Skip to main content

Modifiers in familial dilated cardiomyopathy

Victor Chang Cardiac Research Institute & University of New South Wales

  • Cardiovascular Senior Researcher Grant
Organ System:
  • Cardiovascular
Date Funded:
  • 22 May, 2020
Chief Investigator/s:
  • Professor Diane Fatkin

Project summary

Identification of disease modifiers in familial dilated cardiomyopathy Incorporation of risk factor management as an important component of personally-tailored clinical care for TTNtv-related dilate cardiomyopathy.

What is the issue for NSW?

Dilated cardiomyopathy (DCM) is a costly and often deadly heart muscle disease. It can strike at any age and is a major cause of heart failure in the young and in pregnant women. Consequently, its medical, psychosocial, and productivity costs are substantial. New ways to treat and prevent DCM are urgently required. This is an enormous challenge for patients with genetic causes of DCM, since interventions to change the inevitable effects of underlying gene mutations have not been possible.

Mutations in the TTN gene that result in an abnormally short titin protein (called “TTNtv”) are present in one in every five families and are the most common genetic cause of DCM. By studying hundreds of families, the team has found that some TTNtv-positive relatives experience heart failure in their teens or early twenties, while others have relatively normal heart function until late in life. This marked variability suggests that factors in addition to the TTNtv may be involved.

What does the research aim to do and how?

In this study, the team are investigating the hypothesis that unique combinations of genetic background, other illnesses and lifestyle factors can increase (or reduce) the severity of disease in individual TTNtv carriers.

The first aim is to find out what some of these “modifier” factors might be. This will be done by gathering information about health and lifestyle in a large group of families who have TTNtv-related DCM. The team will also undertake genetic analyses to see if there are any other genetic variants present that might have deleterious effects.

The second aim is to get evidence that suspected modifying factors do in fact alter heart function in the setting of TTNtv. The team will use a unique zebrafish laboratory generated model generated that spontaneously develops DCM during adult life, similar to human TTNtv-related DCM. The team will look to see whether these effects of TTNtv are magnified (or attenuated) in the presence of additional genetic and/or environmental insults.

These cutting-edge studies are only now possible following development of new miniaturised tools for undertaking serial assessment of cardiac function in living fish.

It’s expected that incorporation of risk factor management will emerge as an important component of personally-tailored clinical care. The ability to shift DCM onset potentially by decades and/or reduce disease severity, would have substantial benefits for patients and their families, as well as reducing healthcare costs.