Spatial multi-omic map of human myocardial infarction.

Myocardial infarction is a leading cause of death worldwide1. Although advances have been made in acute treatment, an incomplete understanding of remodelling processes has limited the effectiveness of therapies to reduce late-stage mortality2. Here we generate an integrative high-resolution map of human cardiac remodelling after myocardial infarction using single-cell gene expression, chromatin accessibility and spatial transcriptomic profiling of multiple physiological zones at distinct time points in myocardium from patients with myocardial infarction and controls. Multi-modal data integration enabled us to evaluate cardiac cell-type compositions at increased resolution, yielding insights into changes of the cardiac transcriptome and epigenome through the identification of distinct tissue structures of injury, repair and remodelling. We identified and validated disease-specific cardiac cell states of major cell types and analysed them in their spatial context, evaluating their dependency on other cell types. Our data elucidate the molecular principles of human myocardial tissue organization, recapitulating a gradual cardiomyocyte and myeloid continuum following ischaemic injury. In sum, our study provides an integrative molecular map of human myocardial infarction, represents an essential reference for the field and paves the way for advanced mechanistic and therapeutic studies of cardiac disease.

Cardiac magnetic resonance in advanced heart failure.

Heart failure (HF) is a chronic and progressive disease that often progresses to an advanced stage where conventional therapy is insufficient to relieve patients' symptoms. Despite the availability of advanced therapies such as mechanical circulatory support or heart transplantation, the complexity of defining advanced HF, which requires multiple parameters and multimodality assessment, often leads to delays in referral to dedicated specialists with the result of a worsening prognosis. In this review, we aim to explore the role of cardiac magnetic resonance (CMR) in advanced HF by showing how CMR is useful at every step in managing these patients: from diagnosis to prognostic stratification, hemodynamic evaluation, follow-up and advanced therapies such as heart transplantation. The technical challenges of scanning advanced HF patients, which often require troubleshooting of intracardiac devices and dedicated scans, will be also discussed.

ECPELLA as a bridge-to-decision in refractory cardiogenic shock: a single-centre experience.

BACKGROUND: In refractory cardiogenic shock, temporary mechanical support (tMCS) may be crucial for maintaining tissue perfusion and oxygen delivery. tMCS can serve as a bridge-to-decision to assess eligibility for left ventricular assist device (LVAD) implantation or heart transplantation, or as a bridge-to-recovery. ECPELLA is a novel tMCS configuration combining venoarterial extracorporeal membrane oxygenation with Impella. The present study presents the clinical parameters, outcomes, and complications of patients supported with ECPELLA. METHODS: All patients supported with ECPELLA at University Medical Centre Utrecht between December 2020 and August 2023 were included. The primary outcome was 30-day mortality, and secondary outcomes were LVAD implantation/heart transplantation and safety outcomes. RESULTS: Twenty patients with an average age of 51 years, and of whom 70% were males, were included. Causes of cardiogenic shock were acute heart failure (due to acute coronary syndrome, myocarditis, or after cardiac surgery) or chronic heart failure, respectively 70 and 30% of cases. The median duration of ECPELLA support was 164 h (interquartile range 98-210). In 50% of cases, a permanent LVAD was implanted. Cardiac recovery within 30 days was seen in 30% of cases and 30-day mortality rate was 20%. ECPELLA support was associated with major bleeding (40%), haemolysis (25%), vascular complications (30%), kidney failure requiring replacement therapy (50%), and Impella failure requiring extraction (15%). CONCLUSION: ECPELLA can be successfully used as a bridge to LVAD implantation or as a bridge-to-recovery in patients with refractory cardiogenic shock. Despite a significant number of complications, 30-day mortality was lower than observed in previous cohorts.

Healthcare consumption of patients with left ventricular assist device: real-world data.

