MicroRNA-146a is a therapeutic target and biomarker for peripartum cardiomyopathy

MicroRNA-320a/b is a Therapeutic Target and Biomarker for Peripartum Cardiomyopathy

Peripartum cardiomyopathy (PPCM) was recognized as a clinical entity in the early 1930s; however, the exact mechanism of the disease’s progression remains unknown. The highest incidence of PPCM is in African Americans, and the disease is associated with poor outcomes in elderly and multiparous women. The varying characteristics of patients suggest that genetic susceptibility of the disease could exist. PPCM can be associated with life threatening complications including cardiogenic shock, fatal arrhythmias, and thromboembolic events which can lead to death. Pregnant or lactating PPCM patients can further complicate how clinicians manage them. One recent hypothesis is that 16-kDa N-terminal prolactin fragment (16K PRL) plays a vital role in PPCM by inducing microRNA146a (miRNA146a) which reduces angiogenesis through downregulation of NRAS. miRNAs are small RNAs that were previously described as noncoding RNA that controls the posttranscriptional activity of mRNA. Recent animal studies have identified miRNA146a as a causative factor in PPCM; this discovery is promising and could have clinical implications in future. With growing evidence of miRNA’s involvement in disease, miRNA can add to our current understanding of pathology and could be a potential tool for diagnosis, prognosis, and therapy in PPCM.

Introduction: Peripartum cardiomyopathy (PPCM) presents as left ventricular systolic dysfunction (LVSD) during pregnancy or the post-partum interval. The underlying cause of PPCM remains incompletely defined, with hypotheses suggesting either pregnancy-related environmental (e.g., hormonal, hemodynamic) cause or genetic cause similar to dilated cardiomyopathy (DCM). Hypothesis: If PPCM results principally from pregnancy-related environmental cause, then first-degree relatives (FDRs) of women with PPCM will have lower risk of DCM than FDRs of women with DCM because they cannot share this risk. Conversely, if DCM genetics underlies both PPCM and DCM, then FDRs of women with PPCM or DCM are equally likely to share these genetic factors and will have comparable risks. Aims: In female probands with PPCM or DCM from the DCM Precision Medicine Study, evaluate proband DCM-relevant rare variant genetics; in their FDRs, compare the age-specific cumulative risk of DCM, LVSD, or LV enlargement [LVE]. Methods: Of 452 female probands with DCM, 72 met criteria for PPCM; all underwent exome sequencing and analysis of rare variants in 36 DCM genes. Their 665 FDRs were assessed for DCM, LVSD, or LVE. Hierarchical logit models were used to describe the distribution of the most deleterious variant identified (none, variant of uncertain significance, or pathogenic/likely pathogenic) in probands. For FDRs, binary data on the presence or absence of DCM, LVSD, or LVE at enrollment were used to model age-specific cumulative risk in a Weibull proportional hazards model. Models accounted for site heterogeneity and, in FDRs, intrafamilial correlation. Results: The odds of finding a DCM-relevant rare variant were comparable between female probands with PPCM and DCM (OR=1.07, 95% CI: 0.37-3.11, p=0.90) adjusting for ancestry, ethnicity, and diagnosis age. DCM-relevant rare variants of PPCM probands were similar to those of DCM probands for ClinGen gene evidence category (p=0.55) and variant predicted impact (loss-of-function, missense, or other; p=0.90). Age-specific cumulative risk of DCM, LVSD, or LVE was not different among FDRs of women with PPCM or DCM (HR=0.96, 95% CI: 0.59-1.57, p=0.87) adjusting for proband ancestry and diagnosis age and FDR sex. Conclusion: Data from female probands indicate that PPCM and DCM have a similar rare variant genetic basis. FDRs of both PPCM and DCM probands show similar risks of DCM, LVSD, or LVE, further supporting an underlying genetic cause for PPCM.

Peripartum cardiomyopathy for the clinician: the known and the unknown.

