Factor Xa Inhibition with Apixaban Does Not Influence Cardiac Remodelling in Rats with Heart Failure After Myocardial Infarction

Abstract

Background Heart failure (HF) is considered to be a prothrombotic condition and it has been suggested that coagulation factors contribute to maladaptive cardiac remodelling via activation of the protease-activated receptor 1 (PAR1). We tested the hypothesis that anticoagulation with the factor Xa (FXa) inhibitor apixaban would ameliorate cardiac remodelling in rats with HF after myocardial infarction (MI). Methods and Results Male Sprague-Dawley rats were either subjected to permanent ligation of the left ascending coronary artery (MI) or sham surgery. The MI and sham animals were randomly allocated to treatment with placebo or apixaban in the chow (150 mg/kg/day), starting 2 weeks after surgery. Cardiac function was assessed using echocardiography and histological and molecular markers of cardiac hypertrophy were assessed in the left ventricle (LV). Apixaban resulted in a fivefold increase in anti-FXa activity compared with vehicle, but no overt bleeding was observed and haematocrit levels remained similar in apixaban-and vehicle-treated groups. After 10 weeks of treatment, LV ejection fraction was 42 ± 3% in the MI group treated with apixaban and 37 ± 2 in the vehicle-treated MI group (p > 0.05). Both vehicle-and apixaban-treated MI groups also displayed similar degrees of LV dilatation, LV hypertrophy and interstitial fibrosis. Histological and molecular markers for pathological remodelling were also comparable between groups, as was the activity of signalling pathways downstream of the PAR1 receptor. Conclusion FXa inhibition with apixaban does not influence pathological cardiac remodelling after MI. These data do not support the use of FXa inhibitor in HF patients with the aim to amend the severity of HF.

Ketone Ester Treatment Improves Cardiac Function and Reduces Pathologic Remodeling in Preclinical Models of Heart Failure

“…HF or sham surgery was performed under isoflurane (2.5%) inhalation anesthesia as described previously. 28 , 29 After left-sided thoracotomy, HF was induced by permanent ligating of the proximal portion of the left coronary. Sham-operated rats underwent the same procedure but without the actual ligation.…”

The erythropoietin receptor expressed in skeletal muscle is essential for mitochondrial biogenesis and physiological exercise

“…Following fixation and embedding processes, sections were cut using a microtome and were thereafter processed onto slides. To determine (cardio) myocyte cross sectional area, deparaffinised 3-μm thick sections were stained with 4′,6-diamidino-2-phenylindole (DAPI) (Vector Laboratories, USA) and wheat germ agglutinin (WGA) (Sigma-Aldrich, USA), as described before [60]. Stained transverse sections were visualised with fluorescence microscopy to generate images for analysis (Zeiss KS400, Germany).…”

Suppression of Heart Failure With PAR1 Pepducin Technology in a Pressure Overload Model in Mice

“…14,15 Moreover, forced overexpression of PAR1 in myocytes leads to hypertrophy and impaired left ventricle (LV) function in aged mice. 16 Targeting upstream PAR1 protease agonists with potent anticoagulants against thrombin (ie, dabigatran), which has shown benefit in rodent HF models, 17 or Xa (activated coagulation factor 10) inhibitors (ie, rivaroxaban or apixaban), which have produced equivocal results, 18,19 have shown no clear clinical benefit in improving HF with reduced ejection fraction outcomes 20 including in the large >5000 patient Commander-HF trial. 21 Alternatively, other noncanonical PAR1 agonists, such as MMP1 (matrix metalloprotease-1) 22 and MMP13, 23 may mediate PAR1-dependent cardiac remodeling in HF (Figure 1A).…”