Early microvascular coronary endothelial dysfunction precedes pembrolizumab-induced cardiotoxicity. Preventive role of high dose of atorvastatin.

Immune checkpoint inhibitors (ICIs) exhibit remarkable antitumor activity and immune-related cardiotoxicity of unknown pathomechanism. The aim of the study was to investigate the ICI class-dependent cardiotoxicity in vitro and pembrolizumab's (Pem's) cardiotoxicity in vivo, seeking for translational prevention means. Cytotoxicity was investigated in primary cardiomyocytes and splenocytes, incubated with ipilimumab, Pem and avelumab. Pem's cross-reactivity was assessed by circular dichroism (CD) on biotechnologically produced human and murine PD-1 and in silico. C57BL6/J male mice received IgG4 or Pem for 2 and 5 weeks. Echocardiography, histology, and molecular analyses were performed. Coronary blood flow velocity mapping and cardiac magnetic resonance imaging were conducted at 2 weeks. Human EA.hy926 endothelial cells were incubated with Pem-conditioned media from human mononuclear cells, in presence and absence of statins and viability and molecular signaling were assessed. Atorvastatin (20 mg/kg, daily) was administered in vivo, as prophylaxis. Only Pem exerted immune-related cytotoxicity in vitro. Pem's cross-reactivity with the murine PD-1 was confirmed by CD and docking. In vivo, Pem initiated coronary endothelial and diastolic dysfunction at 2 weeks and systolic dysfunction at 5 weeks. At 2 weeks, Pem induced ICAM-1 and iNOS expression and intracardiac leukocyte infiltration. At 5 weeks, Pem exacerbated endothelial activation and triggered cardiac inflammation. Pem led to immune-related cytotoxicity in EA.hy926 cells, which was prevented by atorvastatin. Atorvastatin mitigated functional deficits, by inhibiting endothelial dysfunction in vivo. We established for the first time an in vivo model of Pem-induced cardiotoxicity. Coronary endothelial dysfunction precedes Pem-induced cardiotoxicity, whereas atorvastatin emerges as a novel prophylactic therapy.

Safety and long-term outcomes of remote cardiac rehabilitation in coronary heart disease patients: A systematic review.

Objective: To systematically review the safety and the long-term mortality and morbidity risk-rates of the remotely-delivered cardiac rehabilitation (RDCR) interventions in coronary heart disease (CHD) patients. Methods: The protocol was registered in the International Prospective Register of Systematic Reviews (CRD42023455471). Five databases (Pubmed, Scopus, Cochrane Central Register of Controlled Trials in the Cochrane Library, Cinahl and Web of Science) were reviewed from January 2012 up to August 2023. Inclusion criteria were: (a) randomized controlled trials, (b) RDCR implementation of at least 12 weeks duration, (c) assessment of safety, rates of serious adverse events (SAEs) and re-hospitalization incidences at endpoints more than 6 months. Three reviewers independently performed data extraction and assessed the risk of bias using the Cochrane Risk of Bias tool. Results: 14 studies were identified involving 2012 participants and a range of RDCR duration between 3 months to 1 year. The incidence rate of exercise-related SAEs was estimated at 1 per 53,770 patient-hours of RDCR exercise. A non-statistically significant reduction in the re-hospitalization rates and the days lost due to hospitalization was noticed in the RDCR groups. There were no exercise-related deaths. The overall study quality was of low risk. Conclusions: RDCR can act as a safe alternative delivery mode of cardiac rehabilitation (CR). The low long-term rates of reported SAEs and re-hospitalization incidences of the RDCR could enhance the uptake rates of CR interventions. However, further investigation is needed in larger populations and longer assessment points.

Ergophysiological evaluation of heart failure patients with reduced ejection fraction undergoing exercise-based cardiac rehabilitation: A systematic review and meta-analysis.

