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Progress in Biophysics and Molecular... 2003The heart is structurally and functionally a highly non-homogenous organ, yet its main function as a pump can only be achieved by the co-ordinated contraction of... (Review)
Review
The heart is structurally and functionally a highly non-homogenous organ, yet its main function as a pump can only be achieved by the co-ordinated contraction of millions of ventricular cells. This apparent contradiction gives rise to the hypothesis that 'well-organised' inhomogeneity may be a pre-requisite for normal cardiac function. Here, we present a set of novel experimental and theoretical tools for the study of this concept. Heterogeneity, in its most condensed form, can be simulated using two individually controlled, mechanically interacting elements (duplex). We have developed and characterised three different types of duplexes: (i) biological duplex, consisting of two individually perfused biological samples (like thin papillary muscles or a trabeculae), (ii) virtual duplex, made-up of two interacting mathematical models of cardiac muscle, and (iii) hybrid duplex, containing a biological sample that interacts in real-time with a virtual muscle. In all three duplex types, in-series or in-parallel mechanical interaction of elements can be studied during externally isotonic, externally isometric, and auxotonic modes of contraction and relaxation. Duplex models, therefore, mimic (patho-)physiological mechano-electric interactions in heterogeneous myocardium at the multicellular level, and in an environment that allows one to control mechanical, electrical and pharmacological parameters. Results obtained using the duplex method show that: (i) contractile elements in heterogeneous myocardium are not 'independent' generators of tension/shortening, as their ino- and lusitropic characteristics change dynamically during mechanical interaction-potentially matching microscopic contractility to macroscopic demand, (ii) mechanical heterogeneity contributes differently to action potential duration (APD) changes, depending on whether mechanical coupling of elements is in-parallel or in-series, which may play a role in mechanical tuning of distant tissue regions, (iii) electro-mechanical activity of mechanically interacting contractile elements is affected by their activation sequence, which may optimise myocardial performance by smoothing intrinsic differences in APD. In conclusion, we present a novel set of tools for the experimental and theoretical investigation of cardiac mechano-electric interactions in healthy and/or diseased heterogeneous myocardium, which allows for the testing of previously inaccessible concepts.
Topics: Animals; Electrophysiology; Heart; Heart Conduction System; Humans; Models, Cardiovascular; Models, Theoretical; Myocardium; Time Factors
PubMed: 12732280
DOI: 10.1016/s0079-6107(03)00017-8 -
Journal of Muscle Research and Cell... Jun 2019Tissue engineering is a complex field where the elements of biology and engineering are combined in an attempt to recapitulate the native environment of the body. Tissue... (Review)
Review
Tissue engineering is a complex field where the elements of biology and engineering are combined in an attempt to recapitulate the native environment of the body. Tissue engineering has shown one thing categorically; that the human body is extremely complex and it is truly a difficult task to generate this in the lab. There have been varied attempts at trying to generate a model for the heart with numerous cell types and different scaffolds or materials. The common underlying theme in these approaches is to combine together matrix material and different cell types to make something similar to heart tissue. Multi-cellularity is an essential aspect of the heart and therefore critical to any approach which would try to mimic such a complex tissue. The heart is made up of many cell types that combine to form complex structures like: deformable chambers, a tri-layered heart muscle, and vessels. Thus, in this review we will summarise how tissue engineering has progressed in modelling the heart and what gaps still exist in this dynamic field.
Topics: Animals; Extracellular Matrix; Humans; Myocardium; Tissue Engineering
PubMed: 31222588
DOI: 10.1007/s10974-019-09528-8 -
Acta Pharmacologica Sinica Sep 2010Calorie restriction (CR) is defined as a reduction in calorie intake below the usual ad libitum intake without malnutrition. Ample of clinical and experimental evidence... (Review)
Review
Calorie restriction (CR) is defined as a reduction in calorie intake below the usual ad libitum intake without malnutrition. Ample of clinical and experimental evidence has demonstrated that CR is capable of retarding aging process and development of cardiovascular disease. Although suppression of reactive oxygen species production and inflammation plays a central role in the favorable cardiovascular effects of CR, the health benefit of CR is believed to be ultimately mediated through a cadre of biochemical and cellular adaptations including redox homeostasis, mitochondrial function, inflammation, apoptosis and autophagy. Despite the apparent beneficial cardiovascular effects of CR, implementation of CR in the health care management is still hampered by apparent applicability issues and health concerns. Here we briefly review the cardiac consequence of CR and discuss whether CR may represent a safe and effective strategy in the management of cardiovascular health.
