New treatments and biomarkers in heart failure, hypertrophic cardiomyopathy, and familial hypercholesterolaemia

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Focus Issue on heart failure and cardiomyopathies, epidemiology, prevention, and healthcare policies contains a State of the Art Review article entitled ‘Therapeutic left-to-right shunting in heart failure’ by Francesco Fioretti from ASST Spedali Civili Hospital and University of Brescia, Italy, and colleagues.1 Heart failure (HF) with reduced or preserved ejection fraction is associated with elevated left atrial pressure at rest due to fluid overload or during exercise, leading to pulmonary venous congestion. Even with available treatments, HF hospitalizations remain high, and improvements in quality-of-life scores and functional capacity are modest.2–10 Thus, there is growing interest in non-pharmacological methods to decompress the left atrium and improve HF symptoms and outcomes. Left-to-right shunts have emerged as a potential therapeutic option to reduce left atrial hypertension, improve quality of life, and impact long-term outcomes. This nascent field carries both potential therapeutic promise and many unanswered questions. Recent data have questioned whether the effects of this therapy vary based on the left ventricular ejection fraction, pulmonary vascular resistance, and/or right ventricular structure and function. This review discusses the basis for left-to-right shunt therapies, synthesizes past and ongoing clinical trials, and offers future directions (Figure 1). Therapeutic left-to-right shunting in heart failure. CS, coronary sinus; CT, computed tomography; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; IAS, interatrial septum; IASD, interatrial shunt device; LA, left atrium; LAP, left atrial pressure; RA, right atrium; RCT, randomized controlled trial.1 The feasibility and impact of high intensity exercise programmes in patients with hypertrophic cardiomyopathy (HCM) are unknown. In a Clinical Research article entitled ‘High intensity exercise programme in patients with hypertrophic cardiomyopathy: a randomized trial’, Joyee Basu from St George’s, University of London, UK, and colleagues conducted a study to determine the feasibility of a high intensity exercise programme and explore safety and efficacy outcomes in patients with HCM.11 Participants were randomized to a 12 week supervised exercise programme (n = 40) in addition to usual care, or usual care alone (n = 40). All participants underwent assessment at baseline and 12 weeks. The exercise group was re-evaluated 6 months post-programme. The primary exploratory safety outcome was a composite of arrhythmia-related events. Exploratory secondary outcomes included changes in (i) cardiorespiratory fitness; (ii) cardiovascular risk factors; and (iii) quality of life, anxiety, and depression scores. Overall, 67 (84%) participants completed the study. There was no difference between groups for the exploratory safety outcome (P = .99). At 12 weeks, the exercise group had a significantly greater increase in peak oxygen consumption (VO2) (+4.1 mL/kg/min) and VO2 at anaerobic threshold (+2.3 mL/kg/min), lower systolic blood pressure (−7.3 mmHg) and body mass index (−0.8 kg/m2), and greater improvement in anxiety and depression scores, compared with the usual care group. Most exercise gains dissipated at 6 months (Figure 2). Change in cardiovascular risk factor profile, cardiorespiratory fitness, psychological scores, and occurrence of arrhythmias in individuals with HCM following participation in a 12 week supervised high intensity programme. AT, anaerobic threshold; BP, blood pressure; BMI, body mass index; CV, cardiovascular; HADS, Hospital Anxiety and Depression Scale.11 The authors concluded that a high intensity exercise programme is feasible in patients with HCM, with apparent cardiovascular and psychological benefits, and no increase in arrhythmias. This manuscript is accompanied by an Editorial by Iacopo Olivotto and Flavio D’Ascenzi from Meyer Children’s Hospital IRCCS in Florence, Italy and the University of Siena, Italy.12 The authors note that the study by Basu et al. contributes new perspectives, beyond safety, to the concept of personalized training in HCM, including feasibility and adherence. However, certain limitations should be noted, partly due to the inherent challenges of such studies, emphasizing the need for larger, more