Safety and effectiveness of glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: insights from the SPUM-ACS study.

AIMS: Data on Glycoprotein IIb/IIIa inhibitors (GPI) use in real world ACS patients following the introduction of potent P2Y12 inhibitors and newer generation stents are scant. Here, we aimed to assess the utilization, effectiveness, and safety of GPI in a large prospective multi-centre cohort of contemporary ACS patients. METHODS AND RESULTS: SPUM-ACS prospectively recruited patients presenting with ACS between 2009 and 2017. The primary endpoint of the present study was major adverse cardiovascular events (MACE), a composite of all-cause death, non-fatal myocardial infarction (MI) and non-fatal stroke at one year. Secondary endpoints were defined as any bleeding events, BARC 3-5 bleeding, and net adverse cardiovascular events (NACE). A total of 4395 ACS patients were included in the analysis. GPI-treated patients had more total coronary artery occlusion (56% vs 35%, p<0.001) and thrombus (60% vs 35%, p<0.001) at angiography. Among the propensity score matched (PSM) population (1992 patients equally split into two groups), GPI-treated patients showed lower risk of MACE (PSM adjusted HR 0.70, 95% CI 0.49-0.99), but a higher risk of any (PSM adj HR 1.46, 95% CI 1.06-1.99) and major bleedings (PSM adj HR 1.73, 95% CI 1.09-2.76), resulting in a neutral effect on NACE (PSM adj HR 0.87, 95% CI 0.65-1.17). These results remained consistent across all subgroups. CONCLUSION: In patients with ACS undergoing PCI and receiving potent P2Y12 inhibitors, we observed a reduced risk of MACE and an increased risk of major bleedings at 1 year in patients treated with GPI. Although the routine use of GPI is currently not recommended, they might be considered in selected patients following a personalized balancing between ischaemic and bleeding risks.

Heart failure, the global pandemic: A call to action consensus statement from the global presidential conclave at the platinum jubilee conference of cardiological society of India 2023.

Heart failure (HF) is emerging as a major public health problem both in high- and low - income countries. The mortality and morbidity due to HF is substantially higher in low-middle income countries (LMICs). Accessibility, availability and affordability issues affect the guideline directed therapy implementation in HF care in those countries. This call to action urges all those concerned to initiate preventive strategies as early as possible, so that we can reduce HF-related morbidity and mortality. The most important step is to have better prevention and treatment strategies for diseases such as hypertension, ischemic heart disease (IHD), type-2 diabetes, and rheumatic heart disease (RHD) which predispose to the development of HF. Setting up dedicated HF-clinics manned by HF Nurses, can help in streamlining HF care. Subsidized in-patient care, financial assistance for device therapy, use of generic medicines (including polypill strategy) will be helpful, along with the use of digital technologies.

Renal denervation in the management of hypertension.

Arterial hypertension is a global leading cause of cardiovascular, cerebrovascular, and renal disease, as well as mortality. Although pharmacotherapy is safe and effective in lowering blood pressure (BP) and cardiovascular disease risk, BP control remains poor, and the mortality rates associated with high BP have been steadily increasing. Device-based therapies have been investigated to overcome barriers to pharmacotherapy, including non-adherence and low rates of persistence to daily medications. Among these device-based therapies, catheter-based renal denervation (RDN) has been most extensively examined over the past 15 years. In this state-of-the-art article, we summarise the rationale for RDN, review the available evidence, provide recommendations for a safe procedure, and discuss the role of RDN in current guidelines and clinical practice.

SGLT2 inhibitors: from glucose-lowering to cardiovascular benefits.

An increasing number of individuals is at high risk of type 2 diabetes (T2D) and its cardiovascular complications, including heart failure (HF), chronic kidney disease (CKD), and premature death. The sodium-glucose cotransporter-2 (SGLT2) protein sits in the proximal tubule of human nephrons to regulate glucose reabsorption, and its inhibition by gliflozins represents the cornerstone of contemporary T2D and HF management. Herein, we aim to provide an updated view on the pleiotropy of gliflozins, provide mechanistic insights and delineate related cardiovascular (CV) benefits. By discussing contemporary evidence obtained in preclinical models and landmark randomized controlled trials, we move from bench to bedside across the broad spectrum of cardio- and cerebrovascular diseases. With robust trials confirming a reduction in major adverse CV events (MACE; composite endpoint of CV death, non-fatal myocardial infarction, and non-fatal stroke), SGLT2 inhibitors strongly mitigate the risk for heart failure hospitalization in diabetics and non-diabetics alike while conferring renoprotection in specific patient populations. Along four major pathophysiological axes (ie, at cardiac, vascular, renal, and systemic levels), we provide insights into key mechanisms that may underlie their beneficial effects, including gliflozins' role in the modulation of vascular inflammation, oxidative stress, cellular energy metabolism and housekeeping mechanisms. We also discuss how this drug class controls hyperglycaemia, ketogenesis, natriuresis, and hyperuricaemia, contributing to their pleiotropic effects. Finally, evolving data in the setting of cerebrovascular diseases and arrythmias are presented, and potential implications for future research and clinical practice are comprehensively reviewed.

