Heart failure: evolving management and new therapeutic targets

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Focus Issue on heart failure and cardiomyopathies contains a Clinical Research article entitled ‘Near-universal prevalence of central adiposity in heart failure with preserved ejection fraction: the PARAGON-HF trial’ by Alexander Peikert from Harvard Medical School, Boston, MA, USA, and colleagues.1 The management of heart failure with preserved ejection fraction (HFpEF) is complex, and obesity plays a key role.2–10 While body mass index (BMI) is the most common anthropometric measure, a measure of central adiposity—the waist-to-height ratio (WHtR)—focuses on body fat content and distribution, is not distorted by bone or muscle mass, sex, or ethnicity, and may be particularly relevant in HFpEF. The PARAGON-HF trial randomized 4796 patients with heart failure (HF) and ejection fraction ≥45% to valsartan or sacubitril/valsartan. The current work characterizes the association of BMI and WHtR with clinical features, outcomes, and the response to neprilysin inhibition. About half (49%) of the participants were considered obese by BMI (≥30 kg/m2), but nearly every patient (96%) had central adiposity (WHtR ≥0.5). Among patients who were not obese (BMI <30 kg/m2), 860 (37%) had marked central adiposity (WHtR ≥0.6). Higher BMI and WHtR were both associated with higher risk of total HF hospitalizations; however, as compared with BMI, WHtR was linearly associated with HF outcomes and identified a higher proportion of patients who had a particularly elevated risk. An obesity–survival paradox (i.e. improved outcomes in those with greater adiposity) was apparent with BMI in unadjusted analyses, but it was not observed with WHtR. Although neprilysin inhibition appeared to have greater effects on HF outcomes in patients with higher BMI and WHtR, analyses of interaction with obesity metrics did not show significant heterogeneity across the range of values for adiposity (Figure 1). Among patients with heart failure (HF) and a preserved ejection fraction (HFpEF, left ventricular ejection fraction ≥45%), body mass index (BMI) was measured in 4796 patients, and waist-to-height ratio (WHtR) was measured in 4534 patients at baseline. Obesity was defined by BMI ≥30 kg/m2, and central adiposity was identified as WHtR ≥0.5. The associations of these metrics with the incidence of the primary composite outcome of total (first and recurrent) HF hospitalizations and cardiovascular (CV) death, total HF hospitalizations, CV death, and all-cause death are depicted as continuous variables1 The authors conclude that in PARAGON-HF, in contrast toBMI, nearly every patient with HFpEF has central adiposity (as assessed by WHtR), and the risks of adverse HF events are more robustly related to WHtR. These data challenge the current reliance on BMI as an appropriate metric of adiposity, and they suggest that—rather than obesity-related HFpEF being regarded as a select HFpEF subgroup—central adiposity is a ubiquitous feature of HFpEF. The manuscript is accompanied by an Editorial by Pedro Marques and João Pedro Ferreira from the University of Porto, Portugal.11 The authors conclude that while BMI will be likely to remain the most used tool to classify and screen for obesity, a more nuanced approach to phenotyping and treatment of obesity in HFpEF is warranted. By incorporating additional metrics of central adiposity and continuing to refine our understanding of obesity-associated subphenotypes, it is possible to improve both the diagnosis and treatment of these patients, ultimately leading to better outcomes in this growing population. Despite guidelines recommending rapid initiation and up-titration of guideline-recommended medical therapy (GRMT) for HF with reduced ejection fraction (HFrEF), its feasibility in daily practice remains unclear.12–14 In a Clinical Research article entitled ‘Newly diagnosed heart failure with reduced ejection fraction: timing, sequencing, and titration of guideline-recommended medical therapy’, Jishnu Malgie from Erasmus University Medical Center, Rotterdam, The Netherlands, and colleagues explore the feasibility of rapid GRMT implementation in de novo HFrEF patients, investigating titration patterns and identifying barriers to effective treatment.15 This analysis focuses on the de novo HFrEF patients included in the TITRATE-HF study, an ongoing prospective HF registry conducted