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ESC Heart Failure Apr 2022Myocardial fluid homeostasis relies on a complex interplay between microvascular filtration, interstitial hydration, cardiomyocyte water uptake and lymphatic removal.... (Review)
Review
Myocardial fluid homeostasis relies on a complex interplay between microvascular filtration, interstitial hydration, cardiomyocyte water uptake and lymphatic removal. Dysregulation of one or more of these mechanisms may result in myocardial oedema. Interstitial and intracellular fluid accumulation disrupts myocardial architecture, intercellular communication, and metabolic pathways, decreasing contractility and increasing myocardial stiffness. The widespread use of cardiac magnetic resonance enabled the identification of myocardial oedema as a clinically relevant imaging finding with prognostic implications in several types of heart failure. Furthermore, growing experimental evidence has contributed to a better understanding of the physical and molecular interactions in the microvascular barrier, myocardial interstitium and lymphatics and how they might be disrupted in heart failure. In this review, we summarize current knowledge on the factors controlling myocardial water balance in the healthy and failing heart and pinpoint the new potential therapeutic avenues.
Topics: Edema; Heart Failure; Humans; Myocardium; Myocytes, Cardiac
PubMed: 35150087
DOI: 10.1002/ehf2.13775 -
Basic Research in Cardiology Dec 2020Resident cardiac macrophages (rcMacs) are integral components of the myocardium where they have key roles for tissue homeostasis and in response to inflammation, tissue... (Review)
Review
Resident cardiac macrophages (rcMacs) are integral components of the myocardium where they have key roles for tissue homeostasis and in response to inflammation, tissue injury and remodelling. In this review, we summarize the current knowledge and limitations associated with the rcMacs studies. We describe their specific role and contribution in various processes such as electrical conduction, efferocytosis, inflammation, tissue development, remodelling and regeneration in both the healthy and the disease state. We also outline research challenges and technical complications associated with rcMac research. Recent technological developments and contemporary immunological techniques are now offering new opportunities to investigate the separate contribution of rcMac in respect to recruited monocytes and other cardiac cells. Finally, we discuss new therapeutic strategies, such as drugs or non-coding RNAs, which can influence rcMac phenotype and their response to inflammation. These novel approaches will allow for a deeper understanding of this cardiac endogenous cell type and might lead to the development of more specific and effective therapeutic strategies to boost the heart's intrinsic reparative capacity.
Topics: Animals; Heart Diseases; Humans; Macrophages; Myocardium; Phagocytosis; Phenotype; Regeneration; Signal Transduction; Ventricular Function, Left; Ventricular Remodeling
PubMed: 33284387
DOI: 10.1007/s00395-020-00836-6 -
Journal of Cardiovascular Pharmacology Jun 2020Cyclic nucleotide phosphodiesterases comprise an 11-member superfamily yielding near 100 isoform variants that hydrolyze cAMP or cGMP to their respective... (Review)
Review
Cyclic nucleotide phosphodiesterases comprise an 11-member superfamily yielding near 100 isoform variants that hydrolyze cAMP or cGMP to their respective 5'-monophosphate form. Each plays a role in compartmentalized cyclic nucleotide signaling, with varying selectivity for each substrate, and conveying cell and intracellular-specific localized control. This review focuses on the 5 phosphodiesterases (PDEs) expressed in the cardiac myocyte capable of hydrolyzing cGMP and that have been shown to play a role in cardiac physiological and pathological processes. PDE1, PDE2, and PDE3 catabolize cAMP as well, whereas PDE5 and PDE9 are cGMP selective. PDE3 and PDE5 are already in clinical use, the former for heart failure, and PDE1, PDE9, and PDE5 are all being actively studied for this indication in patients. Research in just the past few years has revealed many novel cardiac influences of each isoform, expanding the therapeutic potential from their selective pharmacological blockade or in some instances, activation. PDE1C inhibition was found to confer cell survival protection and enhance cardiac contractility, whereas PDE2 inhibition or activation induces beneficial effects in hypertrophied or failing hearts, respectively. PDE3 inhibition is already clinically used to treat acute decompensated heart failure, although toxicity has precluded its long-term use. However, newer approaches including isoform-specific allosteric modulation may change this. Finally, inhibition of PDE5A and PDE9A counter pathological remodeling of the heart and are both being pursued in clinical trials. Here, we discuss recent research advances in each of these PDEs, their impact on the myocardium, and cardiac therapeutic potential.
Topics: Animals; Cardiovascular Agents; Cyclic GMP; Heart Diseases; Humans; Myocardium; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Second Messenger Systems
PubMed: 31651671
DOI: 10.1097/FJC.0000000000000773 -
Methods in Molecular Biology (Clifton,... 2021Procurement and characterization of intact human cells are essential for studies in regenerative medicine and translational medical research. The selection of the...
