Increased Cancer Prevalence in Peripartum Cardiomyopathy

Tobias J Pfeffer; Stella Schlothauer; Stefan Pietzsch; Maria Schaufelberger; Bernd Auber; Melanie Ricke-Hoch; Manuel List; Dominik Berliner; Valeska Abou Moulig; Tobias König; Zolt Arany; Karen Sliwa; Johann Bauersachs; Denise Hilfiker-Kleiner

doi:10.1016/j.jaccao.2019.09.008

Increased Cancer Prevalence in Peripartum Cardiomyopathy

JACC CardioOncol. 2019 Dec 17;1(2):196-205. doi: 10.1016/j.jaccao.2019.09.008. eCollection 2019 Dec.

Affiliations

¹ Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
² Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
³ Department of Human Genetics, Hannover Medical School, Hannover, Germany.
⁴ Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁵ Hatter Institute for Cardiovascular Research in Africa, University of Cape Town, Cape Town, South Africa.

Abstract

Objectives: This study was designed to analyze the prevalence and potential genetic basis of cancer and heart failure in peripartum cardiomyopathy (PPCM).

Background: PPCM manifests as heart failure late in pregnancy or postpartum in women without previous heart disease.

Methods: Clinical history and cancer prevalence were evaluated in a cohort of 236 PPCM patients from Germany and Sweden. Exome sequencing assessed variants in 133 genes associated with cancer predisposition syndromes (CPS) and in 115 genes associated with dilated/hypertrophic cardiomyopathy (DCM/HCM) in 14 PPCM patients with a history of cancer, and in 6 PPCM patients without a history of cancer.

Results: The prevalence of cancer was 16-fold higher (8.9%, 21 of 236 patients) in PPCM patients compared to age-matched women (German cancer registry, Robert-Koch-Institute: 0.59%; p < 0.001). Cancer before PPCM occurred in 12 of 21 patients of whom 11 obtained cardiotoxic cancer therapies. Of those, 17% fully recovered cardiac function by 7 ± 2 months of follow-up compared to 55% of PPCM patients without cancer (p = 0.015). Cancer occurred after PPCM in 10 of 21 patients; 80% had left ventricular ejection fraction of ≥50% after cancer therapy. Whole-exome sequencing in 14 PPCM patients with cancer revealed that 43% (6 of 14 patients) carried likely pathogenic (Class IV) or pathogenic (Class V) gene variants associated with DCM/HCM in CPT2, DSP, MYH7, TTN, and/or with CPS in ATM, ERCC5, NBN, RECQL4, and SLX4. All CPS variants affected DNA damage response genes.

Conclusions: Cardiotoxic cancer therapy before PPCM is associated with delayed full recovery. The high cancer prevalence in PPCM is linked to likely pathogenic/pathogenic gene variants associated with DCM/HCM and/or CPS/DNA damage response-related cancer risk. This may warrant genetic testing and screening for heart failure in pregnant women with a cancer history and screening for cancer in PPCM patients.

Keywords: ATM, ataxia telangiectasia mutated; BMBF, Bundesministerium für Bildung und Forschung; BRCA1, breast cancer 1; CPS, cancer predisposition syndrome; DCM, dilated cardiomyopathy; DDR, DNA damage response; DFG, Deutsche Forschungsgesellschaft; ERCC5, excision repair cross-complementing rodent repair deficiency; FANCA, Fanconi anemia, complementation group; FKRP, fukutin-related protein; HCM, hypertrophic cardiomyopathy; HTX, heart transplantation; LVAD, left ventricular assist device; LVEF, left ventricular ejection fraction; PPCM, peripartum cardiomyopathy; RECQL4, ATP-dependent DNA helicase Q4; RYR1, ryanodine receptor 1; SLX4, structure-specific endonuclease subunit SLX4; TXNRD2, thioredoxin reductase 2; VUS, variants of unknown significance; cancer; cardiotoxicity; genetics; peripartum cardiomyopathy; whole-exome sequencing.