in 48 Dutch hospitals. A detailed logbook for each GRMT drug class was recorded, from diagnosis to 6 months, including initiations, dose adjustments, discontinuations, and reasons for changes. The study included ∼1500 de novo HFrEF patients (median age 70 years; 31% women; median left ventricular ejection fraction 30%). At 6 weeks, 46% of patients were using quadruple therapy. At 6 months, 66% of patients were prescribed quadruple therapy, but only 1.3% achieved target doses for all four drug classes. While side effects accounted for 20%–37% of cases where target doses were not reached, a large proportion was attributed to physicians accepting suboptimal doses. Drug titrations occurred frequently in the first 60 days after diagnosis, fading afterwards. Discontinuation rates for angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, angiotensin receptor–neprilysin inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and sodium–glucose co-transporter 2 inhibitors were 13, 11, 9, 9, 11, and 9%, respectively, primarily due to side effects or intolerances. Rechallenging these drug classes was successful in >83% of patients (Figure 2). Structured Graphical Abstract15 The authors conclude that the TITRATE-HF study demonstrates that rapid initiation of GRMT for HFrEF is feasible in real-world clinical practice. Nonetheless, this study highlights the urgency for a proactive approach and ongoing dose titration of pharmacological therapy beyond the initial first months to fully optimize treatment. The manuscript is accompanied by an Editorial by Kieran F. Docherty, Li Shen, and John J.V. McMurray from the University of Glasgow, UK.16 The authors highlight that while measuring performance is a start, we also need to think about how to improve it. Globally, multilevel, multifaceted approaches are likely to be required. However, local as well as general solutions are needed, targeted to specific institutions, health systems, and countries. In centralized healthcare systems, good performance can be incentivized and poor performance penalized. In many countries, other skilled healthcare professionals (e.g. nurses and pharmacists) can help. Digital tools such as prompts embedded in electronic health records may improve implementation (and facilitate audit and performance monitoring). However, individually, none of these interventions addresses all of the barriers to implementation. Patients have the greatest vested interest, and educated, empowered patients should be powerful allies. There is also a role for implementation trials. The pharmaceutical industry can also help and, in some countries, combination treatments are already available and, eventually, a polypill for HF might be useful. Diuretics play a key role in the treatment of HF.5,17–19 Limited data are available to assess oral diuretic response in outpatients with HF. The natriuretic response prediction equation (NRPE) predicts natriuresis following a loop diuretic dose using a urine sample 2 h after the dose and was validated to accurately predict intravenous diuretic response. In a Clinical Research article entitled ‘Natriuretic response prediction equation for use with oral diuretics in heart failure’, Juan B. Ivey-Miranda from Yale University School of Medicine in New Haven, CT, USA, and colleagues assess how to validate the NRPE’s assessment of oral diuretic response in patients with HF.20 The NRPE was evaluated in two HF patient cohorts receiving oral loop diuretics: Mechanisms of Diuretic Resistance (MDR) and TRANSFORM-Mechanism. Participants received their home oral loop diuretic followed by a supervised timed urine collection including spot urine samples at 1 and 2 h. Patients quantified their self-assessed diuretic response (urine volume) via a standardized survey. A poor diuretic response was defined as cumulative natriuresis <50 mmol over the study visit. The MDR cohort included 318 oral diuretic administrations from 237 patients. The NRPE predicted a poor natriuretic response with an area under the curve (AUC) of 0.87 and similar accuracy to the previously validated intravenous NRPE performance (P = .16). A patient’s ability to self-estimate their diuretic response was poor, with an AUC of 0.57 and significantly worse than the oral NRPE (P < 0.001). In TRANSFORM-Mechanism (110 oral diuretic administrations), the NRPE had similar operating characteristics (AUC 0.89) for poor diuretic response. The authors conclude