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Cardioprotective Effects of Rivaroxaban on Cardiac Remodeling After Experimental Myocardial Infarction in Mice.

ABSTRACT: Background: Direct-activated factor X (FXa) plays an important role in thrombosis and is also involved in inflammation via the protease-activated receptor (PAR)-1 and PAR-2 pathway. We hypothesized that rivaroxaban protects against cardiac remodeling after myocardial infarction (MI). Methods and Results: MI was induced in wild-type mice by permanent ligation of the left anterior descending coronary artery. At day 1 after MI, mice were randomly assigned to the rivaroxaban and vehicle groups. Mice in the rivaroxaban group were provided with a regular chow diet plus rivaroxaban. We evaluated cardiac function by echocardiography, pathology, expression of mRNA and protein at day 7 after MI. Rivaroxaban significantly improved cardiac systolic function, decreased infarct size and cardiac mass compared with the vehicle. Rivaroxaban also downregulated the mRNA expression levels of tumor necrosis factor-α, transforming growth factor-β, PAR-1 and PAR-2 in the infarcted area, and both A-type and B-type natriuretic peptides in the non-infarcted area compared with the vehicle. Furthermore, rivaroxaban attenuated cardiomyocyte hypertrophy and the phosphorylation of extracellular signal-regulated kinase in the non-infarcted area compared with the vehicle. Conclusions: Rivaroxaban protected against cardiac dysfunction in MI model mice. Reduction of PAR-1, PAR-2 and proinflammatory cytokines in the infarcted area may be involved in its cardioprotective effects.

SUBMITTER: Nakanishi N

PROVIDER: S-EPMC7921351 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Objective---Arteriovenous fistulae (AVF) placed for hemodialysis have high flow rates that can stimulate left ventricular (LV) hypertrophy. LV hypertrophy generally portends poor cardiac outcomes, yet clinical studies point to superior cardiac-specific outcomes for patients with AVF when compared to other dialysis modalities. We hypothesize that AVF induce physiologic cardiac hypertrophy with cardioprotective features.Methods---9-11 week C57Bl/6 male and female mice were treated with sham laparotomy or an aortocaval fistula via a 25Ga needle. Cardiac chamber size and function were assessed with serial echocardiography, and cardiac CTA. Hearts were harvested at 5 weeks post-operatively, and collagen content assessed with Masson's trichrome. Bulk mRNA sequencing was performed from LV of sham and AVF mice at 10 days. Differentially expressed genes were analyzed using Ingenuity Pathway Analysis (Qiagen) to identify affected pathways and predict downstream biological effects.Results---Mice with AVF had similar body weight and wet lung mass, but increased cardiac mass compared to sham-operated mice. AVF increased cardiac output while preserving LV systolic and diastolic function, as well as indices of right heart function; all 4 cardiac chambers were enlarged, with slight decrement in relative LV wall thickness. Histology showed preserved collagen density within each of the 4 chambers without areas of fibrosis. RNA sequencing captured 19,384 genes, of which 857 were significantly differentially expressed, including transcripts from extracellular matrix-related genes, ion channels, metabolism, and cardiac fetal genes. Top upstream regulatory molecules predicted include activation of angiogenic (Vegf, Akt1), pro-cardiomyocyte survival (Hgf, Foxm1, Erbb2, Lin9, Areg), and inflammation-related (CSF2, Tgfb1, TNF, Ifng, Ccr2, IL6) genes, as well as the inactivation of cardiomyocyte antiproliferative factors (Cdkn1a, FoxO3, α-catenin). Predicted downstream effects include reduction to heart damage, and increased arrhythmia, angiogenesis, and cardiogenesis. There were no significant sex-dependent differences in the AVF-stimulated cardiac adaptation.Conclusions---AVF stimulate adaptive cardiac hypertrophy in wild-type mice without heart failure or pathological fibrosis. Transcriptional correlates suggest AVF-induced cardiac remodeling has some cardioprotective, although also arrhythmogenic features.

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Cardioprotective Effects of Rivaroxaban on Cardiac Remodeling After Experimental Myocardial Infarction in Mice.

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