Topics: Aging; Animals; Caloric Restriction; Cardiovascular Diseases; Heart; Humans; Myocardium; Signal Transduction
PubMed: 20729873
DOI: 10.1038/aps.2010.146 -
Cells Sep 2020Endoplasmic reticulum (ER) stress is a result of conditions that imbalance protein homeostasis or proteostasis at the ER, for example ischemia, and is a common event in... (Review)
Review
Endoplasmic reticulum (ER) stress is a result of conditions that imbalance protein homeostasis or proteostasis at the ER, for example ischemia, and is a common event in various human pathologies, including the diseased heart. Cardiac integrity and function depend on the active secretion of mature proteins from a variety of cell types in the heart, a process that requires an intact ER environment for efficient protein folding and trafficking to the secretory pathway. As a consequence of ER stress, most protein secretion by the ER secretory pathway is decreased. Strikingly, there is a select group of proteins that are secreted in greater quantities during ER stress. ER stress resulting from the dysregulation of ER Ca levels, for instance, stimulates the secretion of Ca-binding ER chaperones, especially GRP78, GRP94, calreticulin, and mesencephalic astrocyte-derived neurotrophic factor (MANF), which play a multitude of roles outside the cell, strongly depending on the cell type and tissue. Here we review current insights in ER stress-induced secretion of proteins, particularly from the heart, and highlight the extracellular functions of these proteins, ranging from the augmentation of cardiac cell viability to the modulation of pro- and anti-apoptotic, oncogenic, and immune-stimulatory cell signaling, cell invasion, extracellular proteostasis, and more. Many of the roles of ER stress-induced protein secretion remain to be explored in the heart. This article is part of a special issue entitled "The Role of Proteostasis Derailment in Cardiac Diseases."
Topics: Animals; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Heart; Heart Diseases; Humans; Molecular Chaperones; Myocardium; Proteostasis; Signal Transduction; Unfolded Protein Response
PubMed: 32927693
DOI: 10.3390/cells9092066 -
Progress in Biophysics and Molecular... Jan 2011A key aim of the cardiac Physiome Project is to develop theoretical models to simulate the functional behaviour of the heart under physiological and pathophysiological... (Review)
Review
A key aim of the cardiac Physiome Project is to develop theoretical models to simulate the functional behaviour of the heart under physiological and pathophysiological conditions. Heart function is critically dependent on the delivery of an adequate blood supply to the myocardium via the coronary vasculature. Key to this critical function of the coronary vasculature is system dynamics that emerge via the interactions of the numerous constituent components at a range of spatial and temporal scales. Here, we focus on several components for which theoretical approaches can be applied, including vascular structure and mechanics, blood flow and mass transport, flow regulation, angiogenesis and vascular remodelling, and vascular cellular mechanics. For each component, we summarise the current state of the art in model development, and discuss areas requiring further research. We highlight the major challenges associated with integrating the component models to develop a computational tool that can ultimately be used to simulate the responses of the coronary vascular system to changing demands and to diseases and therapies.
