Molecular mechanisms and therapy concepts in peripartum heart failure

• Applicant: Privatdozentin Dr. Melanie Ricke-Hoch, since 2/2021
• Subject Area: Cardiology, Angiology
• Term: from 2016 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 286251789

Peripartum cardiomyopathy (PPCM) occurs in previously healthywomen towards the end of pregnancy or in the months followingdelivery. The etiology of PPCM is unknown but some PPCM patientscarry gene variants in titin, MYH7 and MYBPC3 associated withcardiomyopathy, others have cancer disease or pre-eclampsia. Acommon pathomechanistic pathway of PPCM seems to includeenhanced oxidative stress and the subsequent generation of acleaved prolactin fragment (16 kDa prolactin), which promotes heartfailure via vascular damage. Prolactin blockade with bromocriptine incombination with anticoagulation and standard heart failure therapysupports healing and was included in the guidelines for the treatmentof PPCM. In turn, the use of beta-adrenergic agonists like dobutamineduring acute peripartum heart failure or in cardiogenic shock seems topromote cardiac damage and progression to terminal heart failure.Further physiological analyses of cardiomyocytes from PPCM patientsshowed enhanced sarcomeric Ca2+ sensitivity. Moreover, long-termfollow-up studies demonstrated that many PPCM patients requirelong-term heart medication suggesting ongoing pathologies. Inaddition, PPCM patients have a 15-fold higher risk for cancer diseaseprior and after PPCM. Based on the different pathologies associatedwith PPCM and the long-term need for cardiovascular medication, wehypothesize that PPCM patients need a high extent of personalizedmedicine to target their specific disease entity. In particular, thegenetic condition of patients and its potential role for additionalmorbidities such as cancer will be investigated with the aim to identifybiomarkers, find strategies for optimized treatment and with thissustainable healing. In project part 1, we will focus on gene variantsassociated with cardiomyopathy in PPCM patients and their influenceon the regulation of the dopamine receptor system, the Ca2+sensitivity and the different adenylate cyclases in PPCM. We willinvestigate how these conditions are influenced by specific heartfailure medications. In project part 2, we will investigate why PPCMpatients have an increased cancer risk and whether there is apathophysiological connection between cancer and PPCM at thegenetic level. Hereby, we will analyze whether gene variantsassociated with cardiomyopathies and/or with increased cancer riskper se or in addition with long-term side effects of cancer therapiesare causative for PPCM. A specific focus will be on genes involved inthe cardiac DNA damage response (DDR) system. A potential role ofthe DDR for PPCM will also be analyzed in project part 1. Takentogether, it is our aim to establish personalized diagnostic and therapeutic treatment strategies for PPCM patients considering theirdifferent genetic predispositions and comorbidities, to enableimproved and sustainable healing for these young mothers.

• DFG Programme: Clinical Research Units
• Subproject of: KFO 311: Cardiac and pulmonary failure: mechanical unloading andrepair
• Ehemalige Antragstellerin: Professorin Dr. Denise Hilfiker-Kleiner, until 2/2021