systematic trials. Notably, the study was not powered to assess a difference in arrhythmic events between arms; this is a constant hurdle, given the low event rates in HCM populations. A recent randomized trial of moderate and high intensity exercise training demonstrated an improved fitness without clear superiority of either modality, suggesting that moderate intensity programmes may suffice in promoting well-being and a healthy lifestyle in HCM individuals, particularly in the presence of risk factors advising avoidance of high intensity efforts. Identification of individuals affected by familial hypercholesterolaemia (FH) and their treatment are complex.13–16 Relying only on LDL cholesterol (LDL-C) is challenging as it may not allow distinguishing individuals with FH from hypercholesterolaemic (HC) individuals from the general population. In a Clinical Research article entitled ‘Fibroblast growth factor 5: a novel biomarker for familial hypercholesterolaemia’, Andrea Baragetti from the University of Milan, Italy, and colleagues performed a study to determine whether biomarkers associated with cardiovascular disease (CVD) and/or inflammation identify FH individuals and distinguish them from HC individuals.17 A panel of 264 proteins in plasma was measured and machine learning was used to search for those that can distinguish FH individuals, either genetically proven (genFH) or clinically diagnosed (clinFH), from HC and control individuals. Both genFH and clinFH had elevated plasma levels of fibroblast growth factor 5 (FGF-5) compared with controls (mean area under the curve [AUC] > .990 for both, P < .001) or HC individuals (mean AUC > .990, P < .001), even after matching for LDL-C levels. The authors conclude that FGF-5 could be a biomarker to discriminate individuals with FH from HC individuals. Hypertriglyceridaemia (HTG) is associated with higher cardiovascular risk. Guidelines focus on individuals with triglycerides between 2.3 and 5.6 mmol/L (200 and 499 mg/dL). In a Clinical Research article entitled ‘Expanding the triglyceride range in clinical trials: therapeutic opportunities’, Ask Nordestgaard from Brigham and Women’s Hospital in Boston, MA, USA and colleagues, address the hypotheses of whether triglycerides, not only within this constrained range but also across the full biological range, are associated with cardiovascular risk.18 Multivariable-adjusted hazard ratios for major cardiovascular events (MACE) and death according to baseline triglycerides among ∼180 000 individuals with triglycerides across the full biological range were calculated. Increasing triglycerides across the full range (0.3–11.2 mmol/L) were associated with an increasing risk of MACE. Hazard ratios for major cardiovascular events from lowest to highest triglyceride quartile were 1.0 (referent [range: < 2.5 mmol/L]), 0.95 (range: 2.5 to <3.0 mmol/L), 1.04 (range: 3.0 to <3.6 mmol/L), and 1.13 (range: ≥ 3.6 mmol/L). The authors conclude that future triglyceride-lowering therapy trials may want to consider enrolment across a wider range of triglyceride levels if there is no prior history of pancreatitis or excessive alcohol intake. The manuscript is accompanied by an Editorial by Gerald Watts and Dick Chan from the University of Western Australia.19 The authors note that the cornerstone of treating HTG is weight regulation, increased physical activity, and correction of secondary causes, particularly diabetes and alcohol excess. Many patients with broad-ranging HTG have multiple comorbidities related to central adiposity, diabetes, and metabolic syndrome. For these, intensive lifestyle modifications with adjunctive use of glucagon-like peptide-1 receptor agonist-based therapies may be the treatment regimen of choice for effectively reducing weight, HTG, glycaemia, blood pressure, and MACE. However, even with such an approach and guideline-recommended treatments, there will probably be a degree of residual risk due to HTG related to insufficient weight loss or imperfectly controlled diabetes. Whether this risk is responsive to RNA therapeutics targeted at apolipoprotein C3 and angiopoietin-like protein 3 remains to be tested using appropriately designed trials. Cardiovascular disease, the leading cause of death globally, is sensitive to heat exposure.20 In a Clinical Research article entitled ‘High temperature and cardiovascular disease in Australia under different climatic, demographic, and