BACKGROUND: This systematic review and meta-analysis aims to explore in heart failure (HF) patients with reduced ejection fraction (EF) undergoing exercise-based cardiac rehabilitation the following: 1) the comparison of temporal changes between peak oxygen uptake (VO2peak) and first ventilatory threshold (VO2VT1), 2) the association of VO2peak and VO2VT1 changes with physiological factors, and 3) the differential effects of continuous aerobic exercise (CAE) and interval training (IT) on VO2peak and VO2VT1. METHODS: A systematic literature search was conducted in PubMed, CENTRAL, and Scopus. Inclusion criteria were 1) original research articles using exercise-based cardiac rehabilitation, 2) stable HF patients with reduced EF, 3) available values of VO2peak and VO2VT1 (in mL/kg/min) both at baseline and after exercise training with comparison between these time points. RESULTS: Among the 30 eligible trials, 24 used CAE, 5 IT, and one CAE and IT. Multivariable meta-regression with duration of exercise training and percentage of males as independent variables and the change in VO2peak as a dependent variable showed that the change in VO2peak was negatively associated with duration of exercise training (coefficient=-0.061, p=0.027), implying the possible existence of a waning effect of exercise training on VO2peak in the long term. Multivariable meta-regression demonstrated that both age (coefficient=-0.140, p<0.001) and EF (coefficient=-0.149, p<0.001) could predict the change in VO2VT1, whereas only age (coefficient=-0.095, p=0.022), but not EF (coefficient = 0.082, p = 0.100), could predict the change in VO2peak. The posttraining peak respiratory exchange ratio, as an index of maximum effort during exercise testing, correlated positively with the change in VO2peak (coefficient=-0.021, p=0.044). The exercise-induced changes of VO2peak (p = 0.438) and VO2VT1 (p = 0.474) did not differ between CAE and IT groups. CONCLUSIONS: Improvement of endurance capacity during cardiac rehabilitation may be detected more accurately with the assessment of VO2VT1 rather than VO2peak.

Comprehensive Analysis of 1-Year-Old Female Apolipoprotein E-Deficient Mice Reveals Advanced Atherosclerosis with Vulnerable Plaque Characteristics.

Apolipoprotein E-knockout (Apoe-/-) mice constitute the most widely employed animal model of atherosclerosis. Deletion of Apoe induces profound hypercholesterolemia and promotes the development of atherosclerosis. However, despite its widespread use, the Apoe-/- mouse model remains incompletely characterized, especially at late time points and advanced disease stages. Thus, it is unclear how late atherosclerotic plaques compare to earlier ones in terms of lipid deposition, calcification, macrophage accumulation, smooth muscle cell presence, or plaque necrosis. Additionally, it is unknown how cardiac function and hemodynamic parameters are affected at late disease stages. Here, we used a comprehensive analysis based on histology, fluorescence microscopy, and Doppler ultrasonography to show that in normal chow diet-fed Apoe-/- mice, atherosclerotic lesions at the level of the aortic valve evolve from a more cellular macrophage-rich phenotype at 26 weeks to an acellular, lipid-rich, and more necrotic phenotype at 52 weeks of age, also marked by enhanced lipid deposition and calcification. Coronary artery atherosclerotic lesions are sparse at 26 weeks but ubiquitous and extensive at 52 weeks; yet, left ventricular function was not significantly affected. These findings demonstrate that atherosclerosis in Apoe-/- mice is a highly dynamic process, with atherosclerotic plaques evolving over time. At late disease stages, histopathological characteristics of increased plaque vulnerability predominate in combination with frequent and extensive coronary artery lesions, which nevertheless may not necessarily result in impaired cardiac function.

Standardised Exercise Prescription for Patients with Chronic Coronary Syndrome and/or Heart Failure: A Consensus Statement from the EXPERT Working Group.