The inflammatory spectrum of cardiomyopathies.

Infiltration of the myocardium with various cell types, cytokines and chemokines plays a crucial role in the pathogenesis of cardiomyopathies including inflammatory cardiomyopathies and myocarditis. A more comprehensive understanding of the precise immune mechanisms involved in acute and chronic myocarditis is essential to develop novel therapeutic approaches. This review offers a comprehensive overview of the current knowledge of the immune landscape in cardiomyopathies based on etiology. It identifies gaps in our knowledge about cardiac inflammation and emphasizes the need for new translational approaches to improve our understanding thus enabling development of novel early detection methods and more effective treatments.

Effect of lipid-lowering therapies on C-reactive protein levels: a comprehensive meta-analysis of randomized controlled trials.

Chronic low-degree inflammation is a hallmark of atherosclerotic cardiovascular (CV) disease. To assess the effect of lipid-lowering therapies on C-reactive protein (CRP), a biomarker of inflammation, we conducted a meta-analysis according to the PRISMA guidelines. Databases were searched from inception to July 2023. Inclusion criteria were: (i) randomized controlled trials (RCTs) in human, Phase II, III, or IV; (ii) English language; (iii) comparing the effect of lipid-lowering drugs vs. placebo; (iv) reporting the effects on CRP levels; (v) with intervention duration of more than 3 weeks; (vi) and sample size (for both intervention and control group) over than 100 subjects. The between-group (treatment-placebo) CRP absolute mean differences and 95% confidence intervals were calculated for each drug class separately. A total of 171 668 subjects from 53 RCTs were included. CRP levels (mg/L) were significantly decreased by statins [-0.65 (-0.87 to -0.43), bempedoic acid; -0.43 (-0.67 to -0.20), ezetimibe; -0.28 (-0.48 to -0.08)], and omega-3 fatty acids [omega3FAs, -0.27 (-0.52 to -0.01)]. CRP was reduced by -0.40 (-1.17 to 0.38) with fibrates, although not statistically significant. A slight increase of CRP concentration was observed for proprotein convertase subtilisin/kexin type 9 inhibitors [0.11 (0.07-0.14)] and cholesteryl-ester transfer protein inhibitors [0.10 (0.00-0.21)], the latter being not statistically significant. Meta-regression analysis did not show a significant correlation between changes in CRP and LDL cholesterol (LDL-C) or triglycerides. Statins, bempedoic acid, ezetimibe, and omega3FAs significantly reduce serum CRP concentration, independently of LDL-C reductions. The impact of this anti-inflammatory effect in terms of CV prevention needs further investigation.

Evaluation and management of patients with coronary chronic total occlusions considered for revascularisation. A clinical consensus statement of the European Association of Percutaneous Cardiovascular Interventions (EAPCI) of the ESC, the European Association of Cardiovascular Imaging (EACVI) of the ESC, and the ESC Working Group on Cardiovascular Surgery.

Chronic total occlusions (CTOs) of coronary arteries can be found in the context of chronic or acute coronary syndromes; sometimes they are an incidental finding in those apparently healthy individuals undergoing imaging for preoperative risk assessment. Recently, the invasive management of CTOs has made impressive progress due to sophisticated preinterventional assessment, including advanced non-invasive imaging, the availability of novel and dedicated tools for CTO percutaneous coronary intervention (PCI), and experienced interventionalists working in specialised centres. Thus, it is crucial that referring physicians who see patients with CTO be aware of recent developments and of the initial evaluation requirements for such patients. Besides a careful history and clinical examination, electrocardiograms, exercise tests, and non-invasive imaging modalities are important for selecting the patients most suitable for CTO PCI, while others may be referred to coronary artery bypass graft or optimal medical therapy only. While CTO PCI improves angina and reduces the use of antianginal drugs in patients with symptoms and proven ischaemia, hibernation and/or wall motion abnormalities at baseline or during stress, the effect of CTO PCI on major cardiovascular events is still controversial. This clinical consensus statement specifically focuses on referring physicians, providing a comprehensive algorithm for the preinterventional evaluation of patients with CTO and the current evidence for the clinical effectiveness of the procedure. The proposed care track has been developed by members and with the support of the European Association of Percutaneous Cardiovascular Interventions (EAPCI), the European Association of Cardiovascular Imaging (EACVI), and the European Society of Cardiology (ESC) Working Group on Cardiovascular Surgery.

