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Heart (British Cardiac Society) Sep 2018Although non-invasive perfusion and viability imaging often provide the gateway to coronary revascularisation, current non-invasive imaging methods only report the... (Review)
Review
Although non-invasive perfusion and viability imaging often provide the gateway to coronary revascularisation, current non-invasive imaging methods only report the surrogate markers of inducible hypoperfusion and presence or absence of myocardial scar, rather than actually visualising areas of ischaemia and/or viable myocardium. This may lead to suboptimal revascularisation decisions. Normally respiring (viable) cardiomyocytes convert pyruvate to acetyl-CoA and CO/bicarbonate (via pyruvate dehydrogenase), but under ischaemic conditions characteristically shift this conversion to lactate (by lactate dehydrogenase). Imaging pyruvate metabolism thus has the potential to improve upon current imaging techniques. Using the novel hyperpolarisation technique of dynamic nuclear polarisation (DNP), the magnetic resonance signal of injected [1-C]pyruvate can be transiently magnified >10 000 times over that seen in conventional MR spectroscopy, allowing the characteristic metabolic signatures of ischaemia (lactate production) and viability (CO/bicarbonate production) to be directly imaged. As such DNP imaging of the downstream metabolism of [1-C]pyruvate could surpass the diagnostic capabilities of contemporary ischaemia and viability testing. Here we review the technique, and with brief reference to the salient biochemistry, discuss its potential applications within cardiology. These include ischaemia and viability testing, and further characterisation of the altered metabolism seen at different stages during the natural history of heart failure.
Topics: Heart Failure; Humans; Magnetic Resonance Imaging, Cine; Myocardium
PubMed: 29703741
DOI: 10.1136/heartjnl-2017-312356 -
International Heart Journal Oct 2017The risk of cardiovascular disease increases with age, causing chronic disability, morbidity, and mortality in the elderly. Cardiovascular aging and disease are... (Review)
Review
The risk of cardiovascular disease increases with age, causing chronic disability, morbidity, and mortality in the elderly. Cardiovascular aging and disease are characterized by heart failure, cardiac ischemia-reperfusion injury, cardiomyopathy, hypertension, arterial stiffness, and atherosclerosis. As a cell ages, damaged organelles and abnormal proteins accumulate. A system for removing these cytoplasmic substrates is essential for maintaining homeostasis. Autophagy assists tissue homeostasis by forming a pathway by which these substances are degraded. Growing evidence suggests that autophagy plays a role in age-related and disease states of the cardiovascular system, and it may even be effective in preventing or treating cardiovascular disease. On the other hand, overexpression of autophagy in the heart and arteries can produce detrimental effects. We summarize the current understanding of the close relationship between autophagy and cardiovascular senescence.
Topics: Aging; Autophagy; Cardiovascular Diseases; Humans; Myocardium; Oxidative Stress
PubMed: 28966332
DOI: 10.1536/ihj.17-246 -
Seminars in Cell & Developmental Biology Oct 2021Heart malformation is the leading cause of human birth defects, and many of the congenital heart diseases (CHDs) originate from genetic defects that impact cardiac... (Review)
Review
Heart malformation is the leading cause of human birth defects, and many of the congenital heart diseases (CHDs) originate from genetic defects that impact cardiac development and maturation. During development, the vertebrate heart undergoes a series of complex morphogenetic processes that increase its ability to pump blood. One of these processes leads to the formation of the sheet-like muscular projections called trabeculae. Trabeculae increase cardiac output and permit nutrition and oxygen uptake in the embryonic myocardium prior to coronary vascularization without increasing heart size. Cardiac trabeculation is also crucial for the development of the intraventricular fast conduction system. Alterations in cardiac trabecular development can manifest as a variety of congenital defects such as left ventricular noncompaction. In this review, we discuss the latest advances in understanding the molecular and cellular mechanisms underlying cardiac trabecular development.