Procurement and characterization of intact human cells are essential for studies in regenerative medicine and translational medical research. The selection of the currently available approaches to isolate intact cells depends on the age of the hearts. To isolate cardiomyocytes from the fetal or neonatal myocardium, the myocardium can be minced into small tissue blocks followed by enzyme incubation. However, the fetal and neonatal cardiomyocytes are very soft and the morphology changes from long rod or spindle shape to spheres after isolation. Because of the dense packing of the cardiomyocytes and the strong cell-cell connection in adult myocardium, it is difficult to isolate the cardiomyocytes from adult myocardium by enzyme incubation only. A perfusion method is necessary to deliver the enzyme solution to the deep layers of the myocardium. However, intact hearts, which are very rare, are required for the perfusion method. Therefore, lacking methods to efficiently isolate cardiomyocytes from myocardium of various ages builds a barrier between basic research and clinical studies. Here, we describe a method for the isolation of intact cardiomyocytes from fresh or frozen human myocardium or fresh mouse hearts and the quantification of multinucleation, cardiomyocyte size, cell cycle activity, and total cardiomyocyte count per heart. We generalize this fixation-digestion method by isolating cells from a variety of mouse organs, including the liver, lung, and thymus.
Topics: Animals; Cell Culture Techniques; Cell Separation; Cells, Cultured; Heart; Humans; Mice; Molecular Imaging; Myocardium; Myocytes, Cardiac; Perfusion
PubMed: 32857375
DOI: 10.1007/978-1-0716-0668-1_15 -
Circulation Research Feb 2020The hallmark of most cardiac diseases is the progressive loss of cardiomyocytes. In the perinatal period, cardiomyocytes still proliferate, and the heart shows the... (Review)
Review
The hallmark of most cardiac diseases is the progressive loss of cardiomyocytes. In the perinatal period, cardiomyocytes still proliferate, and the heart shows the capacity to regenerate upon injury. In the adult heart, however, the actual rate of cardiomyocyte renewal is too low to efficiently counteract substantial cell loss caused by cardiac injury. In mammals, cardiac growth by cell number expansion changes to growth by cardiomyocyte enlargement soon after birth, coinciding with a period in which most cardiomyocytes increase their DNA content by multinucleation and nuclear polyploidization. Although cardiomyocyte hypertrophy is often associated with these processes, whether polyploidy is a prerequisite or a consequence of hypertrophic growth is unclear. Both the benefits of cardiomyocyte enlargement over proliferative growth of the heart and the physiological role of polyploidy in cardiomyocytes are enigmatic. Interestingly, hearts in animal species with substantial cardiac regenerative capacity dominantly comprise diploid cardiomyocytes, raising the hypothesis that cardiomyocyte polyploidy poses a barrier for cardiomyocyte proliferation and subsequent heart regeneration. On the contrary, there is also evidence for self-duplication of multinucleated myocytes, suggesting a more complex picture of polyploidy in heart regeneration. Polyploidy is not restricted to the heart but also occurs in other cell types in the body. In this review, we explore the biological relevance of polyploidy in different species and tissues to acquire insight into its specific role in cardiomyocytes. Furthermore, we speculate about the physiological role of polyploidy in cardiomyocytes and how this might relate to renewal and regeneration.
Topics: Animals; Cell Enlargement; Cell Proliferation; DNA; Heart; Humans; Myocardium; Myocytes, Cardiac; Polyploidy; Regeneration; Species Specificity
PubMed: 32078450
DOI: 10.1161/CIRCRESAHA.119.315408 -
Circulation Research Jun 2024Fibroblasts are essential for building and maintaining the structural integrity of all organs. Moreover, fibroblasts can acquire an inflammatory phenotype to accommodate... (Review)
Review
Fibroblasts are essential for building and maintaining the structural integrity of all organs. Moreover, fibroblasts can acquire an inflammatory phenotype to accommodate immune cells in specific niches and to provide migration, differentiation, and growth factors. In the heart, balancing of fibroblast activity is critical for cardiac homeostasis and optimal organ function during inflammation. Fibroblasts sustain cardiac homeostasis by generating local niche environments that support housekeeping functions and by actively engaging in intercellular cross talk. During inflammatory perturbations, cardiac fibroblasts rapidly switch to an inflammatory state and actively communicate with infiltrating immune cells to orchestrate immune cell migration and activity. Here, we summarize the current knowledge on the molecular landscape of cardiac fibroblasts, focusing on their dual role in promoting tissue homeostasis and modulating immune cell-cardiomyocyte interaction. In addition, we discuss potential future avenues for manipulating cardiac fibroblast activity during myocardial inflammation.