Device innovation in cardiovascular medicine: a report from the European Society of Cardiology Cardiovascular Round Table.

Research performed in Europe has driven cardiovascular device innovation. This includes, but is not limited to, percutaneous coronary intervention, cardiac imaging, transcatheter heart valve implantation, and device therapy of cardiac arrhythmias and heart failure. An important part of future medical progress involves the evolution of medical technology and the ongoing development of artificial intelligence and machine learning. There is a need to foster an environment conducive to medical technology development and validation so that Europe can continue to play a major role in device innovation while providing high standards of safety. This paper summarizes viewpoints on the topic of device innovation in cardiovascular medicine at the European Society of Cardiology Cardiovascular Round Table, a strategic forum for high-level dialogue to discuss issues related to the future of cardiovascular health in Europe. Devices are developed and improved through an iterative process throughout their lifecycle. Early feasibility studies demonstrate proof of concept and help to optimize the design of a device. If successful, this should ideally be followed by randomized clinical trials comparing novel devices vs. accepted standards of care when available and the collection of post-market real-world evidence through registries. Unfortunately, standardized procedures for feasibility studies across various device categories have not yet been implemented in Europe. Cardiovascular imaging can be used to diagnose and characterize patients for interventions to improve procedural results and to monitor devices long term after implantation. Randomized clinical trials often use cardiac imaging-based inclusion criteria, while less frequently trials randomize patients to compare the diagnostic or prognostic value of different modalities. Applications using machine learning are increasingly important, but specific regulatory standards and pathways remain in development in both Europe and the USA. Standards are also needed for smart devices and digital technologies that support device-driven biomonitoring. Changes in device regulation introduced by the European Union aim to improve clinical evidence, transparency, and safety, but they may impact the speed of innovation, access, and availability. Device development programmes including dialogue on unmet needs and advice on study designs must be driven by a community of physicians, trialists, patients, regulators, payers, and industry to ensure that patients have access to innovative care.

Artificial intelligence methods for improved detection of undiagnosed heart failure with preserved ejection fraction.

AIM: Heart failure with preserved ejection fraction (HFpEF) remains under-diagnosed in clinical practice despite accounting for nearly half of all heart failure (HF) cases. Accurate and timely diagnosis of HFpEF is crucial for proper patient management and treatment. In this study, we explored the potential of natural language processing (NLP) to improve the detection and diagnosis of HFpEF according to the European Society of Cardiology (ESC) diagnostic criteria. METHODS AND RESULTS: In a retrospective cohort study, we used an NLP pipeline applied to the electronic health record (EHR) to identify patients with a clinical diagnosis of HF between 2010 and 2022. We collected demographic, clinical, echocardiographic and outcome data from the EHR. Patients were categorized according to the left ventricular ejection fraction (LVEF). Those with LVEF ≥50% were further categorized based on whether they had a clinician-assigned diagnosis of HFpEF and if not, whether they met the ESC diagnostic criteria. Results were validated in a second, independent centre. We identified 8606 patients with HF. Of 3727 consecutive patients with HF and LVEF ≥50% on echocardiogram, only 8.3% had a clinician-assigned diagnosis of HFpEF, while 75.4% met ESC criteria but did not have a formal diagnosis of HFpEF. Patients with confirmed HFpEF were hospitalized more frequently; however the ESC criteria group had a higher 5-year mortality, despite being less comorbid and experiencing fewer acute cardiovascular events. CONCLUSIONS: This study demonstrates that patients with undiagnosed HFpEF are an at-risk group with high mortality. It is possible to use NLP methods to identify likely HFpEF patients from EHR data who would likely then benefit from expert clinical review and complement the use of diagnostic algorithms.

Long non-coding RNAs H19 and NKILA are associated with the risk of death and lacunar stroke in the elderly population.

