Immune Activation and Myocardial Recovery in Peripartum Cardiomyopathy

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DESCRIPTION (provided by applicant): This proposal addresses Challenge area 7: Enhancing Clinical Trials: 07-OD(ORDR)-102 for the development of a rare disease genetic patient registry. Peripartum cardiomyopathy (PPCM) is a complication of pregnancy occurring in 1:1800 to 1:3500 births in the United States which remains a major cause of maternal morbidity and mortality. This disorder is defined as a primary myocardial dysfunction (LVEF < 0.45) presenting in the last month of pregnancy or in the first five months post-partum and is clinically indistinguishable from other forms of idiopathic dilated cardiomyopathy. Though its etiology remains unknown, most theories have focused on the immunologic processes of pregnancy and the post partum period. Significant improvement in myocardial function is seen in up to half of patients within six months, but a significant number of patients are left with chronic cardiomyopathy which can progress toward death or cardiac transplantation. This proposal will investigate myocardial recovery in peripartum cardiomyopathy, and the relationship of the postpartum circulating milieu to its pathogenesis and resolution. In particular, it will test the hypothesis that humoral and cellular immune activation in PPCM is associated with myocardial injury and that women with more prolonged immune activation are less likely to recover myocardial function. In addition while prolactin inhibition has been investigated in as a means of immune modulation in murine models of peripartum cardiomyopathy, the relationship of hormonal changes of the post partum period to immune activation remains to be explored. Endomyocardial biopsy is rarely performed in PPCM; however, myocardial inflammation and injury have been demonstrated recently by magnetic resonance imaging (MRI). Previous studies of PPCM have been limited by study number, and the relationship of the extent of myocardial injury to subsequent recovery of PPCM has not been examined. This proposal will develop a multicenter network dedicated to research into the pathogenesis of PPCM and will establish a biologic bank of sufficient size to allow the exploration of the relationships between hormonal and cellular events of pregnancy, systemic immune activation, myocardial inflammation, the development of PPCM and its resolution. In addition, through the development of new biomarkers and noninvasive assessment for this disorder, this investigation will improve the ability of clinicians to delineate those women who will recover from those who will be left with chronic cardiomyopathy and set the stage for future interventional trials in PPCM. . Public Health Relevance: This investigation seeks to improve the treatments available for peripartum cardiomyopathy, a rare complication of pregnancy which remains a major cause of maternal morbidity and mortality. The proposal will establish a multicenter network dedicated to understanding the pathogenesis of this disorder and to developing new innovative biomarkers and imaging techniques to differentiate women who will recover from those with more serious progressive disease.