Experimental and theoretical system analysis for canine myocardial oxygen supply and demand and their determinants

Imperial Users onl

Myocardial Restoration: Is It the Cell or the Architecture or Both?

Myocardial infarction is the leading cause of death in developed countries. Cardiac cell therapy has been introduced to clinical trials for more than ten years but its results are still controversial. Tissue engineering has addressed some limitations of cell therapy and appears to be a promising solution for cardiac regeneration. In this review, we would like to summarize the current understanding about the therapeutic effect of cell therapy and tissue engineering under purview of functional and structural aspects, highlighting actual roles of each therapy towards clinical application

Investigation of synthetic hydrogels as therapy for myocardial infarction

This thesis investigated the potential of synthetic polyethylene glycol (PEG) hydrogels for restoration of biomechanical integrity and for controlled cardiac release of drugs. ... The aim of this study was to directly compare the effect of injecting an enzymatically degradable polyethylene glycol (PEG) hydrogel into the myocardium immediately or seven days after permanent ligation of the left anterior descending artery in rats on pathological remodeling

Control of Whole Heart Geometry by Intramyocardial Mechano-Feedback: A Model Study

Geometry of the heart adapts to mechanical load, imposed by pressures and volumes of the cavities. We regarded preservation of cardiac geometry as a homeostatic control system. The control loop was simulated by a chain of models, starting with geometry of the cardiac walls, sequentially simulating circulation hemodynamics, myofiber stress and strain in the walls, transfer of mechano-sensed signals to structural changes of the myocardium, and finalized by calculation of resulting changes in cardiac wall geometry. Instead of modeling detailed mechano-transductive pathways and their interconnections, we used principles of control theory to find optimal transfer functions, representing the overall biological responses to mechanical signals. As biological responses we regarded tissue mass, extent of contractile myocyte structure and extent of the extra-cellular matrix. Mechano-structural stimulus-response characteristics were considered to be the same for atrial and ventricular tissue. Simulation of adaptation to self-generated hemodynamic load rendered physiologic geometry of all cardiac cavities automatically. Adaptation of geometry to chronic hypertension and volume load appeared also physiologic. Different combinations of mechano-sensors satisfied the condition that control of geometry is stable. Thus, we expect that for various species, evolution may have selected different solutions for mechano-adaptation

Investigating the delivery of IGF-1 with in vitro and in vivo model systems of myocardial infarction

Myocardial infarction (MI) is characterised by the irreversible death of cardiac muscle with loss of up to 1 billion cardiomyocytes (CM). Despite survival post-MI dramatically improving in the last two decades, more than 20% of patients suffering MI will still develop heart failure (HF), an incurable condition where the heart is no longer able to meet the body’s needs for blood supply. Amongst novel therapeutic avenues currently being explored, intramyocardial delivery of cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) holds great promise to replace the lost functional tissue. However, the effects of the ischemic microenvironment on these cells still need to be investigated, and protective strategies need to be developed. This thesis examines the delivery of the pro-survival growth factor Insulin like Growth Factor-1 (IGF-1) in the settings of hiPSC-CMs exposed to acidic pH and through a hydrogel-based approach in an in vivo model of MI. Following MI, the heart switches from aerobic metabolism to anaerobic glycolysis, causing a pH drop to 6.5-6.8. The aim of the first part of this thesis was to mitigate the effects of acidic pH on hiPSC-CMs using the pro-survival growth factor IGF-1. It was shown that acidic pH negatively affects hiPSC-CMs in terms of viability, metabolic activity, cardiac gene expression and CMs yield obtained through differentiation. IGF-1 was able to recover the effects of acidic pH, and it could, therefore, be used as a protective strategy for in vivo cell therapy approaches. Another promising strategy for preventing HF progression following MI is the minimally invasive delivery of injectable hydrogels, which can provide mechanical support to damaged tissue and deliver bioactive factors with pro-survival actions. Here, a thermoresponsive injectable hydrogel composed of a triblock copolymer of polyethylene glycol (PEG) and polycaprolactone (PCL) was synthesised and characterised in vitro and in vivo. The hydrogel was prepared with or without insulin-like growth factor-1 (IGF-1) and injected intramyocardially in a mouse MI model. Echocardiography, strain analysis and histological assessments showed that the injection of the biodegradable thermoresponsive hydrogel was effective in ameliorating pathological remodelling, improving overall cardiac function and myocardial mechanics. In the future, implementing novel therapeutic approaches like the ones presented in this thesis could prevent the progression to HF, improving the quality of life of patients affected by myocardial infarction and limiting the socio-economic burden of the disease.Open Acces

