New insight into the underlying biology of heart failure

IMED Biotech Unit scientists have uncovered a previously unidentified mutation of the heart muscle gene MYBPC3, presenting a new genetic risk factor in heart failure


A genetic variant of MYBPC3 (a key gene in heart muscle formation) is a reported risk factor in hypertrophic cardiomyopathy (HCM), a condition that can lead to heart failure. Until now, the link between this variant and HCM had not been definitively established. Scientists at the joint AstraZeneca and Karolinska Institutet Integrated Cardiometabolic Center (ICMC), Sweden, have discovered a subset of individuals with the variant that also carry a second variant. Published in JAMA Cardiology, it is this combination that provides additional great insights to understanding genetic risk factors for HCM.

HCM is a muscular disorder of the heart, which causes thickening of the heart muscle and abnormal electrical activity. It often has an unpredictable course, and can lead to sudden, severe heart failure that can be fatal. The condition affects over 14 million people worldwide, and over 97 million people carry a genetic variant, MYBPC3D25bp, which is associated with increased risk of HCM. This variant is thought to be a particular risk factor amongst South Asians due to its relatively high prevalence in this population; it was found to be present in 6% of South Asians living in the US who were screened in the study. To investigate the link between MYBPC3D25bp and HCM, researchers characterised the genomes of 47 carriers and 36 non-carriers of the variant and discovered that 10% of carriers had an additional variant now known as D389V. The presence of the both D389V and MYBPC3D25bp together was found to be associated with abnormal heart performance characteristic of HCM. In addition, cultured cardiac cells expressing the combination of variants were enlarged and showed abnormal electrical activity.

The hypothesis that MYBPC3D25bp leads to an increased risk of disease has so far been controversial since not all carriers develop HCM, and evidence supporting the role of MYBPC3D25bp in heart failure has been inconclusive. The fact that the combination of the two variants underlie some of the symptoms associated with MYBPC3D25bp goes some way to explain the increased risk in carriers. It could also help to clarify the controversy around the link: only a subset of MYBPC3D25bp carriers are at risk, so correlation between disease and the variant has not always been clear.

These new findings were made by the ICMC in collaboration with research groups from Cincinnati, Chicago and Singapore. The ICMC is a dedicated research unit at the Karolinska Institutet, in which scientists from AstraZeneca’s IMED Biotech Unit and the university work together to identify new targets in cardiometabolic disease, a priority therapy area for AstraZeneca.

Ralph Knöll, a co-senior author on the study, and an AstraZeneca scientist working at the ICMC, said: “It was exciting to identify this new genetic variant with potentially important clinical implications. This type of research is very important for developing a future precision medicine approach for treating cardiovascular disease. The D389V mutation subpopulation appears to have higher risk of the observed heart failure risk in individuals with the MYBPC3D25bp variant and in future, may be expected to benefit from newly designed drugs targeting these mutations.”

Uncovering this important detail in the link between MYBPC3D25bp and HCM is an important step towards developing a precision medicine approach. By investigating the drivers of the disease through cutting-edge science, effective, targeted therapies can be designed, and this specific combination of genetic variants presents a novel target in the development of treatment for HCM. Identifying the specific genetic mutations responsible for disease states can help devise an intervention that precisely targets the underlying cause of disease, and these ICMC findings are a step towards creating, personalised treatments for HCM in the correct patients.

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