Search

Aims Mechanical circulatory support (MCS) results in substantial improvement of prognosis and functional capacity. Currently, duration of MCS as a bridge to transplantation (BTT) is often prolonged due to shortage of donor hearts. Because long‐term results of exercise capacity after MCS are largely unknown, we studied serial cardiopulmonary exercise tests (CPETs) during the first year after MCS implantation. Methods and results Cardiopulmonary exercise tests at 6 and 12 months after MCS implantation in BTT patients were retrospectively analysed, including clinical factors related to exercise capacity. A total of 105 MCS patients (67% male, 50 ± 12 years) underwent serial CPET at 6 and 12 months after implantation. Power (105 ± 35 to 114 ± 40 W; P ≤ 0.001) and peak VO2 per kilogram (pVO2/kg) improved significantly (16.5 ± 5.0 to 17.2 ± 5.5 mL/kg/min (P = 0.008)). Improvement in pVO2 between 6 and 12 months after LVAD implantation was not related to heart failure aetiology or haemodynamic severity prior to MCS. We identified maximal heart rate at exercise as an important factor for pVO2. Younger age and lower BMI were related to further improvement. At 12 months, 25 (24%) patients had a normal exercise capacity (Weber classification A, pVO2 > 20 mL/kg/min). Conclusions Exercise capacity (power and pVO2) increased significantly between 6 and 12 months after MCS independent of Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile or heart failure aetiology. Heart rate at exercise importantly relates to exercise capacity. This long‐term improvement in exercise capacity is important information for the growing group of long‐term MCS patients as this is critical for the quality of life of patients.

Contains fulltext : 235384.pdf (Publisher’s version ) (Open Access) AIM: Soluble suppression of tumorigenicity-2 (sST2) is a strong prognostic biomarker in heart failure. The emerging understanding of circadian biology in cardiovascular disease may lead to novel applications in prognosis and diagnosis and may provide insight into mechanistic aspects of the disease-biomarker interaction. So far, it is unknown whether sST2 exhibits a diurnal rhythm. Repeated measurements of sST2 may aid in clinical decision making. The goal of this study was to investigate whether sST2 exhibits diurnal variation in patients with heart failure with reduced ejection fraction (HFrEF) and in control subjects, thereby enhancing its diagnostic and prognostic values. METHODS AND RESULTS: The study comprised 32 subjects: 16 HFrEF patients and 16 controls. Blood was collected at seven subsequent time points during a 24 h time period. sST2, N-terminal pro-B-type natriuretic peptide (NT-proBNP), melatonin, and cortisol were measured from serum. Peak values of sST2 clustered at daytime (modal value: 5 p.m.) in 87.6% of all subjects (81.3% of patients, P = 0.021; 93.8% of controls, P = 0.001), and minimum concentrations at night-time (modal value: 5 a.m.) in 84.4% (87.5% of patients, P = 0.004 81.3% of controls, P = 0.021). A cosinor analysis of mean normalized sST2 values revealed significant cosine shaped 24 h oscillations of patients (P = 0.026) and controls (P = 0.037). NT-proBNP in contrast did not show a diurnal rhythm, while melatonin and cortisol patterns were intact in all subjects. CONCLUSIONS: sST2 exhibits a diurnal rhythm with lower values in the morning than in the late afternoon. This new insight could lead to refinement of its diagnostic and prognostic values through specified and consistent sampling times with repeated measurements. For example, by measuring sST2 during the afternoon, when levels are at their highest, false negatives on prognosis prediction could be avoided.

A substantial number of chronic coronary syndrome (CCS) patients undergoing percutaneous coronary intervention (PCI) experience periprocedural myocardial injury or infarction. Accurate diagnosis of these PCI-related complications is required to guide further management given that their occurrence may be associated with increased risk of major adverse cardiac events (MACE). Due to lack of scientific data, the cut-off thresholds of post-PCI cardiac troponin (cTn) elevation used for defining periprocedural myocardial injury and infarction, have been selected based on expert consensus opinions, and their prognostic relevance remains unclear. In this Consensus Document from the ESC Working Group on Cellular Biology of the Heart and European Association of Percutaneous Cardiovascular Interventions (EAPCI), we recommend, whenever possible, the measurement of baseline (pre-PCI) cTn and post-PCI cTn values in all CCS patients undergoing PCI. We confirm the prognostic relevance of the post-PCI cTn elevation >5× 99th percentile URL threshold used to define type 4a myocardial infarction (MI). In the absence of periprocedural angiographic flow-limiting complications or electrocardiogram (ECG) and imaging evidence of new myocardial ischaemia, we propose the same post-PCI cTn cut-off threshold (>5× 99th percentile URL) be used to define prognostically relevant ‘major’ periprocedural myocardial injury. As both type 4a MI and major periprocedural myocardial injury are strong independent predictors of all-cause mortality at 1 year post-PCI, they may be used as quality metrics and surrogate endpoints for clinical trials. Further research is needed to evaluate treatment strategies for reducing the risk of major periprocedural myocardial injury, type 4a MI, and MACE in CCS patients undergoing PCI., Graphical Abstract An overview of the suggested approach to diagnosing the presence of ‘minor’ and prognostically relevant ‘major’ periprocedural myocardial injury (as defined in this Consensus document) and type 4a myocardial infarction (as defined by the 4th Universal Definition of Myocardial Infarction) in chronic coronary syndrome patients undergoing percutaneous coronary intervention. CCS, chronic coronary syndrome; MI, myocardial infarction; PCI, percutaneous coronary intervention.

