Abstract
Cultured cardiomyocytes have been shown to possess significant potential as a model for characterization of mechano-Ca2+, mechano-electric, and mechano-metabolic feedbacks in the heart. However, the majority of cultured cardiomyocytes exhibit impaired electrical, mechanical, biochemical, and metabolic functions. More specifically, the cells do not beat spontaneously (pacemaker cells) or beat at a rate far lower than their physiological counterparts and self-oscillate (atrial and ventricular cells) in culture. Thus, efforts are being invested in ensuring that cultured cardiomyocytes maintain the shape and function of freshly isolated cells. Elimination of contraction during culture has been shown to preserve the mechano-Ca2+, mechano-electric, and mechano-metabolic feedback loops of cultured cells. This review focuses on pacemaker cells, which reside in the sinoatrial node (SAN) and generate regular heartbeat through the initiation of the heart’s electrical, metabolic, and biochemical activities. In parallel, it places emphasis on atrial cells, which are responsible for bridging the electrical conductance from the SAN to the ventricle. The review provides a summary of the main mechanisms responsible for mechano-electrical, Ca2+, and metabolic feedback in pacemaker and atrial cells and of culture methods existing for both cell types. The work concludes with an explanation of how the elimination of mechano-electrical, mechano-Ca2+, and mechano-metabolic feedbacks during culture results in sustained cultured cell function.
Highlights
Cardiac physiology research aims to understand how the heart works under both healthy and pathophysiological conditions, since the prevention and treatment of cardiovascular abnormalities, including arrhythmias, is the most critical goal of biomedical researchers
This review focuses on pacemaker cells, which reside in the sinoatrial node (SAN) and generate regular heartbeat through the initiation of the heart’s electrical, metabolic, and biochemical activities
In order to understand true cardiac physiology, the mammalian cells and tissues must be maintained under conditions similar to those prevailing in the body, with temperature and extracellular conditions being crucial for physiological cell and tissue functioning
Summary
Cardiac physiology research aims to understand how the heart works under both healthy and pathophysiological conditions, since the prevention and treatment of cardiovascular abnormalities, including arrhythmias, is the most critical goal of biomedical researchers. The review provides a summary of the main mechanisms responsible for mechano-electrical, Ca2+, and metabolic feedback in pacemaker and atrial cells (Figure 1) and of the existing culture methods for each cell type. Questioned in the past, it has been firmly established that pacemaker cells possess sarcomeres, the basic contractile unit (Yaniv et al, 2011) Evidence for such feedback was demonstrated in heart failure patients presenting a distended atrial wall (the location of the SAN tissue) as a result of increased venous return post-exercise and saline loading (Andersen et al, 2015). In response to an increase in electrical stimulation, frequency, or Ca2+ transient amplitude, Ca2+ accumulates in the atrial mitochondria and activates enzymes participating in ATP production (Harada et al, 2017) It is not known whether cAMP/PKA and CaMKII signaling regulate ATP production in atrial cells, as has been seen in pacemaker cells. All changes in ionic currents occurred within 24 h of culture and were not altered for 4 days
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