that the natriuretic response to an oral diuretic can be rapidly and accurately assessed with a urine sample collected 2 h after an oral diuretic dose and the NRPE. The manuscript is accompanied by an Editorial by Frederik H. Verbrugge from the University Hospital Brussels, Belgium.21 The author highlights that the results of this important study change our practice. Indeed, it opens up the possibility to integrate an NPRE calculator in the electronic medical record to predict the natriuretic response to diuretics with only the need for a blood and post-diuretic urine sample. It remains to be seen whether such NPRE-guided treatment may favourably influence hard outcomes in patients with HF. The Randomized Controlled Trial of Urine Chemistry Guided Acute Heart Failure Treatment is currently underway to test this hypothesis. and is scheduled to report in the first half of 2027. Cardiac resynchronization therapy (CRT) produces long-term reverse remodelling with greater ATP delivery to the contractile machinery. Whilst the heart retains some metabolic flexibility in non-ischaemic cardiomyopathy, whether this correlates with reverse remodelling is unknown. In a Translational Science article entitled ‘Metabolic flexibility and reverse remodelling of the failing human heart’, Peregrine G. Green from the University of Oxford, UK, and colleagues investigate whether CRT acutely changes cardiac substrate uptake, and whether this translates to favourable reverse remodelling.22 The effect of CRT on cardiac substrate uptake was assessed via direct coronary flow and arteriovenous measurements, with metabolomic/lipidomic analysis on infusions of insulin/glucose and intralipid. Cardiac function was assessed with left ventricular pressure–volume loops during implantation, and cardiac magnetic resonance before and 6 months following CRT, with and without biventricular pacing. Regardless of substrate infusion, CRT acutely improved stroke work without increasing O2 uptake on both insulin/glucose (by 34%, P = .05) and intralipid (by 36%, P = .03). This was followed by a significant increase of fatty acid (FA) uptake on insulin/glucose and increased β-hydroxybutyrate uptake during intralipid infusion. After 6 months, there was a 48% (P < .001) reduction in left ventricular end-diastolic volume, beyond that achievable by acutely shortening or lengthening QRS duration. Reverse remodelling significantly correlated with increased FA uptake, with CRT on insulin/glucose driven by long and medium chain uptake, and increased ketone uptake with CRT on intralipid. The authors conclude that CRT acutely alters the metabolic phenotype of non-ischaemic cardiomyopathy towards a more physiological picture of FA uptake which correlates with reverse remodelling. Retained metabolic flexibility may therefore be critical for subsequent reverse remodelling. The manuscript is accompanied by an Editorial by Henrik Wiggers from Aarhus University Hospital, Denmark.23 The author concludes that we have relied on HF animal models that show beneficial effects of increasing glucose uptake in the failing myocardium. This concept is now challenged by the clinical work of Green and co-workers. Fatty acids in heart failure may be a friend, not foe. Hopefully, future research will provide us with more firm clinical evidence. Due to their role in muscle sarcomeres and in the dynamic cytoskeleton, the myosin superfamily of molecular motors is essential for muscle contractions and, as such, indispensable for the heart to beat. In a Translational Science article entitled ‘Cardiac dysfunction related to cardiac mRNA and protein traffic impairment due to reduced unconventional motor protein myosin-5b expression’, Maren Heimerl from Hannover Medical School, Germany, and colleagues analyse the expression patterns of class-5 myosin motor protein (MYO5b) in the heart.24 RNA-sequencing, quantitative real-time polymerase chain reaction, immunohistochemistry, western blot, immunoprecipitation, and proteomics were performed in mice and human tissues. Functional analyses were performed in mice with a cardiac-specific knockout (KO) of MYO5b, wild-type mice, and in isolated adult cardiomyocytes. Next-generation sequencing screened for MYO5B gene variants in a cohort of sudden cardiac death in the young/sudden infant death syndrome patients. The expression of MYO5b increased during post-natal cardiomyocyte maturation. MYO5b was reduced in end-stage