adaptive scenarios’, Jingwen Liu from The University of Adelaide, Australia, and colleagues assess the burden of CVD attributable to high temperatures across Australia and project future burden in the context of climate change.21 Disability-adjusted life years for CVD, including years of life lost and years lived with disability, were sourced from the Australian Burden of Disease database. A meta-regression model was constructed using location-specific predictors and relative risks from prior literature to estimate relative risks of CVD mortality and morbidity due to high temperatures in the Australian context. The baseline CVD burden attributable to high temperatures in Australia for 2003–18 was calculated, and future burdens under two greenhouse gas emissions scenarios (Representative Concentration Pathways [RCP4.5 and RCP8.5]) for the 2030s and 2050s were projected, considering demographic changes and human adaptation. During the baseline period, high temperatures accounted for 7.3% of the CVD burden in Australia, equivalent to 223.8 disability-adjusted life years per 100 000 population. Future projections suggest a steady increase in the CVD burden across all scenarios examined. By the 2050s, under the RCP8.5 scenario that considers population growth and no adaptation, the total attributable burden of CVD is projected to more than double compared with the baseline, with the Northern Territory facing the most significant increase. These impacts could be mitigated with effective human adaptation to the warming climate. Higher temperatures are expected to exacerbate the burden of CVD. The authors conclude that this study highlights the need for urgent adaptation and mitigation efforts to minimize the negative health impacts of a warming climate on CVD. In a Rapid Communication article entitled ‘Autophagy is required for the therapeutic effects of the NAD+ precursor nicotinamide in obesity-related heart failure with preserved ejection fraction’, Mahmoud Abdellatif from the Medical University of Graz, Austria, and colleagues, note that HF with preserved ejection fraction (HFpEF) is the predominant form of cardiac failure, with limited evidence-based therapies.5,22 Clinical HFpEF is associated with low levels of cardiac nicotinamide adenine dinucleotide (NAD+), and oral supplementation of nicotinamide, an NAD+ precursor, improves pre-clinical HFpEF in several rodent models. However, NAD+ is a pleiotropic molecule and its molecular mode of action against HFpEF remains elusive. Because autophagy is an NAD+-stimulated mechanism that is essential for maintaining cellular homeostasis, particularly in post-mitotic and metabolically stressed cardiomyocytes, the authors speculate that an increase of autophagic flux might contribute to the efficacy of NAD+ supplementation against HFpEF. The authors show that HFpEF development in ZSF1 obese rats was associated with attenuated autophagic activity in the heart, and that reinstating cardiac autophagy with low dose nicotinamide reduced HFpEF severity. Deploying cardiac RNA-seq transcriptome analysis and transgenic autophagy reporter mice, the authors uncovered that attenuated insulin-like growth factor-1 signalling mediates cardiac autophagy induction by nicotinamide. The authors also evaluated the clinical relevance of these observations by analysing circulating NAD+ metabolites in a cohort of obese patients with HFpEF showing that nicotinamide depletion was associated with a more severe HFpEF phenotype and poor prognosis. The authors conclude that the results of this study reaffirm the therapeutic potential of stimulating autophagy through down-regulation of excessive nutrient signalling in cardiometabolic HFpEF, and align with the proposed mechanism of action for gliflozins, the first evidence-based therapy for HFpEF. The issue is also complemented by two Discussion Forum contributions. In a commentary entitled ‘Cardiovascular safety of assisted reproductive technologies: what have we learned and what remains unknown?’, Zhenjiao Liang, Dongna Wang, and Xiaoping Wang from Zhongshan Xiaolan People’s Hospital, China commented on the recent publication ‘Cardiovascular safety of assisted reproductive technologies: what is next?’, by Carlo Andrea Pivato and Giulio Stefanini from Humanitas University in Milan, Italy.23,24 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 Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article.