Implantation of Mouse Embryonic Stem Cell-Derived Cardiac Progenitor Cells Preserves Function of Infarcted Murine Hearts

Stem cell transplantation holds great promise for the treatment of myocardial infarction injury. We recently described the embryonic stem cell-derived cardiac progenitor cells (CPCs) capable of differentiating into cardiomyocytes, vascular endothelium, and smooth muscle. In this study, we hypothesized that transplanted CPCs will preserve function of the infarcted heart by participating in both muscle replacement and neovascularization. Differentiated CPCs formed functional electromechanical junctions with cardiomyocytes in vitro and conducted action potentials over cm-scale distances. When transplanted into infarcted mouse hearts, CPCs engrafted long-term in the infarct zone and surrounding myocardium without causing teratomas or arrhythmias. The grafted cells differentiated into cross-striated cardiomyocytes forming gap junctions with the host cells, while also contributing to neovascularization. Serial echocardiography and pressure-volume catheterization demonstrated attenuated ventricular dilatation and preserved left ventricular fractional shortening, systolic and diastolic function. Our results demonstrate that CPCs can engraft, differentiate, and preserve the functional output of the infarcted heart

Doctor of Philosophy

dissertationDespite a century of research and practice, the clinical accuracy of the electrocardiogram (ECG) to detect and localize myocardial ischemia remains less than satisfactory. Myocardial ischemia occurs when the heart does not receive adequate oxygen-rich blood to keep up with its metabolic requirements, and severe ischemia can lead to myocardial infarction and life-threatening arrhythmias. Early and accurate detection is an essential component of managing this condition. Ischemia is known to be a dynamic condition that reflects a changing imbalance between blood supply and metabolic demand so that it is natural that examination under physical stress conditions or exercise testing (ET) is in widespread clinical use. However, ET is characterized by poor sensitivity (68%) and specificity (77%), limiting its diagnostic usefulness and providing the motivation to address some gaps in our understanding of myocardial ischemia and its ECG signature. This dissertation is composed of three studies. The aim of the first study was to evaluate the conventionally held mechanisms for nontransmural ischemia using intramural electrodes to measure three-dimensional potential distributions in the ventricles of animals exposed to acute ischemia. We demonstrated that contrary to accepted dogma, the electrocar- diographic response of acute myocardial ischemia originated throughout the ventricular wall, i.e., in the subendocardium, midmyocardium, or the subepicardium, under various conditions. Our goal in the second study was to evaluate whether acute myocardial ischemia follows a similar pattern of spatial and temporal evolution as seen in myocardial infarction. Our findings show that the spatial and temporal evolution of acute ischemia is characterized by multiple distinct regions that expand in all three directions, with maximal expansion in the circumferential direction, especially in the early stages of ischemic development. Furthermore, with increased stress, these regions continue to expand and eventually merge into one another, and in the extreme become transmural. The progression of myocardial infarction, by contrast, was very quickly transmural in extent and formed a cohesive block of affected tissues. The aim of the third study was to evaluate the sensitivity of epicardial electrical markers of acute ischemia relative to direct evidence of ischemia derived from intramural electro- grams. The key finding from this study is that the epicardial T-wave is a more sensitive index of acute ischemia than epicardial ST segment changes, especially in the early stages of acute ischemia development