How "Aged Fat" Creates Perfect Storm for Heart Failure

Researchers at the Medical College of Georgia show how age causes a protection against inflammation to decline.

Growing old and gaining weight can both be tough on the heart, but new research shows how the combination creates the perfect storm for heart failure.

Zsolt Bagi, MD, PhD, a vascular biologist, and his colleagues at the Medical College of Georgia introduce the idea of “aged fat” in their study, and it’s as bad as it sounds.1

For more than a decade, studies on obesity have zeroed in on the role of inflammation, which occurs when the body’s immune system activates even though there’s no invader to fight. Researchers have connected the dots among increased levels of stress, lack of sleep, and a rise in inflammation, which causes insulin resistance. Thus, inflammation and weight gain act in a vicious cycle; obesity is associated with “a state of chronic low-level inflammation.”2

The new study, which appears in the journal Arteriosclerosis, Thrombosis, and Vascular Biology, shows how the aging process adds to this toxic mix. Bagi explained that the effect centers on an enzyme called ADAM17, which increases with obesity. Meanwhile, a protein that inhibits ADAM17, called caveolin-1, decreases with age.

Why is this a problem? Years ago researchers learned that ADAM17 could wreak havoc by cutting loose inactive tumor necrosis factor (TNF) from the cell membrane. While it can kill tumors, hence its name, TNF also increases inflammation and can harm the endothelial cells inside blood vessels.

Thus, the “perfect storm” hits when ADAM17 inflicts TNF damage on blood vessels, while the protein that might limit this process declines with age, and the whole process only causes obesity to increase. The result is microvascular damage that harms blood flow to the small capillaries, but not necessarily the plaque that is the obvious sign of heart disease.

As Bagi explained in a statement, “Older obese patients and sometimes women who suffer heart failure go to the cardiac catheterization lab, and the cardiologist finds nothing that would explain their heart failure. They have normal large blood vessels in the heart, and yet the heart failure has developed.”

Bagi and his fellow researchers had found high levels of ADAM17 in human fat and even higher levels in the blood vessels of aged human fat. They used mice to demonstrate the effects of the enzyme. They found high levels of ADAM17 in mice who were fed a high-fat diet, but its activity level took off as the mice aged and gained weight. They studied how ADAM17 behaved in mice who were old and obese, young and obese, and old but lean to isolate the effect of the combination.

To confirm the effect in humans, the team retrieved heart tissue and fat near the heart from surgical patients at the Medical College of Georgia. They found that dilation in small blood vessels was impaired if patients were age 69 or older, and further impaired if the patient was older and obese.

References

1. Dou H, Feher A, Davila AC, et al. Role of adipose tissue endothelial ADAM17 in age-related coronary microvascular dysfunction. Atherioscler Thromb Vasc Biol 2017;37:1180-1193. https://doi.org/10.1161/ATVBAHA.117.309430

2. Wellen KE, Hotamisligil GS, Inflammation, stress, and diabetes. J Clin Invest. 2005; 115(5):1111-1119.