Focus on ischaemic heart disease: secondary prevention, cardiogenic shock, 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, ACVC, vascular biology, and medicine contains the Special Article entitled ‘Management of aortic disease in children with FBN1-related Marfan syndrome’ by Laura Muiño-Mosquera from Ghent University Hospital in Belgium, and colleagues.1 The authors note that Marfan syndrome (MFS) is a hereditary connective tissue disorder with an estimated prevalence of 1:5000–1:10 000 individuals. Marfan syndrome is caused by pathogenic variants in the FBN1 gene encoding the extracellular matrix (ECM) protein fibrillin-1 which is ubiquitous throughout the organism, thereby accounting for the diverse spectrum of manifestations associated with this condition. The diagnosis is usually clinical and based on the revised Ghent nosology. Clinical diagnosis, however, might be challenging because systemic features can be subtle or absent in very young children. Some children might also be diagnosed through predictive genetic testing, following the identification of an affected family member. The most common cardiovascular complication is aortic root dilatation which, untreated, can lead to life-threatening aortic root dissection, mainly occurring in adult patients. Prompt diagnosis, appropriate follow-up, and timely treatment can prevent aortic events. Currently there are no specific recommendations for treatment of children with MFS, and management is greatly based on adult guidelines. Furthermore, due to the scarcity of studies including children, there is a lack of uniform treatment across different centres. This consensus document aims at bridging these gaps of knowledge. This work is a joint collaboration between the paediatric subgroup of the European Network of Vascular Diseases (VASCERN, Heritable Thoracic Aortic Disease Working Group) and the Association for European Paediatric and Congenital Cardiology (AEPC). A group of experts from 12 different centres and eight different countries participated in this effort. This document reviews four main subjects, namely (i) imaging of the aorta at diagnosis and follow-up, (ii) recommendations on medical treatment, (iii) recommendations on surgical treatment, and (iv) recommendations on participation in sport. The issue continues with the Great Debate entitled ‘Great debate: myocardial infarction after cardiac surgery must be redefined’. Peri-operative myocardial injury is still widely debated.2–4 Jolanda Kluin from Erasmus MC in the Netherlands launches the debate with an introduction on the subject matter and statement.5 Mario Gaudino from Weill Cornell Medicine in New York, NY, USA and colleagues subsequently argue the Pro position, and Alan Jaffe from the Mayo Clinic in Rochester, MN, USA and colleagues argue the Contra. The management of cardiogenic shock (CS) remains challenging and is intensely debated.6–10 In a Viewpoint article entitled ‘Cardiogenic shock: do we need a paradigm shift?’, Thomas Lüscher from the Royal Brompton and Harefield Hospitals in London, UK and Holger Thiele from Leipzig University in Germany discuss the evolution of paradigms in treating CS, noting that traditional approaches such as complete revascularization and mechanical circulatory support have not significantly improved outcomes.11 Despite advances in acute coronary syndrome management, CS remains a major challenge, with high mortality rates persisting. Lüscher and Thiele suggest that future treatment strategies should focus on early and targeted inhibition of specific pathways involved in the progression of shock, potentially combined with selective left ventricular unloading, to improve patient outcomes. In a Viewpoint article entitled ‘The DanGer Shock trial: a new dawn but much to uncover’, Enzo Lüsebrink from LMU Munich in Germany, and colleagues remind us that the DanGer Shock trial investigated the use of the Impella CP microaxial pump in patients with CS related to ST-elevation myocardial infarction (MI) and found a significant reduction in 180-day mortality compared with standard care, despite much higher rates of device-related complications.12 The authors indicate that while the results suggest a potential breakthrough in mechanical circulatory support for this patient population, concerns about patient selection, the open-label study design, and country-specific biases highlight the need for further research to fully understand the device’s impact and generalizability. Secondary prevention is a pillar in the treatment of patients with known cardiovascular disease.13–16 In a Fast Track Clinical Research article entitled ‘Variation in secondary prevention of coronary heart disease: the INTERASPIRE study’, John William McEvoy from the University of Galway School of Medicine and National Institute for Prevention and Cardiovascular Health in Newcastle, Ireland, and colleagues remind us that INTERASPIRE is an international study of coronary heart disease (CHD) patients, designed to measure if guideline standards for secondary prevention and cardiac rehabilitation are being achieved in a timely manner.17 Between 2020 and 2023, adults hospitalized in the preceding 6–24 months with incident or recurrent CHD were sampled in 14 countries from all six World Health Organization regions and invited for a standardized interview and examination. Direct age and sex standardization was used for country-level prevalence