Prevent, predict, perform: novel strategies to combat heart failure

Heart failure (HF) is far more than a cardiac condition. It is a complex syndrome driven by haemodynamic stress, metabolic and inflammatory dysregulation, and the intricate interplay of comorbidities. In this issue of the European Journal of Preventive Cardiology, we highlight the value of integrated, personalized strategies that combine biomarker-guided risk assessment, precision pharmacotherapy, and structured non-pharmacologic interventions. Sodium intake remains a critical modifiable factor in HF management. In their review, ‘Differential cardiovascular impacts of sodium salts: unveiling the distinct roles of sodium chloride and sodium bicarbonate—consequences for heart failure patients’, Sadki et al.1 from France highlight that sodium chloride and sodium bicarbonate exert fundamentally different physiological effects. Sodium chloride is known to increase blood pressure, extracellular volume, and RAAS activity. Sodium bicarbonate is haemodynamically neutral, supports muscle preservation, slows kidney function decline, and lowers all-cause mortality in HF patients with chronic kidney disease. The authors recommend shifting towards a specific perspective regarding the salt structure rather than focusing solely on total sodium intake. Behavioural factors can influence HF risk. In ‘Increased fluid accumulation, reduced physical activity and heart rate variability during national holidays in patients with cardiac implantable electronic devices’, Olsson et al.2 from Sweden examined cardiac implantable electronic device measures during national holidays and observed transient decreases in thoracic impedance, heart rate variability, and daily activity, alongside modest reductions in daytime heart rate. Approximately 10% of all values reached thresholds associated with higher HF risk, suggesting that even short-term lifestyle changes can alter the heart’s physiology and may partly account for increased rates of adverse cardiovascular events during holidays. Biomarker-driven approaches improve HF prediction. In ‘Evaluation of large-scale plasma proteomics for prediction of heart failure in individuals with a full range of glucose metabolism profiles’, Zhang et al.3 from China used large-scale plasma proteomics from the UK Biobank and identified a panel of four proteins (NT-proBNP, LTBP2, REN, and GDF15) that, when combined with clinical factors, stratified individuals into high- and low-risk groups with excellent predictive performance (AUC 0.823). These proteins were found to be associated with pathways of cardiac growth, remodelling, oxidative stress, and inflammation, suggesting their importance in identifying and potentially managing individuals at risk. Complementing proteomics, ketone bodies (KBs) have emerged as metabolic biomarkers with additive prognostic value. In ‘Integrating ketone bodies in multi-marker risk prediction of incident heart failure in the multi-ethnic study of atherosclerosis’, Chevli et al.4 from the USA demonstrated that circulating KB, incorporated with NT-proBNP and high-sensitivity troponin in a multi-marker risk score, enhanced 5- and 10-year HF risk prediction. Higher KB concentrations may reflect systemic metabolic dysfunction beyond adaptation and compensation, contributing to metabolic imbalance in HF pathophysiology and highlighting the value of combined biomarker strategies. Gut microbiome-derived metabolites have been recognized as contributors to HF risk. In ‘Risk calculator of multimorbid risk of rehospitalization and death from heart failure: including the contribution of the gut microbiome’, Israr et al.5 developed a risk calculator integrating traditional clinical variables with gut microbiome metabolites, identifying 11 key predictors for 1-year mortality and HF rehospitalization. This tool outperformed conventional models and showed the prognostic value of microbiome-based biomarkers, reinforcing the concept that multi-system interactions, beyond the heart itself, influence HF. Pharmacologic innovations continue to improve outcomes in high-risk populations. Among those, patients with cancer are of particular concern. Bhalraam et al.6 from the UK performed a comprehensive review and meta-analysis of SGLT2 inhibitors in patients with—or with a history of—cancer in ‘Impact of sodium–glucose cotransporter-2 inhibitors on heart failure outcomes in cancer patients and survivors: a systematic review and meta-analysis’. They demonstrated significant reductions in HF hospitalizations (NNT = 39), new HF diagnoses (NNT = 15), and all-cause mortality (NNT = 4). The most benefits observed were patients with breast cancer treated with anthracycline. These results highlight the cardioprotective potential of SGLT2 inhibitors in vulnerable populations exposed to cardiotoxic treatments (Figure 1). Meta-analysis of SGLT2 inhibitor studies on heart failure hospitalizations in cancer patients. This forest plot summarizes eight studies (2022–24) comparing SGLT2 inhibitors to control in cancer patients. The analysis, involving 3374 SGLT2i and 5802 control patients, shows a significant reduction in heart failure events with SGLT2 inhibitor use (RR, 0.49; 