The healthy heart is designed to respond to its workload, to meet the demands of the body. For example, during exercise, the heart increases its function to pump more blood. However, when workload gets very high, such as during diseases like heart failure, the heart’s function becomes weakened. How does this occur? How does the heart augment its function during times of need, but exhibit a decline in function during disease?
To examine this question, Marianne Ruud in the Louch Group performed a detailed study of cardiac muscle cells (cardiomyocytes) exposed to different workloads (Ruud et al., J Physiol, 2024). She specifically focused on membrane invaginations called t-tubules, and their associated calcium handling proteins, which are responsible for triggering the cell’s contraction, and thereby the heartbeat.
Ruud started her study by examining isolated cardiac muscle kept in culture. Here, she applied different degrees of stretch (preload) or resistance to muscle shortening (afterload) and measured the effect on cellular structure. She observed that there is a “bell-shaped” relationship between both types of load and t-tubule density; with moderate amounts of preload or afterload t-tubules are most robustly present.
But where does the healthy heart normally sit on this curve? Ruud observed that subjecting mice to mildly elevated preload or afterload (short-term aortic shunt or banding) caused a compensatory increase in t-tubule density. Similar t-tubule proliferation was observed in human patients with moderately increased preload or afterload (mitral valve regurgitation or aortic stenosis) (see top of figure for example images). T-tubule growth was associated with larger calcium transients, and this was linked to higher expression of two important calcium transporting proteins in the t-tubules; L-type calcium channels and sodium-calcium exchanger. The expression of known mechanosensors and regulators of t-tubule structure were also increased. These data suggest that healthy cardiomyocytes sit on the rising phase of the t-tubule-load relationship, and that compensatory increases in t-tubule density help augment heart function during times of need.
What happens during diseases like heart failure? Ruud observed that the very high workload of this condition was linked to loss of t-tubules in cardiomyocytes from both mice and patients. Thus, the heart is advanced down the descending limb of the t-tubule–load relationship, which is thought to promote declining whole heart function in this disease.
These data provide a new understanding of how the heart’s workload feeds back on its structure and function, and how this process is fine-tuned in health but becomes dysregulated during disease. Understanding this delicate balance is important. For healthy individuals, we hope to advise them on the workload that is best suited for their cardiac healthy, for example by optimizing their exercise regime. For patients, on the other hand, we aim to optimally reduce the workload that their heart experiences to improve the function of their heart.