Topics: Humans; Myocardium; Myocytes, Cardiac
PubMed: 33994094
DOI: 10.1016/j.semcdb.2021.04.022 -
GeroScience Feb 2017Age-related changes in cardiac homeostasis can be observed at the cellular, extracellular, and tissue levels. Progressive cardiomyocyte hypertrophy, inflammation, and... (Review)
Review
Age-related changes in cardiac homeostasis can be observed at the cellular, extracellular, and tissue levels. Progressive cardiomyocyte hypertrophy, inflammation, and the gradual development of cardiac fibrosis are hallmarks of cardiac aging. In the absence of a secondary insult such as hypertension, these changes are subtle and result in slight to moderate impaired myocardial function, particularly diastolic function. While collagen deposition and cross-linking increase during aging, extracellular matrix (ECM) degradation capacity also increases due to increased expression of matrix metalloproteinases (MMPs). Of the MMPs elevated with cardiac aging, MMP-9 has been extensively evaluated and its roles are reviewed here. In addition to proteolytic activity on ECM components, MMPs oversee cell signaling during the aging process by modulating cytokine, chemokine, growth factor, hormone, and angiogenic factor expression and activity. In association with elevated MMP-9, macrophage numbers increase in an age-dependent manner to regulate the ECM and angiogenic responses. Understanding the complexity of the molecular interactions between MMPs and the ECM in the context of aging may provide novel diagnostic indicators for the early detection of age-related fibrosis and cardiac dysfunction.
Topics: Aging; Animals; Extracellular Matrix; Heart; Humans; Matrix Metalloproteinases; Myocardium; Myocytes, Cardiac; Prognosis; Time Factors; Ventricular Dysfunction, Left; Ventricular Remodeling
PubMed: 28299638
DOI: 10.1007/s11357-017-9959-9 -
Philosophical Transactions. Series A,... Jun 2020Models of electrical activation and recovery in cardiac cells and tissue have become valuable research tools, and are beginning to be used in safety-critical... (Review)
Review
Models of electrical activation and recovery in cardiac cells and tissue have become valuable research tools, and are beginning to be used in safety-critical applications including guidance for clinical procedures and for drug safety assessment. As a consequence, there is an urgent need for a more detailed and quantitative understanding of the ways that uncertainty and variability influence model predictions. In this paper, we review the sources of uncertainty in these models at different spatial scales, discuss how uncertainties are communicated across scales, and begin to assess their relative importance. We conclude by highlighting important challenges that continue to face the cardiac modelling community, identifying open questions, and making recommendations for future studies. This article is part of the theme issue 'Uncertainty quantification in cardiac and cardiovascular modelling and simulation'.
Topics: Electrophysiological Phenomena; Heart; Humans; Models, Cardiovascular; Myocardium; Uncertainty
PubMed: 32448070
DOI: 10.1098/rsta.2019.0335 -
Cellular and Molecular Life Sciences :... Jun 2017Cardiac disease remains a major cause of death worldwide. Direct cardiac reprogramming has emerged as a promising approach for cardiac regenerative therapy. After the... (Review)
Review
Cardiac disease remains a major cause of death worldwide. Direct cardiac reprogramming has emerged as a promising approach for cardiac regenerative therapy. After the discovery of MyoD, a master regulator for skeletal muscle, other single cardiac reprogramming factors (master regulators) have been sought. Discovery of cardiac reprogramming factors was inspired by the finding that multiple, but not single, transcription factors were needed to generate induced pluripotent stem cells (iPSCs) from fibroblasts. We first reported a combination of cardiac-specific transcription factors, Gata4, Mef2c, and Tbx5 (GMT), that could convert mouse fibroblasts into cardiomyocyte-like cells, which were designated as induced cardiomyocyte-like cells (iCMs). Following our first report of cardiac reprogramming, many researchers, including ourselves, demonstrated an improvement in cardiac reprogramming efficiency, in vivo direct cardiac reprogramming for heart regeneration, and cardiac reprogramming in human cells. However, cardiac reprogramming in human cells and adult fibroblasts remains inefficient, and further efforts are needed. We believe that future research elucidating epigenetic barriers and molecular mechanisms of direct cardiac reprogramming will improve the reprogramming efficiency, and that this new technology has great potential for clinical applications.