This is a pre-copyedited, author-produced version of an article accepted for publication in Cardiovascular Research (CVR) following peer review. The version of record Perrino, Ferdinandy, Bøtker, Brundel, Collins, Davidson, Den Ruijter, Engel, Gerdts, Girao, Gyöngyösi, Hausenloy, Lecour, Madonna, Marber, Murphy, Pesce, Regitz-Zagrosek, Sluijter, Steffens, Gollmann-Tepeköylü, Van Laake, Van Linthout, Schulz, Ytrehus. Improving translational research in sex-specific effects of comorbidities and risk factors in ischaemic heart disease and cardioprotection: Position paper and recommendations of the ESC Working Group on Cellular Biology of the Heart. Cardiovascular Research (CVR). 2021;117(2):367-385, is available online at: https://doi.org/10.1093/cvr/cvaa155. Ischaemic heart disease (IHD) is a complex disorder and a leading cause of death and morbidity in both men and women. Sex, however, affects several aspects of IHD, including pathophysiology, incidence, clinical presentation, diagnosis as well as treatment and outcome. Several diseases or risk factors frequently associated with IHD can modify cellular signalling cascades, thus affecting ischaemia/reperfusion injury as well as responses to cardioprotective interventions. Importantly, the prevalence and impact of risk factors and several comorbidities differ between males and females, and their effects on IHD development and prognosis might differ according to sex. The cellular and molecular mechanisms underlying these differences are still poorly understood, and their identification might have important translational implications in the prediction or prevention of risk of IHD in men and women. Despite this, most experimental studies on IHD are still undertaken in animal models in the absence of risk factors and comorbidities, and assessment of potential sex-specific differences are largely missing. This ESC WG Position Paper will discuss: (i) the importance of sex as a biological variable in cardiovascular research, (ii) major biological mechanisms underlying sex-related differences relevant to IHD risk factors and comorbidities, (iii) prospects and pitfalls of preclinical models to investigate these associations, and finally (iv) will provide recommendations to guide future research. Although gender differences also affect IHD risk in the clinical setting, they will not be discussed in detail here.

Background Cardiomyopathies, defined as diseases involving mainly the heart muscles, are linked to an estimated 5.9 of 100,000 deaths globally. In sub-Saharan Africa, cardiomyopathies constitute 21.4% of heart failure cases, with dilated cardiomyopathy (DCM) being the most common form. The etiology of DCM is heterogeneous and is broadly categorized as genetic or nongenetic, as well as a mixed disease in which genetics interact with intrinsic and environmental factors. Factors such as age, gender, family history, and ethnicity are nonmodifiable, whereas modifiable risk factors include poor nutrition, physical inactivity, and excessive alcohol consumption, among others. However, the relative contribution of the different risk factors to the etiology of DCM is not known in sub-Saharan Africa, and the prevalence of DCM among heart failure patients has not been systematically studied in the region. Objective The aim of this review is to synthesize available literature from sub-Saharan Africa on the prevalence of DCM among patients with heart failure, as well as the literature on factors associated with DCM. This paper outlines the protocol that will be followed to conduct the systematic review. Methods A limited search of the PubMed database will be performed to identify relevant keywords contained in the title, abstract, and subject descriptors using initial search terms “heart failure,” “cardiomyopathy,” and “sub-Saharan Africa.” These search terms and their synonyms will then be used in an extensive search in PubMed, and will address the first research question on prevalence. To address the second research question on risk factors, the terms “heart failure,” “cardiomyopathy,” and “cardiovascular risk factors” in “Sub-Saharan Africa” will be used, listing them one by one. Articles published from 2000 and in the English language will be included. Indexed articles in PubMed and Embase will be included, as well as the first 300 articles retrieved from a Google Scholar search. Collected data will be organized in Endnote and then uploaded to the Rayyan web app for systematic reviews. Two reviewers will independently select articles against the inclusion criteria. Discrepancies in reviewer selections will be resolved by an arbitrator. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines for reporting systematic reviews will be applied. A map of sub-Saharan Africa with colors to show disease prevalence in each country will be included. For quantitative data, where possible, odds ratios (for categorical outcome data) or standardized mean differences (for continuous data) and their 95% CIs will be calculated. Results The primary outcomes will be the prevalence of DCM among patients with heart failure and cardiovascular risk factors associated with DCM in sub-Saharan Africa. The literature search will begin on January 1, 2021, and data analysis is expected to be completed by April 30, 2021. Conclusions This review will provide information on the current status of the prevalence and associated factors of DCM, and possibly identify gaps, including paucity of data or conflicting results that need to be addressed to improve our understanding of DCM in sub-Saharan Africa. International Registered Report Identifier (IRRID) PRR1-10.2196/18229

Morbidity and mortality from ischaemic heart disease (IHD) and heart failure (HF) remain significant in Europe and are increasing worldwide. Patients with IHD or HF might benefit from novel therapeutic strategies, such as cell-based therapies. We recently discussed the therapeutic potential of cell-based therapies and provided recommendations on how to improve the therapeutic translation of these novel strategies for effective cardiac regeneration and repair. Despite major advances in optimizing these strategies with respect to cell source and delivery method, the clinical outcome of cell-based therapy remains unsatisfactory. Major obstacles are the low engraftment and survival rate of transplanted cells in the harmful microenvironment of the host tissue, and the paucity or even lack of endogenous cells with repair capacity. Therefore, new ways of delivering cells and their derivatives are required in order to empower cell-based cardiac repair and regeneration in patients with IHD or HF. Strategies using tissue engineering (TE) combine cells with matrix materials to enhance cell retention or cell delivery in the transplanted area, and have recently received much attention for this purpose. Here, we summarize knowledge on novel approaches emerging from the TE scenario. In particular, we will discuss how combinations of cell/bio-materials (e.g. hydrogels, cell sheets, prefabricated matrices, microspheres, and injectable matrices) combinations might enhance cell retention or cell delivery in the transplantation areas, thereby increase the success rate of cell therapies for IHD and HF. We will not focus on the use of classical engineering approaches, employing fully synthetic materials, because of their unsatisfactory material properties which render them not clinically applicable. The overall aim of this Position Paper from the ESC Working Group Cellular Biology of the Heart is to provide recommendations on how to proceed in research with these novel TE strategies combined with cell-based therapies to boost cardiac repair in the clinical settings of IHD and HF. © Published on behalf of the European Society of Cardiology. All rights reserved.