INTRODUCTION: Differential expression of long non-coding RNAs (lncRNAs) is a hallmark of cardiovascular aging, cerebrovascular diseases, and neurodegenerative disorders. This research article investigates the association between a panel of lncRNAs and the risk of death and ischemic stroke in a cohort of non-institutionalized elderly subjects. METHOD: A total of 361 healthy individuals aged 75 years old, prospectively recruited in the Vienna Transdanube Aging (VITA) cohort, were included. Expression of lncRNAs at baseline was assessed using quantitative polymerase chain reaction PCR with pre-amplification reaction, using 18S for normalization. The primary endpoint was all-cause mortality; the secondary endpoint was the incidence of new ischemic brain lesions. Death was assessed over a 14-year follow-up, and ischemic brain lesions were evaluated by magnetic resonance imaging (MRI) over a 90-month follow-up. Ischemic brain lesions were divided into large brain infarcts (Ø≥ 1.5 cm) or lacunes (Ø< 1.5 cm) RESULTS: The primary endpoint occurred in 53.5 % of the study population. The incidence of the secondary endpoint was 16 %, with a 3.3 % being large brain infarcts, and a 12.7 % lacunes. After adjustment for potential confounders, the lncRNA H19 predicted the incidence of the primary endpoint (HR 1.194, 95 % C.I. 1.012-1.409, p = 0.036), whereas the lncRNA NKILA was associated with lacunar stroke (HR 0.571, 95 % C.I. 0.375-0.868, p = 0.006). CONCLUSION: In a prospective cohort of non-institutionalized elderly subjects, high levels of lncRNA H19 are associated with a higher risk of death, while low levels of lncRNA NKILA predict an increased risk of lacunar stroke.

Nogo-A is secreted in extracellular vesicles, occurs in blood and can influence vascular permeability.

Nogo-A is a transmembrane protein with multiple functions in the central nervous system (CNS), including restriction of neurite growth and synaptic plasticity. Thus far, Nogo-A has been predominantly considered a cell contact-dependent ligand signaling via cell surface receptors. Here, we show that Nogo-A can be secreted by cultured cells of neuronal and glial origin in association with extracellular vesicles (EVs). Neuron- and oligodendrocyte-derived Nogo-A containing EVs inhibited fibroblast spreading, and this effect was partially reversed by Nogo-A receptor S1PR2 blockage. EVs purified from HEK cells only inhibited fibroblast spreading upon Nogo-A over-expression. Nogo-A-containing EVs were found in vivo in the blood of healthy mice and rats, as well as in human plasma. Blood Nogo-A concentrations were elevated after acute stroke lesions in mice and rats. Nogo-A active peptides decreased barrier integrity in an in vitro blood-brain barrier model. Stroked mice showed increased dye permeability in peripheral organs when tested 2 weeks after injury. In the Miles assay, an in vivo test to assess leakage of the skin vasculature, a Nogo-A active peptide increased dye permeability. These findings suggest that blood borne, possibly EV-associated Nogo-A could exert long-range regulatory actions on vascular permeability.

Drinking patterns of alcohol and risk of major adverse cardiovascular events after an acute coronary syndrome.

AIM: To evaluate the risk of alcohol consumption after acute coronary syndromes (ACS). METHODS: A total of 6557 patients hospitalized for ACS at 4 Swiss centres were followed over 12 months. Weekly alcohol consumption was collected at baseline and 12 months. Binge drinking was defined as consumption of ≥6 units of alcohol on one occasion. Major adverse cardiovascular events (MACE) were defined as a composite of cardiac death, myocardial infarction, stroke or clinically indicated target vessel coronary revascularization. Cox regression analysis was performed to assess the risk of MACE in patients with heavy (>14 standard units/week), moderate (7-14 standard units per week), light consumption (<1 standard unit/week) or abstinence, and with binge drinking episodes, adjusted for baseline differences. RESULTS: At baseline, 817 (13.4%) patients reported heavy weekly alcohol consumption. At one-year follow-up, 695/1667 (41.6%) patients reported having at least one or more episodes of binge drinking per month. The risk for MACE was not significantly higher in those with heavy weekly consumption compared to abstinence (8.6% vs. 10.2%, HR 0.97, 95%CI 0.69-1.36) or light consumption (8.6% vs. 8.5 %, HR 1.41, 95%CI 0.97-2.06). Compared to patients with no-binge drinking, the risk of MACE was dose-dependently higher in those with binge drinking with less than one episode per month (9.2% vs 7.8%, HR 1.61, 95%CI 1.23-2.11), or one or more episodes per month (13.6% vs 7.8%, HR 2.17, 95%CI 1.66-2.83). CONCLUSION: Binge drinking during the year following an ACS, even less than once per month, is associated with worse clinical outcomes.