BACKGROUND: A left ventricular assist device (LVAD) is a life-saving but intensive therapy for patients with end-stage heart failure. We evaluated the healthcare consumption in a cohort of LVAD patients in our centre over 6 years. METHODS: All patients with a primary LVAD implantation at the University Medical Centre Utrecht in Utrecht, the Netherlands from 2016 through 2021 were included in this analysis. Subsequent hospital stay, outpatient clinic visits, emergency department visits and readmissions were recorded. RESULTS: During the investigated period, 226 LVADs were implanted, ranging from 32 in 2016 to 45 in 2020. Most LVADs were implanted in patients aged 40-60 years, while they were supported by or sliding on inotropes (Interagency Registry for Mechanically Assisted Circulatory Support class 2 or 3). Around the time of LVAD implantation, the median total hospital stay was 41 days. As the size of the LVAD cohort increased over time, the total annual number of outpatient clinic visits also increased, from 124 in 2016 to 812 in 2021 (p = 0.003). The numbers of emergency department visits and readmissions significantly increased in the 6­year period as well, with a total number of 553 emergency department visits and 614 readmissions. Over the years, the annual number of outpatient clinic visits decreased by 1 per patient-year follow-up, while the annual numbers of emergency department visits and readmissions per patient-year remained stable. CONCLUSION: The number of patients supported by an LVAD has grown steadily over the last years, requiring a more specialised healthcare in this particular population.

From the freezer to the clinic: Antifreeze proteins in the preservation of cells, tissues, and organs.

Understanding the mechanisms by which natural anti-freeze proteins protect cells and tissues from cold could help to improve the availability of donor organs for transplantation.

Incidence and risk factors of late right heart failure in chronic mechanical circulatory support.

BACKGROUND: Late right heart failure (LRHF) is a common complication during long-term left ventricular assist device (LVAD) support. We aimed to identify risk factors for LRHF after LVAD implantation. METHODS: Patients undergoing primary LVAD implantation between 2006 and 2019 and surviving the perioperative period were included for this study (n = 261). Univariate Cox proportional hazards analysis was used to assess the association of clinical covariates and LRHF, stratified for device type. Variables with p < 0.10 entered the multivariable model. In a subset of patients with complete echocardiography or right catheterization data, this multivariable model was extended. Postoperative cardiopulmonary exercise test data were compared in patients with and without LRHF. RESULTS: Nineteen percentage of patients suffered from LRHF after a median of 12 months, of which 67% required hospitalization. A history of atrial fibrillation (AF) (HR: 2.06 [1.08-3.93], p = 0.029), a higher preoperative body mass index (BMI) (HR: 1.07 [1.01-1.13], p = 0.023), and intensive care unit (ICU) duration (HR: 1.03 [1.00-1.06], p = 0.025) were independent predictors of LHRF in the multivariable model. A significant relation between the severity of tricuspid regurgitation (TR) and LRHF (HR: 1.91 [1.13-3.21], p = 0.016) was found in patients with echocardiographic data. Patients with LRHF demonstrated a lower maximal workload and peak VO2 at 6 months postoperatively. CONCLUSION: A history of AF, BMI, and longer ICU stay may help identify patients at high risk for LRHF. Severity of TR was significantly related to LRHF in a subset of patients.

A circular RNA derived from the insulin receptor locus protects against doxorubicin-induced cardiotoxicity.