Despite improvements in medical therapy and device-based treatment, heart failure (HF) continues to impose enormous burdens on patients and health care systems worldwide. Alterations in autonomic nervous system (ANS) activity contribute to cardiac disease progression, and the recent development of invasive techniques and electrical stimulation devices has opened new avenues for specific targeting of the sympathetic and parasympathetic branches of the ANS. The Heart Failure Association of the European Society of Cardiology recently organized an expert workshop which brought together clinicians, trialists and basic scientists to discuss the ANS as a therapeutic target in HF. The questions addressed were: (i) What are the abnormalities of ANS in HF patients? (ii) What methods are available to measure autonomic dysfunction? (iii) What therapeutic interventions are available to target the ANS in patients with HF, and what are their specific strengths and weaknesses? (iv) What have we learned from previous ANS trials? (v) How should we proceed in the future?

The co‐occurrence of cancer and heart failure (HF) represents a significant clinical drawback as each disease interferes with the treatment of the other. In addition to shared risk factors, a growing body of experimental and clinical evidence reveals numerous commonalities in the biology underlying both pathologies. Inflammation emerges as a common hallmark for both diseases as it contributes to the initiation and progression of both HF and cancer. Under stress, malignant and cardiac cells change their metabolic preferences to survive, which makes these metabolic derangements a great basis to develop intersection strategies and therapies to combat both diseases. Furthermore, genetic predisposition and clonal haematopoiesis are common drivers for both conditions and they hold great clinical relevance in the context of personalized medicine. Additionally, altered angiogenesis is a common hallmark for failing hearts and tumours and represents a promising substrate to target in both diseases. Cardiac cells and malignant cells interact with their surrounding environment called stroma. This interaction mediates the progression of the two pathologies and understanding the structure and function of each stromal component may pave the way for innovative therapeutic strategies and improved outcomes in patients. The interdisciplinary collaboration between cardiologists and oncologists is essential to establish unified guidelines. To this aim, pre‐clinical models that mimic the human situation, where both pathologies coexist, are needed to understand all the aspects of the bidirectional relationship between cancer and HF. Finally, adequately powered clinical studies, including patients from all ages, and men and women, with proper adjudication of both cancer and cardiovascular endpoints, are essential to accurately study these two pathologies at the same time., We describe the co‐occurrence of cancer and heart failure (HF), their potential shared risk factors, and their pathophysiological mechanisms. We advocate intense interaction between cardiologists and oncologists to achieve unifying hypotheses and collaborative pre‐clinical and clinical studies.

Risk factors in the environment such as air pollution and mental stress contribute to the development of chronic non-communicable disease. Air pollution was identified as the leading health risk factor in the physical environment, followed by water pollution, soil pollution/heavy metals/chemicals and occupational exposures, however neglecting the non-chemical environmental health risk factors (e.g. mental stress and noise). Epidemiological data suggest that environmental risk factors are associated with higher risk for cardiovascular, metabolic and mental diseases, including hypertension, heart failure, myocardial infarction, diabetes, arrhythmia, stroke, depression and anxiety disorders. We provide an overview on the impact of the external exposome comprising risk factors/exposures on cardiovascular health with a focus on dysregulation of stress hormones, mitochondrial function, redox balance and inflammation with special emphasis on the circadian clock. Finally, we assess the impact of circadian clock dysregulation on cardiovascular health and the potential of environment-specific preventive strategies or "chrono" therapy for cardioprotection. LINKED ARTICLES: This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.23/issuetoc.

Takotsubo syndrome was featured in various sessions and posters at the recent Heart Failure Congress and World Congress on Acute Heart Failure 2019 held in Athens. The importance and increasing recognition of this acute heart failure syndrome is reflected by the growing activity at Heart Failure Association congresses over the last 8 years. Two dedicated sessions to Takotsubo syndrome with comprehensive lectures from experts in the field and several posters highlighted new scientific progress, important aspects of epidemiology, pathophysiology, risk stratification, and management of the syndrome and discussed gaps in knowledge of this intriguing entity. This paper will summarize the topics discussed in these sessions including the most recent data from large registries, clinical, and pre‐clinical studies presented at the meeting.

Despite improvements in modern cardiovascular therapy, the morbidity and mortality of ischaemic heart disease (IHD) and heart failure (HF) remain significant in Europe and worldwide. Patients with IHD may benefit from therapies that would accelerate natural processes of postnatal collateral vessel formation and/or muscle regeneration. Here, we discuss the use of cells in the context of heart repair, and the most relevant results and current limitations from clinical trials using cell-based therapies to treat IHD and HF. We identify and discuss promising potential new therapeutic strategies that include ex vivo cell-mediated gene therapy, the use of biomaterials and cell-free therapies aimed at increasing the success rates of therapy for IHD and HF. The overall aim of this Position Paper of the ESC Working Group Cellular Biology of the Heart is to provide recommendations on how to improve the therapeutic application of cell-based therapies for cardiac regeneration and repair.