Rare variant genetics have been associated with peripartum cardiomyopathy (PPCM), but the role of genetics remains unsettled. The study sought to compare dilated cardiomyopathy (DCM) genetic risk in first-degree relatives (FDRs) of female patients (probands) with DCM or PPCM to gain causal inference, and to assess DCM-relevant rare variant prevalence in DCM/PPCM probands and population controls. Clinical and genetic data were analyzed from the DCM Precision Medicine Study. Risk of DCM or partial DCM, where partial DCM was defined as left ventricular enlargement or a left ventricular ejection fraction of <50%, was estimated in 665 FDRs from 452 female probands, all of whom had been pregnant; 67 had PPCM and 385 had DCM; prevalence of pathogenic, likely pathogenic, or uncertain significance variants was estimated among probands. The risk of DCM/partial DCM for FDRs of PPCM probands was similar to that for FDRs of DCM probands (hazard ratio, 0.77 [95% CI, 0.47-1.28]). Estimated DCM prevalence among the lowest-risk FDRs of non-Hispanic European ancestry probands with PPCM (7.0% [95% CI, 0%-14.1%] females, 9.0% [95% CI, 1.6%-16.3%] males) exceeded population estimates from a UK Biobank study (0.30% females, 0.63% males). Estimated prevalences of a pathogenic, likely pathogenic, or uncertain significance variant among African ancestry and European ancestry probands with PPCM were 55.4% (95% CI, 33.1%-77.7%) and 66.0% (95% CI, 38.6%-93.3%), respectively. The estimated prevalence of pathogenic/likely pathogenic variants among European ancestry PPCM probands (26.6% [95% CI, 12.6%-40.6%]) exceeded a population estimate from a UK Biobank study (0.6%). The risk of DCM/partial DCM among FDRs was similar regardless of whether their probands had PPCM or DCM. Also, DCM-relevant rare variant findings for females with PPCM or DCM were similar and greater than in population controls, suggesting a similar causal basis for PPCM and DCM. These findings underscore the need for genetic evaluations in all patients with PPCM. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03037632.

High output failure in patients with peripartum cardiomyopathy: A comparative study with dilated cardiomyopathy

Peripartum Cardiomyopathy

33-Year-Old Woman With Postpartum Acute Shortness of Breath

Background:Rare variant genetics have been associated with peripartum cardiomyopathy (PPCM) but the role of genetics remains unsettled.Objective:The study sought to compare dilated cardiomyopathy (DCM) genetic risk in first-degree relatives (FDRs) of female patients with DCM or PPCM (probands), and to assess DCM-relevant rare variant prevalence in DCM/PPCM probands and population controls.Methods:Clinical and genetic data were analyzed from the DCM Precision Medicine Study. Risk of DCM or partial DCM, where pDCM was defined as left ventricular (LV) enlargement or a LV ejection fraction of <50%, was estimated in 665 FDRs from 452 female probands, all of whom had been pregnant, of which 67 had PPCM and 385 had DCM; prevalence of pathogenic, likely pathogenic or uncertain significance variants (P/LP/VUS) was estimated among probands.Results:The risk of DCM/pDCM for FDRs of PPCM probands was similar to that for FDRs of DCM probands (HR, 0.77; 95% CI, 0.47 – 1.28). Estimated DCM prevalence among the lowest-risk FDRs of non-Hispanic EA probands with PPCM (7.0% [95% CI, 0%−14.1%] females, 9.0% [95% CI, 1.6%−16.3%] males) exceeded population estimates from a UK Biobank study (0.30% females, 0.63% males). Estimated prevalences of a P/LP/VUS among AA and EA probands with PPCM were 55.4% (95% CI, 33.1%−77.7%) and 66.0% (95% CI, 38.6%−93.3%), respectively. The estimated prevalence of P/LP variants among EA PPCM probands (26.6%; 95% CI, 12.6%−40.6%) exceeded a population estimate from a UK Biobank study (0.6%).Conclusion:The risk of DCM/pDCM among FDRs was similar regardless of whether their probands had PPCM or DCM. Also, DCM-relevant rare variant findings for females with PPCM or DCM were similar and greater than in population controls suggesting a shared genetic basis for PPCM and DCM. These findings underscore the need for genetic evaluations in all PPCM patients.

Peripartum cardiomyopathy (PPCM) occurs in ≈1:2000 deliveries in the United States and worldwide. The genetic underpinnings of PPCM remain poorly defined. Approximately 10% of women with PPCM harbor truncating variants in TTN (TTNtvs). Whether mutations in other genes can predispose to PPCM is not known. It is also not known if the presence of TTNtvs predicts clinical presentation or outcomes. Nor is it known if the prevalence of TTNtvs differs in women with PPCM and preeclampsia, the strongest risk factor for PPCM. Women with PPCM were retrospectively identified from several US and international academic centers, and clinical information and DNA samples were acquired. Next-generation sequencing was performed on 67 genes, including TTN, and evaluated for burden of truncating and missense variants. The impact of TTNtvs on the severity of clinical presentation, and on clinical outcomes, was evaluated. Four hundred sixty-nine women met inclusion criteria. Of the women with PPCM, 10.4% bore TTNtvs (odds ratio=9.4 compared with 1.2% in the reference population; Bonferroni-corrected P [P*]=1.2×10-46). We additionally identified overrepresentation of truncating variants in FLNC (odds ratio=24.8, P*=7.0×10-8), DSP (odds ratio=14.9, P*=1.0×10-8), and BAG3 (odds ratio=53.1, P*=0.02), genes not previously associated with PPCM. This profile is highly similar to that found in nonischemic dilated cardiomyopathy. Women with TTNtvs had lower left ventricular ejection fraction on presentation than did women without TTNtvs (23.5% versus 29%, P=2.5×10-4), but did not differ significantly in timing of presentation after delivery, in prevalence of preeclampsia, or in rates of clinical recovery. This study provides the first extensive genetic and phenotypic landscape of PPCM and demonstrates that predisposition to heart failure is an important risk factor for PPCM. The work reveals a degree of genetic similarity between PPCM and dilated cardiomyopathy, suggesting that gene-specific therapeutic approaches being developed for dilated cardiomyopathy may also apply to PPCM, and that approaches to genetic testing in PPCM should mirror those taken in dilated cardiomyopathy. Last, the clarification of genotype/phenotype associations has important implications for genetic counseling.

