Molecular mechanisms of peripartum cardiomyopathy: A vascular/hormonal hypothesis.
ABSTRACT: Peripartum cardiomyopathy (PPCM) is characterized by the development of systolic heart failure in the last month of pregnancy or within the first 5 months postpartum. The disease affects between 1:300 and 1:3000 births worldwide. Heart failure can resolve spontaneously but often does not. Mortality rates, like incidence, vary widely based on location, ranging from 0% to 25%. The consequences of PPCM are thus often devastating for an otherwise healthy young woman and her newborn. The cause of PPCM remains elusive. Numerous hypotheses have been proposed, with mixed supporting evidence. Recent work has suggested that PPCM is a vascular disease, triggered by the profound hormonal changes of late gestation. We focus here on these new mechanistic findings, and their potential implication for understanding and treating PPCM.
Project description:PURPOSE OF REVIEW:Peripartum cardiomyopathy (PPCM) is an idiopathic disorder defined as heart failure occurring in women during the last month of pregnancy and up to 5 months postpartum. In this review, we outline recent reports about the disease pathogenesis and management and highlight the use of diagnosis and prognosis biomarkers. RECENT FINDINGS:Novel data strengthen the implication of endothelial function in PPCM pathogenesis. The first international registry showed that patient presentations were similar globally, with heterogeneity in patient management and outcome. Despite large improvement in patient management and treatment, there is still a sub-group of women who die from PPCM or who will not recover their cardiac function. Remarkable advances in the comprehension of disease incidence, pathogenesis, and prognosis could be determined with multi-center and international registries. CLINICAL TRIALS:ClinicalTrials.gov Identifier: NCT02590601.
Project description:Peripartum cardiomyopathy (PPCM) represents new heart failure in a previously heart-healthy peripartum patient. It is necessary to rule out all other known causes of heart failure before accepting a diagnosis of PPCM. The modern era for PPCM in the United States and beyond began with the report of the National Institutes of Health PPCM Workshop in 2000, clarifying all then-currently known aspects of the disease. Since then, hundreds of publications have appeared, an indication of how devastating this disease can be to young mothers and their families and the urgent desire to find solutions for its cause and better treatment. The purpose of this review is to highlight the important advances that have brought us nearer to the solution of this puzzle, focusing on what we have learned about PPCM since 2000; and what still remains unanswered. Despite many improvements in outcome, we still do not know the actual triggers that initiate the pathological process; but realize that cardiac angiogenic imbalances resulting from complex pregnancy-related immune system and hormonal changes play a key role.
Project description:The benefit of the ?1-adrenergic receptor (?1-AR) agonist dobutamine for treatment of acute heart failure in peripartum cardiomyopathy (PPCM) is controversial. Cardiac STAT3 expression is reduced in PPCM patients. Mice carrying a cardiomyocyte-restricted deletion of STAT3 (CKO) develop PPCM. We hypothesized that STAT3-dependent signalling networks may influence the response to ?-AR agonist treatment in PPCM patients and analysed this hypothesis in CKO mice.Follow-up analyses in 27 patients with severe PPCM (left ventricular ejection fraction ?25%) revealed that 19 of 20 patients not obtaining dobutamine improved cardiac function. All seven patients obtaining dobutamine received heart transplantation (n = 4) or left ventricular assist devices (n = 3). They displayed diminished myocardial triglyceride, pyruvate, and lactate content compared with non-failing controls. The ?-AR agonist isoproterenol (Iso) induced heart failure with high mortality in postpartum female, in non-pregnant female and in male CKO, but not in wild-type mice. Iso induced heart failure and high mortality in CKO mice by impairing fatty acid and glucose uptake, thereby generating a metabolic deficit. The latter was governed by disturbed STAT3-dependent signalling networks, microRNA-199a-5p, microRNA-7a-5p, insulin/glucose transporter-4, and neuregulin/ErbB signalling. The resulting cardiac energy depletion and oxidative stress promoted dysfunction and cardiomyocyte loss inducing irreversible heart failure, which could be attenuated by the ?1-AR blocker metoprolol or glucose-uptake-promoting drugs perhexiline and etomoxir.Iso impairs glucose uptake, induces energy depletion, oxidative stress, dysfunction, and death in STAT3-deficient cardiomyocytes mainly via ?1-AR stimulation. These cellular alterations may underlie the dobutamine-induced irreversible heart failure progression in PPCM patients who frequently display reduced cardiac STAT3 expression.