The Earth turns on its axis every 24 h; almost all life on the planet has a mechanism - circadian rhythmicity - to anticipate the daily changes caused by this rotation. The molecular clocks that control circadian rhythms are being revealed as important regulators of physiology and disease. In humans, circadian rhythms have been studied extensively in the cardiovascular system. Many cardiovascular functions, such as endothelial function, thrombus formation, blood pressure and heart rate, are now known to be regulated by the circadian clock. Additionally, the onset of acute myocardial infarction, stroke, arrhythmias and other adverse cardiovascular events show circadian rhythmicity. In this Review, we summarize the role of the circadian clock in all major cardiovascular cell types and organs. Second, we discuss the role of circadian rhythms in cardiovascular physiology and disease. Finally, we postulate how circadian rhythms can serve as a therapeutic target by exploiting or altering molecular time to improve existing therapies and develop novel ones.

Circadian rhythms are biorhythms with a 24-hour period that are regulated by molecular clocks. Several clinical and animal models have been developed to analyze the role of these rhythms in cardiovascular physiology, disease and therapy, but a convenient in vitro model that mimics both molecular and functional circadian effects of the heart is not available. Therefore, we established a neonatal rat cardiomyocyte model that recapitulates in vivo circadian rhythmicity, as measured by anti-phasic oscillatory mRNA expression of two core clock genes, Bmal1 and Per2 and that shows functional dependence on the clock as indicated by an oscillating response in apoptosis induced by doxorubicin, hydroperoxide or hypoxia. In addition, perturbation of the cardiac clock by the use of several compounds including Resveratrol and Ex-527 was found to result in loss of functional rhythmicity. This indicates that neonatal rat cardiomyocytes are a good model to investigate the cardiac circadian clock as well as a system that allows for fast and easy preclinical testing of the influence of compounds on circadian rhythmicity that might have crucial effects on cardiac health.

Summary Stem cell antigen 1-positive (SCA1+) cells (SPCs) have been investigated in cell-based cardiac repair and pharmacological research, although improved cardiac function after injection has been variable and the mode of action remains unclear. Circadian (24-hr) rhythms are biorhythms regulated by molecular clocks that play an important role in (patho)physiology. Here, we describe (1) the presence of a molecular circadian clock in SPCs and (2) circadian rhythmicity in SPC function. We isolated SPCs from human fetal heart and found that these cells possess a molecular clock based on typical oscillations in core clock components BMAL1 and CRY1. Functional analyses revealed that circadian rhythmicity also governs SPC proliferation, stress tolerance, and growth factor release, with large differences between peaks and troughs. We conclude that SPCs contain a circadian molecular clock that controls crucial cellular functions. Taking circadian rhythms into account may improve reproducibility and outcome of research and therapies using SPCs., Highlights • SCA1+ cells are a cell source used in pharmacology studies and cardiac repair • SCA1+ cells possess a molecular circadian (24-hr) clock • Proliferation, stress tolerance, and paracrine secretion follow a circadian pattern • Taking rhythmicity into account may improve studies using SCA1+ cells, SCA1+ cells (SPCs) have been used for pharmacological studies and cell-based cardiac repair. Van Laake and colleagues isolated human SPCs and demonstrated that these cells possess molecular circadian clocks. Functional analyses revealed circadian rhythmicity in SPC proliferation, stress tolerance, and growth factor release. Their findings could improve reproducibility, translation, and outcome of studies using SPCs and other progenitor-like cells.

Korrespondenz zu 10.1093/cvr/cvx049

Coronary artery disease (CAD) is one of the leading causes of death and disability in Europe and worldwide. For patients with multi-vessel CAD, coronary artery bypass graft (CABG) surgery is a common approach for coronary revascularization, and is of proven symptomatic and prognostic benefit. Due to an aging population, higher prevalence of co-morbidities (such as diabetes mellitus, heart failure, hypertension, and renal failure), and a growing requirement for concomitant surgical procedures (such as valve and aortic surgery), higher risk patients are undergoing surgery.1–3 This has resulted in an increased risk of peri-operative myocardial injury (PMI)4 and Type 5 myocardial infarction (MI), both of which are associated with worsened clinical outcomes following CABG surgery. The aetiology and determinants of PMI and Type 5 MI are multi-factorial (see Tables ​Tables11 and ​and22 for summary). Although diagnostic criteria have been proposed for Type 5 MI (based on an elevation in cardiac biomarkers in the 48-h post-operative period and electrocardiogram/angiography/imaging evidence of MI5,13), there is currently no clear definition for prognostically significant PMI, in terms of the level of post-operative cardiac biomarker elevation, which is associated with worsened clinical outcomes following CABG surgery. Table 1 Causes of peri-operative myocardial injury in patients undergoing coronary artery bypass graft surgery

The detrimental effects of myocardial infarction in humans and rodents have a 24-h rhythm. In some human cohorts however, rhythmicity was absent, while the time of maximum damage differs between cohorts. We hypothesized that the type of damage influences the 24-h rhythm in infarct size. Myocardial infarction was induced in 12-week-old C57BL/six mice at four different time-points during the day using either permanent ligation (PL) or 30-min of ischemia followed by reperfusion (IR), with a control group wherein no ligation was applied. Infarct size was measured by echocardiography and histology at a 1-month follow-up. Rhythmicity in infarct size was present in the PL group at the functional and histological level, with maximal damage occurring when the infarct was induced at noon. In the IR group, no circadian rhythm was found. The time of the coronary artery ligation determines the outcome of myocardial infarction. Our data showed that in rodents, the presence of circadian rhythmicity and time of peak infarct size varies between experimental setups.

