Heart failure is a leading cause of morbidity and mortality, with relevant social and economic burden on global healthcare system. Although the development of novel diagnostic tools and the advance in therapies have deeply influenced the diagnosis and treatment of this disease, improving both prognosis and life expectancy of patients, hospitalization is still high, and mortality remains considerable. MicroRNAs are small endogenous RNA molecules that post-transcriptionally regulate gene expression in both physiological and pathological processes. In recent years, microRNA have arisen as attractive therapeutic targets in the treatment of a wide spectrum of pathologies, including heart failure. In cardiac pathology, deregulation of microRNAs expression and function is associated to adverse outcome and heart failure progression. Circulating levels of specific microRNAs have emerged as useful biomarkers for the diagnosis of heart failure or as prognostic indicators. In the present review, we summarize the state of current research on the role of miRNAs as biomarkers for diagnosis and prognosis in patients with heart failure and their use as potential therapeutic targets for this condition.

BACKGROUND: Limited evidence exists on the prognostic role of continuing medical therapy in patients with heart failure (HF) and an ejection fraction (EF) that has improved over time. This study assessed rates of, patient profiles, and associations with morbidity/mortality of renin-angiotensin inhibitors (RASi), angiotensin receptor–neprilysin inhibitors (ARNi), beta-blockers (BBL), and mineralocorticoid receptor antagonists (MRA) withdrawal in patients with HF with improved EF. METHODS: Patients with a first recorded EF <40% and a later EF ≥40% from the Swedish HF registry between June 11, 2000, and December 31, 2023, were included in this retrospective observational study. Withdrawal was defined as a patient on treatment at the first (reduced) but not at the second (improved) registration. The association between withdrawal and time to first cardiovascular mortality/hospitalization for HF with censoring at 1 year was assessed by Cox regression model using overlap weighting. RESULTS: Of 8728 patients with HF with improved EF (median age, 70 years [25th to 75th percentile, 61–78], 2611 [29.9%] women), 96%, 94%, and 46% received RASi/ARNi, BBL, and MRA, respectively, when EF was <40%. The withdrawal rates at the time of the improved EF registration were 4.4% for RASi/ARNi, 3.3% for BBL, and 17.2% for MRA. Predictors of withdrawal included lower use of other HF medications, higher EF at the later EF registration, and a longer time between the 2 EF assessments. After weighting, withdrawal was independently associated with a higher risk of cardiovascular mortality/hospitalization for HF by 38% for RASi/ARNi and 36% for MRA, but not for BBL. Withdrawal of BBL was associated with a higher risk of the primary outcome in the subgroup of patients with an improved EF of 40% to 49% versus ≥50% ( P -interaction 0.03). CONCLUSIONS: In patients with HF with improved EF, HF therapy withdrawal was rare. Withdrawing RASi/ARNi and MRA was associated with higher mortality/morbidity at 1 year. No association was found for BBL withdrawal, albeit with a significant heterogeneity for EF at improvement, suggesting better outcomes with continuing BBL only until EF improves up to 50%. These results are hypothesis-generating and highlight the need for randomized controlled trials testing BBL withdrawal in patients with HF with improved EF.

Introduction: Depression is a common and severe comorbidity among individuals with heart failure (HF). Up to a third of all HF patients are depressed, and an even higher proportion have symptoms of depression. Aim: In this review, we evaluate the relationship between HF and depression, explain the pathophysiology and epidemiology of both diseases and their relationship, and highlight novel diagnostic and therapeutic options for HF patients with depression. Materials and Methods: This narrative review involved keyword searches of PubMed and Web of Science. Review search terms included [“Depression” OR “Depres*” OR “major depr*”] AND [“Heart Failure” OR “HF” OR “HFrEF” OR “HFmrEF” OR “HFpEF” OR “HFimpEF”] in all fields. Studies included in the review met the following criteria: (A) published in a peer-reviewed journal; (B) described the impact of depression on HF and vice versa; and (C) were opinion papers, guidelines, case studies, descriptive studies, randomized control trials, prospective studies, retrospective studies, narrative reviews, and systematic reviews. Results: Depression is an emergent HF risk factor and strongly relates with worse clinical outcomes. HF and depression share multiple pathways, including platelet dis-reactivity, neuroendocrine malfunction, inappropriate inflammation, tachi-arrhythmias, and frailty in the social and community setting. Existing HF guidelines urge evaluation of depression in all HF patients, and numerous screening tools are available. Depression is ultimately diagnosed based on DSM-5 criteria. There are both non-pharmaceutical and pharmaceutical treatments for depression. Regarding depressed symptoms, non-pharmaceutical treatments, such as cognitive-behavioral therapy and physical exercise, have shown therapeutic results, under medical supervision and with an effort level adapted to the patient’s physical resources, together with optimal HF treatment. In randomized clinical studies, selective serotonin reuptake inhibitors, the backbone of antidepressant treatment, did not demonstrate advantage over the placebo in patients with HF. New antidepressant medications are currently being studied and could provide a chance to enhance management, treatment, and control of depression in patients with HF. Conclusions: Despite the substantial link between depression and HF, their combination is underdiagnosed and undertreated. Considering the hopeful yet unclear findings of antidepressant trials, further research is required to identify people who may benefit from antidepressant medication. The goal of future research should be a complete approach to the care of these patients, who are anticipated to become a significant medical burden in the future.

