Ischaemic heart disease: focus on colchicine, drug-coated balloons, and novel therapeutic targets

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Focus Issue on ischaemic heart disease and acute cardiovascular care contains a Special Article entitled ‘Definitions and standardized endpoints for the use of drug-coated balloon in coronary artery disease: consensus document of the Drug Coated Balloon Academic Research Consortium’ by Simone Fezzi from the University of Galway, Ireland, and colleagues.1 The utilization of drug-coated balloons is generating growing interest,2–5 This article is a collaborative effort between academic research organizations and percutaneous coronary intervention societies in Europe, the USA, and Asia. The goal is to standardize study designs and endpoints for clinical trials involving drug-coated balloons, including defining angiographic, intravascular, and non-invasive imaging methods for lesion assessment, alongside considerations for post-revascularization pharmacotherapy. The concept of ‘blended therapy’, which advocates for combining device strategies, is also discussed. This paper delineates study types, endpoint definitions, follow-up protocols, and analytical approaches, aiming to provide consistency and guidance for interventional cardiologists and trialists. Acute right ventricular failure is a complex and rapidly progressive clinical syndrome, whereby the right ventricle fails to provide adequate left ventricular pre-load, dilates, and causes systemic venous congestion. In a State of the Art Review article entitled ‘Acute right ventricular failure: pathophysiology, aetiology, assessment, and management’, George Giannakoulas from Aristotle University of Thessaloniki, Greece, and colleagues explore how previous research in acute heart failure has primarily focused on the left ventricle.6 Yet, a better understanding of right ventricular anatomy, physiology, and pathophysiology, as well as of the diagnosis and management of its acute failure is crucial. Diagnosis mandates a high degree of clinical suspicion, as most signs and symptoms are non-specific. An accurate and prompt identification of the underlying causes, including pulmonary embolism, right ventricular myocardial infarction (MI), acute respiratory distress syndrome, post-cardiac surgery, and decompensated chronic pulmonary hypertension, is therefore essential. This review provides insights into right ventricular anatomy and function and discusses the pathophysiology of acute right ventricular failure, together with its different aetiologies, clinical presentations, diagnosis, and treatment. By 2050, individuals aged 65 and older are projected to constitute >20% of the US population and 29% of the European population, leading to a higher prevalence of chronic diseases, including cardiovascular disease. In a State of the Art Review article entitled ‘Healthy ageing in older adults with cardiovascular disease’, Nathalie Schmanske from the Cleveland Clinic Foundation in Cleveland, OH, USA, and colleagues state that as life expectancy continues to increase due to advancements in medical technology, public health, nutrition, and socioeconomic progress, the population of older adults in the USA and Europe is rapidly growing.7 Cardiovascular disease, the leading cause of death in the USA, poses significant challenges to healthy ageing by contributing to accelerated biological ageing and the development of geriatric syndromes. This state-of-the-art review aims to (i) define healthy ageing for older patients living with cardiovascular disease; (ii) compare chronological vs. biological ageing as it pertains to cardiovascular disease; (iii) describe the impact of geriatric syndromes and provide an approach to management and prevention; and (iv) address the gaps in knowledge and future directions for potential interventions that could promote healthy ageing. Over the last decade, inflammation has emerged as an important therapeutic target for the management of atherosclerotic coronary artery disease.8–17 In a Fast Track Clinical Research article entitled ‘Long-term trials of colchicine for secondary prevention of vascular events: a meta-analysis’, Michelle Samuel from the University of Groningen, The Netherlands, and colleagues focus on colchicine which has emerged as a safe and inexpensive anti-inflammatory medication to target the residual risk of cardiovascular events in the secondary prevention of coronary artery disease.18 New evidence was synthesized in a systematic review and meta-analysis to determine the long-term efficacy and safety of colchicine for the secondary prevention of vascular disease. Randomized controlled trials comparing the incidence of cardiovascular events between patients with clinically manifest vascular disease randomized to colchicine vs. placebo and ≥12 month follow-up were included. The primary efficacy endpoint is major adverse cardiovascular events (MACE) and includes cardiovascular mortality, MI, ischaemic stroke, and urgent coronary revascularization. The DerSimonian and Laird random effects model was used to calculate pooled effect estimates. Six randomized controlled trials (RCTs), with a pooled sample size of 21 800 patients, were included. Over a follow-up of 12–34 months, colchicine reduced the incidence of MACE compared with placebo (pooled hazard ratio 0.75). The reduction in cardiovascular events among colchicine patients was driven by reductions in MIs, ischaemic strokes, and urgent coronary revascularizations (P < 0.05 for all). No differences were detected for safety outcomes (P > .05 for all), including non-cardiovascular deaths (relative risk [RR] 1.08). The authors conclude that this updated meta-analysis of RCTs demonstrates a substantial reduction in MACE, MI, ischaemic stroke, and recurrent coronary revascularization with colchicine compared with placebo. Therefore, the results support the use of colchicine to reduce recurrent cardiovascular events. In another Fast Track Clinical Research article on colchicine entitled ‘Colchicine for secondary prevention of vascular events: a meta-analysis of trials’, Marc-André d’Entremont from McMaster University in Ontario, Canada, and colleagues analyse RCTs of colchicine in secondary prevention of atherosclerotic cardiovascular disease not limited to those with long-term follow up.19 A systematic review and study-level meta-analysis of RCTs was performed comparing colchicine vs. no colchicine in a secondary prevention atherosclerotic