Introduction: Cardiac repolarization abnormalities are among the major causes of ventricular arrhythmias and sudden cardiac death. In humans, cardiac repolarization duration has a 24-h rhythm. Animal studies show that this rhythm is regulated by 24-h rhythms in ion channel function and that disruption of this rhythm leads to ventricular arrhythmias. We hypothesized that 24-h rhythms in QT duration can be used as a predictor for sudden cardiac death and are associated with ventricular arrhythmias. Secondly, we assessed a possible mechanistic explanation by studying the putative role of hERG channel dysfunction.Materials and Methods: In 2 retrospective studies, measures of the 24-h variation in the QT and QTc intervals (QT and QTc diurnality, QTd and QTcd, respectively) have been derived from Holter analyses and compared between groups: 1) 39 post-infarct patients with systolic heart failure (CHF: EF < 35%), of which 14 with, and 25 without a history of ventricular arrhythmias and 2) five patients with proven (LQTS2) and 16 with potential (Sotalol-induced) hERG channel dysfunction vs. 22 controls.Results: QTd was two-fold higher in CHF patients with a history of ventricular arrhythmias (38 ± 15 ms) compared to CHF patients without VT (16 ± 9 ms, p = 0.001). QTd was significantly increased in LQT2 patients (43 ± 24 ms) or those treated with Sotalol (30 ± 10 ms) compared to controls (21 ± 8 ms, p < 0.05 for both).Discussion: QT diurnality presents a novel clinical parameter of repolarization that can be derived from Holter registrations and may be useful for identification of patients at risk for ventricular arrhythmias.

International audience; Ischaemic heart disease and the heart failure that often results, remain the leading causes of death and disability in Europe and worldwide. As such, in order to prevent heart failure and improve clinical outcomes in patients presenting with an acute ST-segment elevation myocardial infarction and patients undergoing coronary artery bypass graft surgery, novel therapies are required to protect the heart against the detrimental effects of acute ischaemia/reperfusion injury (IRI). During the last three decades, a wide variety of ischaemic conditioning strategies and pharmacological treatments have been tested in the clinic-however, their translation from experimental to clinical studies for improving patient outcomes has been both challenging and disappointing. Therefore, in this Position Paper of the European Society of Cardiology Working Group on Cellular Biology of the Heart, we critically analyse the current state of ischaemic conditioning in both the experimental and clinical settings, provide recommendations for improving its translation into the clinical setting, and highlight novel therapeutic targets and new treatment strategies for reducing acute myocardial IRI.

Cardiac remodeling is critical for effective tissue healing, however, excessive production and deposition of extracellular matrix components contribute to scarring and failing of the heart. Despite the fact that novel therapies have emerged, there are still no lifelong solutions for this problem. An urgent need exists to improve the understanding of adverse cardiac remodeling in order to develop new therapeutic interventions that will prevent, reverse, or regenerate the fibrotic changes in the failing heart. With recent advances in both disease biology and cardiac tissue engineering, the translation of fundamental laboratory research toward the treatment of chronic heart failure patients becomes a more realistic option. Here, the current understanding of cardiac fibrosis and the great potential of tissue engineering are presented. Approaches using hydrogel-based tissue engineered heart constructs are discussed to contemplate key challenges for modeling tissue engineered cardiac fibrosis and to provide a future outlook for preclinical and clinical applications.

In this study, we visualize the real-time dynamics of intramyocardial stem-cell injections. This shows a massive, immediate wash-out via venous drainage, accounting for the low retention. The use of carriers reduces this outflow.

Despite advances in myocardial reperfusion therapies, acute myocardial ischaemia/reperfusion injury and consequent ischaemic heart failure represent the number one cause of morbidity and mortality in industrialized societies. Although different therapeutic interventions have been shown beneficial in preclinical settings, an effective cardioprotective or regenerative therapy has yet to be successfully introduced in the clinical arena. Given the complex pathophysiology of the ischaemic heart, large scale, unbiased, global approaches capable of identifying multiple branches of the signalling networks activated in the ischaemic/reperfused heart might be more successful in the search for novel diagnostic or therapeutic targets. High-throughput techniques allow high-resolution, genome-wide investigation of genetic variants, epigenetic modifications, and associated gene expression profiles. Platforms such as proteomics and metabolomics (not described here in detail) also offer simultaneous readouts of hundreds of proteins and metabolites. Isolated omics analyses usually provide Big Data requiring large data storage, advanced computational resources and complex bioinformatics tools. The possibility of integrating different omics approaches gives new hope to better understand the molecular circuitry activated by myocardial ischaemia, putting it in the context of the human ‘diseasome’. Since modifications of cardiac gene expression have been consistently linked to pathophysiology of the ischaemic heart, the integration of epigenomic and transcriptomic data seems a promising approach to identify crucial disease networks. Thus, the scope of this Position Paper will be to highlight potentials and limitations of these approaches, and to provide recommendations to optimize the search for novel diagnostic or therapeutic targets for acute ischaemia/reperfusion injury and ischaemic heart failure in the post-genomic era.