The cardiovascular risk of alcohol consumption and of binge drinking episodes after acute coronary syndrome (ACS) has not been established. Our data suggested the following: After ACS, regular weekly alcohol consumption is not associated with the risk of major adverse cardiovascular events (MACE), except for patients reporting binge drinking who have a two-fold increased risk of MACE within one year of the index event.After ACS, episodes of binge drinking, even less than once per month, are associated with worse clinical outcomes. It is not the frequency, but rather the quantity of alcohol intake in a binge drinking episode, that is associated with worse prognosis in patients after an ACS.

Effects of SARS-COV-2 infection on outcomes in patients hospitalized for acute cardiac conditions. A prospective, multicenter cohort study (Swiss Cardiovascular SARS-CoV-2 Consortium).

Background: Although the severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) causing coronavirus disease 2019 (COVID-19) primarily affects the respiratory system, the disease entity has been associated with cardiovascular complications. This study sought to assess the effect of concomitant SARS-COV-2 infection on clinical outcomes of patients hospitalized primarily for acute cardiac conditions on cardiology wards in Switzerland. Methods: In this prospective, observational study conducted in 5 Swiss cardiology centers during the COVID-19 pandemic, patients hospitalized due to acute cardiac conditions underwent a reverse-transcriptase polymerase chain reaction test at the time of admission and were categorized as SARS-COV-2 positive (cases) or negative (controls). Patients hospitalized on cardiology wards underwent treatment for the principal acute cardiac condition according to local practice. Clinical outcomes were recorded in-hospital, at 30 days, and after 1 year and compared between cases and controls. To adjust for imbalanced baseline characteristics, a subgroup of patients derived by propensity matching was analyzed. Results: Between March 2020 and February 2022, 538 patients were enrolled including 122 cases and 416 controls. Mean age was 68.0 ± 14.7 years, and 75% were men. Compared with controls, SARS-COV-2-positive patients more commonly presented with acute heart failure (35% vs. 17%) or major arrhythmia (31% vs. 9%), but less commonly with acute coronary syndrome (26% vs. 53%) or severe aortic stenosis (4% vs. 18%). Mortality was significantly higher in cases vs. controls in-hospital (16% vs. 1%), at 30 days (19.0% vs. 2.2%), and at 1 year (28.7% vs. 7.6%: p < 0.001 for all); this was driven primarily (up to 30 days) and exclusively (at one-year follow-up) by higher non-cardiovascular mortality, and was accompanied by a greater incidence of worsening renal function in cases vs. controls. These findings were maintained in a propensity-matched subgroup of 186 patients (93 cases and 93 controls) with balanced clinical presentation and baseline characteristics. Conclusions: In this observational study of patients hospitalized for acute cardiac conditions, SARS-COV-2 infection at index hospitalization was associated with markedly higher all-cause and non-cardiovascular mortality throughout one-year follow-up. These findings highlight the need for effective, multifaceted management of both cardiac and non-cardiac morbidities and prolonged surveillance in patients with acute cardiac conditions complicated by SARS-COV-2 infection.

Predictors of outcome in a contemporary cardiac sarcoidosis population: Role of brain natriuretic peptide, left ventricular function and myocardial inflammation.

AIMS: Cardiac sarcoidosis (CS) is a potentially fatal condition that varies in its clinical presentation. Here, we describe baseline characteristics at presentation along with prognosis and predictors of outcome in a sizable and deeply phenotyped contemporary cohort of CS patients. METHODS AND RESULTS: Consecutive CS patients seen at one institution were retrospectively enrolled after undergoing laboratory testing, electrocardiogram, echocardiography, cardiac magnetic resonance (CMR) imaging and 18 F-flourodeoxyglucose positron emission tomography (FDG-PET) at baseline. The composite endpoint consisted of all-cause mortality, aborted sudden cardiac death, major ventricular arrhythmic events, heart failure hospitalization and heart transplantation. A total of 319 CS patients were studied (67% male, 55.4 ± 12 years). During a median follow-up of 2.2 years (range: 1 month-11 years), 8% of patients died, while 33% reached the composite endpoint. The annualized mortality rate was 2.7% and the 5- and 10-year mortality rates were 6.2% and 7.5%, respectively. Multivariate analysis showed serum brain natriuretic peptide (BNP) levels (hazard ratio [HR] 2.41, 95% confidence interval [CI] 1.34-4.31, p = 0.003), CMR left ventricular ejection fraction (LVEF) (HR 0.96, 95% CI 0.94-0.98, p < 0.0001) and maximum standardized uptake value of FDG-PET (HR 1.11, 95% CI 1.04-1.19, p = 0.001) to be independent predictors of outcome. These findings remained robust for different patient subgroups. CONCLUSION: Cardiac sarcoidosis is associated with significant morbidity and mortality, particularly in those with cardiac involvement as the first manifestation. Higher BNP levels, lower LVEF and more active myocardial inflammation were independent predictors of outcomes.

