Abstract:
One of the major medical advances of the twentieth century is the development of cardiac transplantation. Cardiac transplantation is the definitive treatment for end-stage heart disease. Cardiac transplantation relies on organs procured from Brain Dead Donors (DBD). Donation after Circulatory Death (DCD) organs are being increasingly used for renal, liver and lung transplantation. Hearts from DCD donors have not been utilized as there is a fear that they will have sustained irreversible myocardial injury post cardiac arrest. We have a limited understanding of Post cardiac arrest myocardial depression due to the lack of a good physiological model of the disease. Objective: To develop a model of in-vivo cardiac arrest and resuscitation in order to characterize the biology of the associated myocardial dysfunction and test potential therapeutic strategies. Methods and Results: We developed a rodent model of post arrest myocardial depression (DCD model) using extracorporeal membrane oxygenation for resuscitation, followed by invasive haemodynamic measurements. In isolated cardiomyocytes, we assessed mechanical load and Ca2+-induced Ca2+ release (CICR) simultaneously using the microcarbon fiber technique and observed reduced function and myofilament calcium sensitivity in the post arrest group. Additionally, in contrast with findings from Langendorff models of ischemia-reperfusion, there is a marked augmentation of CICR in isolated cells. This increase in calcium serves to maintain contraction in the face of myofilament dysfunction and, it seems to be mediated by autophosphorylation of calcium-calmodulin protein kinase II (CAMKII). It is further dependent on ryanodine receptor calcium but not PKA leading us to speculate that it is triggered by adrenergic activation but maintained by CAMKII. Finally, activation of aldehyde-dehydrogenase II by the small molecule Alda-1 dramatically improved whole animal and cellular contractile performance after arrest, and restored CICR to close to normal levels. Conclusions: Cardiac arrest and reperfusion lead to calcium cardiac memory, which support cardiomyocyte contractility in the face of post arrest myofilament calcium sensitivity. Alda-1 mitigates these effects and improves outcome.Keywords:
Myofilament
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The use of cells derived from human induced pluripotent stem cells as cellular therapy for myocardial injury has yet to be examined in a large-animal model.Immunosuppressed Yorkshire pigs were assigned to 1 of 3 groups: A myocardial infarction group (MI group; distal left anterior descending coronary artery ligation and reperfusion; n=13); a cell-treatment group (MI with 4×10(6) vascular cells derived from human induced pluripotent stem cells administered via a fibrin patch; n=14); and a normal group (n=15). At 4 weeks, left ventricular structural and functional abnormalities were less pronounced in hearts in the cell-treated group than in MI hearts (P<0.05), and these improvements were accompanied by declines in scar size (10.4±1.6% versus 8.3±1.1%, MI versus cell-treatment group, P<0.05). The cell-treated group displayed a significant increase in vascular density and blood flow (0.83±0.11 and 1.05±0.13 mL·min(-1)·g(-1), MI versus cell-treatment group, P<0.05) in the periscar border zone (BZ), which was accompanied by improvements in systolic thickening fractions (infarct zone, -10±7% versus 5±5%; BZ, 7±4% versus 23±6%; P<0.05). Transplantation of vascular cells derived from human induced pluripotent stem cells stimulated c-kit(+) cell recruitment to BZ and the rate of bromodeoxyuridine incorporation in both c-kit(+) cells and cardiomyocytes (P<0.05). Using a magnetic resonance spectroscopic saturation transfer technique, we found that the rate of ATP hydrolysis in BZ of MI hearts was severely reduced, and the severity of this reduction was linearly related to the severity of the elevations of wall stresses (r=0.82, P<0.05). This decline in BZ ATP utilization was markedly attenuated in the cell-treatment group.Transplantation of vascular cells derived from human induced pluripotent stem cells mobilized endogenous progenitor cells into the BZ, attenuated regional wall stress, stimulated neovascularization, and improved BZ perfusion, which in turn resulted in marked increases in BZ contractile function and ATP turnover rate.
Stem Cell Therapy
Cell therapy
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Cardiac myocyte
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Objective Investigate the role of apoptosis in the progress of cardiac dysfunction.Methods The dysfunctional rat heart with volume-overload was prepared. TUNEL method was used to detect apoptosis in myocardium. Results Abnormal apoptosis occurred in dysfunctional hearts. Conclusions It suggested that abnormal apoptosis is involved in the development of cardiac dysfunction.The mechanism may be due to the reduction of contractile tissue.