Coronary heart disease (CHD) is the leading cause of death and disability worldwide. Despite current therapy, the morbidity and mortality for patients with CHD remains significant. The most important manifestations of CHD arise from acute myocardial ischaemia-reperfusion injury (IRI) in terms of cardiomyocyte death and its long-term consequences. As such, new therapeutic interventions are required to protect the heart against the detrimental effects of acute IRI and improve clinical outcomes. Although a large number of cardioprotective therapies discovered in pre-clinical studies have been investigated in CHD patients, few have been translated into the clinical setting, and a significant number of these have failed to show any benefit in terms of reduced myocardial infarction and improved clinical outcomes. Because of this, there is currently no effective therapy for protecting the heart against the detrimental effects of acute IRI in patients with CHD. One major factor for this lack of success in translating cardioprotective therapies into the clinical setting can be attributed to problems with the clinical study design. Many of these clinical studies have not taken into consideration the important data provided from previously published pre-clinical and clinical studies. The overall aim of this ESC Working Group Cellular Biology of the Heart Position Paper is to provide recommendations for optimizing the design of clinical cardioprotection studies, which should hopefully result in new and effective therapeutic interventions for the future benefit of CHD patients.

Background Translational failure for cardiovascular disease is a substantial problem involving both high research costs and an ongoing lack of novel treatment modalities. Despite the progress already made, cell therapy for chronic heart failure in the clinical setting is still hampered by poor translation. We used a murine model of chronic ischemia/reperfusion injury to examine the effect of minimally invasive application of cardiac progenitor cells (CPC) in cardiac remodeling and to improve clinical translation. Methods 28 days after the induction of I/R injury, mice were randomized to receive either CPC (0.5 million) or vehicle by echo-guided intra-myocardial injection. To determine retention, CPC were localized in vivo by bioluminescence imaging (BLI) two days after injection. Cardiac function was assessed by 3D echocardiography and speckle tracking analysis to quantify left ventricular geometry and regional myocardial deformation. Results BLI demonstrated successful injection of CPC (18/23), which were mainly located along the needle track in the anterior/septal wall. Although CPC treatment did not result in overall restoration of cardiac function, a relative preservation of the left ventricular end-diastolic volume was observed at 4 weeks follow-up compared to vehicle control (+5.3 ± 2.1 μl vs. +10.8 ± 1.5 μl). This difference was reflected in an increased strain rate (+16%) in CPC treated mice. Conclusions CPC transplantation can be adequately studied in chronic cardiac remodeling using this study set-up and by that provide a translatable murine model facilitating advances in research for new therapeutic approaches to ultimately improve therapy for chronic heart failure.

Aims Recent clinical studies revealed that positive results of cell transplantation on cardiac function are limited to the short- and mid-term restoration phase following myocardial infarction (MI), emphasizing the need for long-term follow-up. These transient effects may depend on the transplanted cell-type or its differentiation state. We have identified a population of cardiomyocyte progenitor cells (CMPCs) capable of differentiating efficiently into beating cardiomyocytes, endothelial cells, and smooth muscle cells in vitro . We investigated whether CMPCs or pre-differentiated CMPC-derived cardiomyocytes (CMPC-CM) are able to restore the injured myocardium after MI in mice. Methods and results MI was induced in immunodeficient mice and was followed by intra-myocardial injection of CMPCs, CMPC-CM, or vehicle. Cardiac function was measured longitudinally up to 3 months post-MI using 9.4 Tesla magnetic resonance imaging. The fate of the human cells was determined by immunohistochemistry. Transplantation of CMPCs or CMPC-CM resulted in a higher ejection fraction and reduced the extent of left ventricular remodelling up to 3 months after MI when compared with vehicle-injected animals. CMPCs and CMPC-CM generated new cardiac tissue consisting of human cardiomyocytes and blood vessels. Fusion of human nuclei with murine nuclei was not observed. Conclusion CMPCs differentiated into the same cell types in situ as can be obtained in vitro . This excludes the need for in vitro pre-differentiation, making CMPCs a promising source for (autologous) cell-based therapy.

Inadequate cell retention and survival in cardiac stem cell therapy seems to be reducing the therapeutic effect of the injected stem cells. In order to ameliorate their regenerative effects, various biomaterials are being investigated for their potential supportive properties. Here, gelatin microspheres (MS) are utilized as microcarriers to improve the delivery and therapeutic efficacy of cardiac progenitor cells (CPCs) in the ischemic myocardium. The gelatin MS, generated from a water-in-oil emulsion, are able to accommodate the attachment of CPCs, thereby maintaining their cardiogenic potential. In a mouse model of myocardial infarction, we demonstrated the ability of these microcarriers to substantially enhance cell engraftment in the myocardium as indicated by bioluminescent imaging and histological analysis. However, despite an observed tenfold increase in CPC numbers in the myocardium, echocardiography, and histology reveals that mice treated with MS-CPCs show marginal improvement in cardiac function compared to CPCs only. Overall, a straightforward and translational approach is developed to increase the retention of stem cells in the ischemic myocardium. Even though the current biomaterial setup with CPCs as cell source does not translate into improved therapeutic action, coupling this developed technology with stem cell-derived cardiomyocytes can lead to an effective remuscularization therapy.

Regeneration of the myocardium by transplantation of cardiomyocytes is an emerging therapeutic strategy. Human embryonic stem cells (HESC) form cardiomyocytes readily but until recently at low efficiency, so that preclinical studies on transplantation in animals are only just beginning. Here, we show the results of the first long-term (12 weeks) analysis of the fate of HESC-derived cardiomyocytes transplanted intramyocardially into healthy, immunocompromised (NOD-SCID) mice and in NOD-SCID mice that had undergone myocardial infarction (MI). Transplantation of mixed populations of differentiated HESC containing 20–25% cardiomyocytes in control mice resulted in rapid formation of grafts in which the cardiomyocytes became organized and matured over time and the noncardiomyocyte population was lost. Grafts also formed in mice that had undergone MI. Four weeks after transplantation and MI, this resulted in significant improvement in cardiac function measured by magnetic resonance imaging. However, at 12 weeks, this was not sustained despite graft survival. This suggested that graft size was still limiting despite maturation and organization of the transplanted cells. More generally, the results argued for requiring a minimum of 3 months follow-up in studies claiming to observe improved cardiac function, independent of whether HESC or other (adult) cell types are used for transplantation.