95% CI, 0.36–0.66). Individual study risk ratios range from 0.15 to 1.58 with Avula et al. (2023) carrying the highest weight (42.1%). Low to moderate heterogeneity was observed (I² = 28%; P = 0.21). The diamond representing the overall effect clearly favours SGLT2 inhibitors over control, suggesting a protective effect against heart failure events in cancer patients. The number needed to treat is 39. Lifestyle modifications continue to serve as essential complements to drug treatment. In ‘Isometric exercise training in patients with heart failure with preserved ejection fraction: a randomized controlled study’, Edwards et al.7 from the UK demonstrated that a 4-week home-based isometric exercise training (IET) programme in HFpEF patients safely improved resting systolic pressure (− 8.5 ± 2.7 mmHg), mean (− 4.9 ± 2.0 mmHg) and diastolic blood pressure (−4.6 ± 1.8 mmHg), reduced total peripheral resistance, and enhanced advanced echocardiographic measures, including global longitudinal strain, left atrial reservoir strain, and global work efficiency. Structured exercise improves functional capacity in HFpEF regardless of chronotropic incompetence. In a substudy of the OptimEx-Clin trial, ‘Effect of structured exercise training on chronotropic incompetence in patients with heart failure with preserved ejection fraction’, Nasser et al.8 from Belgium showed that both high-intensity interval training (HIIT) and moderate continuous training (MCT) increased peak V̇O₂ (+8–11%) and peak workload (+9 W) over 3 months in 175 elderly patients with HFpEF, while chronotropic dysfunction remained unchanged, highlighting that longer or alternative interventions may be required to restore chronotropic reserve. Exercise training in specialized populations also brings measurable benefits. In ‘Comparative effectiveness of exercise training modalities in heart transplant recipients: a systematic review and network meta-analysis of randomized controlled trials’, De Lima et al.9 from Brazil performed a network meta-analysis of 13 randomized controlled trials with 473 heart transplant recipients and found that both high intensity training (HIT) and combined training (CT) modalities provided the most significant improvements in peak VO₂ (+4.34 mL/kg/min and +3.49 mL/kg/min respectively), as compared with usual care. Also, HIT was superior to moderate-intensity continuous training (MICT) in improving peak VO₂ by an additional 2.09 mL/kg/min. Other modalities (MICT, home-based MICT, and home-based CT) did not significantly outperform usual care. In their report entitled ‘Effect of exercise training in patients with chronotropic incompetence and heart failure with preserved ejection fraction: the TRAINING-HR randomized clinical trial’, Palau et al.10 from Spain further confirmed in 80 symptomatic patients with HFpEF with chronotropic incompetence that supervised multimodal exercise significantly improves exercise capacity. Aerobic, resistance, and inspiratory muscle training significantly improved peak VO₂ (+4.0 mL/kg/min vs. non-supervised), the chronotropic response (Δ-HR +12 b.p.m.), and quality of life (+11–13 KCCQ points). No serious adverse events in HFpEF patients with chronotropic incompetence were reported, highlighting the additive value of supervised interventions. Targeted management of comorbidities is equally of paramount importance. In a prospective HFpEF outpatient cohort study entitled ‘The diagnostic yield of an elaborate workup for comorbidities in a real-life heart failure with preserved ejection fraction outpatient population’, Mourmans et al.11 from the Netherlands reported that in 501 patients who, before evaluation, had a median of three known comorbidities, structured screening identified an additional comorbidity per patient. The most common conditions were also inadequately treated (e.g. sleep apnoea and iron deficiency). Systematic comorbidity assessment was associated with improved individualized management, supporting the holistic care in optimizing HF outcomes. Heart failure has been associated with a higher burden of systemic complications beyond the cardiovascular system, and observational data suggest that up to 16.5% of cancer cases may occur in individuals with pre-existing HF. In a nationwide French cohort study, ‘Increased cancer incidence in patients with pre-existing heart failure: results from a French nationwide cohort study’, Mirabel et al.12 demonstrated that patients with established HF have a significantly elevated risk of developing malignancies, such as colorectal, lung, and haematologic cancers, and also higher all-cause mortality [adjusted HR 1.33 (1.30–1.36)]. Physicians taking care of patients with HF should be aware of this increased risk and sensitive to any clinical hint suggestive for cancer in these patients. All these studies emphasize the concept of a multi-systemic approach to heart failure, which should not be focused only on cardiac incompetence per se. The editors warmly invite readers to read in depth these papers, along with the rapid communications and letters featured in this issue of EJPC. Victor Aboyans (Writing—review & editing [supporting])) and Marina M. Ostojic (Writing—original draft [lead])