Dapagliflozin Treatment and Cardiovascular Outcome in Rbp4/Ttrval30met (Attr-Ca, Transthyretin Cardiac Amyloidosis) Mice

Aim: To investigate the cardiovascular prognosis in ATTR-CA (transthyretin cardiac amyloidosis) mice model with dapagliflozin treatment.Methods: Humanized RBP4/TTRVal50Met and RBP4/TTR mice models were constructed with CRISPR-Cas9 techniques and multiple generations breeding. A total of 6 RBP4/TTR mice received placebo treatment, when 12 RBP4/TTRVal50Met received dapagliflozin (1mg/kg/d, 6 mice) and placebo (6 mice) treatment. Fasting glucose, intraperitoneal glucose tolerance test (IPGTT), and plasma BNP concentration were measured at day 0 (D0), week 2, week 4. BNP, TGF-β, COL1A1 protein levels, and Cola1, TGFβ1, TNFα, IL-1β, BNP relative quantities in cardiac, along with cardiac pathology examination including right ventricular collagen percentage, ventricular septum thickness, left ventricular wall thickness, left ventricular internal diameter were measured at week 4 after treatment procedure.Results: All 18 mice completed the experiment. In placebo treated mice, the cardiac BNP relative quantity was significantly higher in RBP4/TTRVal50Met mice than RBP4/TTR mice. In ATTR-CA mice, the cardiovascular prognosis measurements including heart failure, cardiac inflammation and pathological changes were statistically comparable between those under dapagliflozin and placebo treatment.Conclusion: The results were not in support of dapagliflozin’s therapeutic effects for ATTR-CA. More pre-clinical and clinical researches to validate these findings and demonstrate the underlying mechanisms are still required.