Whereas exercise training, as part of multidisciplinary rehabilitation, is a key component in the management of patients with chronic coronary syndrome (CCS) and/or congestive heart failure (CHF), physicians and exercise professionals disagree among themselves on the type and characteristics of the exercise to be prescribed to these patients, and the exercise prescriptions are not consistent with the international guidelines. This impacts the efficacy and quality of the intervention of rehabilitation. To overcome these barriers, a digital training and decision support system [i.e. EXercise Prescription in Everyday practice & Rehabilitative Training (EXPERT) tool], i.e. a stepwise aid to exercise prescription in patients with CCS and/or CHF, affected by concomitant risk factors and comorbidities, in the setting of multidisciplinary rehabilitation, was developed. The EXPERT working group members reviewed the literature and formulated exercise recommendations (exercise training intensity, frequency, volume, type, session and programme duration) and safety precautions for CCS and/or CHF (including heart transplantation). Also, highly prevalent comorbidities (e.g. peripheral arterial disease) or cardiac devices (e.g. pacemaker, implanted cardioverter defibrillator, left-ventricular assist device) were considered, as well as indications for the in-hospital phase (e.g. after coronary revascularisation or hospitalisation for CHF). The contributions of physical fitness, medications and adverse events during exercise testing were also considered. The EXPERT tool was developed on the basis of this evidence. In this paper, the exercise prescriptions for patients with CCS and/or CHF formulated for the EXPERT tool are presented. Finally, to demonstrate how the EXPERT tool proposes exercise prescriptions in patients with CCS and/or CHF with different combinations of CVD risk factors, three patient cases with solutions are presented.

CTH/MPST double ablation results in enhanced vasorelaxation and reduced blood pressure via upregulation of the eNOS/sGC pathway.

Hydrogen sulfide (H2S), a gasotransmitter with protective effects in the cardiovascular system, is endogenously generated by three main enzymatic pathways: cystathionine gamma lyase (CTH), cystathionine beta synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (MPST) enzymes. CTH and MPST are the predominant sources of H2S in the heart and blood vessels, exhibiting distinct effects in the cardiovascular system. To better understand the impact of H2S in cardiovascular homeostasis, we generated a double Cth/Mpst knockout (Cth/Mpst -/- ) mouse and characterized its cardiovascular phenotype. CTH/MPST-deficient mice were viable, fertile and exhibited no gross abnormalities. Lack of both CTH and MPST did not affect the levels of CBS and H2S-degrading enzymes in the heart and the aorta. Cth/Mpst -/- mice also exhibited reduced systolic, diastolic and mean arterial blood pressure, and presented normal left ventricular structure and fraction. Aortic ring relaxation in response to exogenously applied H2S was similar between the two genotypes. Interestingly, an enhanced endothelium-dependent relaxation to acetylcholine was observed in mice in which both enzymes were deleted. This paradoxical change was associated with upregulated levels of endothelial nitric oxide synthase (eNOS) and soluble guanylate cyclase (sGC) α1 and ß1 subunits and increased NO-donor-induced vasorelaxation. Administration of a NOS-inhibitor, increased mean arterial blood pressure to a similar extent in wild-type and Cth/Mpst -/- mice. We conclude that chronic elimination of the two major H2S sources in the cardiovascular system, leads to an adaptive upregulation of eNOS/sGC signaling, revealing novel ways through which H2S affects the NO/cGMP pathway.

How to optimize the adherence to a guideline-directed medical therapy in the secondary prevention of cardiovascular diseases: a clinical consensus statement from the European Association of Preventive Cardiology.

A key factor to successful secondary prevention of cardiovascular disease (CVD) is optimal patient adherence to treatment. However, unsatisfactory rates of adherence to treatment for CVD risk factors and CVD have been observed consistently over the last few decades. Hence, achieving optimal adherence to lifestyle measures and guideline-directed medical therapy in secondary prevention and rehabilitation is a great challenge to many healthcare professionals. Therefore, in this European Association of Preventive Cardiology clinical consensus document, a modern reappraisal of the adherence to optimal treatment is provided, together with simple, practical, and feasible suggestions to achieve this goal in the clinical setting, focusing on evidence-based concepts.

Epigenetics in the primary and secondary prevention of cardiovascular disease: influence of exercise and nutrition.

Increasing evidence links changes in epigenetic systems, such as DNA methylation, histone modification, and non-coding RNA expression, to the occurrence of cardiovascular disease (CVD). These epigenetic modifications can change genetic function under influence of exogenous stimuli and can be transferred to next generations, providing a potential mechanism for inheritance of behavioural intervention effects. The benefits of exercise and nutritional interventions in the primary and secondary prevention of CVD are well established, but the mechanisms are not completely understood. In this review, we describe the acute and chronic epigenetic effects of physical activity and dietary changes. We propose exercise and nutrition as potential triggers of epigenetic signals, promoting the reshaping of transcriptional programmes with effects on CVD phenotypes. Finally, we highlight recent developments in epigenetic therapeutics with implications for primary and secondary CVD prevention.

