August 12, 2003

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Natural Hormone Could Reverse Heart Damage

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Both of these mice began at the same weight. After 4-6 weeks of leptin infusions, the mouse on the right had significant weight loss and no signs of heart disease.
By altering the signaling pathway of the natural hormone leptin, Johns Hopkins researchers say, doctors may one day be able to minimize or even reverse a dangerous enlarged heart condition linked to obesity. Their report is published in the Aug. 12 issue of the journal Circulation.

Leptin helps regulate body weight and metabolism, but also can affect the heart and blood vessels. The Hopkins researchers studied leptin's effects in a mouse model of obesity that also develops left ventricular hypertrophy (LVH), a condition in which the main pumping chamber of the heart expands and stiffens, preventing proper blood flow to the body. Hypertrophy, which results from stress on the heart (for example, through high blood pressure or obesity), starts off as a compensatory mechanism but soon runs out of control, says lead study author Lili A. Barouch, M.D., an assistant professor of medicine. As the heart muscle is worked harder, it bulks up. But after too much strain, it can become stiff and cease contracting.

In their two-part study, Barouch and colleagues compared the hearts of three groups of mice at 2, 4, and 6 months old. One group lacked the gene for leptin, one group lacked the receptor for leptin, and the third was normal. Progressive obesity developed in the mice lacking leptin or its receptor, and by 6 months of age, researchers observed LVH in these mice but not in the controls. Individual heart cells also showed signs of enlargement.

Next, the Hopkins team divided the 6-month-old obese mice into three groups. Two groups were assigned to lose weight (one by leptin infusions and one by a calorie-restricted diet), while the third group continued to eat its regular diet. After four to six weeks, mice in both diet groups lost the same amount of weight. However, the mice who received leptin infusions had a complete reversal of LVH and a partial shrinkage of enlarged heart cells, whereas the mice on caloric restriction had no change in LVH and a smaller reversal of the enlarged heart cells.

So are leptin infusions headed to your doctor's office? "It's unlikely," Barouch says, as humans process the hormone differently than mice in this model. Obese people have leptin resistance, she says, so more work needs to be done before clinical therapies can be tested.

"If we can figure out the signaling pathways of leptin, we can change or minimize the development of LVH," Barouch says. "This has tremendous clinical implications — LVH is a big problem, particularly among obese patients."

The study was funded by the National Institutes of Health and a Paul Beeson Physician Faculty Scholars in Aging Research Award. Coauthors were Dan E. Berkowitz, M.D., Robert W. Harrison; Christopher P. O'Donnell, M.D.; and Joshua M. Hare, M.D.


Barouch, L.A., et al, "Disruption of Leptin Signaling Contributes to Cardiac Hypertrophy Independently of Body Weight in Mice," Circulation, Aug. 12, 2003, Vol. 108, No. 6.


Johns Hopkins - Division of Cardiology



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