Research Highlight November 26, 2018

Obesity and Congenital Heart Disease: The metabolic connection

Mauro Costa, Ph.D. holding an apple and a cupcake.
A team led by JAX researcher Mauro Costa, Ph.D. has uncovered potential links between genetic heart defects and metabolism in adults. Their findings could be the first steps toward treatments to prevent the progression of heart failure.

 

Congenital heart disease (CHD) is the most common birth defect worldwide, affecting nearly one percent of babies born each year. As surgeons have developed better techniques for correcting the resulting physical defects, infant mortality rates have dropped. However, this change means that there is a growing population of adults living with CHD. Most research on CHD until now has focused on defects in embryonic and early life phases, neglecting to study the consequences of carrying CHD-related genetic mutations throughout an entire lifetime. As a result, scientists don’t fully understand the interactions between the disease and other environmental and lifestyle factors such as stress, hypertension, and obesity over the course of adulthood.        

In order to begin investigating these interactions, a team of JAX researchers led by Dr. Costa designed experiments to study the effect of a high-fat diet on adult mice with CHD. The research group, which operates under the umbrella of the Rosenthal lab, published a paper in Molecular Metabolism detailing their preliminary results. The work from Julia Wilmanns and JAX Scholar Dr. Raghav Pandey represents a major milestone after years of research on an international scale with collaborations from groups in Australia, Germany and US.

The researchers created mice that carried a specific genetic mutation predisposing them to symptoms resembling CHD, and compared those mice to normal mice. When both groups of mice ate high-fat diets and became obese, the normal mice’s hearts stayed the same, whereas the mutated CHD mice developed heart dysfunction.

Analysis revealed that the CHD mice developed impaired body metabolism, which caused heart dysfunction in obesity. Therefore, in the second phase of experiments, Costa’s team tested whether the drug Metformin – which modulate energy in the body and is currently used to treat type 2 diabetes – could protect the CHD mice’s hearts. According to their results, Metformin did prevent the progression of heart failure.

“We wanted to understand the source of the defects rather than just looking at how to correct them. That's what we've been doing for the last 20 years: simply decreasing the slope of the progression of the disease,” says Costa. “All of the drugs we commonly use today treat the symptom but not the cause. We are showing that for some cases, we can treat the cause early on. We’re not completely fixing the problem yet, but we can prevent the progression much earlier.”

With these findings published, the most important next steps are expanding the scope of the mouse studies and linking the findings to human patient data. Those data are just starting to become available – in 2015, the U.S. Center for Disease Control started a four-year nationwide project to gather information on adolescents and adults with CHD across the lifespan.

“We need to know how widespread the things we observed are in the human population,” says Costa. “If patients have genetic mutations, do they have metabolic dysfunction? If those aspects hold true, then we'd push for trying to apply Metformin as a treatment.” He adds that Metformin is an especially attractive and elegant treatment option because it is already approved by the U.S. Food and Drug Administration and generally has few side effects.

“This work fits within the frame of two really big health problems worldwide: increased prevalence of genetic disease predispositions, and obesity,” says Costa. As both trends continue upwards, this research will only become more important.

"Metformin intervention prevents cardiac dysfunction in a murine model of adult congenital heart disease
Author links open overlay panel." https://doi.org/10.1016/j.molmet.2018.11.002

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