Dysfunctional family
Cardiac myocyte
Volume overload
Cardiac Dysfunction
Pressure overload
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Introduction: Calcium-calmodulin-dependent protein kinase II (CaMKII) has emerged as a central mediator of cardiac stress responses which may serve several critical roles in the regulation of cardiac rhythm, cardiac contractility and growth. Sustained and excessive activation of CaMKII during cardiac disease has, however, been linked to arrhythmias, and maladaptive cardiac remodeling, eventually leading to heart failure (HF) and sudden cardiac death. Areas covered: In the current review, the authors describe the unique structural and biochemical properties of CaMKII and focus on its physiological effects in cardiomyocytes. Furthermore, they provide evidence for a role of CaMKII in cardiac pathologies, including arrhythmogenesis, myocardial ischemia and HF development. The authors conclude by discussing the potential for CaMKII as a target for inhibition in heart disease. Expert opinion: CaMKII provides a promising nodal point for intervention that may allow simultaneous prevention of HF progression and development of arrhythmias. For future studies and drug development there is a strong rationale for the development of more specific CaMKII inhibitors. In addition, an improved understanding of the differential roles of CaMKII subtypes is required.
Contractility
Mediator
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Heart failure is the leading cause of death in the Western world, and new and innovative treatments are needed. The GPCR (G protein-coupled receptor) adapter proteins βarr (β-arrestin)-1 and βarr-2 are functionally distinct in the heart. βarr1 is cardiotoxic, decreasing contractility by opposing β1AR (adrenergic receptor) signaling and promoting apoptosis/inflammation post-myocardial infarction (MI). Conversely, βarr2 inhibits apoptosis/inflammation post-MI but its effects on cardiac function are not well understood. Herein, we sought to investigate whether βarr2 actually increases cardiac contractility. Via proteomic investigations in transgenic mouse hearts and in H9c2 rat cardiomyocytes, we have uncovered that βarr2 directly interacts with SERCA2a (sarco[endo]plasmic reticulum Ca2+-ATPase) in vivo and in vitro in a β1AR-dependent manner. This interaction causes acute SERCA2a SUMO (small ubiquitin-like modifier)-ylation, increasing SERCA2a activity and thus, cardiac contractility. βarr1 lacks this effect. Moreover, βarr2 does not desensitize β1AR cAMP-dependent procontractile signaling in cardiomyocytes, again contrary to βarr1. In vivo, post-MI heart failure mice overexpressing cardiac βarr2 have markedly improved cardiac function, apoptosis, inflammation, and adverse remodeling markers, as well as increased SERCA2a SUMOylation, levels, and activity, compared with control animals. Notably, βarr2 is capable of ameliorating cardiac function and remodeling post-MI despite not increasing cardiac βAR number or cAMP levels in vivo. In conclusion, enhancement of cardiac βarr2 levels/signaling via cardiac-specific gene transfer augments cardiac function safely, that is, while attenuating post-MI remodeling. Thus, cardiac βarr2 gene transfer might be a novel, safe positive inotropic therapy for both acute and chronic post-MI heart failure.
Contractility
Ventricular remodeling
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Introduction: Post-cardiac arrest myocardial stunning is often lethal in the first few hours after resuscitation. We previously reported this stunning is reversed by cooling via an Akt-dependent pr...
Contractility
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Introduction: Adult mice have limited potential for cardiac regeneration, and permanent damage to cardiomyocytes after cardiac injury leads to a decrease in cardiac contractile function. Conversely...
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Heart failure (HF) is characterized by molecular and cellular defects which jointly contribute to decreased cardiac pump function. During the development of the initial cardiac damage which leads to HF, adaptive responses activate physiological countermeasures to overcome depressed cardiac function and to maintain blood supply to vital organs in demand of nutrients. However, during the chronic course of most HF syndromes, these compensatory mechanisms are sustained beyond months and contribute to progressive maladaptive remodeling of the heart which is associated with a worse outcome. Of pathophysiological significance are mechanisms which directly control cardiac contractile function including ion- and receptor-mediated intracellular signaling pathways. Importantly, signaling cascades of stress adaptation such as intracellular calcium (Ca(2+)) and 3'-5'-cyclic adenosine monophosphate (cAMP) become dysregulated in HF directly contributing to adverse cardiac remodeling and depression of systolic and diastolic function. Here, we provide an update about Ca(2+) and cAMP dependent signaling changes in HF, how these changes affect cardiac function, and novel therapeutic strategies which directly address the signaling defects.
Contractility
Calcium in biology
Pathophysiology
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