Platelets and Cardiac Arrhythmia

Jong, Jonas S.S.G. de; Dekker, Lukas

doi:10.3389/fphys.2010.00166

Cited by 23 publications

(14 citation statements)

References 93 publications

(115 reference statements)

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“…It has been argued that a systematic examination of the role of platelets in VF initiation during ischemia is long overdue. 18 We have tested whether VF is facilitated by the activation of platelets trapped within the ischemic territory, resulting in the release of proarrhythmic secretome. A novel in vitro model system permitted myocardial ischemia to be induced in isolated rat hearts in the absence or presence of an autologous infusion of platelets.…”

Section: Clinical Perspective On P 1001mentioning

confidence: 99%

Trapped Platelets Activated in Ischemia Initiate Ventricular Fibrillation

Dhanjal

Medina

Leem

et al. 2013

Circ: Arrhythmia and Electrophysiology

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Background-We tested the hypothesis that ischemia-induced ventricular fibrillation (VF) is facilitated by platelets, trapped regionally in the ischemic zone and activated to release arrhythmogenic secretome. Methods and Results-In a randomized study in blood-free, buffer-perfused isolated rat hearts, ischemic zone territory (34±1% of left ventricle) was selected so that ischemia evoked VF in only 42% of controls. VF incidence was increased to 91% (P<0.05) by coronary ligation-induced trapping of freshly prepared autologous platelets (infused before and during coronary ligation, with trapping confirmed by 111 In-labeled platelet autoradiographic imaging). Trapping of platelet secretome prepared ex vivo, or platelet-sized fluorospheres, did not increase ischemia-induced VF incidence. Secretome alone did, however, evoke VF in 2 sham coronary-ligated hearts. Perfusion did not activate infused platelets in sham coronary-ligated hearts, whereas ligation activated trapped platelets (assessed by thromboxane release). In a separate study, trapping whole-heparinized blood mimicked the ability of trapped platelets to increase VF incidence. This effect was not prevented by >5 days oral pretreatment in vivo with clopidogrel (10 mg/kg per day) or indomethacin (2.4 mg/kg per day). Conclusions-Platelets facilitate VF during acute ischemia independently of their ability to participate in occlusive thrombosis.Moreover, the effect is unresponsive to antiplatelet drugs commonly used. Labile secretome constituents appear to be responsible. This opens a novel avenue for antiarrhythmic drug research. (Circ Arrhythm Electrophysiol. 2013;6:995-1001.)

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Section: Clinical Perspective On P 1001mentioning

confidence: 99%

Trapped Platelets Activated in Ischemia Initiate Ventricular Fibrillation

Dhanjal

Medina

Leem

et al. 2013

Circ: Arrhythmia and Electrophysiology

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“…There are, however, several lines of evidence to suggest that platelets and their “secretome” can affect cardiomyocyte function independent of their role in occlusive coronary thrombosis and ischemia. From a pathophysiological context, numerous small signaling molecules that are released from platelet-dense granules (ADP/ATP, histamine, and serotonin) and thromboxane A 2 can exert positive inotropic effects on cardiomyocytes ( 11 ). There have been a number of reports that have indirectly implicated platelets in exacerbating ischemia-induced ventricular fibrillation, while a more recent publication by Dhanjal et al ( 13 ) provided evidence for a direct role in increasing the incidence of ventricular fibrillation ( 31 ).…”

Section: Modulation Of Cardiomyocyte Function By Plateletsmentioning

confidence: 99%

Do platelets promote cardiac recovery after myocardial infarction: roles beyond occlusive ischemic damage