Project description:<b>Background:</b>Peripartum cardiomyopathy (PPCM) is an idiopathic cardiomyopathy presenting with acute heart failure during the peripartum period. It is common in patients of African ancestry. Currently, there is paucity of data on the burden, predictors and outcomes of PPCM in Uganda. This study aimed to investigate the prevalence, predictors and six-month outcomes of PPCM in an adult cohort attending a tertiary specialised cardiology centre in Kampala, Uganda.<br><br><b>Methods:</b>This study consecutively enrolled 236 women presenting with features of acute heart failure in the peripartum period. Clinical evaluation and echocardiography were performed on all the enrolled women. PCCM was defined according to recommendations of the Heart Failure Association of the European Society of Cardiology Working Group on PPCM. Poor outcome at six months of follow-up was defined as presence of any of the following: death of a mother or her baby, New York Heart Association (NYHA) functional class III-IV or failure to achieve complete recovery of left ventricular function (left ventricular ejection fraction ?55%).<br><br><b>Results:</b>The median age, BMI and parity of the study participants was 31.5 (25.5-38.0) years, 28.3 (26.4-29.7) and 3 (2-4) respectively. The prevalence of PPCM was 17.4% (n = 41/236). Multiple pregnancy was the only predictor of PPCM in this study population (OR 4.3 95% CI 1.16-16.05, p = 0.029). Poor outcome at six-months was observed in about 54% of the patients with PPCM (n = 4, 9.8% in NYHA functional class III-IV and n = 22, 53.7% with LVEF <55%). No maternal or foetal mortality was documented.<br><br><b>Conclusion:</b>PPCM is relatively common in Uganda and is associated with multiple pregnancy. Poor outcomes especially absence of complete recovery of left ventricular function are also common. Large studies to further investigate long-term maternal and foetal outcomes in Uganda are justified.
Project description:Peripartum cardiomyopathy (PPCM) is rare but life-threatening. We herein report the case of a 48-year-old woman with PPCM after oocyte donation and delivery of twins. Two weeks after delivery, she suffered from severe symptoms of heart failure [orthopnea, New York Heart Association (NYHA) class IV, pulmonary edema and a reduced left ventricular ejection fraction of 18%]. Although standard heart failure therapy was effective for diminishing the congestion, it was not sufficient to improve her symptoms or left ventricular systolic dysfunction. During admission, we added bromocriptine. A year later after the onset, she was in a good state with an improved left ventricular systolic function.
Project description:The burden of pregnancy-related heart disease has dramatically increased over the last decades due to the increasing age at first pregnancy and higher prevalence of cardiovascular risk factors such as diabetes, hypertension, and obesity. Pregnancy is associated with physiological changes in the cardiovascular system, including hemodynamic, metabolic, and hormonal adaptations to meet the increased metabolic demands of the mother and fetus. It has been postulated that pregnancy may act as a cardiovascular stress test to identify women at high risk for heart disease, where the inability to adequately adapt to the physiologic stress of pregnancy may reveal the presence of genetic susceptibility to cardiovascular disease or accelerate the phenotypic expression of both inherited and acquired heart diseases, such as peripartum cardiomyopathy (PPCM). PPCM is a rare and incompletely understood clinical condition. Despite recent advances in the understanding of its pathogenesis, PPCM is not attributable to a well-defined pathological mechanism, and therefore, its diagnosis still relies on the exclusion of overlapping dilated phenotypes. Cardiac imaging plays a key role in any peripartum woman with signs and symptoms of heart failure in establishing the diagnosis, ruling out life-threatening complications, guiding therapy and conveying prognostic information. Echocardiography represents the first-line imaging technique, given its robust diagnostic yield and its favorable cost-effectiveness. Cardiovascular magnetic resonance is a biologically safe high-throughput modality that allows accurate morpho-functional assessment of the cardiovascular system in addition to the unique asset of myocardial tissue characterization as a pivotal piece of information in the pathophysiological puzzle of PPCM. In this review, we will highlight current evidence on the role of multimodality imaging in the differential diagnosis, prognostic assessment, and understanding of the pathophysiological basis of PPCM.
Project description:Peripartum cardiomyopathy (PPCM) is the development of heart failure during late pregnancy to months postpartum with potential fatal outcome. However, the disease is not well-studied in Asia.We aimed to investigate the epidemiology and clinical outcomes of PPCM in Taiwan.Electronic medical records were retrieved from Taiwan National Health Insurance Research Database from 1997 to 2011. Patients with PPCM were separated into 3 groups based on the timing of diagnosis. Early: PPCM diagnosed first to ninth month of pregnancy. Traditional: PPCM diagnosed last month of pregnancy till fifth month post-delivery. Late: PPCM diagnosed sixth to twelfth month post-delivery. Primary outcomes defined as cardiac death, all-cause mortality, and major adverse cardiovascular events (MACE) within 1 year.A total of 3,506,081 deliveries during 1997 to 2011 were retrieved and 925 patients with PPCM were identified. Overall incidence of PPCM was 1:3,790 during the 15 years. Early, Traditional, and Late group each had 88, 742, and 95 patients. Cardiac death occurred in 31 patients, all-cause mortality in 72 patients, and MACE in 65 patients. Late group had 2- to 3-fold event rates in cardiac death, all-cause mortality, and MACE compared with Early and Traditional groups. Cumulative incidence showed significant differences for cardiac death (P?=?.0011), all-cause mortality (P?=?.0031), and MACE (P?=?.0014) among 3 groups. Multivariate Cox model showed Late group had significantly worse outcomes after adjusted for clinical variables compared with 2 other groups.Our study is the largest national cohort among Asian countries that showed timing of diagnosis of PPCM had different outcomes. Late diagnosis portended significantly increased morbidity and mortality, even after adjusted for clinical variables.