Background— Chronic heart failure is characterized by left ventricular remodeling and reactivation of a fetal gene program; the underlying mechanisms are only partly understood. Here we provide evidence that cardiac microRNAs, recently discovered key regulators of gene expression, contribute to the transcriptional changes observed in heart failure. Methods and Results— Cardiac transcriptome analyses revealed striking similarities between fetal and failing human heart tissue. Using microRNA arrays, we discovered profound alterations of microRNA expression in failing hearts. These changes closely mimicked the microRNA expression pattern observed in fetal cardiac tissue. Bioinformatic analysis demonstrated a striking concordance between regulated messenger RNA expression in heart failure and the presence of microRNA binding sites in the respective 3′ untranslated regions. Messenger RNAs upregulated in the failing heart contained preferentially binding sites for downregulated microRNAs and vice versa. Mechanistically, transfection of cardiomyocytes with a set of fetal microRNAs induced cellular hypertrophy as well as changes in gene expression comparable to the failing heart. Conclusions— Our data support a novel mode of regulation for the transcriptional changes in cardiac failure. Reactivation of a fetal microRNA program substantially contributes to alterations of gene expression in the failing human heart.

Of the medical conditions currently being discussed in the context of possible treatments based on cell transplantation therapy, few have received more attention than the heart. Much focus has been on the potential application of bone marrow-derived cell preparations, which have already been introduced into double-blind, placebo-controlled clinical trials. The consensus is that bone marrow may have therapeutic benefit but that this is not based on the ability of bone marrow cells to transdifferentiate into cardiac myocytes. Are there potential stem cell sources of cardiac myocytes that may be useful in replacing those lost or dysfunctional after myocardial infarction? Here, this question is addressed with a review of the recent literature.

Background—Endoglin, an accessory receptor for transforming growth factor-β in vascular endothelial cells, is essential for angiogenesis during mouse development. Mutations in the human gene cause hereditary hemorrhagic telangiectasia type 1 (HHT1), a disease characterized by vascular malformations that increase with age. Although haploinsufficiency is the underlying cause of the disease, HHT1 individuals show great heterogeneity in age of onset, clinical manifestations, and severity.Methods and Results—In situ hybridization and immunohistochemical analysis of mouse and human hearts revealed that endoglin is upregulated in neoangiogenic vessels formed after myocardial infarction. Microvascularity within the infarct zone was strikingly lower in mice with reduced levels of endoglin (Eng+/−) compared with wild-type mice, which resulted in a greater deterioration in cardiac function as measured by magnetic resonance imaging. This did not appear to be because of defects in host inflammatory cell numbers in the infarct zone, which accumulated to a similar extent in wild-type and heterozygous mice. However, defects in vessel formation and heart function inEng+/−mice were rescued by injection of mononuclear cells from healthy human donors but not by mononuclear cells from HHT1 patients.Conclusions—These results establish defective vascular repair as a significant component of the origin of HHT1. Because vascular damage or inflammation occurs randomly, it may also explain disease heterogeneity. More generally, the efficiency of vascular repair may vary between individuals because of intrinsic differences in their mononuclear cells.

International audience; Ischaemic heart disease (IHD) remains the leading cause of death and disability worldwide. As a result, novel therapies are still needed to protect the heart from the detrimental effects of acute ischaemia-reperfusion injury, in order to improve clinical outcomes in IHD patients. In this regard, although a large number of novel cardioprotective therapies discovered in the research laboratory have been investigated in the clinical setting, only a few of these have been demonstrated to improve clinical outcomes. One potential reason for this lack of success may have been the failure to thoroughly assess the cardioprotective efficacy of these novel therapies in suitably designed preclinical experimental animal models. Therefore, the aim of this Position Paper by the European Society of Cardiology Working Group Cellular Biology of the Heart is to provide recommendations for improving the preclinical assessment of novel cardioprotective therapies discovered in the research laboratory, with the aim of increasing the likelihood of success in translating these new treatments into improved clinical outcomes.

International audience; The morbidity and mortality from ischemic heart disease (IHD) remain significant worldwide. The treatment for acute myocardial infarction has improved over the past decades, including early reperfusion of occluded coronary arteries. Although it is essential to re-open the artery as soon as possible, paradoxically this leads to additional myocardial injury, called acute ischemia-reperfusion injury (IRI), for which currently no effective therapy is available. Therefore, novel therapeutic strategies are required to protect the heart from acute IRI in order to reduce myocardial infarction size, preserve cardiac function and improve clinical outcomes in patients with IHD. In this review article, we will first outline the pathophysiology of acute IRI and review promising therapeutic strategies for cardioprotection. These include novel aspects of mitochondrial function, epigenetics, circadian clocks, the immune system, microvesicles, growth factors, stem cell therapy and gene therapy. We discuss the therapeutic potential of these novel cardioprotective strategies in terms of pharmacological targeting and clinical application.

