Termination of a tachyarrhythmia by flunarizine is not a specific marker for a triggered mechanism

Vitebskiy, Sergey; Khrestian, Celeen M.; Waldo, Albert L.

doi:10.1016/j.hrthm.2007.08.018

Cited by 5 publications

(3 citation statements)

References 27 publications

(39 reference statements)

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“…The experiments with verapamil and ryanodine suggest that Ca 2ϩ loading might be critical for some forms of spontaneous electrical activity occurring in AF-related atrial pathologies and support the role of DADs as a trigger mechanism for spontaneous activity in the atrium. In contrast, flunarizine has also been shown to terminate reentrant rhythms like atrial flutter in the canine sterile pericarditis model, illustrating that the response to flunarizine cannot be taken as an argument for the existence of Ca 2ϩ -related cellular proarrhythmic mechanisms (591). In sheep atria exposed to acute stretch and adrenocholinergic stimulation (perfusion with high concentrations of isoproterenol and acetylcholine), both caffeine and ryanodine inhibited breakthroughs showing radial spread of activation during AF.…”

Section: Alterations Of Atrial Ca 2؉ Handling and Abnormal Impulsementioning

confidence: 98%

Pathophysiological Mechanisms of Atrial Fibrillation: A Translational Appraisal

Schotten

Verheule²,

Kirchhof³

et al. 2011

Physiological Reviews

1,057

919

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Atrial fibrillation (AF) is an arrhythmia that can occur as the result of numerous different pathophysiological processes in the atria. Some aspects of the morphological and electrophysiological alterations promoting AF have been studied extensively in animal models. Atrial tachycardia or AF itself shortens atrial refractoriness and causes loss of atrial contractility. Aging, neurohumoral activation, and chronic atrial stretch due to structural heart disease activate a variety of signaling pathways leading to histological changes in the atria including myocyte hypertrophy, fibroblast proliferation, and complex alterations of the extracellular matrix including tissue fibrosis. These changes in electrical, contractile, and structural properties of the atria have been called "atrial remodeling." The resulting electrophysiological substrate is characterized by shortening of atrial refractoriness and reentrant wavelength or by local conduction heterogeneities caused by disruption of electrical interconnections between muscle bundles. Under these conditions, ectopic activity originating from the pulmonary veins or other sites is more likely to occur and to trigger longer episodes of AF. Many of these alterations also occur in patients with or at risk for AF, although the direct demonstration of these mechanisms is sometimes challenging. The diversity of etiological factors and electrophysiological mechanisms promoting AF in humans hampers the development of more effective therapy of AF. This review aims to give a translational overview on the biological basis of atrial remodeling and the proarrhythmic mechanisms involved in the fibrillation process. We pay attention to translation of pathophysiological insights gained from in vitro experiments and animal models to patients. Also, suggestions for future research objectives and therapeutical implications are discussed.

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Section: Alterations Of Atrial Ca 2؉ Handling and Abnormal Impulsementioning

confidence: 98%

Pathophysiological Mechanisms of Atrial Fibrillation: A Translational Appraisal

Schotten

Verheule²,

Kirchhof³

et al. 2011

Physiological Reviews

1,057

919

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“…channel blocker that has been used to prevent migraine headaches [1], control intraocular pressure [2], and eliminate atrial flutter [3]. In addition, flunarizine possesses cytoprotective activity in some model systems.…”

Section: Introductionmentioning

confidence: 99%

The Ca2+ channel blocker flunarizine induces caspase-10-dependent apoptosis in Jurkat T-leukemia cells

