Single nucleotide polymorphisms and their association with QTc and left ventricular function in peripartum cardiomyopathy
Authors: Shaboodien G , Viljoen C , Ndibangwi P , Hovelmann J , Pearce L , Haidari S , Kotta M C , Dagradi F , Spazzolini C , Kraus S , Ntusi N , Schwartz P , Sliwa K 
Published: November 2023

Abstract

Background
Peripartum cardiomyopathy (PPCM) is a form of pregnancy-associated heart failure that affects previously healthy women toward the end of pregnancy or in the months following delivery. PPCM is associated with left ventricular (LV) non-recovery in about half of patients, with 10% dying within the first year after diagnosis. Recent clinical investigations have also shown that about 50% of patients with PPCM have a prolonged QTc at presentation, which was a predictor of poor outcome (death, readmission, persistent poor LV function) by 6 months. The mechanism of QT prolongation in PPCM, however, remains poorly understood. In this study, we tested the hypothesis that SNPs, known to be associated with long QT syndrome (LQTS), could be used to predict the QT intervals in patients with PPCM.

Methods
We recruited forty-three patients with PPCM and genotyped them for 12 single nucleotide polymorphisms (SNPs) known to have an association with the QT interval: AGT (rs699); NOS1AP (rs16847548); CYP11B2 (rs1799998); NOS1AP (rs4657139); AKAP9 (rs7808587); AKAP9 (rs2961024); AKAP9 (rs11772585); AGTR1 (rs5186); AKAP9 (rs2282972); KCNQ1 (rs2074238); KCNH2 (rs1805123); ACE (rs4646994). These variants were correlated with clinical and echocardiographic parameters, as well as the QT interval, as corrected by the Bazett’s formula (QTcB).

Results
The median age of this cohort was 30.4 years (IQR 25.3-34.9). More than half (74%) of patients presented with a New York Heart Association (NYHA) functional class III or IV. Overall, the median LVEDD at presentation was 58mm (IQR 53-63), LVEF 31% (IQR 24-36) and QTcB (in lead V3) 450ms (IQR 429-476). SNP analysis showed that 40% of the PPCM cohort that had the NOS1AP (rs16847548) variant were associated with significantly longer QTc in V3 (471ms [443-480] vs 441ms [426-458], p=0.028; the NOS1AP (rs16847548) variant was also associated with both prolonged QTc and LVEF &lt; 35% (47.1 vs 15.4%, p=0.024). Our results also showed that PPCM patients with the AKAP9 (rs2282972) variant had a shorter QTc in lead II (468ms [425-490] vs 431ms [415.0-459.5], p=0.012), a smaller LVEDD (63.0 [57.0-67.5] vs 57.0 [53.0-59.5]; p= 0.022) and were likely to have both a shorter QTc and LVEF &lt; 35% (57.1 vs 24.1, p=0.033). None of the other SNPs showed any significance.

Conclusion
Our study found that, in a cohort of PPCM patients, the NOS1AP (rs16847548) variant is associated with a prolonged QTc and the AKAP9 (rs2282972) variant is associated with a shorter QTc interval. As prolonged QTc and severely impaired LV function are well-known predictors of poor outcome, we postulate that NOS1AP could be used a marker of outcome in PPCM patients. We also postulate that the AKAP9 variant, known to be associated with a decreased risk for a cardiac event, might also indicate a decreased the risk in a certain subset of our PPCM patients. However, a larger study is needed to determine whether these SNPs may have a prognostic value in PPCM.