Why the study?
It was unknown whether early initiation of dapagliflozin or combining dapagliflozin with sacubitril-valsartan in different orders would exert greater cardioprotection than sacubitril-valsartan alone in post-myocardial infarction heart failure.
Does the sequential administration of dapagliflozin and sacubitril-valsartan improve cardiac function in a rat model of post-MI heart failure?
Does the sequential administration of dapagliflozin and sacubitril-valsartan improve cardiac function in a rat model of post-MI heart failure?
In a rat model of post-MI heart failure, initiating dapagliflozin first followed by sacubitril-valsartan two weeks later provided superior cardioprotection compared to the reverse sequence or monotherapy.
May support testing dapagliflozin before sacubitril-valsartan post-MI; hypothesis-generating for human sequencing trials.
Background: Based on previous research, both dapagliflozin (DAPA) and sacubitril-valsartan (S/V) improve the prognosis of patients with heart failure (HF). Our study aims to investigate whether the early initiation of DAPA or the combination of DAPA with S/V in different orders would exert a greater protective effect on heart function than that of S/V alone in post-myocardial infarction HF (post-MI HF). Methods: Rats were randomized into six groups: (A) Sham; (B) MI; (C) MI + S/V (1st d); (D) MI + DAPA (1st d); (E) MI + S/V (1st d) + DAPA (14th d); (F) MI + DAPA (1st d) + S/V (14th d). The MI model was established in rats via surgical ligation of the left anterior descending coronary artery. Histology, Western blotting, RNA-seq, and other approaches were used to explore the optimal treatment to preserve the heart function in post-MI HF. A daily dose of 1 mg/kg DAPA and 68 mg/kg S/V was administered. Results: The results of our study revealed that DAPA or S/V substantially improved the cardiac structure and function. DAPA and S/V monotherapy resulted in comparable reduction in infarct size, fibrosis, myocardium hypertrophy, and apoptosis. The administration of DAPA followed by S/V results in a superior improvement in heart function in rats with post-MI HF than those in other treatment groups. The administration of DAPA following S/V did not result in any additional improvement in heart function as compared to S/V monotherapy in rats with post-MI HF. Our findings further suggest that the combination of DAPA and S/V should not be administered within 3 days after acute myocardial infarction (AMI), as it resulted in a considerable increase in mortality. Our RNA-Seq data revealed that DAPA treatment after AMI altered the expression of genes related to myocardial mitochondrial biogenesis and oxidative phosphorylation. Conclusions: Our study revealed no notable difference in the cardioprotective effects of singular DAPA or S/V in rats with post-MI HF. Based on our preclinical investigation, the most effective treatment strategy for post-MI HF is the administration of DAPA during the 2 weeks, followed by the addition of S/V to DAPA later. Conversely, adopting a therapeutic scheme whereby S/V was administered first, followed by later addition of DAPA, failed to further improve the cardiac function compared to S/V monotherapy.
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Tao et al. (2023) studied this question.
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