Conrad¹,

Furlong²,

Doucette³

et al. 2010

Apoptosis

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Flunarizine is a Ca(2+) channel blocker that can be either cytoprotective or cytotoxic, depending on the cell type that is being examined. We show here that flunarizine was cytotoxic for Jurkat T-leukemia cells, as well as for other hematological maligancies, but not for breast or colon carcinoma cells. Treatment of Jurkat cells with flunarizine resulted in caspase-3 activation, poly (ADP-ribose) polymerase cleavage, and laddering of DNA fragments, all of which are hallmarks of apoptosis. Flunarizine-induced DNA fragmentation was inhibited by the caspase-3 inhibitor z-DEVD-fmk, the caspase-8/caspase-10 inhibitor z-IETD-fmk, and the caspase-10 inhibitor z-AEVD-fmk, but was not reduced in caspase-8-deficient Jurkat cells, indicating the involvement of caspase-10 upstream of caspase-3 activation. Interestingly, FADD recruitment to a death receptor was not involved since flunarizine caused DNA fragmentation in FADD-deficient Jurkat cells. Flunarizine treatment of Jurkat cells also resulted in reactive oxygen species production, dissipation of mitochondrial transmembrane potential, release of cytochrome c from mitochondria, and caspase-9 activation, although none of these events were necessary for apoptosis induction. Collectively, these findings indicate that flunarizine triggers apoptosis in Jurkat cells via FADD-independent activation of caspase-10. Flunarizine warrants further investigation as a potential anti-cancer agent for the treatment of hematological malignancies.

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“…Generally, blocking calcium channels flattens APD restitution curve 8,19,20 and prevents spiral wave breakup, 8,19,20 which is contradictory to what we observed in the flunarizine group. However, flunarizine also blocks sodium channels 21 and slows down conduction time, 22 which we suspect broadens CV restitution during ischemia and increases the incidence of nonstable pattern.…”

Section: Discussionmentioning

confidence: 88%

Long-Duration Ventricular Fibrillation Exhibits 2 Distinct Organized States

Zheng

Dosdall

et al. 2013

Circ: Arrhythmia and Electrophysiology

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Background Previous studies showed that endocardial activation during long-duration ventricular fibrillation (VF) exhibits organized activity. We identified and quantified the different types of organized activity. Methods and Results Two 64-electrode basket catheters were inserted, respectively, into the left ventricle and right ventricle of dogs to record endocardial activation from the endocardium during 7 minutes of VF (controls, n=6). The study was repeated with the KATP channel opener pinacidil (n=6) and the calcium channel blocker flunarizine (n=6). After 2 minutes of VF without drugs, 2 highly organized left ventricular endocardial activation patterns were observed: (1) ventricular electric synchrony pattern, in which endocardial activation arose focally and either had a propagation sequence similar to sinus rhythm or arose near papillary muscles, and (2) stable pattern, in which activation was regular and repeatable, sometimes forming a stable re-entrant circuit around the left ventricular apex. Between 3 and 7 minutes of VF, the percent of time ventricular electric synchrony was present was control=25%, flunarizine=24% (P=0.44), and pinacidil=0.1% (P<0.001) and the percent of time stable pattern was present was control=71%, flunarizine=48% (P<0.001), and pinacidil=56% (P<0.001). The remainder of the time, nonstable re-entrant activation with little repeatability was present. Conclusions After 3 minutes, VF exhibits 2 highly organized endocardial activation patterns 96% of the time, one potentially arising focally in the Purkinje system that was prevented with a KATP channel opener but not a calcium channel blocker and the other potentially arising from a stable re-entrant circuit near the apical left ventricular endocardium.

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Termination of a tachyarrhythmia by flunarizine is not a specific marker for a triggered mechanism

Abstract: Background-Prior studies indicated that tachyarrhythmia termination by flunarizine demonstrates a triggered mechanism. This concept was not confirmed in atrial tachyarrhythmias.

Cited by 5 publications

References 27 publications

Pathophysiological Mechanisms of Atrial Fibrillation: A Translational Appraisal

Pathophysiological Mechanisms of Atrial Fibrillation: A Translational Appraisal

The Ca2+ channel blocker flunarizine induces caspase-10-dependent apoptosis in Jurkat T-leukemia cells

Long-Duration Ventricular Fibrillation Exhibits 2 Distinct Organized States

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