnosis of iCMP.

Abstract Aims Murine models implicate phosphodiesterase 9A (PDE9A) as a nitric oxide‐independent regulator of cyclic guanosine monophosphate and promising novel therapeutic target in heart failure (HF) with preserved ejection fraction (HFpEF). This study describes PDE9A expression in endomyocardial biopsies (EMBs) and peripheral blood mononuclear cells (PBMNCs) from patients with different HF phenotypes. Methods and results Endomyocardial biopsies and PBMNCs were obtained from patients with HFpEF (n = 24), HF with reduced ejection fraction (n = 22), and inflammatory cardiomyopathy (n = 24) and patients without HF (n = 7). PDE9A expression was increased in EMBs and PBMNCs from patients with HFpEF as compared with other HF phenotypes or subjects without HF. Endomyocardial PDE9A expression in HFpEF correlated with the inflammatory cell count in EMBs, but not with cardiac fibrosis or left ventricular diastolic wall stress. PDE9A expression in PBMNCs was increased in HFpEF patients with higher high‐sensitivity C‐reactive protein levels and in response to pro‐inflammatory stimulation. As a validation cohort, 719 patients with HFpEF and 1106 subjects without HF were identified from the LIFE‐Heart study. PDE9A expression in PBMNCs was obtained from array data and displayed an age‐dependent distribution. PDE9A levels were elevated and conferred increased risk for HFpEF in middle‐aged subjects, but not in elderly HFpEF patients. Following age adjustment, lower PDE9A expression in PBMNCs was associated with worse survival in patients with HFpEF (log‐rank test P‐value