Effectiveness of Home-Based Cardiac Rehabilitation, Using Wearable Sensors, as a Multicomponent, Cutting-Edge Intervention: A Systematic Review and Meta-Analysis.

Exercise-based cardiac rehabilitation is a highly recommended intervention towards the advancement of the cardiovascular disease (CVD) patients' health profile; though with low participation rates. Although home-based cardiac rehabilitation (HBCR) with the use of wearable sensors is proposed as a feasible alternative rehabilitation model, further investigation is needed. This systematic review and meta-analysis aimed to evaluate the effectiveness of wearable sensors-assisted HBCR in improving the CVD patients' cardiorespiratory fitness (CRF) and health profile. PubMed, Scopus, Cinahl, Cochrane Library, and PsycINFO were searched from 2010 to January 2022, using relevant keywords. A total of 14 randomized controlled trials, written in English, comparing wearable sensors-assisted HBCR to center-based cardiac rehabilitation (CBCR) or usual care (UC), were included. Wearable sensors-assisted HBCR significantly improved CRF when compared to CBCR (Hedges' g = 0.22, 95% CI 0.06, 0.39; I2 = 0%; p = 0.01), whilst comparison of HBCR to UC revealed a nonsignificant effect (Hedges' g = 0.87, 95% CI -0.87, 1.85; I2 = 96.41%; p = 0.08). Effects on physical activity, quality of life, depression levels, modification of cardiovascular risk factors/laboratory parameters, and adherence were synthesized narratively. No significant differences were noted. Technology tools are growing fast in the cardiac rehabilitation era and promote exercise-based interventions into a more home-based setting. Wearable-assisted HBCR presents the potential to act as an adjunct or an alternative to CBCR.

Galectin-3 interferes with tissue repair and promotes cardiac dysfunction and comorbidities in a genetic heart failure model.

Galectin-3, a biomarker for heart failure (HF), has been associated with myocardial fibrosis. However, its causal involvement in HF pathogenesis has been questioned in certain models of cardiac injury-induced HF. To address this, we used desmin-deficient mice (des-/-), a model of progressive HF characterized by cardiomyocyte death, spontaneous inflammatory responses sustaining fibrosis, and galectin-3 overexpression. Genetic ablation or pharmacological inhibition of galectin-3 led to improvement of cardiac function and adverse remodeling features including fibrosis. Over the course of development of des-/- cardiomyopathy, monitored for a period of 12 months, galectin-3 deficiency specifically ameliorated the decline in systolic function accompanying the acute inflammatory phase (4-week-old mice), whereas a more pronounced protective effect was observed in older mice, including the preservation of diastolic function. Interestingly, the cardiac repair activities during the early inflammatory phase were restored under galectin-3 deficiency by increasing the proliferation potential and decreasing apoptosis of fibroblasts, while galectin-3 absence modulated macrophage-fibroblast coupled functions and suppressed both pro-fibrotic activation of cardiac fibroblasts and pro-fibrotic gene expression in the des-/- heart. In addition, galectin-3 also affected the emphysema-like comorbid pathology observed in the des-/- mice, as its absence partially normalized lung compliance. Collectively galectin-3 was found to be causally involved in cardiac adverse remodeling, inflammation, and failure by affecting functions of cardiac fibroblasts and macrophages. In concordance with this role, the effectiveness of pharmacological inhibition in ameliorating cardiac pathology features establishes galectin-3 as a valid intervention target for HF, with additive benefits for treatment of associated comorbidities, such as pulmonary defects. Schematic illustrating top to bottom, the detrimental role of galectin-3 (Gal3) in heart failure progression: desmin deficiency-associated spontaneous myocardial inflammation accompanying cardiac cell death (reddish dashed border) is characterized by infiltration of macrophages (round cells) and up-regulation of Lgals3 (encoding secretable galectin-3, green) and detrimental macrophage-related genes (Ccr2 and Arg1). In this galectin-3-enriched milieu, the early up-regulation of profibrotic gene expression (Tgfb1, Acta2, Col1a1), in parallel to the suppression of proliferative activities and a potential of senescence induction by cardiac fibroblasts (spindle-like cells), collectively promote des-/- cardiac fibrosis and dysfunction establishing heart failure (left panel). Additionally, galectin-3+ macrophage-enrichment accompanies the development of emphysema-like lung comorbidities. In the absence of galectin-3 (right panel), the effect of macrophage-fibroblast dipole and associated events are modulated (grey color depicts reduced expression or activities) leading to attenuated cardiac pathology in the des-/-Lgals3-/- mice. Pulmonary comorbidities are also limited.

