Mapping molecular signals that go awry in heart failure

Dilated cardiomyopathy (DCM) is one of the most common inherited heart diseases – but we don’t know why.

Afflicting as many as one in five Canadians, DCM occurs when a functioning heart muscle begins to dilate, or stretch, for no apparent reason. This enlarged heart can no longer maintain its normal rhythm and pump the blood around the body, which leads to heart failure. While we know that some forms of DCM  are rooted in genetics, its molecular culprits remain poorly understood.

A new study from the Ted Rogers Centre has revealed widespread differences in protein biochemistry between healthy and diseased hearts. In so doing, it expands our understanding of heart physiology and opens the door for ideas to improve detection and treatment of DCM.

The paper was published in the Proceedings of the National Academy of Sciences of the U.S.A in November 2016.

Novel study

Led by Ted Rogers Centre Education Fund recipient Uros Kuzmanov, the research team mapped changes in protein signalling pathways in heart cells that lead to DCM. Specifically, in a mouse model of the disease, they measured protein “phosphorylation” in heart tissue – a biochemical reaction where a phosphate group is added onto a protein to make it more, or less, active, or to change its position in the cell, or to mark it for destruction.

Via this phosphoproteomic method, they were able to study how sick hearts activate or dampen entire protein signalling pathways – and in so doing, become vulnerable to heart failure. No such study had yet been accomplished at this level of scale in the study of DCM.

The research team uncovered hundreds of signalling pathways that went off course in DCM hearts. They generated the very first comprehensive map of molecular signaling events – including those unexpected – that go awry in heart failure.

What’s next: similar analyses in human tissue. If, as expected, they detect similar signalling changes, a human map could lead to promising new drug targets or biomarkers for early detection.

“We expect to be able to detect specific changes in signalling pathways in different cardiac patients,” said Kuzmanov.

“And our approach is not limited to the DCM — it could be applied to all heart disease.”