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Nature Jul 2023The function of a cell is defined by its intrinsic characteristics and its niche: the tissue microenvironment in which it dwells. Here we combine single-cell and spatial...
The function of a cell is defined by its intrinsic characteristics and its niche: the tissue microenvironment in which it dwells. Here we combine single-cell and spatial transcriptomics data to discover cellular niches within eight regions of the human heart. We map cells to microanatomical locations and integrate knowledge-based and unsupervised structural annotations. We also profile the cells of the human cardiac conduction system. The results revealed their distinctive repertoire of ion channels, G-protein-coupled receptors (GPCRs) and regulatory networks, and implicated FOXP2 in the pacemaker phenotype. We show that the sinoatrial node is compartmentalized, with a core of pacemaker cells, fibroblasts and glial cells supporting glutamatergic signalling. Using a custom CellPhoneDB.org module, we identify trans-synaptic pacemaker cell interactions with glia. We introduce a druggable target prediction tool, drug2cell, which leverages single-cell profiles and drug-target interactions to provide mechanistic insights into the chronotropic effects of drugs, including GLP-1 analogues. In the epicardium, we show enrichment of both IgG and IgA plasma cells forming immune niches that may contribute to infection defence. Overall, we provide new clarity to cardiac electro-anatomy and immunology, and our suite of computational approaches can be applied to other tissues and organs.
Topics: Humans; Cell Communication; Cellular Microenvironment; Fibroblasts; Glutamic Acid; Heart; Ion Channels; Multiomics; Myocardium; Myocytes, Cardiac; Neuroglia; Pericardium; Plasma Cells; Receptors, G-Protein-Coupled; Sinoatrial Node; Heart Conduction System
PubMed: 37438528
DOI: 10.1038/s41586-023-06311-1 -
Cells Jul 2023Pathological cardiac hypertrophy is a key risk factor for the development of heart failure and predisposes individuals to cardiac arrhythmia and sudden death. While... (Review)
Review
Pathological cardiac hypertrophy is a key risk factor for the development of heart failure and predisposes individuals to cardiac arrhythmia and sudden death. While physiological cardiac hypertrophy is adaptive, hypertrophy resulting from conditions comprising hypertension, aortic stenosis, or genetic mutations, such as hypertrophic cardiomyopathy, is maladaptive. Here, we highlight the essential role and reciprocal interactions involving both cardiomyocytes and non-myocardial cells in response to pathological conditions. Prolonged cardiovascular stress causes cardiomyocytes and non-myocardial cells to enter an activated state releasing numerous pro-hypertrophic, pro-fibrotic, and pro-inflammatory mediators such as vasoactive hormones, growth factors, and cytokines, i.e., commencing signaling events that collectively cause cardiac hypertrophy. Fibrotic remodeling is mediated by cardiac fibroblasts as the central players, but also endothelial cells and resident and infiltrating immune cells enhance these processes. Many of these hypertrophic mediators are now being integrated into computational models that provide system-level insights and will help to translate our knowledge into new pharmacological targets. This perspective article summarizes the last decades' advances in cardiac hypertrophy research and discusses the herein-involved complex myocardial microenvironment and signaling components.
Topics: Humans; Endothelial Cells; Cardiomegaly; Myocardium; Myocytes, Cardiac; Heart Failure; Fibrosis
PubMed: 37443814
DOI: 10.3390/cells12131780 -
Biomedicine & Pharmacotherapy =... Jul 2023Myocardial ischemia-reperfusion injury is a common condition in cardiovascular diseases, and the mechanism of its occurrence involves multiple complex metabolic pathways... (Review)
Review
Myocardial ischemia-reperfusion injury is a common condition in cardiovascular diseases, and the mechanism of its occurrence involves multiple complex metabolic pathways and signaling pathways. Among these pathways, glucose metabolism and lipid metabolism play important roles in regulating myocardial energy metabolism. Therefore, this article focuses on the roles of glucose metabolism and lipid metabolism in myocardial ischemia-reperfusion injury, including glycolysis, glucose uptake and transport, glycogen metabolism and the pentose phosphate pathway; and triglyceride metabolism, fatty acid uptake and transport, phospholipid metabolism, lipoprotein metabolism, and cholesterol metabolism. Finally, due to the different alterations and development of glucose metabolism and lipid metabolism in myocardial ischemia-reperfusion, there are also complex interregulatory relationships between them. In the future, modulating the equilibrium between glucose metabolism and lipid metabolism in cardiomyocytes and ameliorating aberrations in myocardial energy metabolism represent highly promising novel strategies for addressing myocardial ischemia-reperfusion injury. Therefore, a comprehensive exploration of glycolipid metabolism can offer novel theoretical and clinical insights into the prevention and treatment of myocardial ischemia-reperfusion injury.