Cardiopulmonary assessment prior to returning to high-hazard occupations post-symptomatic COVID-19 infection: a position statement of the Aviation and Occupational Cardiology Task Force of the European Association of Preventive Cardiology.

This article provides an overview of the recommendations of the Aviation and Occupational Cardiology Task Force of the European Association of Preventive Cardiology on returning individuals to work in high-hazard occupations (such as flying, diving, and workplaces that are remote from healthcare facilities) following symptomatic Coronavirus Disease 2019 (COVID-19) infection. This process requires exclusion of significant underlying cardiopulmonary disease and this consensus statement (from experts across the field) outlines the appropriate screening and investigative processes that should be undertaken. The recommended response is based on simple screening in primary healthcare to determine those at risk, followed by first line investigations, including an exercise capacity assessment, to identify the small proportion of individuals who may have circulatory, pulmonary, or mixed disease. These individuals can then receive more advanced, targeted investigations. This statement provides a pragmatic, evidence-based approach for those (in all occupations) to assess employee health and capacity prior to a return to work following severe disease, or while continuing to experience significant post-COVID-19 symptoms (so-called 'long-COVID' or post-COVID-19 syndrome).

Cardiovascular risk in high-hazard occupations: the role of occupational cardiology.

Work is beneficial for health, but many individuals develop cardiovascular disease (CVD) during their working lives. Occupational cardiology is an emerging field that combines traditional cardiology sub-specialisms with prevention and risk management unique to specific employment characteristics and conditions. In some occupational settings incapacitation through CVD has the potential to be catastrophic due to the nature of work and/or the working environment. These are often termed 'hazardous' or 'high-hazard' occupations. Consequently, many organizations that employ individuals in high-hazard roles undertake pre-employment medicals and periodic medical examinations to screen for CVD. The identification of CVD that exceeds predefined employer (or regulatory body) risk thresholds can result in occupational restriction, or disqualification, which may be temporary or permanent. This article will review the evidence related to occupational cardiology for several high-hazard occupations related to aviation and space, diving, high altitude, emergency workers, commercial transportation, and the military. The article will focus on environmental risk, screening, surveillance, and risk management for the prevention of events precipitated by CVD. Occupational cardiology is a challenging field that requires a broad understanding of general cardiology, environmental, and occupational medicine principles. There is a current lack of consensus and contemporary evidence which requires further research. Provision of evidence-based, but individualized, risk stratification and treatment plans is required from specialists that understand the complex interaction between work and the cardiovascular system. There is a current lack of consensus and contemporary evidence in occupational cardiology and further research is required.

Protein tyrosine phosphatase receptor-ζ1 deletion triggers defective heart morphogenesis in mice and zebrafish.

