Background-Cardiac hypertrophy and subsequent heart failure triggered by chronic hypertension represent major challenges for cardiovascular research. Beyond neurohormonal and myocyte signaling pathways, growing evidence suggests inflammatory signaling pathways as therapeutically targetable contributors to this process. We recently reported that microRNA-155 is a key mediator of cardiac inflammation and injury in infectious myocarditis. Here, we investigated the impact of microRNA-155 manipulation in hypertensive heart disease. Methods and Results-Genetic loss or pharmacological inhibition of the leukocyte-expressed microRNA-155 in mice markedly reduced cardiac inflammation, hypertrophy, and dysfunction on pressure overload. These alterations were macrophage dependent because in vivo cardiomyocyte-specific microRNA-155 manipulation did not affect cardiac hypertrophy or dysfunction, whereas bone marrow transplantation from wild-type mice into microRNA-155 knockout animals rescued the hypertrophic response of the cardiomyocytes and vice versa. In vitro, media from microRNA-155 knockout macrophages blocked the hypertrophic growth of stimulated cardiomyocytes, confirming that macrophages influence myocyte growth in a microRNA-155-dependent paracrine manner. These effects were at least partly mediated by the direct microRNA-155 target suppressor of cytokine signaling 1 (Socs1) because Socs1 knockdown in microRNA-155 knockout macrophages largely restored their hypertrophy-stimulating potency. Conclusions-Our findings reveal that microRNA-155 expression in macrophages promotes cardiac inflammation, hypertrophy, and failure in response to pressure overload. These data support the causative significance of inflammatory signaling in hypertrophic heart disease and demonstrate the feasibility of therapeutic microRNA targeting of inflammation in heart failure. hypertension-induced target organ damage and hypertrophy, is a potent promoter of inflammation. 5 The signaling mechanisms that mediate these effects, however, remain largely obscure. In this study, we show that microRNA-155 (miR-155) expression by macrophages is a powerful mediator of cardiac hypertrophy and failure through the upregulation of proinflammatory paracrine signaling. Clinical Perspective on p 1432MicroRNAs are small noncoding RNAs that inhibit gene expression of complementary target genes at the posttranscriptional level. 6 Although others have studied the implication of cardiomyocyte-or fibroblast-derived microRNAs, 7-9 inflammatory microRNAs have hitherto remained unaddressed in pressure overload-induced heart disease. MiR-155 expression is upregulated in a multitude of inflammatory diseases, including rheumatoid arthritis and multiple sclerosis. MethodsAn expanded Methods section is available in the online-only Data Supplement. Animal StudiesAll mouse experiments were performed according to the local relevant guidelines; group sizes are summarized in the Table. Male miR-155 knockout (KO) and wild-type (WT) C57Bl/6J mice (10-12 weeks old) 13 were su...

Our data show that cardiac microRNA dysregulation is a characteristic of both human and mouse viral myocarditis. The inflammatory microRNA-155 is upregulated during acute myocarditis, contributes to the adverse inflammatory response to viral infection of the heart, and is a potential therapeutic target for viral myocarditis.

Aims  To investigate the effects of spironolactone on fibrosis and cardiac function in people at increased risk of developing heart failure. Methods and results  Randomized, open-label, blinded-endpoint trial comparing spironolactone (50 mg/day) or control for up to 9 months in people with, or at high risk of, coronary disease and raised plasma B-type natriuretic peptides. The primary endpoint was the interaction between baseline serum galectin-3 and changes in serum procollagen type-III N-terminal pro-peptide (PIIINP) in participants assigned to spironolactone or control. Procollagen type-I C-terminal pro-peptide (PICP) and collagen type-1 C-terminal telopeptide (CITP), reflecting synthesis and degradation of type-I collagen, were also measured. In 527 participants (median age 73 years, 26% women), changes in PIIINP were similar for spironolactone and control [mean difference (mdiff): −0.15; 95% confidence interval (CI) −0.44 to 0.15 μg/L; P = 0.32] but those receiving spironolactone had greater reductions in PICP (mdiff: −8.1; 95% CI −11.9 to −4.3 μg/L; P < 0.0001) and PICP/CITP ratio (mdiff: −2.9; 95% CI −4.3 to −1.5; <0.0001). No interactions with serum galectin were observed. Systolic blood pressure (mdiff: −10; 95% CI −13 to −7 mmHg; P < 0.0001), left atrial volume (mdiff: −1; 95% CI −2 to 0 mL/m2; P = 0.010), and NT-proBNP (mdiff: −57; 95% CI −81 to −33 ng/L; P < 0.0001) were reduced in those assigned spironolactone. Conclusions  Galectin-3 did not identify greater reductions in serum concentrations of collagen biomarkers in response to spironolactone. However, spironolactone may influence type-I collagen metabolism. Whether spironolactone can delay or prevent progression to symptomatic heart failure should be investigated.

Over the last decade, parvovirus B19 (B19V) has frequently been linked to the pathogenesis of myocarditis (MC) and its progression towards dilated cardiomyopathy (DCM). The exact role of the presence of B19V and its load remains controversial, as this virus is also found in the heart of healthy subjects. Moreover, the prognostic relevance of B19V prevalence in endomyocardial biopsies still remains unclear. As a result, it is unclear whether the presence of B19V should be treated. This review provides an overview of recent literature investigating the presence of B19V and its pathophysiological relevance in MC and DCM, as well as in normal hearts. In brief, no difference in B19V prevalence is observed between MC/DCM and healthy control hearts. Therefore, the question remains open whether and how cardiac B19V may be of pathogenetic importance. Findings suggest that B19V is aetiologically relevant either in the presence of other cardiotropic viruses, or when B19V load is high and/or actively replicating, which both may maintain myocardial (low-grade) inflammation. Therefore, future studies should focus on the prognostic relevance of the viral load, replicative status and virus co-infections. In addition, the immunogenetic background of MC/DCM patients that makes them susceptible to develop heart failure upon presence of B19V should be more thoroughly investigated.