Topics: Humans; Myocardial Reperfusion Injury; Glucose; Lipid Metabolism; Myocardial Ischemia; Myocardium
PubMed: 37141734
DOI: 10.1016/j.biopha.2023.114827 -
Cellular & Molecular Biology Letters Oct 2023Early and prompt reperfusion therapy has markedly improved the survival rates among patients enduring myocardial infarction (MI). Nonetheless, the resulting adverse... (Review)
Review
Early and prompt reperfusion therapy has markedly improved the survival rates among patients enduring myocardial infarction (MI). Nonetheless, the resulting adverse remodeling and the subsequent onset of heart failure remain formidable clinical management challenges and represent a primary cause of disability in MI patients worldwide. Macrophages play a crucial role in immune system regulation and wield a profound influence over the inflammatory repair process following MI, thereby dictating the degree of myocardial injury and the subsequent pathological remodeling. Despite numerous previous biological studies that established the classical polarization model for macrophages, classifying them as either M1 pro-inflammatory or M2 pro-reparative macrophages, this simplistic categorization falls short of meeting the precision medicine standards, hindering the translational advancement of clinical research. Recently, advances in single-cell sequencing technology have facilitated a more profound exploration of macrophage heterogeneity and plasticity, opening avenues for the development of targeted interventions to address macrophage-related factors in the aftermath of MI. In this review, we provide a summary of macrophage origins, tissue distribution, classification, and surface markers. Furthermore, we delve into the multifaceted roles of macrophages in maintaining cardiac homeostasis and regulating inflammation during the post-MI period.
Topics: Humans; Animals; Mice; Myocardial Infarction; Macrophages; Inflammation; Heart Failure; Myocardium; Mice, Inbred C57BL
PubMed: 37858035
DOI: 10.1186/s11658-023-00491-4 -
Biomolecules Dec 2023Myostatin (growth differentiation factor 8) is a member of the transforming growth factor-β superfamily. It is secreted mostly by skeletal muscles, although small... (Review)
Review
Myostatin (growth differentiation factor 8) is a member of the transforming growth factor-β superfamily. It is secreted mostly by skeletal muscles, although small amounts of myostatin are produced by the myocardium and the adipose tissue as well. Myostatin binds to activin IIB membrane receptors to activate the downstream intracellular canonical Smad2/Smad3 pathway, and additionally acts on non-Smad (non-canonical) pathways. Studies on transgenic animals have shown that overexpression of myostatin reduces the heart mass, whereas removal of myostatin has an opposite effect. In this review, we summarize the potential diagnostic and prognostic value of this protein in heart-related conditions. First, in myostatin-null mice the left ventricular internal diameters along with the diastolic and systolic volumes are larger than the respective values in wild-type mice. Myostatin is potentially secreted as part of a negative feedback loop that reduces the effects of the release of growth-promoting factors and energy reprogramming in response to hypertrophic stimuli. On the other hand, both human and animal data indicate that myostatin is involved in the development of the cardiac cachexia and heart fibrosis in the course of chronic heart failure. The understanding of the role of myostatin in such conditions might initiate a development of targeted therapies based on myostatin signaling inhibition.
Topics: Mice; Humans; Animals; Myostatin; Muscle, Skeletal; Myocardium; Signal Transduction; Proteins
PubMed: 38136649
DOI: 10.3390/biom13121777 -
Nature Communications May 2024Sleep disorders increase the risk and mortality of heart disease, but the brain-heart interaction has not yet been fully elucidated. Cuproptosis is a copper-dependent...
Sleep disorders increase the risk and mortality of heart disease, but the brain-heart interaction has not yet been fully elucidated. Cuproptosis is a copper-dependent type of cell death activated by the excessive accumulation of intracellular copper. Here, we showed that 16 weeks of sleep fragmentation (SF) resulted in elevated copper levels in the male mouse heart and exacerbated myocardial ischemia-reperfusion injury with increased myocardial cuproptosis and apoptosis. Mechanistically, we found that SF promotes sympathetic overactivity, increases the germination of myocardial sympathetic nerve terminals, and increases the level of norepinephrine in cardiac tissue, thereby inhibits VPS35 expression and leads to impaired ATP7A related copper transport and copper overload in cardiomyocytes. Copper overload further leads to exacerbated cuproptosis and apoptosis, and these effects can be rescued by excision of the sympathetic nerve or administration of copper chelating agent. Our study elucidates one of the molecular mechanisms by which sleep disorders aggravate myocardial injury and suggests possible targets for intervention.
