16
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      Rationale and design of a randomized, controlled multicentre clinical trial to evaluate the effect of bromocriptine on left ventricular function in women with peripartum cardiomyopathy

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Background

          Peripartum cardiomyopathy (PPCM) is an idiopathic heart disease that develops in the last month of pregnancy and/or the first months following delivery in previously healthy women and may lead to acute heart failure. A cleaved fragment of the nursing hormone prolactin is considered essential in the pathophysiology of PPCM. To date, no specific therapy has been tested for PPCM in a randomized controlled trial of adequate size.

          Aims

          The purpose of this trial is to investigate the safety of the dopamin-D2-receptor agonist bromocriptine and its effects on left ventricular (LV) function in women with PPCM.

          Methods

          This is an 11 center German trial with a prospective randomized controlled open-label design. The trial enrolls females with newly diagnosed PPCM according to European Society of Cardiology criteria with a LV ejection fraction (LVEF) <35 %. Patients are randomized 1:1 to either best supportive care (BSC) including standard heart failure therapy plus 8 weeks of bromocriptine therapy (2.5 mg b.i.d. for 14 days and 2.5 mg q.d. from day 15 to 56) or to BSC plus 1 week of low-dose bromocriptine (2.5 mg q.d.) with anticoagulant therapy at a prophylactic dose administered during the period of bromocriptine treatment in both groups. The primary endpoint is change in LVEF from baseline to 6 months follow-up as assessed by cardiac magnetic resonance imaging (or echocardiography if CMR is not tolerated). The secondary endpoints are hospitalization for worsening heart failure, heart transplantation, and all-cause mortality during follow-up or a combination of these endpoints. A total of 60 patients will be recruited (including 6 potential dropouts) giving a power of 0.9 for an expected LVEF change of 10.8 % between treatment groups at 6 months.

          Perspective

          This trial will provide important knowledge on potential benefits and safety of prolonged inhibition of prolactin release with bromocriptine in addition to standard heart failure therapy in newly diagnosed PPCM.

          Trial registration: ClinicalTrials.gov Identifier: NCT00998556.

          Related collections

          Most cited references18

          • Record: found
          • Abstract: found
          • Article: not found

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

          Peripartum cardiomyopathy (PPCM) is a life-threatening pregnancy-associated cardiomyopathy in previously healthy women. Although PPCM is driven in part by the 16-kDa N-terminal prolactin fragment (16K PRL), the underlying molecular mechanisms are poorly understood. We found that 16K PRL induced microRNA-146a (miR-146a) expression in ECs, which attenuated angiogenesis through downregulation of NRAS. 16K PRL stimulated the release of miR-146a-loaded exosomes from ECs. The exosomes were absorbed by cardiomyocytes, increasing miR-146a levels, which resulted in a subsequent decrease in metabolic activity and decreased expression of Erbb4, Notch1, and Irak1. Mice with cardiomyocyte-restricted Stat3 knockout (CKO mice) exhibited a PPCM-like phenotype and displayed increased cardiac miR-146a expression with coincident downregulation of Erbb4, Nras, Notch1, and Irak1. Blocking miR-146a with locked nucleic acids or antago-miRs attenuated PPCM in CKO mice without interrupting full-length prolactin signaling, as indicated by normal nursing activities. Finally, miR-146a was elevated in the plasma and hearts of PPCM patients, but not in patients with dilated cardiomyopathy. These results demonstrate that miR-146a is a downstream-mediator of 16K PRL that could potentially serve as a biomarker and therapeutic target for PPCM.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Peripartum cardiomyopathy: National Heart, Lung, and Blood Institute and Office of Rare Diseases (National Institutes of Health) workshop recommendations and review.