AIMS: Cardiotoxicity leading to heart failure (HF) is a growing problem in many cancer survivors. As specific treatment strategies are not available, RNA discovery pipelines were employed and a new and powerful circular RNA (circRNA)-based therapy was developed for the treatment of doxorubicin-induced HF. METHODS AND RESULTS: The circRNA sequencing was applied and the highly species-conserved circRNA insulin receptor (Circ-INSR) was identified, which participates in HF processes, including those provoked by cardiotoxic anti-cancer treatments. Chemotherapy-provoked cardiotoxicity leads to the down-regulation of Circ-INSR in rodents and patients, which mechanistically contributes to cardiomyocyte cell death, cardiac dysfunction, and mitochondrial damage. In contrast, Circ-INSR overexpression prevented doxorubicin-mediated cardiotoxicity in both rodent and human cardiomyocytes in vitro and in a mouse model of chronic doxorubicin cardiotoxicity. Breast cancer type 1 susceptibility protein (Brca1) was identified as a regulator of Circ-INSR expression. Detailed transcriptomic and proteomic analyses revealed that Circ-INSR regulates apoptotic and metabolic pathways in cardiomyocytes. Circ-INSR physically interacts with the single-stranded DNA-binding protein (SSBP1) mediating its cardioprotective effects under doxorubicin stress. Importantly, in vitro transcribed and circularized Circ-INSR mimics also protected against doxorubicin-induced cardiotoxicity. CONCLUSION: Circ-INSR is a highly conserved non-coding RNA which is down-regulated during cardiotoxicity and cardiac remodelling. Adeno-associated virus and circRNA mimics-based Circ-INSR overexpression prevent and reverse doxorubicin-mediated cardiomyocyte death and improve cardiac function. The results of this study highlight a novel and translationally important Circ-INSR-based therapeutic approach for doxorubicin-induced cardiac dysfunction.

Left ventricular assist device implantation and clinical outcomes in the Netherlands.

BACKGROUND: Left ventricular assist device (LVAD) therapy is an established treatment for advanced heart failure with reduced ejection fraction. We evaluated the characteristics and clinical outcomes of patients implanted with an LVAD in the Netherlands. METHODS: Patients implanted with an LVAD in the Netherlands between 2016 and 2020 were included in the analysis. Baseline characteristics entered into this registry, as well as clinical outcomes (death on device, heart transplantation) and major adverse events (device dysfunction, major bleeding, major infection and cerebrovascular event), were evaluated. RESULTS: A total of 430 patients were implanted with an LVAD; mean age was 55 ± 13 years and 27% were female. The initial device strategy was bridge to transplant (BTT) in 50%, destination therapy (DT) in 29% and bridge to decision (BTD) in the remaining 21%. After a follow-up of 17 months, 97 (23%) patients had died during active LVAD support. Survival was 83% at 1 year, 76% at 2 years and 54% at 5 years. Patients implanted with an LVAD as a BTT had better outcomes compared with DT at all time points (1 year 86% vs 72%, 2 years 83% vs 59% and 5 years 58% vs 33%). Major adverse events were frequently observed, most often major infection, major bleeding and cerebrovascular events (0.84, 0.33 and 0.09 per patient-year at risk, respectively) and were similar across device strategies. Patients supported with HeartMate 3 had a lower incidence of major adverse events. CONCLUSIONS: Long-term survival on durable LVAD support in the Netherlands is over 50% after 5 years. Major adverse events, especially infection and bleeding, are still frequently observed, but decreasing with the contemporary use of HeartMate 3 LVAD.

Toxicity and efficacy of chronomodulated chemotherapy: a systematic review.

Timing chemotherapy on the basis of the body's intrinsic circadian clock-ie, chronomodulated chemotherapy-might improve efficacy and reduce treatment toxicity. This systematic review summarises the available clinical evidence on the effects of chronomodulated chemotherapy from randomised, controlled trials in adult patients with cancer, published between the date of database inception and June 1, 2021. This study complies with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and was registered on the International Prospective Register of Systematic Reviews (CRD42020177878). The protocol was published on Oct 21, 2020, before study initiation. The primary outcome measures comprised toxicity incidence, overall survival, progression-free survival, and objective response rate. Of 1455 identified abstracts, 18 studies including 2547 patients were selected. Studies were heterogeneous in study design, treatment, and population. 14 (77%) of 18 studies reported differences among groups in toxicity. 11 (61%) studies reported that chronomodulated chemotherapy resulted in a significant decrease in toxicity while maintaining anti-cancer activity. Two (11%) studies showed that chronomodulated chemotherapy reduced some toxic effects but increased others, and one (6%) study reported worse toxicity outcomes than standard chemotherapy. Three (17%) studies reported improved efficacy (survival measures, objective response rate, or time to treatment failure) of chronomodulated chemotherapy, and no studies reported a decrease in efficacy. In conclusion, most studies provide evidence of the reduction of toxicity resulting from chronomodulated chemotherapy, while efficacy is maintained. More and larger, carefully designed, randomised, controlled trials are needed to provide recommendations for clinical practice.