estimation. Overall, ∼4500 (21% female) CHD patients were interviewed a median of 1 year after index hospitalization. Among all participants, 25% were obese. Only 39% achieved a blood pressure < 130/80 mmHg and 17% an LDL cholesterol of <1.4 mmol/L. Of those smoking at hospitalization, 48% persisted at interview. Of those with known diabetes, 55% achieved glycated haemoglobin (HbA1c) of <7%. A further 9.8% had undetected diabetes, and 27% had impaired glucose tolerance. Females were less likely to achieve the targets. Overall, just 9% reported attending cardiac rehabilitation and 1% achieved the study definition of optimal guideline adherence. The authors conclude that INTERASPIRE demonstrates inadequate and heterogeneous international implementation of guideline standards for secondary prevention in the first year after CHD hospitalization, with geographic and sex disparity. The contribution is accompanied by an Editorial by William Weintraub from Georgetown University School of Medicine in Washington, DC, USA and William Boden from Boston University Avedisian and Chobanian School of Medicine in Boston, MA, USA.18 The authors highlight that it is critically important to underscore that prevention is both proven and cost-effective, given the enormous financial impact of cardiovascular disease comprising direct healthcare costs, loss of productivity, and resource utilization that could be directed to other important societal needs. These important INTERASPIRE study findings represent not only a sobering indictment on the extremely low rates of achieving treatment guideline standards in CHD patients but also a compelling worldwide narrative and call to action to address the 21st century CHD pandemic more systematically through a more effective global investment in evidence-based prevention across the spectrum of age, gender, and geographic disparities. In the treatment of CS related to acute MI (AMI), extracorporeal life support (ECLS) has surged >10-fold over the past decade. In a Fast Track Clinical Research article, presented as a Rapid Communication, entitled ‘Routine extracorporeal life support in infarct-related cardiogenic shock: 1-year results of the ECLS-SHOCK trial’, Steffen Desch from the University of Leipzig in Germany, and colleagues remind us that recent randomized controlled trials and an individual patient data meta-analysis have demonstrated that early, non-selective ECLS use does not improve short-term survival compared with medical therapy alone.19 The ECLS-SHOCK trial is an investigator-initiated, randomized, international, multicentre, open-label trial with the primary objective to examine whether early routine ECLS in addition to usual medical treatment improves survival in patients with CS complicating AMI with planned revascularization compared with usual medical care alone. The design of the trial and 30-day outcomes have been published previously. In the current contribution, the authors report the results at 1-year follow-up. At 1 year, all-cause mortality was 55% in the ECLS group and 56% in the control group, without a significant difference between the treatment strategies (Figure 1). These results were consistent across all subgroups (sex, age <65 vs. ≥ 65 years, ST-segment elevation vs. non-ST-segment elevation AMI, anterior vs. non-anterior ST-segment elevation AMI, lactate levels ≤6 vs. > 6 mmol/L, diabetes vs. no diabetes, and cardiopulmonary resuscitation vs. no resuscitation before enrolment). In the surviving patients, the rates of severe neurological deficit, myocardial reinfarction, repeat revascularization, and rehospitalization for heart failure were similar at 1 year. Clinical outcomes at 1 year. AMI-CS, cardiogenic shock related to acute myocardial infarction; CI, confidence interval; CPC, cerebral performance category; ECLS, extracorporeal life support; HR, hazard ratio; RR, relative risk19 The authors conclude that the ECLS-SHOCK trial provides robust evidence that routine ECLS does not improve 1-year survival in patients with AMI-CS undergoing planned revascularization. Other forms of mechanical circulatory support and—probably more important—strict patient selection excluding patients with risk of hypoxic brain injury may offer advantages, as recently demonstrated with a microaxial flow pump after 6 months. Non-HDL cholesterol (non-HDL-C) provides an estimate of lipid-associated risk.20–22 In a Fast Track Clinical Research contribution entitled ‘Intensive early and sustained lowering of non-high-density lipoprotein cholesterol after myocardial infarction and prognosis: the SWEDEHEART registry’, Jessica Schubert from Uppsala University in Sweden and colleagues study the relationship between non-HDL-C levels after MI and risk of adverse outcomes.23 From the SWEDEHEART registry, > 56 000 patients with MI were included. Outcomes were major adverse cardiovascular events (MACE: death, MI, and ischaemic stroke), death, and non-fatal MI. Non-HDL-C was assessed at admission, 2 months, and 1 year. Target achievement (<2.2 mmol/L) of non-HDL-C, timing thereof, and outcomes were assessed. During a median follow-up of 5.4 years, 9549 had MACE, 5427 died, and 3946 had re-MI.The long-term hazard ratio (HR) for MACE in the lowest vs. the highest quartile of achieved non-HDL-C at 1 year was 0.76. Short-term results were also consistent when assessing non-HDL-C levels at 2 months, including early events up to 1 year (HR 0.80). Similar results