HomeCirculationVol. 123, No. 2Letter by Baruteau et al Regarding Article, “Peripartum Cardiomyopathy as a Part of Familial Dilated Cardiomyopathy” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBLetter by Baruteau et al Regarding Article, “Peripartum Cardiomyopathy as a Part of Familial Dilated Cardiomyopathy” Alban-Elouen Baruteau, MD, Erwan Donal, MD, PhD and Jean-Claude Daubert, MD, PhD Alban-Elouen BaruteauAlban-Elouen Baruteau CHU RennesService de Cardiologie et Maladies VasculairesUniversité de Rennes 1Rennes, France (Baruteau, Donal, Daubert) Search for more papers by this author , Erwan DonalErwan Donal CHU RennesService de Cardiologie et Maladies VasculairesUniversité de Rennes 1Rennes, France (Baruteau, Donal, Daubert) Search for more papers by this author and Jean-Claude DaubertJean-Claude Daubert CHU RennesService de Cardiologie et Maladies VasculairesUniversité de Rennes 1Rennes, France (Baruteau, Donal, Daubert) Search for more papers by this author Originally published18 Jan 2011https://doi.org/10.1161/CIRCULATIONAHA.110.971978Circulation. 2011;123:e8We have read with great interest the article by van Spaendonck-Zwarts et al, which strongly suggests that a subset of peripartum cardiomyopathy (PPCM) is part of the spectrum of familial dilated cardiomyopathy.1 Entering PPCM in the field of familial dilated cardiomyopathy strongly modifies thinking on PPCM pathogenesis and management. We respectfully disagree in accepting the authors' interpretations of study findings. To our mind, they underestimate the clinical implication of their results and recommend overly restrictive indications for familial echocardiographic screening, which led us to write this letter.In the first systematic approach examining the familiality and genetics of PPCM, they found that cardiological screening of first-degree relatives of 3 PPCM patients who did not show full recovery revealed unknown dilated cardiomyopathy in all 3 families. Unfortunately, they decided not to perform such a familial screening in the 7 PPCM patients who experienced a complete normalization of left ventricular size and function. They also recommend “presymptomatic cardiological screening for covert dilated cardiomyopathy in first-degree family members of PPCM patients without recovery of left ventricular function and dimensions.”1Familial occurrence of PPCM was suggested in the literature by 6 previous anecdotal cases reporting a total of 8 kinships with more than 1 member affected by PPCM.1–3 Catastrophic outcomes were reported in 5 of these 6 publications with no recovery, death or heart transplantation for intractable heart failure in PPCM patients.However, this is not consistent with our experience, and our case report was the only one assessing a familial occurrence in 2 sisters who experienced severe PPCM with a favorable outcome and a full recovery.3 Both sisters presented dilated cardiomyopathy in the peripartum period with severe systolic dysfunction (left ventricular ejection fraction respectively 20% and 40%). They were aggressively supported in a timely manner, including inotropic support and extracorporeal membrane oxygenation for 1 of them and long-term medical treatment including a β-blocker agent and angiotensin-converting enzyme inhibitor. Full recovery was assessed by cardiac magnetic resonance imaging and transthoracic echocardiography, respectively, at 12- and 3-month follow-ups.In the current era of heart failure management, PPCM prognosis appears to be better than previously reported, with a left ventricular function normalization rate of 54%.4 Our observation shows that full recovery does not authorize elimination of a familial covert dilated cardiomyopathy.Therefore we suggest that cardiological screening be recommended to all first-degree relatives of PPCM patients, regardless of gender, even in the case of normalization of left ventricular size and function. It should allow presymptomatic diagnosis of unknown familial dilated cardiomyopathy in relatives. Despite the fact that it was recommended 10 years ago by the National Institutes of Health on PPCM,5 the impact of such a screening strategy remains to be assessed in large-scale studies.Alban-Elouen Baruteau, MDErwan Donal, MD, PhDJean-Claude Daubert, MD, PhD CHU Rennes Service de Cardiologie et Maladies Vasculaires Université de Rennes 1 Rennes, FranceDisclosuresNone.