Minimally Invasive Ways of Determining Circadian Rhythms in Humans.

Circadian rhythm exerts a critical role in mammalian health and disease. A malfunctioning circadian clock can be a consequence, as well as the cause of several pathophysiologies. Clinical therapies and research may also be influenced by the clock. Since the most suitable manner of revealing this rhythm in humans is not yet established, we discuss existing methods and seek to determine the most feasible ones.

Validity and success rate of noninvasive mean arterial blood pressure measurements in cf-LVAD patients: A technical review.

BACKGROUND: The life expectancy of patients with a continuous flow left ventricular assist device (cf-LVAD) is increasing. Adequate determination and regulation of mean arterial pressure (MAP) is important to prevent adverse events. Given the low pulsatility characteristics in these patients, standard blood pressure equipment is inadequate to monitor MAP and not recommended. We provide an overview of currently available noninvasive techniques, using an extensive search strategy in three online databases (Pubmed, Scopus and Google Scholar) to find validation studies using invasive intra-arterial blood pressure measurement as a reference. Mean differences with the reference values smaller than 5 ± 8 mm Hg were considered acceptable. OBSERVATIONS: After deduplication, screening, and exclusion of incorrect sources, eleven studies remained with 3139 successful MAP measurements in 386 patients. Four noninvasive techniques, using Doppler, pulse oximetry, finger cuff volume clamp, or slow upper arm cuff deflation, were identified and evaluated for validity and success rate in cf-LVAD patients. Here, a comprehensive technical background of the blood pressure measurement methods is provided in combination with a clinical use comparison. Of the reported noninvasive techniques, slow cuff devices performed most optimally (mean difference 1.3 ± 5.2 mm Hg). CONCLUSIONS: Our results are encouraging and indicate that noninvasive blood pressure monitoring options with acceptable validity and success rate are available. Further technical development and validation is warranted for the growing population of patients on long-term cf-LVAD support.

LVEF by Multigated Acquisition Scan Compared to Other Imaging Modalities in Cardio-Oncology: a Systematic Review.

PURPOSE OF REVIEW: The prevalence of cancer therapy-related cardiac dysfunction (CTRCD) is increasing due to improved cancer survival. Serial monitoring of cardiac function is essential to detect CTRCD, guiding timely intervention strategies. Multigated radionuclide angiography (MUGA) has been the main screening tool using left ventricular ejection fraction (LVEF) to monitor cardiac dysfunction. However, transthoracic echocardiography (TTE) and cardiac magnetic resonance imaging (CMR) may be more suitable for serial assessment. We aimed to assess the concordance between different non-radiating imaging modalities with MUGA to determine whether they can be used interchangeably. RECENT FINDINGS: In order to identify relevant studies, a PubMed search was performed. We included cross-sectional studies comparing MUGA LVEF to that of 2D TTE, 3D TTE, and CMR. From 470 articles, 22 were selected, comprising 1017 patients in total. Among others, this included three 3D TTE, seven 2D harmonic TTE + contrast (2DHC), and seven CMR comparisons. The correlations and Bland-Altman limits of agreement varied for CMR but were stronger for 3D TTE and 2DHC. Our findings suggest that MUGA and CMR should not be used interchangeably whereas 3D TTE and 2DHC are appropriate alternatives following an initial MUGA scan. We propose a multimodality diagnostic imaging strategy for LVEF monitoring in patients undergoing cancer treatment.

Prognostically relevant periprocedural myocardial injury and infarction associated with percutaneous coronary interventions: a Consensus Document of the ESC Working Group on Cellular Biology of the Heart and European Association of Percutaneous Cardiovascular Interventions (EAPCI).

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.

Circadian clocks: from stem cells to tissue homeostasis and regeneration.

