Shared genetic etiology of peripartum and dilated cardiomyopathies

Background: Peripartum cardiomyopathy (PPCM) shares some clinical features with idiopathic dilated cardiomyopathy, a disorder caused by mutations in over 40 genes, including TTN, which encodes the sarcomere protein titin. Methods: We sequenced 43 genes, with variants that have been associated with dilated cardiomyopathy, in 172 women with peripartum cardiomyopathy. We compared the prevalence of different types of variant (nonsense, frameshift, and splicing) in these women with the prevalence of these variants in persons with dilated cardiomyopathy and population controls. Results: We identified 26 distinct rare truncating variants in eight genes in women with PPCM. The prevalence of truncating variants (26 in 172 [15%]) was significantly higher than in a reference population of 60,706 individuals (4.7%, P=1.3x10-7), but was similar to a cohort of 332 dilated cardiomyopathy cases (55 in 332 [17%], P=0.81). Two thirds of identified truncating variants were in TTN ([10%], P=2.7x10-10 versus 1.4% in reference population), almost all located in the titin A-band. Seven of the TTN truncating variants were previously reported in cases of idiopathic dilated cardiomyopathy. In a clinically well-characterized cohort of women with PPCM (n=83), the presence of TTN truncating variants correlated with lower ejection fraction at one-year follow-up (P=0.005). Conclusions: The distribution of truncating variants in a large series of women with PPCM is remarkably similar to that found in idiopathic dilated cardiomyopathy. TTN truncating variants are the most prevalent genetic predisposition of each disorder

Pathophysiology and epidemiology of peripartum cardiomyopathy

Cardiovascular diseases are a major cause of complications in pregnancy worldwide, and the number of patients who develop cardiac problems during pregnancy is increasing. Peripartum cardiomyopathy (PPCM) is a potentially life-threatening heart disease that emerges towards the end of pregnancy or in the first months postpartum, in previously healthy women. Symptoms and signs of PPCM are similar to those in patients with idiopathic dilated cardiomyopathy. The incidence varies geographically, most likely because of socioeconomic and genetic factors. The syndrome is associated with a high morbidity and mortality, and diagnosis is often delayed. Various mechanisms have been investigated, including the hypothesis that unbalanced peripartum or postpartum oxidative stress triggers the proteolytic cleavage of the nursing hormone prolactin into a potent antiangiogenic, proapoptotic, and proinflammatory 16 kDa fragment. This theory provides the basis for the discovery of disease-specific biomarkers and promising novel therapeutic targets. In this Review, we describe the latest understanding of the epidemiology, pathophysiology, and novel treatment strategies for patients with PPCM

Comorbidities and co-existing conditions in heart failure around pregnancy

It is estimated that 0.2 to 4% of all pregnancies in industrialized countries are complicated by cardiovascular diseases (CVD) with increasing number of women who develop cardiac problems during pregnancy [1]. Indeed, pregnancy challenges the cardiovascular system and may lead to disease states such as hypertensive complications with its severe forms preeclampsia and the HELLP syndrome (H: hemolysis, EL: elevated liver enzymes, LP: low platelets counts) [2]. Especially the phase towards the end of pregnancy, during delivery and postpartum is a special challenge for the cardiovascular system since it has to cope with massive hormonal fluctuations, fluid changes and mechanical stress. Alterations in metabolism (subclinical insulin resistance in pregnancy) and immune response (repressed in pregnancy and activated after delivery) take place as well. Moreover, endothelial stress promotes hypertensive disorders and additional enhanced coagulation activity lead to higher risk for myocardial infarction and stroke and cardiomyopathies as outlined below. It is therefore not surprising that acceleration of heart failure towards the end of the second trimester, under delivery or in the early postpartum phase is frequently observed in women with pre-existing cardiomyopathies or pulmonary hypertension and is associated with adverse maternal and perinatal outcome [3]. Moreover, the cardiac stress model “pregnancy” may even unmask unrecognized genetic and non-genetic heart diseases [2, 4, 5]