failing human hearts and infarcted murine hearts. Heterozygous rare and probably pathogenic missense MYO5B gene variants were identified in three patients of a cohort of young patients who died of sudden cardiac death in the young/sudden infant death syndrome. The MYO5b-KO mice revealed impaired electric conductance and metabolism, and developed sarcomeric disarrangement, heart failure, and death with altered mRNA levels for genes involved in sarcomere organization, FA, and glucose metabolism, ion channel subunits, and Ca2+ homeostasis prior to HF. The authors conclude that MYO5b is the major MYO5 gene expressed in post-natal cardiomyocytes where it transports vesicles, proteins, and multi-protein complexes. Among these are complexes affecting electric conductance, sarcomere homeostasis, cell metabolism, and cytoskeletal organization. Impairment in MYO5b expression and function promotes cardiac dysfunction, heart failure, and death. The manuscript is accompanied by an Editorial by Thomas Thum from Hannover Medical School, Germany.25 The author concludes that the discovery that MYO5b governs mRNA and protein trafficking in the heart represents an important addition to our understanding of cardiac function. By regulating metabolic homeostasis, sarcomere integrity, and electrical conduction, MYO5b emerges as a key player in maintaining cardiac health. The identification of MYO5B mutations in patients experiencing sudden cardiac death further underscores its clinical significance and should be explored further. Metals serve as cofactors for a host of metalloenzymes involved in mitochondrial metabolic reprogramming. Modifications in metal homeostasis are linked to epigenetic mechanisms. In a Translational Science article entitled ‘SLC31A1 loss depletes mitochondrial copper and promotes cardiac fibrosis’, Bin Tu from The Second Affiliated Hospital of Anhui Medical University in Hefei, China and colleagues focus on the poorly understood epigenetic mechanisms through which metal affects cardiac fibrosis.26 The metal content of mouse heart samples was measured using inductively coupled plasma mass spectrometry. Lower copper concentrations were accompanied by SLC31A1 down-regulation and mitochondrial copper depletion leading to cardiac fibrosis. Fibroblast-specific SLC31A1 deficiency enhanced mitochondrial copper depletion, augmented glycolysis, promoted fibroblast proliferation, and triggered cardiac fibrosis. The authors conclude that this study identifies a novel epigenetic mechanism through which copper deficiency increases mitochondrial copper depletion and promotes cardiac fibrosis. Findings provide new insights for the development of preventive measures for cardiac fibrosis.This manuscript is accompanied by an Editorial by Julian U.G. Wagner from Goethe University Frankfurt, Germany.27 The author notes that the study by Tu et al. thoroughly demonstrates the importance of ion metabolism and mitochondrial function in the development of cardiac fibrosis. The study shows on multiple levels how cardiovascular diseases trigger epigenetic changes that lead to copper depletion in mitochondria of cardiac fibroblasts. The disturbed copper availability not only results in impaired mitochondrial function but was also shown to have epigenetic potential by acting on histones. These data provide ample possibilities to tackle the development of cardiac fibrosis and might be the path towards novel therapeutic options. The issue is also complemented by two Discussion Forum contributions. In a commentary entitled ‘Post-capillary pulmonary hypertension in heart failure: addressing statistical and methodological issues in research’, Guang Xiong from The First Affiliated Hospital of Guangxi Medical University, China, commented on the recent publication ‘Post-capillary pulmonary hypertension in heart failure: impact of current definition in the PH-HF multicentre study’, by Charles Fauvel from Rouen University Hospital, France and Centre Hospitalier Universitaire de Lille, France, and colleagues.28,29 Fauvel and Lamblin reply in a separate comment.30 The editors hope that this issue of the European Heart Journal will be of interest to its readers. Dr. Crea reports speaker fees from Abbott, Amgen, Astra Zeneca, BMS, Chiesi, Daiichi Sankyo, Menarini outside the submitted work. With thanks to Lindsay Washington, Johanna Huggler, Amelia Meier-Batschelet, and Martin Meyer for help with compilation of this article.