The circadian clock is an evolutionarily conserved timekeeper that adapts body physiology to diurnal cycles of around 24 h by influencing a wide variety of processes such as sleep-to-wake transitions, feeding and fasting patterns, body temperature, and hormone regulation. The molecular clock machinery comprises a pathway that is driven by rhythmic docking of the transcription factors BMAL1 and CLOCK on clock-controlled output genes, which results in tissue-specific oscillatory gene expression programs. Genetic as well as environmental perturbation of the circadian clock has been implicated in various diseases ranging from sleep to metabolic disorders and cancer development. Here, we review the origination of circadian rhythms in stem cells and their function in differentiated cells and organs. We describe how clocks influence stem cell maintenance and organ physiology, as well as how rhythmicity affects lineage commitment, tissue regeneration, and aging.

Circadian networks in human embryonic stem cell-derived cardiomyocytes.

Cell-autonomous circadian oscillations strongly influence tissue physiology and pathophysiology of peripheral organs including the heart, in which the circadian clock is known to determine cardiac metabolism and the outcome of for instance ischemic stress. Human pluripotent stem cells represent a powerful tool to study developmental processes in vitro, but the extent to which human embryonic stem (ES) cell-derived cardiomyocytes establish circadian rhythmicity in the absence of a systemic context is unknown. Here we demonstrate that while undifferentiated human ES cells do not possess an intrinsic functional clock, oscillatory expression of known core clock genes emerges spontaneously during directed cardiac differentiation. We identify a set of clock-controlled output genes that contain an oscillatory network of stress-related transcripts. Furthermore, we demonstrate that this network results in a time-dependent functional response to doxorubicin, a frequently used anti-cancer drug with known cardiotoxic side effects. Taken together, our data provide a framework from which the effect of oscillatory gene expression on cardiomyocyte physiology can be modeled in vitro, and demonstrate the influence of a functional clock on experimental outcome.

Defined Engineered Human Myocardium With Advanced Maturation for Applications in Heart Failure Modeling and Repair.

BACKGROUND: Advancing structural and functional maturation of stem cell-derived cardiomyocytes remains a key challenge for applications in disease modeling, drug screening, and heart repair. Here, we sought to advance cardiomyocyte maturation in engineered human myocardium (EHM) toward an adult phenotype under defined conditions. METHODS: We systematically investigated cell composition, matrix, and media conditions to generate EHM from embryonic and induced pluripotent stem cell-derived cardiomyocytes and fibroblasts with organotypic functionality under serum-free conditions. We used morphological, functional, and transcriptome analyses to benchmark maturation of EHM. RESULTS: EHM demonstrated important structural and functional properties of postnatal myocardium, including: (1) rod-shaped cardiomyocytes with M bands assembled as a functional syncytium; (2) systolic twitch forces at a similar level as observed in bona fide postnatal myocardium; (3) a positive force-frequency response; (4) inotropic responses to ß-adrenergic stimulation mediated via canonical ß1- and ß2-adrenoceptor signaling pathways; and (5) evidence for advanced molecular maturation by transcriptome profiling. EHM responded to chronic catecholamine toxicity with contractile dysfunction, cardiomyocyte hypertrophy, cardiomyocyte death, and N-terminal pro B-type natriuretic peptide release; all are classical hallmarks of heart failure. In addition, we demonstrate the scalability of EHM according to anticipated clinical demands for cardiac repair. CONCLUSIONS: We provide proof-of-concept for a universally applicable technology for the engineering of macroscale human myocardium for disease modeling and heart repair from embryonic and induced pluripotent stem cell-derived cardiomyocytes under defined, serum-free conditions.

Neonatal rat cardiomyocytes as an in vitro model for circadian rhythms in the heart.

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.

Position Paper of the European Society of Cardiology Working Group Cellular Biology of the Heart: cell-based therapies for myocardial repair and regeneration in ischemic heart disease and heart failure.

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.

Variation within Variation: Comparison of 24-h Rhythm in Rodent Infarct Size between Ischemia Reperfusion and Permanent Ligation.

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.