Genetic Link for a ‘Heavy Heart’

 6 October 2011   Research News

Genetic Link for a 'Heavy Heart'CSC Scientists discover key gene for cardiac hypertrophy

Elevated left ventricular mass – also called hypertrophy – is an enlarging of the heart’s muscle mass associated with conditions such as hypertension. It is an accurate indicator of heart failure, and is thought to have a strong genetic component. However, studies have up until now failed to find a hypertrophy gene. Many studies focused on how blood pressure regulates hypertrophy, but it was also known that blood pressure couldn’t be the full story.

Taking advantage of recent step-changes in integrative systems-genetics approaches, Professor Stuart Cook of CSC Molecular Cardiology led a team of international researchers who instead looked at pathways underlying blood pressure-independent hypertrophy, commonly seen in obesity and type 2 diabetes. Using powerful genetic analyses, they investigated a hypertrophy ‘quantitative trait locus’ or QTL – essentially a region of DNA containing genes that underlie a quantitative genetic trait. The analysis is particularly successful in identifying causative genes for particular diseases. In this instance, they found that a faulty version of a gene called Endog, which was previously thought only to be important in cell death, was the culprit.

“Our study shows that the Endog gene actually plays an important role in the enlargement of the heart, which can lead to heart failure and eventually death in the worst cases,” said Stuart. “We found that a faulty copy of this gene causes the heart to become thick and fatty, making it ‘heavy’ with poor function.”

“It does this by interfering with the heart cells’ energy source – the mitochondria. Like any other muscle in our body, the heart needs energy to keep it pumping. If the mitochondria don’t work properly, the heart struggles to make enough energy and the cells produce toxic by-products, called reactive oxidative species, which increase thickening of the heart wall.”

The heart is rich in mitochondria; it needs a huge number to be resistant to fatigue, and to keep pumping blood around the body.

“Our findings give us a new insight into how the mitochondria exert control over the thickness of main chamber of the heart,” added Professor Cook. “We can now start to investigate new ways to develop treatments which target the mitochondria and toxic oxidative molecules.”

Professor Amanda Fisher, Director of the MRC Clinical Sciences Centre, said, “What’s fascinating about this study is that it identifies the function of a gene which was totally unpredicted to be involved in enlargement of the heart. This discovery emphasises the importance of deciphering the genetic code of a broad range of mammals alongside that of humans eventually to allow us explore new avenues for better targeted drugs.”

Professor Peter Weissberg, Medical Director of the British Heart Foundation, said, “The finding could pave the way for new treatments to prevent the development of a heavy heart. Hopefully, in the future, we’ll be able to target the root cause of some patients’ heart conditions rather than treating the resulting symptoms.”


McDermott-Roe, C., Ye, J., Ahmed, R., Sun, X.-M., Serafin, A., Ware, J., Bottolo, L., Muckett, P., Canas, X., Zhang, J., Rowe, G. C., Buchan, R., Lu, H., Braithwaite, A., Mancini, M., Hauton, D., Marti, R., Garcia-Arumi, E., Hubner, N., Jacob, H., Serikawa, T., Zidek, V., Papousek, F., Kolar, F., Cardona, M., Ruiz-Meana, M., Garcia-Dorado, D., Comella, J. X., Felkin, L. E., Barton, P. J. R., Arany, Z., Pravenec, M., Petretto, E., Sanchis, D., Cook, S. A. (2011). Endonuclease g is a novel determinant of cardiac hypertrophy and mitochondrial function. Nature 478 (7367), 114-118.