Abstract 324: Dronedarone Alters the Sensitivity of Cardiac Mitochondria to Permeability Transition Pore Opening

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Abstract

Introduction: Dronedarone (DR) is a new antiarrhythmic agent that was design to minimize side effects of Amiodarone. However, in clinical trials was shown to worsen heart failure (HF) and increased mortality. The mechanisms for these adverse effects are not known. Since mitochondria are critical for maintaining cardiac energetics and regulate, we hypothesized that DR increases sensitivity towards opening of mitochondrial permeability transition pore (mPTP) that underlies mitochondrial failure and cell death.

Methods: Mitochondria were isolated from left atrial appendage tissue of patients undergoing bypass cardiac surgery (n=3). Patients did not have any history of HF or atrial fibrillation. To induce mPTP, mitochondria were exposed with sequential additions of Ca2+ (Fluo-5N) in the presence of 5, 10, 20 μM of DR. The opening of mPTP was determined by monitoring abrupt release of Ca2+, rapid loss of membrane potential (ΔΨ) and mitochondrial swelling.

Results: DR accelerated Ca2+-induced mPTP opening starting at 5 μM concentration (Fig). At concentration of 20 μM, it completely depolarized mitochondria abolishing capacity for Ca2+ handling and responsiveness to cyclosporine A (CsA), an inhibitor of mPTP.

Conclusion: In isolated human cardiac mitochondria from patients without history of HF DR at clinically relevant concentration increased sensitivity of mitochondria to Ca2+ induced mPTP opening. In failing heart this can be compromised and needs to be studied.

Dronedarone accelerates Ca2+-induced mPTP opening in mitochondria isolated from human left atrial appendage.

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