Heart failure (HF) is an increasingly prevalent disease with a major impact on morbidity and mortality worldwide. Continuous advancements in diagnostic and therapeutic strategies have significantly improved patient outcomes; however, precise biomarkers and novel therapeutic targets are still needed. In recent years, microRNAs (miRNAs) have emerged as promising biomarkers and potential therapeutic targets in HF. They consist of small, noncoding RNA molecules that regulate gene expression post-transcriptionally and are detectable in both tissues and blood, with disease-specific expression profiles that make them attractive candidates for non-invasive diagnosis, prognostic risk stratification, and even therapeutic interventions. In HF, miRNAs contribute to pathogenesis by modulating fibrosis, apoptosis, hypertrophy, and inflammation. The aim of this review is to analyze the role of circulating and tissue miRNAs in HF as biomarkers and as therapeutic targets. The future management of HF should include strategies to modulate miRNA expression in order to modify the disease trajectory and improve clinical outcomes.

Sodium–glucose cotransporter 2 inhibitors (iSGLT2) have become the fourth pillar of the medical treatment for heart failure with reduced ejection fraction (HFrEF). However, the mechanisms of action of iSGLT2 remain poorly understood. The effectiveness of combined ARNI and iSGLT2 therapy in left ventricular (LV) remodeling is still under study. We aim to investigate the effects of ARNI + iSGLT2 combination therapy in patients affected by HFrEF in terms of ventricular remodeling using speckle tracking echocardiography (STE). In this observational study, 136 patients with HFrEF taking ARNI were enrolled. All patients were evaluated at baseline (before iSGLT2), at 3 months and at 12 months from the beginning of iSGLT2 therapy. Echocardiographic parameters, including STE analysis and volumetric and LV contractile function indices, were collected at the three timepoints. The objectives were (1) to evaluate the effects of ARNI + iSGLT2 combination therapy on ultrasound (US) measurements; (2) to evaluate the effects on the variation of laboratory data indicative of HF (NT-pro-BNP); and (3) to evaluate the medium-long term impact of the ARNI + iSGLT2 combination therapy in terms of major cardiovascular events (MACVE). After only three months of combined ARNI + iSGLT2 therapy, we reported a significant improvement in ventricular and atrial volumetric indices, systolic function indices and myocardial deformation parameters assessed by STE. We also reported a significant decrease in NTproBNP levels. This trend was confirmed at 12 months follow-up. Furthermore, narrowing down the analysis to patients who were already treated with ARNI when they started taking iSGLT2, we reported similar results in the improvement of US parameters and NTproBNP levels. Our study has shown that the ARNI + iSGLT2 combination therapy leads to a clinical improvement and positive ventricular remodeling. Even the single introduction of additional iSGLT-2 in HFrEF patients on an otherwise optimized therapy resulted in a significant improvement in US and laboratory variables. The results of our study suggest implementing iSGLT-2 therapy as soon as possible, as the structural and functional cardiac improvements achieved by these drugs are achieved in the short term and maintained in the long term.

Heart failure (HF) is a systemic syndrome in which cardiac dysfunction is closely linked to multiorgan involvement, including the gastrointestinal tract. Increasing evidence highlights the relevance of the gut–heart axis in HF pathophysiology, whereby intestinal hypoperfusion, congestion, and barrier dysfunction promote gut microbiota dysbiosis, systemic inflammation, and adverse cardiovascular outcomes. In parallel, the advent of novel HF therapies, particularly sodium–glucose cotransporter 2 inhibitors (SGLT2i) and the angiotensin receptor–neprilysin inhibitor sacubitril/valsartan, has markedly improved clinical outcomes across HF phenotypes. Beyond their established cardiovascular benefits, these therapies may exert pleiotropic effects that extend to the intestinal environment and the gut microbiota. Through integrated actions on hemodynamics, neurohormonal activation, metabolic pathways, and inflammatory processes, recent data suggest that novel HF drugs may indirectly influence the gut-microbial composition and function. Conversely, the gut microbiota may modulate drug efficacy and result in interindividual variability in therapeutic responses, suggesting a bidirectional interaction between pharmacological treatment and the gut ecosystem. This narrative review summarizes current evidence of gut microbiota alterations in HF and critically examines emerging data on interactions between the gut microbiota and novel HF therapies, focusing on SGLT2 inhibitors and sacubitril/valsartan. Understanding this crosstalk may support the development of microbiota-informed, personalized therapeutic strategies in heart failure.