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Heart Failure Reviews Nov 2023Cardiovascular disease (CVD) has reached epidemic proportions and is a leading cause of death worldwide. One of the long-standing goals of scientists is to repair heart... (Review)
Review
Cardiovascular disease (CVD) has reached epidemic proportions and is a leading cause of death worldwide. One of the long-standing goals of scientists is to repair heart tissue damaged by various forms of CVD such as cardiac hypertrophy, dilated cardiomyopathy, myocardial infarction, heart fibrosis, and genetic and developmental heart defects such as heart valve deformities. Damaged or defective heart tissue has limited regenerative capacity and results in a loss of functioning myocardium. Advances in transcriptomic profiling technology have revealed that long noncoding RNA (lncRNA) is transcribed from what was once considered "junk DNA." It has since been discovered that lncRNAs play a critical role in the pathogenesis of various CVDs and in myocardial regeneration. This review will explore how lncRNAs impact various forms of CVD as well as those involved in cardiomyocyte regeneration. Further, we discuss the potential of lncRNAs as a therapeutic modality for treating CVD.
Topics: Humans; Cardiovascular Diseases; RNA, Long Noncoding; Myocardium; Cardiomegaly; Myocytes, Cardiac
PubMed: 37796408
DOI: 10.1007/s10741-023-10342-1 -
International Journal of Molecular... Oct 2023Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease and the leading cause of sudden cardiac death in young people. Mutations in genes that... (Review)
Review
Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease and the leading cause of sudden cardiac death in young people. Mutations in genes that encode structural proteins of the cardiac sarcomere are the more frequent genetic cause of HCM. The disease is characterized by cardiomyocyte hypertrophy and myocardial fibrosis, which is defined as the excessive deposition of extracellular matrix proteins, mainly collagen I and III, in the myocardium. The development of fibrotic tissue in the heart adversely affects cardiac function. In this review, we discuss the latest evidence on how cardiac fibrosis is promoted, the role of cardiac fibroblasts, their interaction with cardiomyocytes, and their activation via the TGF-β pathway, the primary intracellular signalling pathway regulating extracellular matrix turnover. Finally, we summarize new findings on profibrotic genes as well as genetic and non-genetic factors involved in the pathophysiology of HCM.
Topics: Humans; Adolescent; Cardiomyopathy, Hypertrophic; Myocardium; Myocytes, Cardiac; Fibroblasts; Fibrosis
PubMed: 37834293
DOI: 10.3390/ijms241914845 -
Biomedicine & Pharmacotherapy =... Sep 2023Myocardial ischemiareperfusion injury (MIRI) is defined as the additional damage that occurs during the process of restoring blood flow to the heart tissue after...
Myocardial ischemiareperfusion injury (MIRI) is defined as the additional damage that occurs during the process of restoring blood flow to the heart tissue after ischemia-induced damage. Ozone is a powerful oxidizer, but low concentrations of ozone can protect various organs from oxidative stress. Some studies have demonstrated a link between ozone and myocardioprotection, but the mechanism remains unclear. To establish an in vivo animal model of ischemiareperfusion injury (I/R), this study utilized C57 mice, while an in vitro model of hypoxia-reoxygenation (H/R) injury was developed using H9c2 cardiomyocytes to simulate ischemiareperfusion injury. Ozone pretreatment was used in in vitro and in vivo experiments. Through this research, we found that ozone therapy can reduce myocardial injury, and further studies found that ozone regulates the expression levels of these ferroptosis-related proteins and transcription factors in the H/R model, which were screened by bioinformatics. In particular, nuclear translocation of Nrf2 was enhanced by pretreatment with ozone, inhibited ferroptosis and ameliorated oxidative stress by initiating the expression of Slc7a11 and Gpx4. Significantly, Nrf2 gene silencing reverses the protective effects of ozone in the H/R model. In summary, our results suggest that ozone protects the myocardium from I/R damage through the Nrf2/Slc7a11/Gpx4 signaling pathway, highlighting the potential of ozone as a new coronary artery disease therapy.
Topics: Animals; Mice; NF-E2-Related Factor 2; Ferroptosis; Myocardium; Myocytes, Cardiac; Heart Injuries; Ozone; Reperfusion Injury
PubMed: 37487441
DOI: 10.1016/j.biopha.2023.115185 -
Advanced Science (Weinheim,... Sep 2023Myocardial infarction (MI) causes excessive damage to the myocardium, including the epicardium. However, whether pluripotent stem cell-derived epicardial cells (EPs) can...