Antibody-mediated PCSK9 neutralization worsens outcome after bare-metal stent implantation in mice.

AIMS: Despite advances in pharmacotherapy and device innovation, in-stent restenosis (ISR) and stent thrombosis (ST) remain serious complications following percutaneous coronary intervention (PCI) procedure with stent implantation. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme involved in plasma cholesterol homeostasis and recently emerged as a therapeutic target for hypercholesterolemia. Antibody-based PCSK9 inhibition is increasingly used in different subsets of patients, including those undergoing PCI. However, whether PCSK9 inhibition affects outcome after stent implantation remains unknown. METHODS AND RESULTS: 12 to 14 weeks old C57Bl/6 mice underwent carotid artery bare-metal stent implantation. Compared to sham intervention, stent implantation was associated with increased expression of several inflammatory mediators, including PCSK9. The increase in PCSK9 protein expression was confirmed in the stented vascular tissue, but not in plasma. To inhibit PCSK9, alirocumab was administered weekly to mice before stent implantation. After 6 weeks, histological examination revealed increased intimal hyperplasia in the stented segment of alirocumab-treated animals compared to controls. In vitro, alirocumab promoted migration and inhibited the onset of senescence in primary human vascular smooth muscle cells (VSMC). Conversely, it blunted the migration and increased the senescence of endothelial cells (EC). CONCLUSION: Antibody-based PCSK9 inhibition promotes in-stent intimal hyperplasia and blunts vascular healing by increasing VSMC migration, while reducing that of EC. This effect is likely mediated, at least in part, by a differential effect on VSMC and EC senescence. The herein-reported data warrant additional investigations concerning the use of PCSK9 inhibitors in patients undergoing PCI with stent implantation.

Circulating GDF11 exacerbates myocardial injury in mice and associates with increased infarct size in humans.

AIMS: The heart rejuvenating effects of circulating growth differentiation factor 11 (GDF11), a transforming growth factor-ß superfamily member that shares 90% homology with myostatin (MSTN), remains controversial. Here, we aimed to probe the role of GDF11 in acute myocardial infarction (MI), a frequent cause of heart failure and premature death during ageing. METHODS AND RESULTS: In contrast to endogenous Mstn, myocardial Gdf11 declined during the course of ageing and was particularly reduced following ischaemia/reperfusion (I/R) injury, suggesting a therapeutic potential of GDF11 signalling in MI. Unexpectedly, boosting systemic Gdf11 by recombinant GDF11 delivery (0.1 mg/kg body weight over 30 days) prior to myocardial I/R augmented myocardial infarct size in C57BL/6 mice irrespective of their age, predominantly by accelerating pro-apoptotic signalling. While intrinsic cardioprotective signalling pathways remained unaffected by high circulating GDF11, targeted transcriptomics and immunomapping studies focusing on GDF11-associated downstream targets revealed attenuated Nkx2-5 expression confined to CD105-expressing cells, with pro-apoptotic activity, as assessed by caspase-3 levels, being particularly pronounced in adjacent cells, suggesting an indirect effect. By harnessing a highly specific and validated liquid chromatography-tandem mass spectrometry-based assay, we show that in prospectively recruited patients with MI circulating GDF11 but not MSTN levels incline with age. Moreover, GDF11 levels were particularly elevated in those at high risk for adverse outcomes following the acute event, with circulating GDF11 emerging as an independent predictor of myocardial infarct size, as estimated by standardized peak creatine kinase-MB levels. CONCLUSION: Our data challenge the initially reported heart rejuvenating effects of circulating GDF11 and suggest that high levels of systemic GDF11 exacerbate myocardial injury in mice and humans alike. Persistently high GDF11 levels during ageing may contribute to the age-dependent loss of cardioprotective mechanisms and thus poor outcomes of elderly patients following acute MI.