The platelet paradox of injury versus protection in myocardial infarction—has it been overlooked?

Kleinbongard, Petra; Andreadou, Ioanna; Vilahur, Gemma

doi:10.1007/s00395-021-00876-6

Cited by 14 publications

(20 citation statements)

References 58 publications

(71 reference statements)

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“…The majority of patients in our study were administered the oral P2Y12 inhibitor, ticagrelor prior to PPCI, whereas in the prior positive studies, clopidogrel was predominantly used [1,12,46]. Animal studies have reported ticagrelor to have cardioprotective effects [34,45,47,48], and this may have attenuated the benefits of limb RIC in our CMR substudy. However, in the main CONDI-2/ERIC-PPCI trial, there was no difference in clinical outcomes with RIC, when stratified by whether ticagrelor was given or not.…”

Section: Discussionmentioning

confidence: 93%

Effect of remote ischaemic conditioning on infarct size and remodelling in ST-segment elevation myocardial infarction patients: the CONDI-2/ERIC-PPCI CMR substudy

et al. 2021

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The effect of limb remote ischaemic conditioning (RIC) on myocardial infarct (MI) size and left ventricular ejection fraction (LVEF) was investigated in a pre-planned cardiovascular magnetic resonance (CMR) substudy of the CONDI-2/ERIC-PPCI trial. This single-blind multi-centre trial (7 sites in UK and Denmark) included 169 ST-segment elevation myocardial infarction (STEMI) patients who were already randomised to either control (n = 89) or limb RIC (n = 80) (4 × 5 min cycles of arm cuff inflations/deflations) prior to primary percutaneous coronary intervention. CMR was performed acutely and at 6 months. The primary endpoint was MI size on the 6 month CMR scan, expressed as median and interquartile range. In 110 patients with 6-month CMR data, limb RIC did not reduce MI size [RIC: 13.0 (5.1–17.1)% of LV mass; control: 11.1 (7.0–17.8)% of LV mass, P = 0.39], or LVEF, when compared to control. In 162 patients with acute CMR data, limb RIC had no effect on acute MI size, microvascular obstruction and LVEF when compared to control. In a subgroup of anterior STEMI patients, RIC was associated with lower incidence of microvascular obstruction and higher LVEF on the acute scan when compared with control, but this was not associated with an improvement in LVEF at 6 months. In summary, in this pre-planned CMR substudy of the CONDI-2/ERIC-PPCI trial, there was no evidence that limb RIC reduced MI size or improved LVEF at 6 months by CMR, findings which are consistent with the neutral effects of limb RIC on clinical outcomes reported in the main CONDI-2/ERIC-PPCI trial.

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Section: Discussionmentioning

confidence: 93%

Effect of remote ischaemic conditioning on infarct size and remodelling in ST-segment elevation myocardial infarction patients: the CONDI-2/ERIC-PPCI CMR substudy

et al. 2021

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“…The number of other platelet-dependent endothelial barrier protective mechanisms have been also proposed involving production of platelet–derived trophic factors (e.g. VEGF, BDNF) ( Nachman and Rafii, 2008 ), Ang-1 ( Braun et al, 2020 ), sphingosine-1 phosphate (S1P), stromal cell derived factor 1α (SDF1α), transforming growth factor β1 (TGFβ1), and adenosine nucleotides ( Kleinbongard et al, 2021 ). Importantly, platelet-dependent protection of the endothelial barrier was described for various inflammatory stimuli, including primary cancer ( Lax et al, 2017 ; Ho-Tin-Noé et al, 2018 ), as well as in case of cardioprotection following ischemia/reperfusion ( Kleinbongard et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…VEGF, BDNF) ( Nachman and Rafii, 2008 ), Ang-1 ( Braun et al, 2020 ), sphingosine-1 phosphate (S1P), stromal cell derived factor 1α (SDF1α), transforming growth factor β1 (TGFβ1), and adenosine nucleotides ( Kleinbongard et al, 2021 ). Importantly, platelet-dependent protection of the endothelial barrier was described for various inflammatory stimuli, including primary cancer ( Lax et al, 2017 ; Ho-Tin-Noé et al, 2018 ), as well as in case of cardioprotection following ischemia/reperfusion ( Kleinbongard et al, 2021 ). However, the importance of platelet-dependent protective mechanisms has not yet been confirmed in the context of local inflammation alongside pulmonary metastasis.…”