Myocardial infarction (MI) causes excessive damage to the myocardium, including the epicardium. However, whether pluripotent stem cell-derived epicardial cells (EPs) can be a therapeutic approach for infarcted hearts remains unclear. Here, the authors report that intramyocardial injection of human embryonic stem cell-derived EPs (hEPs) at the acute phase of MI ameliorates functional worsening and scar formation in mouse hearts, concomitantly with enhanced cardiomyocyte survival, angiogenesis, and lymphangiogenesis. Mechanistically, hEPs suppress MI-induced infiltration and cytokine-release of inflammatory cells and promote reparative macrophage polarization. These effects are blocked by a type I interferon (IFN-I) receptor agonist RO8191. Moreover, intelectin 1 (ITLN1), abundantly secreted by hEPs, interacts with IFN-β and mimics the effects of hEP-conditioned medium in suppression of IFN-β-stimulated responses in macrophages and promotion of reparative macrophage polarization, whereas ITLN1 downregulation in hEPs cancels beneficial effects of hEPs in anti-inflammation, IFN-I response inhibition, and cardiac repair. Further, similar beneficial effects of hEPs are observed in a clinically relevant porcine model of reperfused MI, with no increases in the risk of hepatic, renal, and cardiac toxicity. Collectively, this study reveals hEPs as an inflammatory modulator in promoting infarct healing via a paracrine mechanism and provides a new therapeutic approach for infarcted hearts.
Topics: Swine; Mice; Humans; Animals; Human Embryonic Stem Cells; Myocardium; Myocytes, Cardiac; Myocardial Infarction; Macrophages
PubMed: 37505480
DOI: 10.1002/advs.202300470 -
Circulation. Cardiovascular Imaging Nov 2023Infiltrative cardiomyopathies comprise a broad spectrum of inherited or acquired conditions caused by deposition of abnormal substances within the myocardium. Increased... (Review)
Review
Infiltrative cardiomyopathies comprise a broad spectrum of inherited or acquired conditions caused by deposition of abnormal substances within the myocardium. Increased wall thickness, inflammation, microvascular dysfunction, and fibrosis are the common pathological processes that lead to abnormal myocardial filling, chamber dilation, and disruption of conduction system. Advanced disease presents as heart failure and cardiac arrhythmias conferring poor prognosis. Infiltrative cardiomyopathies are often diagnosed late or misclassified as other more common conditions, such as hypertrophic cardiomyopathy, hypertensive heart disease, ischemic or other forms of nonischemic cardiomyopathies. Accurate diagnosis is also critical because clinical features, testing methodologies, and approach to treatment vary significantly even within the different types of infiltrative cardiomyopathies on the basis of the type of substance deposited. Substantial advances in noninvasive cardiac imaging have enabled accurate and early diagnosis. thereby eliminating the need for endomyocardial biopsy in most cases. This scientific statement discusses the role of contemporary multimodality imaging of infiltrative cardiomyopathies, including echocardiography, nuclear and cardiac magnetic resonance imaging in the diagnosis, prognostication, and assessment of response to treatment.
Topics: Humans; American Heart Association; Cardiomyopathies; Heart; Heart Failure; Myocardium; Magnetic Resonance Imaging
PubMed: 37916407
DOI: 10.1161/HCI.0000000000000081 -
Molecular Aspects of Medicine Oct 2023Heart failure is a leading cause of mortality and hospitalization worldwide. Cardiac fibrosis, resulting from the excessive deposition of collagen fibers, is a common... (Review)
Review
Heart failure is a leading cause of mortality and hospitalization worldwide. Cardiac fibrosis, resulting from the excessive deposition of collagen fibers, is a common feature across the spectrum of conditions converging in heart failure. Eventually, either reparative or reactive in nature, in the long-term cardiac fibrosis contributes to heart failure development and progression and is associated with poor clinical outcomes. Despite this, specific cardiac antifibrotic therapies are lacking, making cardiac fibrosis an urgent unmet medical need. In this context, a better patient phenotyping is needed to characterize the heterogenous features of cardiac fibrosis to advance toward its personalized management. In this review, we will describe the different phenotypes associated with cardiac fibrosis in heart failure and we will focus on the potential usefulness of imaging techniques and circulating biomarkers for the non-invasive characterization and phenotyping of this condition and for tracking its clinical impact. We will also recapitulate the cardiac antifibrotic effects of existing heart failure and non-heart failure drugs and we will discuss potential strategies under preclinical development targeting the activation of cardiac fibroblasts at different levels, as well as targeting additional extracardiac processes.
