Abstract: TH-PO156
Etelcalcetide Improves Cardiac Dysfunction in Mice on a High Phosphate Diet
Session Information
- CKD-MBD: Targets and Outcomes
November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Bone and Mineral Metabolism
- 401 Bone and Mineral Metabolism: Basic
Authors
- Leifheit-Nestler, Maren, Hannover Medical School, Hannover, Germany
- Vogt, Isabel, Hannover Medical School, Hannover, Germany
- Grund, Andrea, Hannover Medical School, Hannover, Germany
- Richter, Beatrice, Hannover Medical School, Hannover, Germany
- Haffner, Dieter, Hannover Medical School, Hannover, Germany
Background
High phosphate levels stimulate the synthesis of the phosphaturic hormone parathyroid hormone (PTH) and fibroblast growth factor (FGF) 23 and are associated with increased cardiovascular morbidity and mortality. In the secondary analysis of the EVOLVE trial, cinacalcet significantly reduced levels of PTH and FGF23 in patients on hemodialysis, and the latter was associated with a lower rate of cardiovascular events and death. Intravenous administration of etelcalcetide reduced FGF23 and improved the progression of left ventricular (LV) hypertrophy in hemodialysis patients. In the present study, we examined the specific cardiac effects of etelcalcetide in mice on a high phosphate diet (HPD).
Methods
After four months on a 2% HPD, male C57BL/6N mice were additionally treated with 1 mg/kg body weight/day etelcalcetide (KP-2326) via osmotic minipumps for two more months and compared to mice receiving HPD with vehicle or a 0.8% normal phosphate diet (NPD). The heart function was examined by echocardiography and parameters of the mineral metabolism were determined.
Results
Compared to the NPD group, mice on HPD had significantly higher serum phosphate, FGF23 and PTH levels and increased phosphaturia, which was associated with progressive kidney injury. Mice on HPD show a dilated left ventricle with decreased anterior and posterior wall thickness and increased LV end-systolic and end-diastolic diameters and volumes. Ejection fraction and fractional shortening were reduced in mice on HPD, indicating impaired systolic function. Etelcalcetide reduced HPD-induced FGF23 and PTH levels by 80% and 75%, respectively, and resulted in a significant reduction in serum calcium levels, but had no effect on persistent hyperphosphatemia and phosphaturia. Etelcalcetide effectively ameliorated the HPD-induced LV dilatation and systolic dysfunction.
Conclusion
In mice, HPD leads to hyperphosphatemia and high plasma FGF23 and PTH concentrations with subsequent LV dilatation and systolic dysfunction. Administration of etelcalcetide effectively prevents the HPD-induced pathological cardiac phenotype despite the presence of hyperphosphatemia, which is at least partly due to the normalization of the high plasma FGF23 and PTH levels.
Funding
- Commercial Support –