Peripartum cardiomyopathy (PPCM) is a rare heart disease, occurring in previously heart-healthy women during the last month of pregnancy or the first months after delivery due to left ventricular (LV) systolic dysfunction. A common pathomechanistic pathway of PPCM includes increased oxidative stress and the subsequent generation of a cleaved prolactin fragment (16kDa PRL), which promotes the onset of heart failure (HF) in a microRNA (miR)-146a-dependent manner. Inhibition of prolactin secretion with the dopamine D2 receptor (D2R) agonist bromocriptine combined with standard HF therapy supports cardiac recovery. This study examined whether treatment with the more selective D2R agonist cabergoline prevents HF development in an experimental PPCM mouse model and might be used as an alternative treatment regime for PPCM. Postpartum (PP) female PPCM-prone mice with a cardiomyocyte restricted STAT3-deficiency (αMHC-Cretg/+ ; Stat3fl/fl ; CKO) were treated over two consecutive nursing periods with cabergoline (CKO Cab, 0.5mg/kg/day) and were compared with bromocriptine treated CKO (CKO Br) and postpartum-matched WT and CKO mice. Cabergoline treatment in CKO PP mice preserved cardiac function [fractional shortening (FS): CKO Cab: 34.5±9.4% vs. CKO: 22.1±9%, P<0.05] and prevented the development of cardiac hypertrophy, fibrosis, and inflammation as effective as bromocriptine therapy (FS: CKO Br: 33.4±5.6%). The myocardial up-regulation of the PPCM biomarkers plasminogen inhibitor activator 1 (PAI-1) and miR-146a were prevented by both cabergoline and bromocriptine therapy. A small cohort of three PPCM patients from the German PPCM Registry was treated with cabergoline (1mg per week for 2weeks, followed by 0.5mg per week for another 6weeks) due to a temporary unavailability of bromocriptine. All PPCM patients initially presented with a severely reduced LV ejection fraction (LVEF: 26±2%). However, at 6months of follow-up, LV function (LVEF: 56±2%) fully recovered in all three PPCM patients, and no adverse events were detected. In the experimental PPCM mouse model, the selective D2R agonist cabergoline prevents the onset of postpartum HF similar to bromocriptine. In PPCM patients, cabergoline treatment was safe and effective as all patients fully recovered. Cabergoline might serve as a promising alternative to bromocriptine. However, these findings are based on experimental data and a small case series and thus have to be interpreted with caution and should be validated in a larger clinical trial.

Cardiomyopathy in pregnancy: A retrospective study

Peripartum cardiomyopathy and pre-eclampsia: two tips of the same iceberg.

Objective To characterize the cardiac magnetic resonance (CMR) features of peripartum cardiomyopathy(PPCM) and idiopathic dilated cardiomyopathy (IDCM) , and to explore the value of MRI in the diagnosis of PPCM. Methods Ten cases of PPCM and 10 cases of Idiopathic dilated cardiomyopathy (IDCM) were included in this study. With 1.5 T MRI scanner, the heart shape (atrioventricular size, hypertrabeculation, thickness of the thinnest ventricular wall), function (ventricular wall movement and the overall function), cardiomyopathy perfusion were comprehensively evaluated. Paired samplest-test andFisher exact probability method were used for statistical analysis. Results Between PPCM and IDCM group, there was no statistical significant difference in the atrioventricular size, cardiac output(CO), end diastolic volume(EDV), ejection fraction (EF), end systolic volume (ESV) and stroke volume (SV) (P> 0.05). IDCM and PPCM group both showed ventricular wall thinning on MRI, with 4 cases of PPCM and 3 cases of IDCM presenting hypertrabeculation in the left ventricular apex. Seven cases of PPCM and 4 cases of IDCM depicted left ventricular local dysfunction, while 3 cases of PPCM and 6 cases of IDCM had abnormal integral movement. Two cases of PPCM appeared local delayed enhancement, while 4 cases of IDCM showed intramural delayed enhancement. After one year of follow-up, heart function recovered in 10 cases of PPCM and 4 cases of IDCM. Conclusions MRI diagnosis using multiple sequences is an ideal method in the evaluation of PPCM. Although there were no differences in cardiac morphology and function between PPCM and IDCM, the prognosis of PPCM is better than IDCM. Key words: Magnetic resonance imaging; Cardiomyopathies; Diagnosis