Project description:Pregnancy is associated with marked physiological changes challenging the cardiovascular system. Among the more severe pregnancy associated cardiovascular complications, peripartum cardiomyopathy (PPCM) is a potentially life-threatening heart disease emerging towards the end of pregnancy or in the first postpartal months in previously healthy women. A major challenge is to distinguish the peripartum discomforts in healthy women (fatigue, shortness of breath, and oedema) from the pathological symptoms of PPCM. Moreover, pregnancy-related pathologies such as preeclampsia, myocarditis, or underlying genetic disease show overlapping symptoms with PPCM. Difficulties in diagnosis and the discrimination from other pathological conditions in pregnancy may explain why PPCM is still underestimated. Additionally, underlying pathophysiologies are poorly understood, biomarkers are scarce and treatment options in general limited. Experience in long-term prognosis and management including subsequent pregnancies is just beginning to emerge. This review focuses on novel aspects of physiological and pathophysiological changes of the maternal cardiovascular system by comparing normal conditions, hypertensive complications, genetic aspects, and infectious disease in PPCM-pregnancies. It also presents clinical and basic science data on the current state of knowledge on PPCM and brings them in context thereby highlighting promising new insights in diagnostic tools and therapeutic approaches and management.
Project description:OBJECTIVE:The aim of this work was to evaluate the hypothesis that the distribution of circulating immune cell subsets, or their activation state, is significantly different between peripartum cardiomyopathy (PPCM) and healthy postpartum (HP) women. BACKGROUND:PPCM is a major cause of maternal morbidity and mortality, and an immune-mediated etiology has been hypothesized. Cellular immunity, altered in pregnancy and the peripartum period, has been proposed to play a role in PPCM pathogenesis. METHODS:The Investigation of Pregnancy-Associated Cardiomyopathy (IPAC) study enrolled 100 women presenting with a left ventricular ejection fraction of <0.45 within 2 months of delivery. Peripheral T-cell subsets, natural killer (NK) cells, and cellular activation markers were assessed by flow cytometry in PPCM women early (<6 wk), 2 months, and 6 months postpartum and compared with those of HP women and women with non-pregnancy-associated recent-onset cardiomyopathy (ROCM). RESULTS:Entry NK cell levels (CD3-CD56+CD16+; reported as % of CD3- cells) were significantly (P?<?.0003) reduced in PPCM (6.6?±?4.9% of CD3- cells) compared to HP (11.9?±?5%). Of T-cell subtypes, CD3+CD4-CD8-CD38+ cells differed significantly (P?<?.004) between PPCM (24.5?±?12.5% of CD3+CD4-CD8- cells) and HP (12.5?±?6.4%). PPCM patients demonstrated a rapid recovery of NK and CD3+CD4-CD8-CD38+ cell levels. However, black women had a delayed recovery of NK cells. A similar reduction of NK cells was observed in women with ROCM. CONCLUSIONS:Compared with HP control women, early postpartum PPCM women show significantly reduced NK cells, and higher CD3+CD4-CD8-CD38+ cells, which both normalize over time postpartum. The mechanistic role of NK cells and "double negative" (CD4-CD8-) T regulatory cells in PPCM requires further investigation.
Project description:Probenecid has been used for decades in the treatment of gout but recently has also been found to improve outcomes in patients with heart failure via stimulation of the transient receptor potential vanilloid 2 (TRPV2) channel in cardiomyocytes. This study tested the use of probenecid on a novel mouse model of peripartum cardiomyopathy (PPCM) as a potential treatment option. A human mutation of the human heat shock protein 20 (Hsp20-S10F) in mice has been recently shown to result in cardiomyopathy, when exposed to pregnancies. Treatment with either probenecid or control sucrose water was initiated after the first pregnancy in both wild type and Hsp20-S10F mice. Serial echocardiography was performed during subsequent pregnancies and hearts were collected after the third pregnancies for staining and molecular analysis. Hsp20-S10F mice treated with probenecid had decreased mortality, hypertrophy, TRPV2 expression and molecular parameters of heart failure. Probenecid treatment also decreased apoptosis as evidenced by an increase in the level of Bcl-2/Bax. Probenecid improved survival in a novel mouse model of PPCM and may be an appropriate therapy for humans with PPCM as it has a proven safety and tolerability in patients with heart failure.