Introduction Coronary artery disease (CAD) and its main consequence-myocardial infarction (MI) are the UK’s biggest killers. Most of these deaths occur either acutely post-MI or chronically as a result of pathological cardiac remodelling eventually leading to heart failure. Recent genome-wide association studies (GWAS) elucidated a potential link between the PMCA1 gene, atp2b1, and these diseases.

Objective PMCA1 has been shown to associate with many of the key features predisposing to the development of heart failure. Given the GWAS findings this study aims to investigate the potential role of PMCA1 in the post-MI remodelling process.

Methods Moderate and severe MI via permanent ligation of the LAD coronary artery, alongside a sham procedure was induced in either wild type or mice expressing a heterozygous mutation of the PMCA1 gene (PMCA1^Ht). Occurrence of ischemia was confirmed by evaluation of plasma levels of cardiac troponin I (cTnI) and histologically. Post-surgery the animals were kept for either 1 or 4 weeks. Electrocardiography (ECG) and echocardiography were performed in vivo to assess cardiac function. To further characterise the cardiac response in vitro, histological analysis was performed at both time points.

Results 24 hours post LAD coronary artery ligation a significant increase in the plasma cTnI levels was recorded in both WT and PMCA1^Ht mice. However, overall survival 4 weeks post-surgery was significantly lower in WT-MI mice when compared to PMCA1^Ht-MI mice and both WT and PMCA1^Ht sham control groups. In addition, a significant difference in infarct size was observed when WT-MI hearts were compared to their PMCA1^Ht counterparts 1 week post-surgery. Interestingly, whilst both WT and PMCA1^Ht MI-treated mice showed a significant deterioration in cardiac function 1 week post-surgery there were differences seen in cardiac structure between the two groups. For example, echocardiography revealed that the WT-MI hearts were significantly more hypertrophic when compared to their PMCA1^Ht counterparts shown by a significant increase in the LV diameters alongside a significant difference in the normalised heart weight to tibia length ratios. ECG revealed significantly longer QT intervals and considerably more extra-systolic events among the WT-MI mice. Whilst histological analysis of cardiomyocyte size showed a significantly exacerbated hypertrophic response in the remote regions of WT-MI mice compared to PMCA1^Ht-MI mice.

Conclusion Heterozygous deletion of PMCA1 might serve a protective role in the heart following both moderate and severe MI. The protective mechanism most likely develops in the early post-operative phase, as an MI of similar extent is associated with higher mortality rates in WT mice. Future work will aim to elucidate the mechanism producing this phenotype mainly focusing on the potential role that PMCA1 might serve in the process.