#977 Etelcalcetide improve left ventricular hypertrophy by suppressing the renin-angiotensin-aldosterone system and cardiac fibroblast growth factor 23

Abstract Background and Aims Calcimimetics are allosteric activators of the calcium-sensing receptor (CaSR) and are employed as therapeutic agents for managing secondary hyperparathyroidism in chronic kidney disease (CKD) patients undergoing dialysis. Although they have shown potential in reducing cardiovascular diseases and suppressing left ventricular hypertrophy (LVH), the mechanisms underlying these effects are not fully elucidated. In this study, we focused on exploring the mechanisms behind the suppression of LVH by calcimimetics using CKD, LVH, and CKD+LVH model rats. Specifically, we investigated the impact on CKD-mineral bone disorder (CKD-MBD) parameters, the renin-angiotensin-aldosterone system (RAAS), and calcineurin/nuclear factor of activated T cells (CaN/NFAT) pathway. Method In this study, we used etelcalcetide (ET) as a calcimimetic agent. At 8 weeks of age, LVH was induced in rats through transverse aortic coarctation, and CKD was induced by 5/6 nephrectomy at 9 and 10 weeks of age. The rats were divided into the four main groups: the sham group, the CKD group, the LVH group, and the CKD+LVH group. Each of the latter three groups were further subdivided into a vehicle-treated group and an ET-treated group for a duration of eight weeks. At 19 weeks of age, echocardiography was conducted on all rats prior to sacrifice. Subsequently, the rats were sacrificed, and blood and urine analyses, mRNA expression analysis, and renal histological analysis were performed. We evaluated LVH, CKD-MBD, RAAS, and CaN/NFAT pathways across these seven groups. Results In both the CKD and CKD+LVH groups, serum levels of parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) were significantly elevated, and these elevations were mitigated by ET. However, in the LVH group, serum PTH and FGF23 levels were not elevated, and ET did not induce any changes. No significant alterations in serum levels of phosphorus, calcium, 25(OH)vitamin, and 1,25(OH)2vitaminD levels due to ET were observed in any of the groups. Interestingly, ET suppressed the increase in myocardial weight/body weight ratios and the area of cardiomyocytes not only in the CKD and CKD+LVH group but also in the LVH group, despite no changes in serum PTH and FGF23 levels. Regarding the RAAS, ET attenuated the increase in serum aldosterone levels, expressions of cardiac angiotensin-converting enzyme (ACE), cardiac angiotensinogen, and cardiac angiotensin II in the LVH group and the CKD+LVH group. The expression of cardiac FGF23, which increased in the LVH group and the CKD+LVH group, was decreased by ET. Moreover, there was a significant correlation between cardiac RAAS parameters and cardiac FGF23 expressions. No alteration was observed in the CaN/NFAT pathway in response to ET. Conclusion Our findings indicated that ET effectively suppressed LVH in the CKD group and the CKD+LVH group, and it was also effective in the LVH group, independent of changes in serum CKD-MBD parameters. This suggests that ET may exert its LVH-suppressing effects through the RAAS pathway and cardiac FGF23.