Topics: Biomechanical Phenomena; Coronary Circulation; Coronary Vessels; Heart; Humans; Models, Cardiovascular; Myocardium
PubMed: 21040741
DOI: 10.1016/j.pbiomolbio.2010.10.001 -
The Israel Medical Association Journal... Apr 2006Ventricular remodeling and heart failure are the inevitable consequences of myocardial infarction. Current options to cure myocardial infarction and subsequent heart... (Review)
Review
Ventricular remodeling and heart failure are the inevitable consequences of myocardial infarction. Current options to cure myocardial infarction and subsequent heart failure suffer from specific limitations. Thus, alternative, additional long-term therapeutic strategies are needed to cure this costly and deadly disease. Cardiac regeneration is a promising new therapeutic option. Through cellular and molecular therapies, the concept of in situ "growing" heart muscle, vascular tissue and manipulating the extracellular matrix environment promises to revolutionize the approach of treating heart disease. Recent studies have suggested that stem cells resident within the bone marrow or peripheral blood can be recruited to the injured heart. The regeneration of damaged heart tissue may include the mobilization of progenitor or stem cells to the damaged area or stimulation of a regenerative program within the organ. There is now evidence accumulating that the heart contains resident stem cells that can be induced to develop into cardiac muscle and vascular tissue. The present review aims to describe the potential, the current status and the future challenges of myocardial regeneration by adult stem cells.
Topics: Guided Tissue Regeneration; Heart; Heart Failure; Humans; Myocardial Infarction; Myocardium; Stem Cell Transplantation; Stem Cells; Ventricular Remodeling
PubMed: 16671368
DOI: No ID Found -
Physiological Reviews Jan 1999"Remodeling" implies changes that result in rearrangement of normally existing structures. This review focuses only on permanent modifications in relation to clinical... (Review)
Review
"Remodeling" implies changes that result in rearrangement of normally existing structures. This review focuses only on permanent modifications in relation to clinical dysfunction in cardiac remodeling (CR) secondary to myocardial infarction (MI) and/or arterial hypertension and includes a special section on the senescent heart, since CR is mainly a disease of the elderly. From a biological point of view, CR is determined by 1 ) the general process of adaptation which allows both the myocyte and the collagen network to adapt to new working conditions; 2) ventricular fibrosis, i.e., increased collagen concentration, which is multifactorial and caused by senescence, ischemia, various hormones, and/or inflammatory processes; 3) cell death, a parameter linked to fibrosis, which is usually due to necrosis and apoptosis and occurs in nearly all models of CR. The process of adaptation is associated with various changes in genetic expression, including a general activation that causes hypertrophy, isogenic shifts which result in the appearance of a slow isomyosin, and a new Na+-K+-ATPase with a low affinity for sodium, reactivation of genes encoding for atrial natriuretic factor and the renin-angiotensin system, and a diminished concentration of sarcoplasmic reticulum Ca2+-ATPase, beta-adrenergic receptors, and the potassium channel responsible for transient outward current. From a clinical point of view, fibrosis is for the moment a major marker for cardiac failure and a crucial determinant of myocardial heterogeneity, increasing diastolic stiffness, and the propensity for reentry arrhythmias. In addition, systolic dysfunction is facilitated by slowing of the calcium transient and the downregulation of the entire adrenergic system. Modifications of intracellular calcium movements are the main determinants of the triggered activity and automaticity that cause arrhythmias and alterations in relaxation.
Topics: Animals; Contractile Proteins; Heart Diseases; Humans; Myocardium; Ventricular Remodeling
PubMed: 9922372
DOI: 10.1152/physrev.1999.79.1.215 -
Cells Jun 2020Adult stem/progenitor are a small population of cells that reside in tissue-specific niches and possess the potential to differentiate in all cell types of the organ in... (Review)
Review
Adult stem/progenitor are a small population of cells that reside in tissue-specific niches and possess the potential to differentiate in all cell types of the organ in which they operate. Adult stem cells are implicated with the homeostasis, regeneration, and aging of all tissues. Tissue-specific adult stem cell senescence has emerged as an attractive theory for the decline in mammalian tissue and organ function during aging. Cardiac aging, in particular, manifests as functional tissue degeneration that leads to heart failure. Adult cardiac stem/progenitor cell (CSC) senescence has been accordingly associated with physiological and pathological processes encompassing both non-age and age-related decline in cardiac tissue repair and organ dysfunction and disease. Senescence is a highly active and dynamic cell process with a first classical hallmark represented by its replicative limit, which is the establishment of a stable growth arrest over time that is mainly secondary to DNA damage and reactive oxygen species (ROS) accumulation elicited by different intrinsic stimuli (like metabolism), as well as external stimuli and age. Replicative senescence is mainly executed by telomere shortening, the activation of the p53/p16/Rb molecular pathways, and chromatin remodeling. In addition, senescent cells produce and secrete a complex mixture of molecules, commonly known as the senescence-associated secretory phenotype (SASP), that regulate most of their non-cell-autonomous effects. In this review, we discuss the molecular and cellular mechanisms regulating different characteristics of the senescence phenotype and their consequences for adult CSCs in particular. Because senescent cells contribute to the outcome of a variety of cardiac diseases, including age-related and unrelated cardiac diseases like diabetic cardiomyopathy and anthracycline cardiotoxicity, therapies that target senescent cell clearance are actively being explored. Moreover, the further understanding of the reversibility of the senescence phenotype will help to develop novel rational therapeutic strategies.