            Peripartum cardiomyopathy (PPCM) is a rare life-threatening cardiomyopathy of unknown cause that occurs in the peripartum period in previously healthy women. In April 1997, the National Heart, Lung, and Blood Institute (NHLBI) and the Office of Rare Diseases of the National Institutes of Health (NIH) convened a Workshop on Peripartum Cardiomyopathy to foster a systematic review of information and to develop recommendations for research and education. Fourteen workshop participants were selected by NHLBI staff and represented cardiovascular medicine, obstetrics, immunology, and pathology. A representative subgroup of 8 participants and NHLBI staff formed the writing group for this article and updated the literature on which the conclusions were based. The workshop was an open meeting, consistent with NIH policy. Data presented at the workshop were augmented by a MEDLINE search for English-language articles published from 1966 to July 1999, using the terms peripartum cardiomyopathy, cardiomyopathy, and pregnancy. Articles on the epidemiology, pathogenesis, pathophysiology, diagnosis, treatment, and prognosis of PPCM were included. RECOMMENDATION PROCESS: After discussion of data presented, workshop participants agreed on a standardized definition of PPCM, a general clinical approach, and the need for a registry to provide an infrastructure for future research. Peripartum cardiomyopathy is a rare lethal disease about which little is known. Diagnosis is confined to a narrow period and requires echocardiographic evidence of left ventricular systolic dysfunction. Symptomatic patients should receive standard therapy for heart failure, managed by a multidisciplinary team. If subsequent pregnancies occur, they should be managed in collaboration with a high-risk perinatal center. Systematic data collection is required to answer important questions about incidence, treatment, and prognosis.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Phenotyping and outcome on contemporary management in a German cohort of patients with peripartum cardiomyopathy

              Peripartum cardiomyopathy (PPCM) is a life-threatening heart disease developing towards the end of pregnancy or in the months following delivery in previously healthy women in terms of cardiac disease. Enhanced oxidative stress and the subsequent cleavage of the nursing hormone Prolactin into an anti-angiogenic 16 kDa subfragment emerged as a potential causal factor of the disease. We established a prospective registry with confirmed PPCM present in 115 patients (mean baseline left ventricular ejection fraction, LVEF: 27 ± 9 %). Follow-up data (6 ± 3 months) showed LVEF improvement in 85 % and full recovery in 47 % while 15 % failed to recover with death in 2 % of patients. A positive family history of cardiomyopathy was present in 16.5 %. Pregnancy-associated hypertension was associated with a better outcome while a baseline LVEF ≤ 25 % was associated with a worse outcome. A high recovery rate (96 %) was observed in patients obtaining combination therapy with beta-blocker, angiotensin-converting enzyme (ACE) inhibitors/angiotensin-receptor-blockers (ARBs) and bromocriptine. Increased serum levels of Cathepsin D, the enzyme that generates 16 kDa Prolactin, miR-146a, a direct target of 16 kDa Prolactin, N-terminal-pro-brain-natriuretic peptide (NT-proBNP) and asymmetric dimethylarginine (ADMA) emerged as biomarkers for PPCM. In conclusion, low baseline LVEF is a predictor for poor outcome while pregnancy-induced hypertensive disorders are associated with a better outcome in this European PPCM cohort. The high recovery rate in this collective is associated with a treatment concept using beta-blockers, ACE inhibitors/ARBs and bromocriptine. Increased levels of Cathepsin D activity, miR-146a and ADMA in serum of PPCM patients support the pathophysiological role of 16 kDa Prolactin for PPCM and may be used as a specific diagnostic marker profile. Electronic supplementary material The online version of this article (doi:10.1007/s00395-013-0366-9) contains supplementary material, which is available to authorized users.
                Bookmark

                Author and article information

                Contributors
                +49-511-532-5402 , haghikia.arash@mh-hannover.de
                Journal
                Clin Res Cardiol
                Clin Res Cardiol
                Clinical Research in Cardiology
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                1861-0684
                1861-0692
                31 May 2015
                31 May 2015
                2015
                : 104
                : 11
                : 911-917
                Affiliations
                [ ]Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
                [ ]Department of Cardiology and Angiology, University Hospital Muenster, Muenster, Germany
                [ ]Department of Internal Medicine I, Comprehensive Heart Failure Center, University Hospital of Wuerzburg, Würzburg, Germany
                [ ]Department of Internal Medicine III, University Hospital of Saarland, Homburg/Saar, Germany
                Article
                869
                10.1007/s00392-015-0869-5
                4623094
                26026286
                5de0c011-e185-4098-add5-fb0312f64768
                © The Author(s) 2015

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 2 April 2015
                : 13 May 2015
                Categories
                Trial Design
                Custom metadata
                © Springer-Verlag Berlin Heidelberg 2015

                Cardiovascular Medicine
                peripartum cardiomyopathy,bromocriptine,prolactin,heart failure
                Cardiovascular Medicine
                peripartum cardiomyopathy, bromocriptine, prolactin, heart failure

                Comments

                Comment on this article