Electrocardiogram after Chloroquine and Emetine

Sanghvi, L. M.; Mathur, B B

doi:10.1161/01.cir.32.2.281

Cited by 27 publications

(7 citation statements)

References 23 publications

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“…Although rare, treatment with the antimalarial drug chloroquine has also been associated with acquired arrhythmias. Prolonged therapy with chloroquine can lead to electrocardiographic changes including T-wave depression or inversion and prolonged QRS and QT intervals (7,8). Prolonged QT intervals caused by chloroquine can induce torsade de pointes (9,10).…”

Section: Hergmentioning

confidence: 99%

Molecular Determinants of Voltage-dependent Human Ether-a-Go-Go Related Gene (HERG) K+ Channel Block

Sánchez-Chapula¹,

Navarro‐Polanco²,

Culberson³

et al. 2002

Journal of Biological Chemistry

174

139

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The structural determinants for the voltage-dependent block of ion channels are poorly understood. Here we investigate the voltage-dependent block of wild-type and mutant human ether-a-go-go related gene (HERG) K ؉ channels by the antimalarial compound chloroquine. The block of wild-type HERG channels expressed in Xenopus oocytes was enhanced as the membrane potential was progressively depolarized. The IC 50 was 8.4 ؎ 0.9 M when assessed during 4-s voltage clamp pulses to 0 mV. Chloroquine also slowed the apparent rate of HERG deactivation, reflecting the inability of drug-bound channels to close. Mutation to alanine of aromatic residues (Tyr-652 or Phe-656) located in the S6 domain of HERG greatly reduced the potency of channel block by chloroquine (IC 50 > 1 mM at 0 mV). However, mutation of Tyr-652 also altered the voltage dependence of the block. In contrast to wild-type HERG, block of Y652A HERG channels was diminished by progressive membrane depolarization, and complete relief from block was observed at ؉40 mV. HERG channel block was voltage-independent when the hydroxyl group of Tyr-652 was removed by mutating the residue to Phe. Together thesefindingsindicateacriticalroleforTyr-652involtage-dependent block of HERG channels. Molecular modeling was used to define energy-minimized dockings of chloroquine to the central cavity of HERG. Our experimental findings and modeling suggest that chloroquine preferentially blocks open HERG channels by cationand -stacking interactions with Tyr-652 and Phe-656 of multiple subunits. HERG1 (1) encodes the pore-forming subunits of channels that conduct the rapid delayed rectifier K ϩ current, I Kr (2, 3). Mutation of HERG is a common cause of inherited long QT syndrome, a disorder of cardiac repolarization that predisposes affected individuals to torsade de pointes arrhythmia and sudden death (4). Acquired long QT syndrome is far more common than inherited long QT syndrome and is most often caused by block of HERG channels as a side effect of treatment with commonly used medications including antiarrhythmic, antihistamine, antibiotic, and psychoactive agents (5, 6). Although rare, treatment with the antimalarial drug chloroquine has also been associated with acquired arrhythmias. Prolonged therapy with chloroquine can lead to electrocardiographic changes including T-wave depression or inversion and prolonged QRS and QT intervals (7,8). Prolonged QT intervals caused by chloroquine can induce torsade de pointes (9, 10). At the cellular level, chloroquine decreases the maximum upstroke velocity due to block of sodium current and prolongs the duration of action potentials due to block of inward rectifier current (I K1 ) and I Kr (11). Elucidating the molecular mechanisms of HERG channel block by chloroquine and other drugs may enable the rational design of new pharmaceuticals devoid of this unwanted side effect.The structural basis of HERG channel block by several potent drugs was recently investigated using alanine-scanning mutagenesis (12). Mutation of several amino acid res...

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Section: Hergmentioning

confidence: 99%

Molecular Determinants of Voltage-dependent Human Ether-a-Go-Go Related Gene (HERG) K+ Channel Block

Sánchez-Chapula¹,

Navarro‐Polanco²,

Culberson³

et al. 2002

Journal of Biological Chemistry

174

139

View full text Add to dashboard Cite

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“…The therapeutic use of CQ has resulted in death from poisoning by the drug, which has been attributed to an effect on the cardiovascular system [37]. Essien and Ette [38] reported didesethylchloroquine to have greater potency than CQ in producing cardiodepression, and attributed this effect to its molecular structure.…”

Section: Resultsmentioning

confidence: 99%

Effect of Chloroquine on Rat Liver Microsomes.

Deepalakshmi

Parasakthy

Shanthi

et al. 1995

J. Clin. Biochem. Nutr.

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“…Pathological accumulation of metabolic byproducts within the myocardium leads to concentric hypertrophy with or without restrictive physiology and conduction abnormalities. Resting electrocardiograms may reveal ST-segment depression, T wave inversions and QT interval prolongation at therapeutic doses [60]. Third degree AV block may precede symptoms of congestive heart failure by years [61][62][63][64].…”

Section: Discussionmentioning

confidence: 99%

Hydroxychloroquine and Chloroquine Induced Cardiomyopathy: A Concise Review

Kariyanna¹,

Doodnauth²,

Shetty³

et al. 2021

IJCEMS

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Hydroxychloroquine and Chloroquine are commonly used for the treatment of malaria and autoimmune conditions.Most recently, hydroxychloroquine has been implicated in the treatment armamentarium of Severe acute respiratory syndrome (SARS) caused by SARS-associated coronavirus-2. A rare, underreported side effect of hydroxychloroquine and chloroquine is cardiotoxicity. The cardiomyopathy occurs as a result of inhibition of lysosomal enzymes causing lysosomal dysfunction and intra-cellular accumulation of metabolic byproducts in the myocardium, leading to hypertrophy with or without restrictive physiology and resultant conduction abnormalities. Based on our review of 57 reported cases of hydroxychloroquine or chloroquine induced cardiomyopathy, dyspnea was the most common associated symptom. The most common rhythms seen on EKG were as follows: complete heart block (18.75%), right bundle branch block (RBBB) (18.75%). The most common findings on echocardiography were left ventricular hypertrophy (LVH) (54%), systolic dysfunction (48%) and diastolic dysfunction (32%). A definitive diagnosis is established by endomyocardial biopsy which demonstrates the presence of curvilinear inclusion bodies. The outcome following cessation of the offending agent ranges from complete reversal in 45% of the cases to continued progression with need for cardiac transplantation or even death in 17.5% of the cases.

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Electrocardiogram after Chloroquine and Emetine

Cited by 27 publications

References 23 publications

Molecular Determinants of Voltage-dependent Human Ether-a-Go-Go Related Gene (HERG) K+ Channel Block

Molecular Determinants of Voltage-dependent Human Ether-a-Go-Go Related Gene (HERG) K+ Channel Block

Effect of Chloroquine on Rat Liver Microsomes.

Hydroxychloroquine and Chloroquine Induced Cardiomyopathy: A Concise Review

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