Abstract
Cardiac ischemic events increase the risk for arrhythmia, heart attack, heart failure, and death and are the leading mortality condition globally. Reperfusion therapy is the first line of treatment for this condition, and although it significantly reduces mortality, cardiac ischemia remains a significant threat. New therapeutic strategies are under investigation to improve the ischemia survival rate; however, the current preclinical models to validate these fail to predict the human outcome. We report the development of a functional human cardiac in vitro system for the study of conduction velocity under ischemic conditions. The system is a bioMEMs platform formed by human iPSC derived cardiomyocytes patterned on microelectrode arrays and maintained in serum-free conditions. Electrical activity changes of conduction velocity, beat frequency, and QT interval (the QT-interval measures the period from onset of depolarization to the completion of repolarization) or action potential length can be evaluated over time and under the stress of ischemia. The optimized protocol induces >80% reduction in conduction velocity, after a 4 h depletion period, and a partial recovery after 72 h of oxygen and nutrient reintroduction. The sensitivity of the platform for pharmacological interventions was challenged with a gap junction modulator (ZP1609), known to prevent or delay the depression of conduction velocity induced by ischemic metabolic stress. ZP1609 significantly improved the drastic drop in conduction velocity and enabled a greater recovery. This model represents a new preclinical platform for studying cardiac ischemia with human cells, which does not rely on biomarker analysis and has the potential for screening novel cardioprotective drugs with readouts that are closer to the measured clinical parameters.
Highlights
Ischemic heart disease can occur as a consequence of a wide range of cardiovascular conditions, influenced by genetic background and lifestyle, and is currently the leading cause of death from noncommunicable diseases.1 During cardiac ischemia, the blood supply to the heart is partially or completely blocked, inducing damage in the affected area
This model represents a new preclinical platform for studying cardiac ischemia with human cells, which does not rely on biomarker analysis and has the potential for screening novel cardioprotective drugs with readouts that are closer to the measured clinical parameters
We evaluated the toxicity of these compounds on nonpatterned cardiomyocytes under control conditions, and human iPSC derived cardiomyocyte viability was not affected after 24 h or one-week treatment with either peptide at 5 lM in HSL2 medium, indicating that the molecules may be safe for long-term treatment [Fig. 2(a)]
Summary
Ischemic heart disease can occur as a consequence of a wide range of cardiovascular conditions, influenced by genetic background and lifestyle, and is currently the leading cause of death from noncommunicable diseases. During cardiac ischemia, the blood supply to the heart is partially or completely blocked, inducing damage in the affected area. Ischemic heart disease can occur as a consequence of a wide range of cardiovascular conditions, influenced by genetic background and lifestyle, and is currently the leading cause of death from noncommunicable diseases.. The blood supply to the heart is partially or completely blocked, inducing damage in the affected area. The lack of oxygen induces a metabolic shift from oxidative phosphorylation to anaerobic glycolysis, which limits the cellular energy source to only glucose and amino acids until exhaustion, instead of fatty acids. The shortage of blood flow to the ischemic region induces a buildup of waste products in the extracellular space, decreasing the pH.. Alteration in the ion homeostasis promotes changes in the excitation-contraction apparatus of the cardiomyocytes, such as arrhythmias.. The electrical propagation in the cardiomyocytes will be affected due to losses in cell-cell connections, affecting the conduction velocity of the tissue. The shortage of blood flow to the ischemic region induces a buildup of waste products in the extracellular space, decreasing the pH. Alteration in the ion homeostasis promotes changes in the excitation-contraction apparatus of the cardiomyocytes, such as arrhythmias. The electrical propagation in the cardiomyocytes will be affected due to losses in cell-cell connections, affecting the conduction velocity of the tissue.
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