Topics: Animals; Myocytes, Cardiac; Male; Copper; Myocardial Reperfusion Injury; Mice; Sleep Deprivation; Apoptosis; Mice, Inbred C57BL; Copper-Transporting ATPases; Norepinephrine; Myocardium; Sympathetic Nervous System; Disease Models, Animal
PubMed: 38714741
DOI: 10.1038/s41467-024-48227-y -
Physiological Reviews Apr 2024Acute myocardial infarction (AMI) is the leading cause of cardiovascular death and remains the most common cause of heart failure. Reopening of the occluded artery,... (Review)
Review
Acute myocardial infarction (AMI) is the leading cause of cardiovascular death and remains the most common cause of heart failure. Reopening of the occluded artery, i.e., reperfusion, is the only way to save the myocardium. However, the expected benefits of reducing infarct size are disappointing due to the reperfusion paradox, which also induces specific cell death. These ischemia-reperfusion (I/R) lesions can account for up to 50% of final infarct size, a major determinant for both mortality and the risk of heart failure (morbidity). In this review, we provide a detailed description of the cell death and inflammation mechanisms as features of I/R injury and cardioprotective strategies such as ischemic postconditioning as well as their underlying mechanisms. Due to their biological properties, the use of mesenchymal stromal/stem cells (MSCs) has been considered a potential therapeutic approach in AMI. Despite promising results and evidence of safety in preclinical studies using MSCs, the effects reported in clinical trials are not conclusive and even inconsistent. These discrepancies were attributed to many parameters such as donor age, in vitro culture, and storage time as well as injection time window after AMI, which alter MSC therapeutic properties. In the context of AMI, future directions will be to generate MSCs with enhanced properties to limit cell death in myocardial tissue and thereby reduce infarct size and improve the healing phase to increase postinfarct myocardial performance.
Topics: Humans; Myocardial Infarction; Myocardium; Cardiovascular Physiological Phenomena; Heart Failure; Mesenchymal Stem Cells
PubMed: 37589393
DOI: 10.1152/physrev.00009.2023 -
Methodist DeBakey Cardiovascular Journal 2023
Topics: Humans; Heart; Myocardium; Regeneration; Myocytes, Cardiac
PubMed: 38028972
DOI: 10.14797/mdcvj.1307 -
The Journal of General Physiology Sep 2023Structural and functional studies of heart muscle are important to gain insights into the physiological bases of cardiac muscle contraction and the pathological bases of...
Structural and functional studies of heart muscle are important to gain insights into the physiological bases of cardiac muscle contraction and the pathological bases of heart disease. While fresh muscle tissue works best for these kinds of studies, this is not always practical to obtain, especially for heart tissue from large animal models and humans. Conversely, tissue banks of frozen human hearts are available and could be a tremendous resource for translational research. It is not well understood, however, how liquid nitrogen freezing and cryostorage may impact the structural integrity of myocardium from large mammals. In this study, we directly compared the structural and functional integrity of never-frozen to previously frozen porcine myocardium to investigate the consequences of freezing and cryostorage. X-ray diffraction measurements from hydrated tissue under near-physiological conditions and electron microscope images from chemically fixed porcine myocardium showed that prior freezing has only minor effects on structural integrity of the muscle. Furthermore, mechanical studies similarly showed no significant differences in contractile capabilities of porcine myocardium with and without freezing and cryostorage. These results demonstrate that liquid nitrogen preservation is a practical approach for structural and functional studies of myocardium.
Topics: Humans; Swine; Animals; Cryopreservation; Freezing; Myocardium; Myocardial Contraction; Nitrogen; Mammals
PubMed: 37398997
DOI: 10.1085/jgp.202313345 -
Hellenic Journal of Cardiology : HJC =... 2023Paediatric cardiomyopathies form a heterogeneous group of disorders characterized by structural and electrical abnormalities of the heart muscle, commonly due to a gene... (Review)
Review
Paediatric cardiomyopathies form a heterogeneous group of disorders characterized by structural and electrical abnormalities of the heart muscle, commonly due to a gene variant of the myocardial cell structure. Mostly inherited as a dominant or occasionally recessive trait, they might be part of a syndromic disorder of underlying metabolic or neuromuscular defects or combine early developing extracardiac abnormalities (i.e., Naxos disease). The annual incidence of 1 per 100,000 children appears higher during the first two years of life. Dilated and hypertrophic cardiomyopathy phenotypes share an incidence of 60% and 25%, respectively. Arrhythmogenic right ventricular cardiomyopathy (ARVC), restrictive cardiomyopathy, and left ventricular noncompaction are less commonly diagnosed. Adverse events such as severe heart failure, heart transplantation, or death usually appear early after the initial presentation. In ARVC patients, high-intensity aerobic exercise has been associated with worse clinical outcomes and increased penetrance in at-risk genotype-positive relatives. Acute myocarditis in children has an incidence of 1.4-2.1 cases/per 100,000 children per year, with a 6-14% mortality rate during the acute phase. A genetic defect is considered responsible for the progression to dilated cardiomyopathy phenotype. Similarly, a dilated or arrhythmogenic cardiomyopathy phenotype might emerge with an episode of acute myocarditis in childhood or adolescence. This review provides an overview of childhood cardiomyopathies focusing on clinical presentation, outcome, and pathology.
Topics: Adolescent; Humans; Child; Myocarditis; Cardiomyopathies; Myocardium; Arrhythmogenic Right Ventricular Dysplasia; Phenotype
PubMed: 36870438
DOI: 10.1016/j.hjc.2023.02.007