Heart disease is a leading cause of death, and cardiomyopathy weakens the heart’s ability to pump blood effectively. However, evolution may hold the key to new treatments. Research on small mammals with ultra-rapid heart rate reveals natural genetic adaptations that improve heart relaxation without affecting the heart rate. These evolutionary insights could inspire breakthrough therapies, transforming care for heart conditions by mimicking nature’s ingenious solutions.
Heart disease is a leading cause of death worldwide, and disorders that weaken the heart’s ability to pump blood (cardiomyopathy) play a major role. If left untreated, these disorders can lead to irregular heartbeat, heart failure and even sudden cardiac arrest. Despite advancements, treatment options remain limited. Exciting research shows how insight from small mammals with ultra-rapid heart rate could inspire new therapies, potentially transforming care for heart conditions.
“Our study found that certain small mammals, such as shrews, naturally skip a key segment of a heart protein, improving relaxation without affecting heart rate. This provides new insight into managing such conditions as diastolic heart failure and enhancing understanding of how the heart functions across species. These natural genetic adaptations could inspire new therapeutic strategies,” explains William Joyce, a Postdoctoral Fellow from the Section of Zoophysiology of the Department of Biology at Aarhus University when conducting the study.
A threat to heart health
Heart muscle disorders, known as cardiomyopathy, make it difficult for the heart to pump blood effectively. This can lead to serious problems such as irregular heartbeat and even sudden cardiac arrest. Sarcomeric proteins are at the core of the heart’s ability to pump – key components that enable the heart to contract and relax properly.
“These proteins, which form the heart’s machinery, are promising targets for new heart disease treatments. Myosin modulators, for instance, can fine-tune heart muscle contraction, offering hope for people with cardiomyopathy.”
Although much progress has been made in developing drugs that target myosin, another important part of the heart’s machinery has received less attention: the cardiac thin filament. This structure works closely with myosin to keep the heart functioning smoothly. However, potential therapies focusing on the thin filament remain largely unexplored.
“Finding it there was no coincidence,” says Joyce. “The heart relies on hundreds of proteins, and cardiac troponin I stood out as crucial in how the body's emergency response hormone, adrenaline, affects the function of the heart.”
Harnessing evolutionary insight
The researchers started with a fascinating question: could small mammals with incredibly rapid heart rate help to understand how the human heart works? Shrews, for example, have a heart rate that can soar to 1,500 beats per minute, making them an ideal case study.
“The basis of it,” Joyce explains, “was examining protein data from GenBank, the National Center for Biotechnology Information database of protein sequences, and building alignments for these proteins. So this is bioinformatics but is fairly straightforward.” To advance the project, he began collaborating with an international team, including Kevin L. Campbell of the University of Manitoba, Winnipeg, Canada, a leading authority on shrew and mole evolution.
The COVID-19 pandemic influenced the direction of the work. With limited access to laboratories, the team primarily relied on computational methods such as genome identification and annotation, transcriptomics—a mapping of which genes are active in cells—and an analysis of evolutionary selection.
“This was one of the first projects I tackled during the pandemic,” Joyce recalls. “Suddenly, we could not access the laboratory for months, so I focused on this.”
Nature’s ingenious modifications
Their analysis revealed a fascinating genetic difference in shrews: the absence of exon 3 in the TNNI3 gene, which encodes cardiac troponin I. This region has a key role in regulating how the heart responds to calcium, a critical element for muscle contraction and relaxation.
“And this part of troponin I interacts with troponin C. That is the key point of the deletion,” Joyce explains.
The deletion of exon 3 in shrews is a natural evolutionary adaptation that helps their hearts relax more quickly.
“There are probably lots of factors that contribute to that heart rate, and we have managed to pinpoint one,” Joyce adds.
Bats provided additional insight. Unlike shrews, bats can adjust how they use exon 3, enabling them to adapt their heart function to different situations.
“Bats sometimes express exon 3 and sometimes skip it. It could depend on their activity levels, but this requires further study.”
Exploring how this helps heart function
The genetic adaptation helps the heart relax more efficiently without changing the heart rate itself.
“Previous studies on transgenic mice harbouring a similar mutation to the one that evolved in shrews found improved cardiac relaxation. The heart rate itself does not change directly.”
For shrews, like all mammals, blood pressure stays fairly constant. However, their extremely rapid heart rate creates a different challenge: ensuring that the heart has enough time to refill with blood between beats.
“The interesting thing is that the blood pressure across mammals – from shrews to elephants – is surprisingly similar. The real challenge for shrews is not getting blood into the arteries; it is how rapidly their heart can refill between beats.”
The discovery shows how skipping exon 3 – in which the gene can either include or exclude this segment – naturally occurs in several species with high metabolism and high heart rates.
A new frontier in cardiac therapy
This groundbreaking research opens the door to new treatments by mimicking the evolutionary changes found in animals. Scientists aim to replicate a natural process called exon skipping in humans, specifically targeting the TNNI3 gene, which could improve how the heart relaxes.
“This offers hope for people with such conditions as diastolic heart failure, for which current treatment options are limited. What makes the shrew research so exciting is that it demonstrates a new way to manipulate troponin independently of adrenaline,” explains Joyce. “Whether we can replicate this in human cells? You have caught me a few weeks too early, since that is exactly what we are working towards now.”
By applying lessons from evolution, the research connects basic biology with real-world medical applications.
“For me, as an evolutionary biologist, seeing how proteins can evolve to change their function is fascinating. This insight could be applied to early treatments of heart failure, potentially in combination with beta-blockers,” concludes William Joyce.