Topics: Animals; Cellular Reprogramming; Fibroblasts; Humans; Myocardium; Myocytes, Cardiac; Translational Research, Biomedical; Wound Healing
PubMed: 28197667
DOI: 10.1007/s00018-017-2466-4 -
Biochimica Et Biophysica Acta Dec 2016Acetylation of proteins as a post-translational modification is gaining rapid acceptance as a cellular control mechanism on par with other protein modification... (Review)
Review
Acetylation of proteins as a post-translational modification is gaining rapid acceptance as a cellular control mechanism on par with other protein modification mechanisms such as phosphorylation and ubiquitination. Through genetic manipulations and evolving proteomic technologies, identification and consequences of transcription factor acetylation is beginning to emerge. In this review, we summarize the field and discuss newly unfolding mechanisms and consequences of transcription factor acetylation in normal and stressed hearts. This article is part of a Special Issue entitled: The role of post-translational protein modifications on heart and vascular metabolism edited by Jason R.B. Dyck & Jan F.C. Glatz.
Topics: Acetylation; Animals; Cardiovascular Diseases; Humans; Myocardium; Protein Processing, Post-Translational; Transcription Factors
PubMed: 27543804
DOI: 10.1016/j.bbadis.2016.08.011 -
Journal of Molecular and Cellular... Apr 2016Altered fibroblast behavior can lead to pathologic changes in the heart such as arrhythmia, diastolic dysfunction, and systolic dysfunction. Computational models are... (Review)
Review
Altered fibroblast behavior can lead to pathologic changes in the heart such as arrhythmia, diastolic dysfunction, and systolic dysfunction. Computational models are increasingly used as a tool to identify potential mechanisms driving a phenotype or potential therapeutic targets against an unwanted phenotype. Here we review how computational models incorporating cardiac fibroblasts have clarified the role for these cells in electrical conduction and tissue remodeling in the heart. Models of fibroblast signaling networks have primarily focused on fibroblast cell lines or fibroblasts from other tissues rather than cardiac fibroblasts, specifically, but they are useful for understanding how fundamental signaling pathways control fibroblast phenotype. In the future, modeling cardiac fibroblast signaling, incorporating -omics and drug-interaction data into signaling network models, and utilizing multi-scale models will improve the ability of in silico studies to predict potential therapeutic targets against adverse cardiac fibroblast activity.
Topics: Animals; Arrhythmias, Cardiac; Computer Simulation; Extracellular Matrix; Fibroblasts; Fibrosis; Humans; Models, Biological; Myocardium; Myocytes, Cardiac; Phenotype; Signal Transduction
PubMed: 26608708
DOI: 10.1016/j.yjmcc.2015.11.020 -
BMJ (Clinical Research Ed.) Oct 1995
Topics: Calcium Channels; Humans; Myocardial Ischemia; Myocardium; Potassium Channels; Terminology as Topic
PubMed: 7580534
DOI: 10.1136/bmj.311.7010.890 -
Biological & Pharmaceutical Bulletin 2015Loss of cardiac myocytes plays a critical role in the pathogenesis of cardiovascular disorders. A decrease in the number of cardiac myocytes in cardiac diseases results... (Review)
Review
Loss of cardiac myocytes plays a critical role in the pathogenesis of cardiovascular disorders. A decrease in the number of cardiac myocytes in cardiac diseases results in sustained, irreversible contractile failure of myocardium. Therefore prevention of cardiac cell death is a potential therapeutic strategy for various heart diseases. It is well accepted that three types of phenomena such as apoptosis, necrosis, and autophagy may be involved in myocardial cell death. Apoptosis is a highly regulated process that is promoted via death receptor pathway in the plasma membrane or via mitochondrial pathway. Necrosis is induced via mitochondrial swelling, cell rupture, and subsequent inflammation. Autophagy is a cell survival mechanism that involves degradation and recycling of cytoplasmic components. As compared with the other two mechanisms, autophagy may mediate cell death under specific conditions. These three types of cell death in the myocardium are discussed in this article.
Topics: Apoptosis; Autophagy; Cell Death; Cell Survival; Heart Diseases; Humans; Myocardium; Myocytes, Cardiac; Necrosis
PubMed: 26235571
DOI: 10.1248/bpb.b15-00288