Safety and efficacy of reperfusion therapies in acute ischemic stroke related to left ventricular thrombus: A retrospective cohort study.

BACKGROUND: Left ventricular thrombus (LVT) is a source of cardiogenic embolic stroke. Conflicting data exist in the literature regarding the utilization of intravenous thrombolysis (IVT) at the acute phase of stroke in presence of LVT. We sought to assess the efficacy and safety of reperfusion therapies (IVT and/or thrombectomy) in patients with LVT. METHODS: We retrospectively analyzed patients with acute ischemic stroke and proven LVT and divided them in two groups: an intervention group with patients treated by reperfusion therapies and a control group with untreated patients. RESULTS: Between 2009 and 2021, 3890 patients were treated by reperfusion therapies in the Lyon stroke center, 33 of whom (0.9%) had LVT. We identified 27 control patients. There were more embolic recurrences at six months in the intervention group than in the control group (nine recurrences versus three, P=0.03, OR=13.56, 95% CI [1.5;195]). Only two early embolic recurrences (< 24h) occurred, both in the IVT group. There was a 4.8-fold decrease in the median NIHSS score between baseline and 24h follow-up in the intervention group (P<0.0001), and the two groups exhibited similar six-month mortality. At stroke onset, cardiopathy was known in 70% of patients, while LVT was known in 30%. CONCLUSION: Acute reperfusion therapies seem to be effective in the context of stroke in patients with LVT. However, further studies are needed to support the hypothesis that stroke recurrence might be related to the use of IVT.

Inhibition of myocardial reperfusion injury by ischemic postconditioning requires sirtuin 3-mediated deacetylation of cyclophilin D.

RATIONALE: How ischemic postconditioning can inhibit opening of the mitochondrial permeability transition pore (PTP) and subsequent cardiac myocytes death at reperfusion remains unknown. Recent studies have suggested that de-acetylation of cyclophilin D (CyPD) by sirtuin 3 (SIRT3) can modulate its binding to the PTP. OBJECTIVE: The aim of the present study was to examine whether ischemic postconditioning (PostC) might activate SIRT3 and consequently prevent lethal myocardial reperfusion injury through a deacetylation of CyPD. METHODS AND RESULTS: Using hypoxia-reoxygenation (H/R) in H9C2 cells, we showed that SIRT3 overexpression prevented CyPD acetylation, limited PTP opening and reduced cell death by 24%. In vitro modification of the CyPD acetylation status in MEFs by site-directed mutagenesis altered capacity of PTP opening by calcium. Calcium Retention Capacity (CRC) was significantly decreased with CyPD-KQ that mimics acetylated protein compared with CyPD WT (871 ± 266 vs 1193 ± 263 nmoles Ca(2+)/mg protein respectively). Cells expressing non-acetylable CyPD mutant (CyPD-KR) displayed 20% decrease in cell death compared to cells expressing CyPD WT after H/R. Correspondingly, in mice we showed that cardiac ischemic postconditioning could not reduce infarct size and CyPD acetylation in SIRT3 KO mice, and was unable to restore CRC in mitochondria as it is observed in WT mice. CONCLUSIONS: Our study suggests that the increased acetylation of CyPD following myocardial ischemia-reperfusion facilitates PTP opening and subsequent cell death. Therefore ischemic postconditioning might prevent lethal reperfusion injury through an increased SIRT3 activity and subsequent attenuation of CyPD acetylation at reperfusion.