Topics: Aging; Humans; Myocardium; Stem Cells
PubMed: 32604861
DOI: 10.3390/cells9061558 -
Biomolecules Aug 2020Cardiovascular disease is the leading cause of death worldwide. Current palliative treatments can slow the progression of heart failure, but ultimately, the only... (Comparative Study)
Comparative Study Review
Cardiovascular disease is the leading cause of death worldwide. Current palliative treatments can slow the progression of heart failure, but ultimately, the only curative treatment for end-stage heart failure is heart transplantation, which is only available for a minority of patients due to lack of donors' hearts. Explorative research has shown the replacement of the damaged and lost myocardium by inducing cardiac regeneration from preexisting myocardial cells. Lower vertebrates, such as the newt and zebrafish, can regenerate lost myocardium through cardiomyocyte proliferation. The preexisting adult cardiomyocytes replace the lost cells through subsequent dedifferentiation, proliferation, migration, and re-differentiation. Similarly, neonatal mice show complete cardiac regeneration post-injury; however, this regenerative capacity is remarkably diminished one week after birth. In contrast, the adult mammalian heart presents a fibrotic rather than a regenerative response and only shows signs of partial pathological cardiomyocyte dedifferentiation after injury. In this review, we explore the cellular and molecular responses to myocardial insults in different adult species to give insights for future interventional directions by which one can promote or activate cardiac regeneration in mammals.
Topics: Animals; Cell Differentiation; Humans; Myocardium; Myocytes, Cardiac; Regeneration
PubMed: 32825069
DOI: 10.3390/biom10091204 -
Cells Mar 2021Cardiac fibrosis is a common finding that is associated with the progression of heart failure (HF) and impacts all chambers of the heart. Despite intense research, the... (Review)
Review
Cardiac fibrosis is a common finding that is associated with the progression of heart failure (HF) and impacts all chambers of the heart. Despite intense research, the treatment of HF has primarily focused upon strategies to prevent cardiomyocyte remodeling, and there are no targeted antifibrotic strategies available to reverse cardiac fibrosis. Cardiac fibrosis is defined as an accumulation of extracellular matrix (ECM) proteins which stiffen the myocardium resulting in the deterioration cardiac function. This occurs in response to a wide range of mechanical and biochemical signals. Integrins are transmembrane cell adhesion receptors, that integrate signaling between cardiac fibroblasts and cardiomyocytes with the ECM by the communication of mechanical stress signals. Integrins play an important role in the development of pathological ECM deposition. This review will discuss the role of integrins in mechano-transduced cardiac fibrosis in response to disease throughout the myocardium. This review will also demonstrate the important role of integrins as both initiators of the fibrotic response, and modulators of fibrosis through their effect on cardiac fibroblast physiology across the various heart chambers.
Topics: Fibroblasts; Fibrosis; Homeostasis; Humans; Integrins; Myocardium; Myocytes, Cardiac; Ventricular Remodeling
PubMed: 33807373
DOI: 10.3390/cells10040770