cardiovascular disease population. A fixed-effect inverse variance model was applied using the intention-to-treat population from the included trials. The primary outcome was the composite of cardiovascular death, MI, or stroke. Nine trials, including 30 659 patients with known coronary artery disease or stroke, were included. Compared with no colchicine, patients randomized to colchicine had an RR of 0.88 (P = .002) for the primary composite outcome, with an RR of 0.94 for cardiovascular death (P = .5), an RR of 0.84 for MI (P = .016), and an RR of 0.90 for stroke (P = .09). Colchicine was associated with an RR of 1.35 for hospitalization for gastrointestinal events (P = 0.004), with no increase in hospitalization for pneumonia, newly diagnosed cancers, or non-cardiovascular death (Figure 1). Structured Graphical Abstract19 The authors conclude that in patients with prior coronary disease or stroke, colchicine reduces the composite of cardiovascular death, MI, or stroke by 12%. Both meta-analyses are accompanied by an Editorial by Stuart J. Pocock and Guiomar Mendieta from the London School of Hygiene & Tropical Medicine, UK and Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) in Madrid, Spain.20 The authors underline that the benefits of colchicine treatment appear largely confined to coronary artery disease patients, mainly post-MI. While the reductions in risk of MI and coronary revascularization are statistically significant, they are modest absolute benefits and are not backed up by any corresponding evidence regarding mortality and stroke. No safety signals of serious concern have been found, and the increase in absolute risk in hospitalization for gastrointestinal events is low. Previous studies have suggested that serine carboxypeptidase 1 (Scpep1) is involved in vascular diseases; however, its role in cardiac diseases remains unclear. In a Translational Science article entitled ‘Scpep1 inhibition attenuates myocardial infarction-induced dysfunction by improving mitochondrial bioenergetics’, Guilin Chen from Wenzhou Medical University, China, and colleagues aim to explore the role of Scpep1 in regulating cardiac homeostasis during MI.21 The impact of Scpep1 deficiency or cardiac-specific knockdown and Scpep1 overexpression on heart function was evaluated in mice with MI. The downstream functional mediators of Scpep1 were elucidated using proteomic analysis and confirmed by employing loss- and gain-of-function strategies. Circulating and cardiac Scpep1 levels were up-regulated in mice with MI. Genetic ablation or cardiac-specific knockdown of Scpep1 alleviated MI-induced cardiac dysfunction and damage in mice. In contrast, cardiac-specific Scpep1 overexpression aggravated these adverse effects. Mechanistically, Scpep1 exacerbated MI-induced cardiac dysfunction and damage by impaired mitochondrial bioenergetics via binding to Pex3 to promote its degradation, ultimately contributing to mitochondrial fission and apoptosis. Moreover, the expressional profiles of Scpep1 in plasma samples and heart tissues of patients with MI or ischaemic cardiomyopathy were in line with those observed in the mouse models. In addition, pharmaceutical inhibition of Scpep1 notably improved MI-induced cardiac dysfunction and damage by improving mitochondrial fragmentation and bioenergetics post-MI (Figure 2). Cardiac lysosome-derived Scpep1, a novel lysosomal serine carboxypeptidase, contributes to MI-induced cardiac dysfunction and damage by reducing Pex3 protein levels, promoting mitochondrial fragmentation, and suppressing bioenergetics. Thus, pharmacological inhibition of Scpep1 by KT-182, a selective inhibitor of Scpep1, protects against MI. Scpep1, serine carboxypeptidase 1; MI, myocardial infarction; DRP1, dynamin-related protein 1; FIS1, mitochondrial fission 1; OPA1, optic atrophy 1; MFN, mitofusin; ETC, electron transport chain; OXPHOS, oxidative phosphorylation; ATP, adenosine triphosphate; Cyt, cytochrome c; Cas3/9, cleaved caspase 3/921 The authors conclude that Scpep1 deficiency mitigates MI by improving Pex3-mediated mitochondrial fission and subsequent cardiomyocyte apoptosis. Scpep1 constitutes a potential therapeutic target for attenuating MI-induced cardiac dysfunction. This manuscript is accompanied by an Editorial by Christopher G.R. Perry and Gary Sweeney from York University in Toronto, Canada.22 The authors highlight that the results of the study by Chen et al. identify a new signalling axis mediating MI-related cardiomyopathy. Specifically, the finding that Scpep1 ablation is cardioprotective whereas Scpep1 exacerbates cardiac trauma following an MI opens up a new therapeutic direction for treating this debilitating condition. The study underscores the significance of mitochondrial fission and fragmentation, particularly noting that the absence of Scpep1 significantly alleviated the increase in mitochondrial fission induced by MI, while also leading to a reduction in mitochondrial fusion. This observation is supported by the elevated levels of mitochondrial fusion markers and the diminished levels of fission markers in the cardiac tissue of Scpep1 knockout mice. The pre-clinical evidence using a Scpep1 inhibitor supports continued research into treatments targeting this mechanistic axis. New mechanistic questions arise related to the role of lysosomal serine proteases in mediating cardiomyopathy in response to MI, particularly in relation to low oxygen availability that occurs during ischaemia. Preliminary evidence of mitochondrial responses to altered Scpep1 activity during anoxia or following MI support further research into more precise mechanisms by which mitochondria contribute to MI-related pathology, and whether Scpep1 targeting of mitochondrial Pex3 may mediate this relationship. The issue is also complemented by two Discussion Forum contributions. In a commentary entitled ‘Does revascularization improve survival in adult frail patients with acute coronary syndrome?’, Juan Sanchis, Héctor Bueno, and Albert Ariza-Solé from the University of València, Spain, Centro Nacional de Investigaciones Cardiovasculares (CNIC) in Madrid, Spain, and L’Hospitalet de Llobregat, in Barcelona, Spain, comment on the recent contribution ‘Revascularization in frail patients with acute coronary syndromes: a retrospective longitudinal study’ by Marius Roman from the University of Leicester in the UK.23,24 Roman et al. reply in a separate comment.25 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.