Clues to a dangerous complication of pregnancy

Now, a research team led by investigators at Beth Israel Deaconess Medical Center (BIDMC) has uncovered important new clues behind this dangerous condition, providing the first clear evidence that peripartum cardiomyopathy (PPCM) is a vascular disease, brought about by an imbalance of angiogenic proteins in the heart during the peripartum period, just prior to and immediately following delivery. Described in the Advance On-Line issue of the journal Nature, the findings also explain the underlying mechanisms of PPCM, helping to explain why preeclampsia and multiple births are risk factors and suggesting that proangiogenic therapies may be beneficial treatments. PPCM affects approximately one in 3,000 pregnant women with no known history of heart disease. Symptoms can be mild or severe, and include shortness of breath, caused by the heart's diminished pumping ability. About one-half of women who develop PPCM will spontaneously recover, but for others, the condition will grow worse, even to the point that they require a heart transplant. "It's been a real mystery," says senior author Zoltan Arany, MD, PhD, an investigator in the CardioVascular Institute at BIDMC and Assistant Professor of Medicine at Harvard Medical School. "The majority of women who develop this condition are otherwise healthy, even active. We know that the real stressors of pregnancy occur in the first trimester. Why then, are these mothers-to-be developing such serious problems at the end of pregnancy? We think we have now come up with a number of important insights into this life-threatening condition." Through a series of experiments in both animal models and humans, the authors made a number of important discoveries that add up to a strong argument that PPCM is a "two-hit" disease that develops when, first, signals released late in pregnancy to prevent normal blood vessel growth are excessively elevated and, second, for unknown reasons, proangiogenic defenses are insufficient. Angiogenesis, the process by which new blood vessels grow and develop, can be turned on by a gene called PGC1-alpha, which is a primary focus of research in the Arany laboratory. It was while studying this molecule in heart muscle that the investigation first unfolded. "We had recently demonstrated that PGC1-alpha could regulate blood vessel density in skeletal muscle," explains Arany. "As we pursued experiments to determine if this was also the case in heart muscle, we made the observation that female mice lacking PGC1-alpha in their hearts invariably died after one or two pregnancies and that the animals' hearts were enlarged and fibrotic. We realized that the mice had developed peripartum cardiomyopathy and that we now had a model of the disease."