Section: Discussionmentioning

confidence: 99%

Direct Thrombin Inhibitor Dabigatran Compromises Pulmonary Endothelial Integrity in a Murine Model of Breast Cancer Metastasis to the Lungs; the Role of Platelets and Inflammation-Associated Haemostasis

et al. 2022

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Activation of the coagulation cascade favours metastatic spread, but antithrombotic therapy might also have detrimental effects on cancer progression. In this study, we characterized the effects of dabigatran, a direct reversible thrombin inhibitor, on the pulmonary endothelial barrier and metastatic spread in a murine model of breast cancer metastasis. Dabigatran etexilate (100 mg kg−1) was administered to mice twice daily by oral gavage. Pulmonary metastasis, pulmonary endothelium permeability in vivo, and platelet reactivity were evaluated after intravenous injection of 4T1 breast cancer cells into BALB/c mice. The effect of dabigatran on platelet-dependent protection of pulmonary endothelial barrier in the presence of an inflammatory stimulus was also verified in vitro using human lung microvascular endothelial cell (HLMVEC) cultures. Dabigatran-treated mice harbored more metastases in their lungs and displayed increased pulmonary endothelium permeability after cancer cell injection. It was not associated with altered lung fibrin deposition, changes in INFγ, or complement activation. In the in vitro model of the pulmonary endothelial barrier, dabigatran inhibited platelet-mediated protection of pulmonary endothelium. In a murine model of breast cancer metastasis, dabigatran treatment promoted pulmonary metastasis by the inhibition of platelet-dependent protection of pulmonary endothelial barrier integrity.

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“…RIC delayed thrombotic occlusion in patients undergoing primary coronary intervention, suggesting beneficial effects on inhibition of thrombosis by reducing platelet reactivity 24 . Specific platelet P2Y 12 receptor antagonists also induced cardioprotection beyond the inhibition of platelet aggregation 25 , 26 . Inhibition of platelet activation and thrombus formation might have beneficial effects during microvascular surgery with potential high risk of thrombotic complication.…”

Section: Discussionmentioning

confidence: 99%

Effects of ischemic conditioning on head and neck free flap oxygenation: a randomized controlled trial

Min

Choe

Kim

et al. 2022

Sci Rep

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Flap failure after microvascular reconstructive surgery is a rare but devastating complication caused by reperfusion injury and tissue hypoperfusion. Remote ischemic conditioning (RIC) provides protection against ischemia/reperfusion injury and reduces tissue infarction. We hypothesized that RIC would enhance flap oxygenation and exert organ-protective effects during head and neck free flap reconstructive surgery. Adult patients undergoing free flap transfer surgery for head and neck cancer were randomized to receive either RIC or sham-RIC during surgery. RIC consisted of four cycles of 5-min ischemia and 5-min reperfusion applied to the upper or lower extremity. The primary endpoint, tissue oxygen saturation of the flap, was measured by near-infrared spectroscopy on the first postoperative day. Organ-protective effects of RIC were evaluated with infarct size of rat hearts perfused with plasma dialysate from patients received RIC or sham-RIC. Between April 2018 and July 2019, 50 patients were randomized (each n = 25) and 46 were analyzed in the RIC (n = 23) or sham-RIC (n = 23) groups. Tissue oxygen saturation of the flap was similar between the groups (85 ± 12% vs 83 ± 9% in the RIC vs sham-RIC groups; P = 0.471). Myocardial infarct size after treatment of plasma dialysate was significantly reduced in the RIC group (44 ± 7% to 26 ± 6%; P = 0.018) compared to the sham-RIC group (42 ± 6% to 37 ± 7%; P = 0.388). RIC did not improve tissue oxygenation of the transferred free flap in head and neck cancer reconstructive surgery. However, there was evidence of organ-protective effects of RIC in experimental models.Trial registration: Registry number of ClinicalTrials.gov: NCT03474952.

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The platelet paradox of injury versus protection in myocardial infarction—has it been overlooked?

Cited by 14 publications

References 58 publications

Effect of remote ischaemic conditioning on infarct size and remodelling in ST-segment elevation myocardial infarction patients: the CONDI-2/ERIC-PPCI CMR substudy

Effect of remote ischaemic conditioning on infarct size and remodelling in ST-segment elevation myocardial infarction patients: the CONDI-2/ERIC-PPCI CMR substudy

Direct Thrombin Inhibitor Dabigatran Compromises Pulmonary Endothelial Integrity in a Murine Model of Breast Cancer Metastasis to the Lungs; the Role of Platelets and Inflammation-Associated Haemostasis

Effects of ischemic conditioning on head and neck free flap oxygenation: a randomized controlled trial

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