Summer is in full swing and it's getting hot again in the labs & offices. Time to take a short break with our Paper of the Month June. In this issue, we take a look at the evolution of heart valves and what role mechanical forces play.
Leading the present work were Dr. Renee Chow, now group leader at the Australian Regenerative Medicine Institute in Melbourne, together with Dr. Julien Vermot of the Department of Bioengineering at Imperial College London.
Taking on the leading cause of death
Across the globe, cardiovascular diseases (CVDs) are the leading cause of death. According to estimates of the WHO, 17.9 million deaths worldwide in 2019 were attributable to CVDs, which translates to 32% of all fatalities. Therefore, early detection of cardiovascular disease is crucial in order to start treatment with counseling and medication to essentially save human lives.
Addressing behavioral risk factors like tobacco use, unhealthy eating, obesity, inactivity, and problematic alcohol consumption, can help to reduce a fair share of cardiovascular illnesses. But in order to treat those illnesses effectively, it is even more crucial to comprehend the inner workings and development of our hearts.
While many disorders in the group of cardiovascular diseases affect our blood vessels, which supply different parts of the body, congenital heart diseases hinder the normal development and functioning of the heart. The research by Chow, Vermot and their team therefore addresses an important issue and provides us with further insights for the development of future strategies for the treatment of heart disease.
Fig. 1: Illustration of the cardiovascular system (heart, blood vessels, and blood) supplying all parts of the body with oxygen and nutrients.
Unraveling the principles of heart valve development
Heart valve development is a complex process involving the formation and remodeling of valve structures. Abnormalities in this process can lead to congenital heart defects. Chow et al. therefore tried to explore the role of cardiac forces in the process of heart valve delamination using zebrafish as model organism.
To gain a deeper understanding, the researchers used a combination of genetic manipulations, computational modeling, and live imaging techniques to examine the effects of altered mechanical forces on heart valve development. Their techniques revealed that the appropriate delamination of heart valve cells depends on the mechanical stresses generated by the beating heart. When these forces are disturbed, the development of the valves is flawed, and heart function is compromised.
Or, in simpler terms, the way heart valve cells separate from each other properly depends on the pressures created by the beating of the heart. If these pressures are disrupted, the growth of the valves goes wrong, and it affects how the heart works.
Fig. 2: Alteration of mechanical forces in the heart of a zebrafish achieved by glutathione bead injection. Left The blood flow at the ventricle is occluded by the bead, resulting in reversed atrioventricular flow. Right Without the bead the reversed blood flow is prevented by the atrioventricular valve. The blood can therefore flow out of the bulbus arteriosus.
A key player in this process is the Nfat signaling pathway. Chow and her team identified that Nfat acts on luminal endocardial cells (inner lining of the heart) and is regulated by blood flow depending on the luminal side. Regulation of Nfat occurs when heart valve progenitors prepare for detachment. Inhibition of Nfat signaling results in thickened, hyperplastic valves and defects in delamination, which in turn can lead to decreased heart function.
These results suggest that further research and more detailed understanding of the role of cardiac forces and Nfat signaling may play a major role in the clinical diagnosis and treatment of congenital heart defects in humans. Above all, it is important to keep in mind that the outcomes so far can’t be applied to people. The fact that the human heart has four chambers as opposed to the zebrafish's two means that some aspects of heart valve development may be controlled differently.
In conclusion, Chow's research shows that cardiac forces significantly influence Nfat signaling, which in turn causes heart valve delamination in zebrafish. The findings may help increase our understanding of and ability to treat cardiovascular illnesses by shedding light on the intricate interplay between mechanical forces and molecular signaling throughout the formation of the heart.