Hyperkalemia often occurs among heart failure (HF) patients, particularly when treated with renin-angiotensin-aldosterone system inhibitors (RAASi). Even modest potassium levels variations raise the risk of mortality and prompt patients to discontinue disease-modifying treatment, as RAASi. Novel potassium binders (NPB), patiromer and sodium zirconium cyclosilicate, are effective in reducing potassium levels and are approved for the treatment of hyperkalemia in HF, but whether their use results in a real optimization of HF treatment remains to be seen. The aim of the present meta-analysis was to assess the efficacy of NPB on the optimization of RAASi therapy in HF patients. PubMed, Web of Science and Clinicaltrial.gov were searched without restrictions from inception to 06 August 2022 to identify valuable articles. The studies that met the inclusion criteria were analyzed. The prespecified primary outcome was the optimization of RAASi therapy in HF patients, defined as the proportion of patients on RAASi at the end of follow-up. Secondary outcomes were hyperkalemia events, reduction in potassium levels, and adverse drugs reactions. Six studies with a total of 1390 patients were included. NPB improved RAASi therapy optimization in HF by 14% (95% CI: 4-26%), decreased hyperkalemia events by 29% (95% CI: 55-92%), and reduced potassium levels by 0.31 mEq/L (95% CI: 0.18-0.44) compared to placebo, maintaining a good safety profile. NPB are effective in allowing RAASi therapy optimization in patients affected by HF, in reducing hyperkalemia events and potassium levels. CRD42022351811 URL: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=351811.

Renin-angiotensin-aldosterone system (RAAS) inhibition is a mainstay of the pharmacological treatment of heart failure with reduced ejection fraction (HFrEF). In the last years RAAS blockade has been improved by the introduction of the Angiotensin Receptor-Neprilysin Inhibitor (ARNI) sacubitril/valsartan, that combines RAAS inhibition with the block of neprilysin, boosting the positive effects of natriuretic peptides. The PARADIGM-HF trial demonstrated a significant advantage of sacubitril/valsartan over enalapril on the reduction of cardiovascular (CV) mortality and heart failure hospitalizations rates. Then, several randomized clinical trials and observational studies investigated its role in different clinical settings and its efficacy has been fully recognized in the most recent HFrEF European and USA guidelines. The effects of sacubitril/valsartan on major CV outcomes are associated with reduction of NT-proBNP levels and reverse cardiac remodeling and mitral regurgitation, recognized as one of the mechanistic effects of the drug explaining the favorable prognostic effects. A careful evaluation of patients' clinical profile is relevant to implement the use of ARNI in the clinical practice and to obtain the maximal treatment efficacy. The present Position Paper reports the opinion of the Italian Society of Cardiology on the optimal blockade of the RAAS system in HF patients with the aim of fostering widespread implementation of scientific evidence and practice guidelines in the medical community.

Aortic stenosis (AS) is a very common valve disease and is associated with high mortality once it becomes symptomatic. Arterial hypertension (HT) has a high prevalence among patients with AS leading to worse left ventricle remodeling and faster degeneration of the valve. HT also interferes with the assessment of the severity of AS, leading to an underestimation of the real degree of stenosis. Treatment of HT in AS has not historically been pursued due to the fear of excess reduction in afterload without a possibility of increasing stroke volume due to the fixed aortic valve, but most recent evidence shows that several drugs are safe and effective in reducing BP in patients with HT and AS. RAAS inhibitors and beta-blockers provide benefit in selected populations based on their profile of pharmacokinetics and pharmacodynamics. Different drugs, on the other hand, have proved to be unsafe, such as calcium channel blockers, or simply not easy enough to handle to be recommended in clinical practice, such as PDE5i, MRA or sodium nitroprusside. The present review highlights all available studies on HT and AS to guide antihypertensive treatment.