Increased Cancer Prevalence in Peripartum Cardiomyopathy

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.

Graphical abstract

Figure 1

Cardiac Status at 7 ± 2 Months Follow-Up in PPCM Patients Stratified According to Cancer Diagnosis Cardiac status at 7 ± 2 months follow-up in PPCM patients stratified according to cancer diagnosis. Comparison of cardiac status at 7 ± 2 months follow-up in PPCM patients without cancer and with cancer before and after PPCM (A), and in PPCM patients who had cancer before PPCM (B). Red column = nonrecovery (LVEF ≤35%, HTX, LVAD implantation, or death); yellow column = partial recovery (LVEF >35% to 49%); green column = full recovery (LVEF ≥50%). The p values were calculated using chi square test; *p < 0.05. HTX = heart transplantation; LVAD = left ventricular assist device; LVEF = left ventricular ejection fraction; PPCM = peripartum cardiomyopathy.

Central Illustration

Potential Connections Among Cancer, Cancer Therapies, and the Genetic Predisposition for Cardiomyopathy and Cancer in PPCM Patients DNA damage plays a central role in the development of cancer and also contributes to the development of heart failure. Mutations associated with cardiomyopathy render the heart more sensitive to stress induced by cardiotoxic treatment and pregnancy. Therefore, patients with mutations associated with DDR have a significantly elevated risk of developing cancer. Exposure to cardiotoxic cancer therapy, which either alone or in combination with mutations associated with DCM/HCM increases the risk for developing PPCM. Furthermore, heart failure may promote early onset cancer in CPS mutation carriers and thereby can explain, at least in part, the higher cancer risk in patients after PPCM. CPS = cancer predisposition syndrome; DCM = dilated cardiomyopathy; DDR = DNA damage response; HCM = hypertrophic cardiomyopathy; PPCM = peripartum cardiomyopathy.