Direct oral anticoagulants for atrial fibrillation in early postoperative valve repair or bioprosthetic replacement.

OBJECTIVE: Despite increased use of direct oral anticoagulants (DOACs), limited evidence guides their use in the early postoperative period after bioprosthetic valve implantation in patients with atrial fibrillation. Our objective was to describe the efficacy and safety of DOACs and warfarin in the first 3 months after surgical bioprosthetic valve replacement or repair in patients with atrial fibrillation. METHODS: This was a retrospective, registry-informed cohort study of surgical patients who underwent bioprosthetic valve replacement or repair, had concomitant atrial fibrillation and received oral anticoagulation at discharge. The primary efficacy outcome was a composite of death, ischemic stroke, transient ischemic attack, and systemic embolism; the primary safety outcome was a composite of major bleeding. Key secondary outcomes were comparative analyses of primary outcomes, temporal anticoagulation prescribing patterns, and 30-day readmission rates. RESULTS: A total of 1743 patients were included. Of the 570 patients in the DOAC group, 17 (2%) met the composite efficacy outcome and 55 (10%) met the composite safety outcome. Of the 1173 patients receiving warfarin, 41 (3%) and 114 (10%) met the composite efficacy and safety outcomes, respectively. Comparative secondary analysis was not statistically significant for either the efficacy (adjusted odds ratio, 0.85; 95% confidence interval, 0.46-1.55, P = .59) or safety (adjusted odds ratio, 0.94; 95% confidence interval, 0.66-1.34, P = .76) outcomes. The 30-day readmission rates were similar between both groups. CONCLUSIONS: Our results suggest DOACs may be safe and effective alternatives to warfarin in the early postoperative period after valve repair or surgical bioprosthetic replacement. Confirmation awaits adequately powered prospective studies.

Doxorubicin induces de novo expression of N-terminal-truncated matrix metalloproteinase-2 in cardiac myocytes.

Anthracyclines, such as doxorubicin, are commonly prescribed antineoplastic agents that cause irreversible cardiac injury. Doxorubicin cardiotoxicity is initiated by increased oxidative stress in cardiomyocytes. Oxidative stress enhances intracellular matrix metalloproteinase-2 (MMP-2) by direct activation of its full-length isoform and (or) de novo expression of an N-terminal-truncated isoform (NTT-MMP-2). As MMP-2 is localized to the sarcomere, we tested whether doxorubicin activates intracellular MMP-2 in neonatal rat ventricular myocytes (NRVM) and whether it thereby proteolyzes two of its identified sarcomeric targets, α-actinin and troponin I. Doxorubicin increased oxidative stress within 12 h as indicated by reduced aconitase activity. This was associated with a twofold increase in MMP-2 protein levels and threefold higher gelatinolytic activity. MMP inhibitors ARP-100 or ONO-4817 (1 µM) prevented doxorubicin-induced MMP-2 activation. Doxorubicin also increased the levels and activity of MMP-2 secreted into the conditioned media. Doxorubicin upregulated the mRNA expression of both full-length MMP-2 and NTT-MMP-2. α-Actinin levels remained unchanged, whereas doxorubicin downregulated troponin I in an MMP-independent manner. Doxorubicin induces oxidative stress and stimulates a robust increase in MMP-2 expression and activity in NRVM, including NTT-MMP-2. The sarcomeric proteins α-actinin and troponin I are, however, not targeted by MMP-2 under these conditions.