Walsh

Poole

2018

American Journal of Physiology-Heart and Circulatory Physiology

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Our understanding of platelet function has traditionally focused on their roles in physiological hemostasis and pathological thrombosis, with the latter being causative of vessel occlusion and subsequent ischemic damage to various tissues. In particular, numerous in vivo studies have implicated causative roles for platelets in the pathogenesis of ischemia-reperfusion (I/R) injury to the myocardium. However, platelets clearly have more complex pathophysiological roles, particularly as a result of the heterogeneous nature of biologically active cargo secreted from their granules or contained within released microparticles or exosomes. While some of these released mediators amplify platelet activation and thrombosis through autocrine or paracrine amplification pathways, they can also regulate diverse cellular functions within the localized microenvironment and recruit progenitor cells to the damage site to facilitate repair processes. Notably, there is evidence to support cardioprotective roles for platelet mediators during I/R injury. As such, it is becoming more widely appreciated that platelets fulfill a host of physiological and pathological roles beyond our basic understanding. Therefore, the purpose of this perspective is to consider whether platelets, through their released mediators, can assume a paradoxically beneficial role to promote cardiac recovery after I/R injury.

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“…Importantly, however, little is known about the effects of clofazimine on the reactivity of human platelets, cells which are not only key mediators of thrombosis, but which are also major drivers of neutrophil-mediated inflammation, largely mediated via upregulated expression of the adhesion molecule, CD62P (P-selectin), stored in cytoplasmic α-granules ( Wagner, 2005 ). In addition to pro-thrombotic activity, platelets also possess pro-arrhythmogenic potential ( de Jong and Dekker, 2010 ). Accordingly, the current study has been undertaken with the primary objective of investigating the effects of clofazimine, as well as those of the first-line anti-TB drugs, isoniazid and rifampicin, on expression of the key mediator, CD62P, by agonist-activated platelets in vitro , as well as the modulatory potential of the membrane-stabilizing agent, α-tocopherol.…”

Section: Introductionmentioning

confidence: 99%

Clofazimine, but Not Isoniazid or Rifampicin, Augments Platelet Activation in vitro

et al. 2018

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Although the inclusion of the cationic amphiphilic, anti-mycobacterial agent, clofazimine, in the chemotherapeutic regimens of patients with multidrug-resistant tuberculosis (TB) has contributed to improved outcomes, concerns remain about the cardiotoxic potential of this agent. Accordingly, the current study was undertaken with the primary objective of investigating the effects of clofazimine, on the reactivity of human platelets in vitro, a seemingly unexplored, mechanism of cardiotoxicity. Platelet-rich plasma (PRP) prepared from the blood of healthy, adult humans was treated with clofazimine (0.625–10 mg/L), or the primary anti-TB agents, isoniazid and rifampicin (at final concentrations of 5 and 10 mg/L), followed by addition of either adenosine 5′-diphosphate (ADP) or thrombin and measurement of platelet activation according to the magnitude of expression of CD62P (P-selectin), as well as the CD62P-mediated formation of heterotypic neutrophil:platelet (NP) aggregates, using flow cytometry. Clofazimine, but neither isoniazid nor rifampicin, caused dose-related potentiation of both ADP- and thrombin-activated expression of CD62P by platelets, achieving statistical significance at threshold concentrations of 0.625 and 2.5 mg/L, respectively, as well as significant formation of N:P aggregates. These stimulatory effects of clofazimine on platelet activation were partly attenuated by pre-treatment of PRP with the membrane-stabilizing agent, α-tocopherol, possibly consistent with a membrane-disruptive mechanism. In conclusion, clofazimine, at concentrations within the therapeutic range, augments platelet activation in vitro, probably by a mechanism linked to membrane destabilization. If operative in vivo, these pro-thrombotic activities of clofazimine may predispose for development of microvascular occlusion, exacerbating an already existing high risk for development of TB-associated cardiovascular disease.

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Platelets and Cardiac Arrhythmia

Cited by 23 publications

References 93 publications

Trapped Platelets Activated in Ischemia Initiate Ventricular Fibrillation

Trapped Platelets Activated in Ischemia Initiate Ventricular Fibrillation

Do platelets promote cardiac recovery after myocardial infarction: roles beyond occlusive ischemic damage

Clofazimine, but Not Isoniazid or Rifampicin, Augments Platelet Activation in vitro

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