Topics: Humans; Homeostasis; Animals; Fibroblasts; Myocardium; Inflammation; Myocarditis; Myocytes, Cardiac; Cell Communication
PubMed: 38843287
DOI: 10.1161/CIRCRESAHA.124.323892 -
Nature Reviews. Cardiology Jun 2021For therapeutic materials to be successfully delivered to the heart, several barriers need to be overcome, including the anatomical challenges of access, the mechanical... (Review)
Review
For therapeutic materials to be successfully delivered to the heart, several barriers need to be overcome, including the anatomical challenges of access, the mechanical force of the blood flow, the endothelial barrier, the cellular barrier and the immune response. Various vectors and delivery methods have been proposed to improve the cardiac-specific uptake of materials to modify gene expression. Viral and non-viral vectors are widely used to deliver genetic materials, but each has its respective advantages and shortcomings. Adeno-associated viruses have emerged as one of the best tools for heart-targeted gene delivery. In addition, extracellular vesicles, including exosomes, which are secreted by most cell types, have gained popularity for drug delivery to several organs, including the heart. Accumulating evidence suggests that extracellular vesicles can carry and transfer functional proteins and genetic materials into target cells and might be an attractive option for heart-targeted delivery. Extracellular vesicles or artificial carriers of non-viral and viral vectors can be bioengineered with immune-evasive and cardiotropic properties. In this Review, we discuss the latest strategies for targeting and delivering therapeutic materials to the heart and how the knowledge of different vectors and delivery methods could successfully translate cardiac gene therapy into the clinical setting.
Topics: Drug Delivery Systems; Gene Transfer Techniques; Genetic Vectors; Humans; Myocardium
PubMed: 33500578
DOI: 10.1038/s41569-020-00499-9 -
Seminars in Cell & Developmental Biology Apr 2020The mammalian hearts have the least regenerative capabilities among tissues and organs. As such, heart regeneration has been and continues to be the ultimate goal in the... (Review)
Review
The mammalian hearts have the least regenerative capabilities among tissues and organs. As such, heart regeneration has been and continues to be the ultimate goal in the treatment against acquired and congenital heart diseases. Uncovering such a long-awaited therapy is still extremely challenging in the current settings. On the other hand, this desperate need for effective heart regeneration has developed various forms of modern biotechnologies in recent years. These involve the transplantation of pluripotent stem cell-derived cardiac progenitors or cardiomyocytes generated in vitro and novel biochemical molecules along with tissue engineering platforms. Such newly generated technologies and approaches have been shown to effectively proliferate cardiomyocytes and promote heart repair in the diseased settings, albeit mainly preclinically. These novel tools and medicines give somehow credence to breaking down the barriers associated with re-building heart muscle. However, in order to maximize efficacy and achieve better clinical outcomes through these cell-based and/or cell-free therapies, it is crucial to understand more deeply the developmental cellular hierarchies/paths and molecular mechanisms in normal or pathological cardiogenesis. Indeed, the morphogenetic process of mammalian cardiac development is highly complex and spatiotemporally regulated by various types of cardiac progenitors and their paracrine mediators. Here we discuss the most recent knowledge and findings in cardiac progenitor cell biology and the major cardiogenic paracrine mediators in the settings of cardiogenesis, congenital heart disease, and heart regeneration.
Topics: Animals; Humans; Myocardium; Myocytes, Cardiac; Paracrine Communication; Pluripotent Stem Cells; Regeneration; Tissue Engineering
PubMed: 31862220
DOI: 10.1016/j.semcdb.2019.10.011 -
Circulation Jun 2022
Topics: Humans; Muscle, Skeletal; Myocardium; Myocytes, Cardiac; Troponin; Troponin T
PubMed: 35696457
DOI: 10.1161/CIRCULATIONAHA.122.059935 -
Biochimica Et Biophysica Acta.... May 2020The post-translational modification of serine and threonine residues of nuclear, cytosolic, and mitochondrial proteins by O-linked β-N-acetyl glucosamine (O-GlcNAc) has... (Review)
Review
The post-translational modification of serine and threonine residues of nuclear, cytosolic, and mitochondrial proteins by O-linked β-N-acetyl glucosamine (O-GlcNAc) has long been seen as an important regulatory mechanism in the cardiovascular system. O-GlcNAcylation of cardiac proteins has been shown to contribute to the regulation of transcription, metabolism, mitochondrial function, protein quality control and turnover, autophagy, and calcium handling. In the heart, acute increases in O-GlcNAc have been associated with cardioprotection, such as those observed during ischemia/reperfusion. Conversely, chronic increases in O-GlcNAc, often associated with diabetes and nutrient excess, have been shown to contribute to cardiac dysfunction. Traditionally, many studies have linked changes in O-GlcNAc with nutrient availability and as such O-GlcNAcylation is often seen as a nutrient driven process. However, emerging evidence suggests that O-GlcNAcylation may also be regulated by non-nutrient dependent mechanisms, such as transcriptional and post-translational regulation. Therefore, the goals of this review are to provide an overview of the impact of O-GlcNAcylation in the cardiovascular system, how this is regulated and to discuss the emergence of regulatory mechanisms other than nutrient availability.
Topics: Acetylglucosamine; Animals; Cardiovascular Diseases; Disease Models, Animal; Feeding Behavior; Heart; Humans; Myocardium; N-Acetylglucosaminyltransferases; Nutrients; Protein Processing, Post-Translational; Stress, Physiological
PubMed: 32014551
DOI: 10.1016/j.bbadis.2020.165712