BS37 Investigation of the role of PMCA1 in heart failure with preserved ejection fraction

Accounting for nearly 50% of all heart failure cases, the prevalence of heart failure with preserved ejection fraction (HFpEF) is increasing. HFpEF patients will often present with typical heart failure symptoms including shortness of breath, fatigue, swollen ankles and legs, while echocardiography shows a normal left ventricular (LV) ejection fraction (EF) >=50%. Clinical studies have demonstrated that HFpEF is strongly associated with comorbidities such as hypertension, diabetes mellitus and obesity. Unlike heart failure with reduced ejection fraction (HFrEF), current treatments and therapies are ineffective, leading to relatively high hospitalization and mortality. It is therefore important that we gain a deeper understanding of the pathophysiological mechanisms underlying the development of HFpEF to help identify a more effective phenotype-specific treatment. We hypothesise that plasma membrane calcium ATPase 1 (PMCA1), a gene that we have shown to be critical in the development of raised blood pressure with ageing, will be key to the progression of HFpEF. This project aims to investigate the molecular mechanisms underlying the development of HFpEF and the role of PMCA1 in its progressive development. To test this hypothesis, a hypertensive and metabolic disease mouse model (two-hit model) was used to recapitulate typical human symptoms. 6-week-old male PMCA1 heterozygous global knockout mice (PMCA1Ht) and WT littermates were fed a 60% high fat diet (HFD) with 0.6 g/L Nw-nitro-L-arginine methyl ester (L-NAME) in the drinking water. To diagnose HFpEF in mice, blood pressure (BP), echocardiography, and unconscious electrocardiography (ECG) were measured at intervals to assess the cardiovascular function. Intravenous glucose tolerance test (IGTT) was performed to assess the glucose metabolic capacity and to determine if mice were developing diabetes. Mice were also subjected to an exercise tolerance test to determine if they display exercise incapability. We observed that after 5 weeks of feeding, both systolic and diastolic BP increased in HFD+L-NAME fed mice. After 15 weeks of HFD+L-NAME feeding, both SBP and DBP were significantly higher in PMCA1Ht mice compared with WT control. However, this phenomenon was not found on standard chow diet fed mice. Following 20 weeks of HFD+L-NAME feeding, mice displayed diastolic dysfunction with an increased E/E' ratio was apparent by echocardiography. This was coupled with a trend towards decreasing isovolumic relaxation time (IVRT) and increasing left ventricle diastolic time (DT), indicative of worsening diastolic function. Moreover, mice showed impaired exercise capacity after 20 weeks of HFD+L-NAME feeding, with reduced running distance and time. Mice of both genotypes on the HFD+L-NAME started to show damaged glucose metabolic ability after 10 weeks of HFD+L-NAME feeding. Interestingly, PMCA1Ht mice demonstrated better glucose metabolic ability after 20 weeks of feeding, indicating that PMCA1 might influence the glucose metabolism. To date, this study indicates that PMCA1 might play a role in HFpEF progression by influencing blood pressure regulation and glucose metabolic capacity. Future work will focus on unveiling the molecular mechanism underlying these phenotypic changes, which may provide a better understanding of the progression of HFpEF. Conflict of Interest No conflict of Interest