were observed for all outcomes. Patients achieving both early and sustained targets had the lowest risk of outcomes (HR 0.80) vs. patients achieving target early or late (Figure 2). (A) Non-HDL-C values at myocardial infarction admission and early and late goal achievement. (B) Adjusted Cox proportional hazards models and event rates per 100 person-years are presented, adjusted for age at 1-year follow-up, statin intensity at admission, systolic blood pressure at 1-year follow-up, smoking at 1-year follow-up, sex, statin intensity at 1-year follow-up, body mass index at 1-year follow-up, history of diabetes, creatinine at admission, non-HDL-C at admission, and left ventricular ejection fraction at admission. MACE is the composite outcome of all-cause mortality, myocardial infarction, or ischaemic stroke. MACE, major adverse cardiovascular event; MI, myocardial infarction; non-HDL-C, non-HDL cholesterol; IQR, interquartile range; CI, confidence interval23 The authors conclude that the lowest achieved levels both at 2 months and at 1 year of non-HDL-C are associated with better outcome. The lowest risk is observed when targets are achieved within 2 months of MI and sustained thereafter. These findings challenge the current stepwise approach for cholesterol lowering after MI, which inevitably results in delaying goal attainment and possible harm. The contribution is accompanied by an Editorial by Sophie Van Linthout from the Berlin Institute of Health (BIH) at Charité—Universitätsmedizin Berlin in Germany and Bart De Geest.24 The authors conclude that the thought-provoking study of Schubert et al. highlights the challenges for application of lipid-lowering clinical trial results in the real world. Vascular smooth muscle cell (VSMC) senescence is crucial for the development of atherosclerosis. In a Translational Science contribution entitled ‘TRAP1 drives smooth muscle cell senescence and promotes atherosclerosis via HDAC3-primed histone H4 lysine 12 lactylation’, Xuesong Li from the Nanjing Medical University in China, and colleagues note that tumour necrosis factor receptor-associated protein 1 (TRAP1), a metabolic regulator associated with ageing, might be implicated in atherosclerosis.25 As the role of TRAP1 in atherosclerosis remains elusive, this study aimed to examine the function of TRAP1 in VSMC senescence and atherosclerosis. TRAP1 expression was measured in the aortic tissue of patients and mice with atherosclerosis using western blot and quantitative reverse transcription–PCR (RT–qPCR). Senescent VSMC models were established by oncogenic Ras, and cellular senescence was evaluated by measuring senescence-associated β-galactosidase expression and other senescence markers. Chromatin immunoprecipitation analysis was performed to explore the potential role of TRAP1 in atherosclerosis. VSMC-specific TRAP1 deficiency mitigated VSMC senescence and atherosclerosis via metabolic reprogramming. Mechanistically, TRAP1 significantly increased aerobic glycolysis, leading to elevated lactate production. Accumulated lactate promoted histone H4 lysine 12 lactylation (H4K12la) by down-regulating the unique histone lysine delactylase HDAC3. H4K12la was enriched in the senescence-associated secretory phenotype (SASP) promoter, activating SASP transcription and exacerbating VSMC senescence. In VSMC-specific Trap1 knockout ApoeKo mice (ApoeKoTrap1SMCKo), the plaque area, senescence markers, H4K12la, and SASP were reduced. Additionally, pharmacological inhibition and proteolysis-targeting chimera (PROTAC)-mediated TRAP1 degradation effectively attenuated atherosclerosis in vivo. The authors conclude that this study reveals a novel mechanism by which mitonuclear communication orchestrates gene expression in VSMC senescence and atherosclerosis. TRAP1-mediated metabolic reprogramming increases lactate-dependent H4K12la via HDAC3, promoting SASP expression and offering a new therapeutic direction for VSMC senescence and atherosclerosis. The contribution is accompanied by an Editorial by Nicolle Kränkel from the Deutsches Herzzentrum der Charité (DHZC) University Hospital Berlin in Germany.26 Kränkel notes that the impressive amount of work performed by the group brings together several pieces of the puzzle, some of them novel and some of them described before. The work is noteworthy in its consequent pursuit of the translational arc from highlighting the tight and fundamental interaction between energy sensing and cellular decision-making to the effective translation of the mechanism to potential applications. Nevertheless, interesting questions still remain for future studies. Those include deeper understanding of the molecular processes modulating the balance between lactylation and other histone modifications, including acetylation and methylation, at the various residues with relevance to specific (disease-associated) transcriptional programmes. The issue is also complemented by two Discussion Forum contributions. In a commentary entitled ‘Cardiovascular disease risk communication alone is not enough: why a recent review may be misleading’, Sophie Griffiths from the University of Manchester in the UK and colleagues comment on the recent publication ‘Cardiovascular disease risk communication and prevention: a meta-analysis’ by Mina Bakhit from Bond University in Australia.27,28 Bakhit et al. respond in a separate comment.29 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.