Topics: Humans; Myocardium; Heart Failure; Fibroblasts; Biomarkers; Fibrosis
PubMed: 37384998
DOI: 10.1016/j.mam.2023.101194 -
Frontiers in Immunology 2023Acute myocardial infarction (MI) is a prevalent and highly fatal global disease. Despite significant reduction in mortality rates with standard treatment regimens, the... (Review)
Review
Acute myocardial infarction (MI) is a prevalent and highly fatal global disease. Despite significant reduction in mortality rates with standard treatment regimens, the risk of heart failure (HF) remains high, necessitating innovative approaches to protect cardiac function and prevent HF progression. Cardiac resident macrophages (cMacs) have emerged as key regulators of the pathophysiology following MI. cMacs are a heterogeneous population composed of subsets with different lineage origins and gene expression profiles. Several critical aspects of post-MI pathophysiology have been shown to be regulated by cMacs, including recruitment of peripheral immune cells, clearance and replacement of damaged myocardial cells. Furthermore, cMacs play a crucial role in regulating cardiac fibrosis, risk of arrhythmia, energy metabolism, as well as vascular and lymphatic remodeling. Given the multifaceted roles of cMacs in post-MI pathophysiology, targeting cMacs represents a promising therapeutic strategy. Finally, we discuss novel treatment strategies, including using nanocarriers to deliver drugs to cMacs or using cell therapies to introduce exogenous protective cMacs into the heart.
Topics: Humans; Myocardium; Myocardial Infarction; Myocytes, Cardiac; Macrophages; Heart Failure
PubMed: 37457720
DOI: 10.3389/fimmu.2023.1207100 -
Nature Nov 2023Pumping of the heart is powered by filaments of the motor protein myosin that pull on actin filaments to generate cardiac contraction. In addition to myosin, the...
Pumping of the heart is powered by filaments of the motor protein myosin that pull on actin filaments to generate cardiac contraction. In addition to myosin, the filaments contain cardiac myosin-binding protein C (cMyBP-C), which modulates contractility in response to physiological stimuli, and titin, which functions as a scaffold for filament assembly. Myosin, cMyBP-C and titin are all subject to mutation, which can lead to heart failure. Despite the central importance of cardiac myosin filaments to life, their molecular structure has remained a mystery for 60 years. Here we solve the structure of the main (cMyBP-C-containing) region of the human cardiac filament using cryo-electron microscopy. The reconstruction reveals the architecture of titin and cMyBP-C and shows how myosin's motor domains (heads) form three different types of motif (providing functional flexibility), which interact with each other and with titin and cMyBP-C to dictate filament architecture and function. The packing of myosin tails in the filament backbone is also resolved. The structure suggests how cMyBP-C helps to generate the cardiac super-relaxed state; how titin and cMyBP-C may contribute to length-dependent activation; and how mutations in myosin and cMyBP-C might disturb interactions, causing disease. The reconstruction resolves past uncertainties and integrates previous data on cardiac muscle structure and function. It provides a new paradigm for interpreting structural, physiological and clinical observations, and for the design of potential therapeutic drugs.
Topics: Humans; Cardiac Myosins; Carrier Proteins; Connectin; Cryoelectron Microscopy; Myocardium
PubMed: 37914935
DOI: 10.1038/s41586-023-06691-4 -
American Journal of Physiology. Heart... Nov 2023With sparse treatment options, cardiac disease remains a significant cause of death among humans. As a person ages, mitochondria breakdown and the heart becomes less...
With sparse treatment options, cardiac disease remains a significant cause of death among humans. As a person ages, mitochondria breakdown and the heart becomes less efficient. Heart failure is linked to many mitochondria-associated processes, including endoplasmic reticulum stress, mitochondrial bioenergetics, insulin signaling, autophagy, and oxidative stress. The roles of key mitochondrial complexes that dictate the ultrastructure, such as the mitochondrial contact site and cristae organizing system (MICOS), in aging cardiac muscle are poorly understood. To better understand the cause of age-related alteration in mitochondrial structure in cardiac muscle, we used transmission electron microscopy (TEM) and serial block facing-scanning electron microscopy (SBF-SEM) to quantitatively analyze the three-dimensional (3-D) networks in cardiac muscle samples of male mice at aging intervals of 3 mo, 1 yr, and 2 yr. Here, we present the loss of cristae morphology, the inner folds of the mitochondria, across age. In conjunction with this, the three-dimensional (3-D) volume of mitochondria decreased. These findings mimicked observed phenotypes in murine cardiac fibroblasts with CRISPR/Cas9 knockout of (some members of the MICOS complex), and , which showed poorer oxidative consumption rate and mitochondria with decreased mitochondrial length and volume. In combination, these data show the need to explore if loss of the MICOS complex in the heart may be involved in age-associated mitochondrial and cristae structural changes. This article shows how mitochondria in murine cardiac changes, importantly elucidating age-related changes. It also is the first to show that the MICOS complex may play a role in outer membrane mitochondrial structure.
Topics: Humans; Male; Mice; Animals; Mitochondria; Myocardium; Heart; Aging; Signal Transduction; Mitochondrial Proteins
PubMed: 37624101
DOI: 10.1152/ajpheart.00202.2023 -
Arteriosclerosis, Thrombosis, and... May 2024
Review
Topics: Lymphangiogenesis; Humans; Animals; Lymphatic Vessels; Cardiovascular Diseases; Signal Transduction; Myocardium
PubMed: 38657034
DOI: 10.1161/ATVBAHA.123.319572