A great deal of evidence has revealed an important link between gut microbiota and the heart. In particular, the gut microbiota plays a key role in the onset of cardiovascular (CV) disease, including heart failure (HF). In HF, splanchnic hypoperfusion causes intestinal ischemia resulting in the translocation of bacteria and their metabolites into the blood circulation. Among these metabolites, the most important is Trimethylamine N-Oxide (TMAO), which is responsible, through various mechanisms, for pathological processes in different organs and tissues. In this review, we summarise the complex interaction between gut microbiota and CV disease, particularly with respect to HF, and the possible strategies for influencing its composition and function. Finally, we highlight the potential role of TMAO as a novel prognostic marker and a new therapeutic target for HF.

Diabetes mellitus (DM) is a glucose metabolism disorder characterized by chronic hyperglycemia resulting from a deficit of insulin production and/or action. DM affects more than 1 in 10 adults, and it is associated with an increased risk of cardiovascular morbidity and mortality. Cardiovascular disease (CVD) accounts for two thirds of the overall deaths in diabetic patients, with coronary artery disease (CAD) and ischemic cardiomyopathy as the main contributors. Hyperglycemic damage on vascular endothelial cells leading to endothelial dysfunction represents the main initiating factor in the pathogenesis of diabetic vascular complications; however, the underlying pathophysiological mechanisms are still not entirely understood. This review addresses the current knowledge on the pathophysiological links between DM and CAD with a focus on the role of epigenetic modifications, including DNA methylation, histone modifications and noncoding RNA control. Increased knowledge of epigenetic mechanisms has contributed to the development of new pharmacological treatments (“epidrugs”) with epigenetic targets, although these approaches present several challenges. Specific epigenetic biomarkers may also be used to predict or detect the development and progression of diabetes complications. Further studies on diabetes and CAD epigenetics are needed in order to identify possible new therapeutic targets and advance personalized medicine with the prediction of individual drug responses and minimization of adverse effects.

Heart failure with preserved ejection fraction (HFpEF) is a common clinical syndrome frequently seen in elderly patients, the incidence of which is steadily increasing due to an ageing population and the increasing incidence of diseases, such as diabetes, hypertension, obesity, chronic renal failure, and so on. It is a multifactorial disease with different phenotypic aspects that share left ventricular diastolic dysfunction, and is the cause of about 50% of hospitalizations for heart failure in the Western world. Due to the complexity of the disease, no specific therapies have been identified for a long time. Sodium-Glucose Co-Transporter 2 Inhibitors (SGLT2-Is) and Glucagon-Like Peptide Receptor Agonists (GLP-1 RAs) are antidiabetic drugs that have been shown to positively affect heart and kidney diseases. For SGLT2-Is, there are precise data on their potential benefits in heart failure with reduced ejection fraction (HFrEF) as well as in HFpEF; however, insufficient evidence is available for GLP-1 RAs. This review addresses the current knowledge on the cardiac effects and potential benefits of combined therapy with SGLT2-Is and GLP-1RAs in patients with HFpEF.

Atherosclerosis is a chronic inflammatory disease characterized by lipid and inflammatory cell deposits in the inner layer of large- and medium-sized elastic and muscular arteries. Diabetes mellitus (DM) significantly increases the risk of cardiovascular diseases and the overall and cardiovascular mortality, and it is a pro-atherogenic factor that induces atherosclerosis development and/or accelerates its progression through a multifactorial process. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a new class of drugs, belonging to the armamentarium to fight type 2 DM, that have shown robust reductions in atherosclerotic events and all-cause mortality in all studies. Preclinical studies have shown that GLP-1RAs play a role in the immunomodulation of atherosclerosis, affecting multiple pathways involved in plaque development and progression. In this review, we wanted to explore the translational power of such preclinical studies by analyzing the most recent clinical trials investigating the atheroprotective effect of GLP-1RAs.

Diabetes mellitus (DM) is a metabolic disorder characterized by chronic hyperglycemia and associated with an increased risk of morbidity and mortality, primarily from cardiovascular and renal diseases. Sodium-glucose cotransporter 2 inhibitors (SGLT2-Is) are novel drugs for the treatment of type 2 DM and heart failure (HF). SGLT2-Is mediate protective effects on both the renal and cardiovascular systems. This review addresses the current knowledge on the biomolecular mechanisms of the cardiorenal protective effects of SGLT2-Is, which appear to act mainly through non-glucose-mediated pathways. Cardiorenal protection mechanisms lead to reduced chronic renal disease progression and improved myocardial and coronary endothelial function. Concomitantly, it is possible to observe reflected changes in biomarkers linked with diabetic kidney disease and HF.

Much evidence reveals an important link between gut microbiota and the heart. In particular, the gut microbiota plays a key role in the onset of cardiovascular (CV) disease, including heart failure (HF). In HF, splanchnic hypoperfusion causes intestinal ischemia resulting in the translocation of bacteria and their metabolites into the blood circulation. Among these, the most important is the Trimethylamine N-Oxide (TMAO), which is responsible through various mechanisms for pathological processes in different organs and tissues. In this review, we summarise the complex interaction between gut microbiota and CV disease, particularly with HF, and the possible strategies to influence its composition and function. Finally, we highlight the potential role of TMAO as a novel prognostic marker and new therapeutic target of HF.