Heart failure, progressive and potentially fatal weakening of the heart muscle, is associated with both obesity and diabetes, but the mechanisms by which damage occurs are not well-understood, said senior author Heinrich Taegtmeyer, M.D., Ph.D., professor of cardiology.

"In cardiology, we've long been concerned about fat accumulating in the artery walls and blocking the flow of blood to the heart. What we are finding now is that the buildup of fat doesn't stop in the blood vessels, it's actually worse in heart muscle cells," Taegtmeyer said. "We also report in this paper that diabetes and obesity appear to cause metabolic irregularities in the heart tissue."

Gene expression and protein findings in the paper provide potential long-term targets for treating heart failure, which afflicts 5 million U.S. patients annually.

Researchers examined 27 failing hearts that were removed during transplants and compared them to eight donor hearts that were not failing but were otherwise unsuitable for transplant.

Eight of the failing hearts (30 percent) showed high levels of triglycerides “ a fat storage and transport molecule. Levels of triglycerides in failing hearts were four times the level in obese or diabetic patients as they were in non-failing hearts.

The research team associated this buildup of triglycerides in the heart muscle, called lipotoxicity, with dysfunctional expression of genes related to the heart's metabolism of fatty acids, its contractile function, and an inflammatory protein known to contribute to insulin resistance.

The human results track with a rat model of the lipotoxic heart, which has been shown to cause improper cardiac contraction in the rodents, said first author Saumya Sharma, M.D., a cardiology fellow and researcher in Taegtmeyer's lab.

A normal heart derives two-thirds of its energy requirement by metabolizing fatty acids, which are carried in triglycerides, Sharma said. Lipotoxic hearts store some triglycerides in the muscle tissue rather than metabolizing them.

In obese people, Taegtmeyer and his team theorize that this occurs because the person's fat cells, which capture and store excess triglycerides, fill up. Because people have a set number of fat cells, once they are full, excess fat lodges in muscle tissue, where it wreaks molecular havoc.

"The heart is a muscle, too, and it's not spared from this onslaught of fat," Taegtmeyer explained. "The heart is designed to contract, but if lipids (fat) displace its contractile proteins, that results in impaired heart function."

Taegtmeyer and colleagues are testing this hypothesis among obese patients who have elected to have bariatric surgery (surgical reduction of stomach size). Patients in the study volunteer to have their cardiac function analyzed and to provide a small sample of thigh muscle tissue before and after their surgery. Taegtmeyer's team will then assess whether weight loss after surgery results in improved heart function and decreased levels of lipids in muscle tissue.

Earlier research by Taegtmeyer showed that diabetes causes toxic levels of lipids and glucose to build up in the heart.

uthouston/