Coronary artery disease is the single most common cause of death in Europe, accounting for 1.8 million deaths in Europe each year. There are around 7.4 million people living with cardiovascular disease in the UK, more than twice as many people than with cancer and Alzheimer’s disease combined and causing more than a quarter (28 per cent) of all deaths in the UK. Blockage of one of the arteries supplying blood to the heart results in a lack of oxygen in the downstream heart muscle and subsequent death of the starved cells (myocardial infarction/heart attack). The dead heart muscle is replaced by fibrous scar tissue in those fortunate enough to survive the heart attack, providing a necessary solution in replacing necrotic muscle to close the ventricular wall. However, the non-contractile fibrous tissue will never be replaced by new heart muscle, and may cause severe contractile dysfunction, resulting in heart failure and even recurring myocardial infarction. The combination of improved treatments for cardiovascular disease, increased public awareness of the risk factors, and government strategies aimed at helping people live a healthy lifestyle has reduced mortality rates, meaning that the number of people who survive a heart attack is steadily increasing. This impressive improvement in survival rate as well as the increasingly elderly populations, however, also mean more people living with the long term effects of reduced heart function and heart failure, costing the UK economy £9 billion per year, with this number steadily increasing every year.
Complete regeneration of the adult heart after injury is a feature exclusive to a limited number of species, including lower vertebrates such as the zebrafish and salamander. Injury to a zebrafish heart results in a spectacular scar-free regeneration process, with the wound tissue completely being replaced with new, functional cardiac muscle. If we can discover what fundamental mechanisms drive natural heart regeneration in fish, we can directly apply this knowledge to heal the human heart after a heart attack and during heart failure. Differences in inflammation and scarring are thought to be important differences between animals that can regenerate their hearts and animals that cannot, but not much is known about how these processes regulate heart regeneration.
In this project we use Astyanax mexicanus, the Mexican cavefish, as well as zebrafish, to study the mechanisms underlying scarring and inflammation during heart regeneration. Astyanax mexicanus is a single fish species comprising cave-dwelling and surface populations. These two populations arose around 10.000 - 8 million years ago when flooding caused surface fish living in rivers in Northern Mexico to enter the caves. River levels retreated over time and many caves never reconnected to the river and the fish evolved into different cavefish populations, whilst remaining the same species capable of interbreeding with their surface fish counterparts. During their independent evolution in the caves, the fish lost their eyes and pigment, redundant in the absence of light. Instead, they developed other features that helped survive in a cave. We found that, like zebrafish, the river surface fish regenerate their heart, while, cavefish cannot and form a permanent fibrotic scar, similar to the human injury response.
Comparing heart regeneration versus scarring in the same species allows us to focus directly on the mechanisms underlying this difference.
