Accelerating developments in heart failure

Heart failure remains a leading cause of morbidity and mortality globally. Within the last 5 years, many new developments have been seen in the area of heart failure, including completely new therapies, mechanistic insights, as well as novel strategies to phenotype and segment the condition. Ten reviews and two original articles provide an updated overview on specific new developments in the area of heart failure. A collection of reviews focuses on the specific forms of heart failure and/or its comorbidities. Borlaug et al.1 focus on the emerging problem of obesity and heart failure with preserved ejection fraction (HFpEF), which represents indeed one of the greatest unmet health problems in the field of cardiovascular medicine in the 21st century. A better understanding of the specific underlying pathophysiological mechanisms of obese HFpEF, as well as a better phenomapping and stratification of patients with this condition, is an essential prerequisite to develop novel, more targeted, and in the future, perhaps even more individualized, therapies. The review of Borlaug et al.1 summarizes the current understanding of the cardiovascular and non-cardiovascular features of the obese phenotype of HFpEF and sheds some light on potential new therapeutic entry points. Obesity is closely related to changes in cardiac metabolism, a topic that was reviewed by Capone et al.2 in this Spotlight issue.2 Specifically, the authors discuss the current evidence on changes in energy metabolism in HFpEF and highlight clinical and translational challenges surrounding metabolic-centred therapies in HFpEF. In a related original article, Benn et al.3 convincingly showed a high body mass index to be causally related in the observed increases in the risk of both heart failure incidence and mortality. To arrive at this conclusion, they used observational and Mendelian randomization analyses in >1 000 000 individuals derived from specific studies and publicly available databases. Another comorbidity associated with heart failure development is cancer, and the field of cardio-oncology is indeed rapidly emerging, as heart failure and cancer affect one another in a bidirectional way. Patients with heart failure are at increased risk for developing cancer, and heart failure is associated with accelerated tumour growth. In this review of de Wit et al.4, an excellent overview of mechanisms involved in this bidirectional connection between heart failure and cancer is provided, including a description of targeted anti-cancer therapies with cardiotoxic potential. More specifically, a review about transthyretin cardiac amyloidosis (ATTR-CA) focuses on this increasingly recognized cause of heart failure and mortality. This specific cardiac disorder was mostly ignored years ago, but it has now occupied centre stage, as advances in non-invasive diagnosis, coupled with the development of effective treatments, have enabled ATTR-CA to progress from the stage of a rare and untreatable disease to a treatable form of heart failure. Here, Porcari et al.5 also highlight new therapies able to slow or halt ATTR-CA progression and increase survival. A further recognition of the last decade is that inflammatory pathways play crucial roles in the development of heart failure, especially HFpEF. The review of Pugliese et al.6 focuses specifically on this important topic. Indeed, HFpEF is often characterized by a persistent increase in inflammatory biomarkers, and inflammation per se may be a key driver of the development and progression of HFpEF and associated comorbidities. The authors finely review the role of inflammation in HFpEF and the possible implications for future trials employing anti-inflammatory strategies. The segmentation of heart failure into pathophysiologic subtypes remains an important task for future developments. Phenomapping strategies are the focus of the review article of Peters et al.7 presented here in this Spotlight article. Phenomapping is the process of applying statistical learning techniques to patient data to identify distinct subgroups based on patterns in the data and can help in a better understanding of different heart failure phenotypes. The authors summarize not only new methodologies but also highlight that there are still limited implications for clinical care and clinical trials, due to the inherent limitations of aggregating and utilizing phenomapping results. Future directions may use phenomapping to optimize the likelihood of clinical trial successes or to drive discovery in the mechanisms of the disease process of heart failure. Another collection of reviews in this Spotlight issue deals with current and upcoming therapeutic approaches in heart failure. Current therapeutics in heart failure are reviewed by Khan et al.8 They highlight the fact that current therapeutics with clinical benefits in heart failure have so far targeted a wide range of different heart failure phenotypes and question whether the ideal therapeutic targets have been identified in specific phenotypes, which may help achieve maximum benefit. The authors also highlight the mechanism of action of current therapeutic strategies, as well as the pathophysiological pathways they target, and importantly, highlight the remaining knowledge gaps regarding the mode of action of these interventions such as for sodium-glucose cotransporter-2 inhibitors. In terms of potential new therapeutic approaches, Dulce et al.9 investigated the long-term existing hypothesis that the activation of the growth hormone-releasing hormone (GHRH) receptor signalling pathway may prevent and reverse diastolic dysfunction in patients with HFpEF. Experimentally, synthetic agonists of the GHRH receptors reduce myocardial fibrosis, cardiomyocyte hypertrophy, and improve performance in animal models of ischaemic cardiomyopathy, independent of the growth hormone axis. As reported in their original paper, the authors administered either a vehicle or a potent synthetic agonist of GHRH, called MR-356, for 4 weeks to mice 4 weeks following the initiation of Ang-II infusion. Indeed, MR-356 both prevented and reversed the development of the pathological phenotype in vivo and ex vivo. Thus, the activation of GHRH receptors with potent, synthetic GHRH agonists may provide a novel therapeutic approach to the management of the myocardial alterations associated with the HFpEF syndrome, although clinical evidence on this has been missing so far. B-type natriuretic peptides are well known and exert pleiotropic cardiovascular, endocrine, renal, and metabolic actions via the particulate guanylyl cyclase A receptor and the second messenger, cGMP. Sangaralingham et al.10 review important insights into the biology of the natriuretic peptide system and their role in precision medicine and present the emerging field of peptide engineering and the development of novel designer natriuretic peptides for the treatment of heart failure. In the field of cardiac transplantation, xenotransplantation has long held promise, particularly given the worldwide shortage of human hearts for transplantation. Reichart et al.11 discuss pig heart xenotransplantation as a concept, including pathobiological aspects related to immune rejection, coagulation dysregulation, and detrimental overgrowth of the heart. The authors also highlight that an adequate regulatory and ethical framework and stringent criteria for the selection of patients will be critical for the safe clinical development of cardiac xenotransplantation in the coming years. Finally, McKinsey et al.12 present novel molecular targets and the application of upcoming cellular therapies, epigenetic modifications, and uses of regulatory RNAs to more specifically address heart failure. A focus is made on non-coding RNA-based strategies that reached the phase of clinical development including Phase 1b and Phase 2 studies to counteract cardiac remodelling and heart failure.13,14