Transplantation of human embryonic stem cell-derived cardiomyocytes (hESC-CM) has been shown to improve the function of the rodent heart 1 month after myocardial infarction (MI). However, the mechanistic basis and optimal delivery strategies are unclear. We investigated the influence of the number of injected cells, resulting graft size, and possible paracrine mechanisms in this process. MI was induced in NOD-SCID mice ( n = 84) followed by injection of enriched hESC-CM at different dosages, hESC-non-CM derivatives, culture medium, or no injection. Cardiac function was monitored for 12 weeks with 9.4 T MRI ( n = 70). Grafts were identified by epifluorescence of a transgenic GFP marker and characterized by immunofluorescence. Vascularity and paracrine effects were investigated immunohistochemically. Transplantation of differentiated hESCs improved short, mid-, and long-term cardiac performance and survival, although only cardiomyocytes formed grafts. A mid-term (4 weeks) cardiomyocyte-specific enhancement was associated with elevated vascular density around the graft and attenuated compensatory remodeling. However, increasing the number of hESC-CM for injection did not enhance heart function further. Moreover, we observed that small graft size was associated with a better functional outcome. HESC-CM increased myocardial vascularization and enhanced heart function in mice after MI, but larger graft size was associated with reduced functional improvement. Future studies should focus on advanced delivery strategies and mechanisms of action rather than increasing graft size.

Cell transplantation may restore heart function in disease associated with loss or dysfunction of cardiomyocytes. Recently, Laflamme et al reported an improvement in cardiac function in immunodeficient rats 4 weeks after coronary artery ligation and injection of human embryonic stem cell–derived cardiomyocytes (hESC-CMs). We have recently carried out a comparable study transplanting hESC-CMs to the hearts of mice with myocardial infarction. Our findings were similar up to the 4-week time point, with significant improvements in cardiac function. However, our follow-up was longer, and, at 3 months, the difference between mice receiving cardiomyocytes and those receiving other cells was no longer significant. Hypothesizing that the improvement observed by Laflamme et al may have been more likely to be sustained long term because the grafts in their study appeared larger, we injected 3 times as many cells. Although this resulted in a significantly increased graft size, we again observed a functional improvement at 1 month but not at 3 months. Our results show that midterm data in these kinds of experiments must be interpreted with caution and longer-term follow-up is essential to draw conclusions on the efficacy of cardiac cell transplantation. Furthermore, our findings demonstrate the unlikely success of merely generating and injecting more cells of the same type to increase functional improvement.

A key aspect of cardiac cell–based therapy is the proper integration of newly formed cardiomyocytes into the remnant myocardium after injury. In this issue, Aratyn-Schaus et al. (2016. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201508026) describe an in vitro model for heterogeneous cardiomyocyte coupling in which force transmission between cells can be measured.

We have developed a mouse severe combined immunodeficient (SCID) model of myocardial infarction based on permanent coronary artery occlusion that allows long-term functional analysis of engrafted human embryonic stem cell-derived cardiomyocytes, genetically marked with green fluorescent protein (GFP), in the mouse heart. We describe methods for delivery of dissociated cardiomyocytes to the left ventricle that minimize scar formation and visualization and validation of the identity of the engrafted cells using the GFP emission spectrum, and histological techniques compatible with GFP epifluorescence, for monitoring phenotypic changes in the grafts in vivo. In addition, we describe how magnetic resonance imaging can be adapted for use in mice to monitor cardiac function non-invasively and repeatedly. The model can be adapted to include multiple control or other cell populations. The procedure for a cohort of six mice can be completed in a maximum of 13 weeks, depending on follow-up, with 30 h of hands-on time.

Background—Chronic heart failure is characterized by left ventricular remodeling and reactivation of a fetal gene program; the underlying mechanisms are only partly understood. Here we provide evidence that cardiac microRNAs, recently discovered key regulators of gene expression, contribute to the transcriptional changes observed in heart failure. Methods and Results—Cardiac transcriptome analyses revealed striking similarities between fetal and failing human heart tissue. Using microRNA arrays, we discovered profound alterations of microRNA expression in failing hearts. These changes closely mimicked the microRNA expression pattern observed in fetal cardiac tissue. Bioinformatic analysis demonstrated a striking concordance between regulated messenger RNA expression in heart failure and the presence of microRNA binding sites in the respective 3 untranslated regions. Messenger RNAs upregulated in the failing heart contained preferentially binding sites for downregulated microRNAs and vice versa. Mechanistically, transfection of cardiomyocytes with a set of fetal microRNAs induced cellular hypertrophy as well as changes in gene expression comparable to the failing heart. Conclusions—Our data support a novel mode of regulation for the transcriptional changes in cardiac failure. Reactivation of a fetal microRNA program substantially contributes to alterations of gene expression in the failing human heart. (Circulation. 2007;116:258-267.)

Cardiac fibroblasts play a key role in chronic heart failure. The conversion from cardiac fibroblast to myofibroblast as a result of cardiac injury, will lead to excessive matrix deposition and a perpetuation of pro-fibrotic signaling. Cardiac cell therapy for chronic heart failure may be able to target fibroblast behavior in a paracrine fashion. However, no reliable human fibrotic tissue model exists to evaluate this potential effect of cardiac cell therapy. Using a gelatin methacryloyl hydrogel and human fetal cardiac fibroblasts (hfCF), we created a 3D in vitro model of human cardiac fibrosis. This model was used to study the possibility to modulate cellular fibrotic responses. Our approach demonstrated paracrine inhibitory effects of cardiac progenitor cells (CPC) on both cardiac fibroblast activation and collagen synthesis in vitro and revealed that continuous cross-talk between hfCF and CPC seems to be indispensable for the observed anti-fibrotic effect.