Protein tyrosine phosphatase receptor-ζ1 (PTPRZ1) is a transmembrane tyrosine phosphatase receptor highly expressed in embryonic stem cells. In the present work, gene expression analyses of Ptprz1-/- and Ptprz1+/+ mice endothelial cells and hearts pointed to an unidentified role of PTPRZ1 in heart development through the regulation of heart-specific transcription factor genes. Echocardiography analysis in mice identified that both systolic and diastolic functions are affected in Ptprz1-/- compared with Ptprz1+/+ hearts, based on a dilated left ventricular (LV) cavity, decreased ejection fraction and fraction shortening, and increased angiogenesis in Ptprz1-/- hearts, with no signs of cardiac hypertrophy. A zebrafish ptprz1-/- knockout was also generated and exhibited misregulated expression of developmental cardiac markers, bradycardia, and defective heart morphogenesis characterized by enlarged ventricles and defected contractility. A selective PTPRZ1 tyrosine phosphatase inhibitor affected zebrafish heart development and function in a way like what is observed in the ptprz1-/- zebrafish. The same inhibitor had no effect in the function of the adult zebrafish heart, suggesting that PTPRZ1 is not important for the adult heart function, in line with data from the human cell atlas showing very low to negligible PTPRZ1 expression in the adult human heart. However, in line with the animal models, Ptprz1 was expressed in many different cell types in the human fetal heart, such as valvar, fibroblast-like, cardiomyocytes, and endothelial cells. Collectively, these data suggest that PTPRZ1 regulates cardiac morphogenesis in a way that subsequently affects heart function and warrant further studies for the involvement of PTPRZ1 in idiopathic congenital cardiac pathologies.NEW & NOTEWORTHY Protein tyrosine phosphatase receptor ζ1 (PTPRZ1) is expressed in fetal but not adult heart and seems to affect heart development. In both mouse and zebrafish animal models, loss of PTPRZ1 results in dilated left ventricle cavity, decreased ejection fraction, and fraction shortening, with no signs of cardiac hypertrophy. PTPRZ1 also seems to be involved in atrioventricular canal specification, outflow tract morphogenesis, and heart angiogenesis. These results suggest that PTPRZ1 plays a role in heart development and support the hypothesis that it may be involved in congenital cardiac pathologies.

European Society of Cardiology Quality Indicators for Cardiovascular Disease Prevention: developed by the Working Group for Cardiovascular Disease Prevention Quality Indicators in collaboration with the European Association for Preventive Cardiology of the European Society of Cardiology.

AIMS: To develop a set of quality indicators (QIs) for the evaluation of the care and outcomes for atherosclerotic cardiovascular disease (ASCVD) prevention. METHODS AND RESULTS: The Quality Indicator Committee of the European Society of Cardiology (ESC) formed the Working Group for Cardiovascular Disease Prevention Quality Indicators in collaboration with Task Force members of the 2021 ESC Guidelines on Cardiovascular Disease Prevention in Clinical Practice and the European Association of Preventive Cardiology (EAPC). We followed the ESC methodology for QI development, which involved (i) the identification of the key domains of care for ASCVD prevention by constructing a conceptual framework of care, (ii) the development of candidate QIs by conducting a systematic review of the literature, (iii) the selection of the final set of QIs using a modified Delphi method, and (iv) the evaluation of the feasibility of the developed QIs. In total, 17 main and 14 secondary QIs were selected across six domains of care for ASCVD prevention: (i) structural framework, (ii) risk assessment, (iii) care for people at risk for ASCVD, (iv) care for patients with established ASCVD, (v) patient education and experience, and (vi) outcomes. CONCLUSION: We present the 2021 ESC QIs for Cardiovascular Disease Prevention, which have been co-constructed with EAPC using the ESC methodology for QI development. These indicators are supported by evidence from the literature, underpinned by expert consensus and aligned with the 2021 ESC Guidelines on Cardiovascular Disease Prevention in Clinical Practice to offer a mechanism for the evaluation of ASCVD prevention care and outcomes.

Exercise intensity assessment and prescription in cardiovascular rehabilitation and beyond: why and how: a position statement from the Secondary Prevention and Rehabilitation Section of the European Association of Preventive Cardiology.

A proper determination of the exercise intensity is important for the rehabilitation of patients with cardiovascular disease (CVD) since it affects the effectiveness and medical safety of exercise training. In 2013, the European Association of Preventive Cardiology (EAPC), together with the American Association of Cardiovascular and Pulmonary Rehabilitation and the Canadian Association of Cardiac Rehabilitation, published a position statement on aerobic exercise intensity assessment and prescription in cardiovascular rehabilitation (CR). Since this publication, many subsequent papers were published concerning the determination of the exercise intensity in CR, in which some controversies were revealed and some of the commonly applied concepts were further refined. Moreover, how to determine the exercise intensity during resistance training was not covered in this position paper. In light of these new findings, an update on how to determine the exercise intensity for patients with CVD is mandatory, both for aerobic and resistance exercises. In this EAPC position paper, it will be explained in detail which objective and subjective methods for CR exercise intensity determination exist for aerobic and resistance training, together with their (dis)advantages and practical applications.