Abstract：
:Various drugs are reported to prolong the QT-interval on the surface ECG, thereby increasing the risk of developing a potentially fatal arrhythmia known as Torsades de Pointes (TdP). TdP case reports for these drugs have often been associated with risk factors such as overdosing, concomitant drugs and/or existing pathophysiological conditions. A few cases appear to be devoid of these factors. To determine what role genetic variation in the hERG gene plays in drug-induced arrhythmias, we screened DNA samples collected from 105 atrial-fibrillation patients treated with dofetilide for polymorphisms, seven of whom developed TdP. An uncommon missense change, R1047L, was identified in two of seven patients who experienced TdP as compared with five of 98 individuals who were free of TdP. Included in the affected individuals was the only subject homozygous for this SNP. Cellular electrophysiological studies revealed a 10-mV positive shift in the steady-state activation curve of the 1047L hERG channel stably expressed in HEK-293 cells as compared with the wild-type (WT) channel. The activation and inactivation kinetics of the 1047L current were significantly slower than the WT (P < 0.05) at given membrane potentials. A computer simulation using a rabbit ventricular myocyte model indicated that same extent of changes in the I(Kr) channel may result in an approximately 15% prolongation in the action potential duration. Our study suggests that 1047L leads to a functional impairment of the hERG channel, which may contribute to the higher incidence of TdP in 1047L carriers when challenged with a channel blocker.
journal_name
J Mol Cell Cardioljournal_title
Journal of molecular and cellular cardiologyauthors
Sun Z,Milos PM,Thompson JF,Lloyd DB,Mank-Seymour A,Richmond J,Cordes JS,Zhou Jdoi
10.1016/j.yjmcc.2004.09.001keywords:
subject
Has Abstractpub_date
2004-11-01 00:00:00pages
1031-9issue
5eissn
0022-2828issn
1095-8584pii
S0022-2828(04)00271-8journal_volume
37pub_type
杂志文章abstract：:Defective sarcoplasmic reticulum (SR) Ca2+ handling is evident in cardiomyopathy and may be mediated by selective dysregulation of SR Ca2+ handling proteins. To assess whether regulation of SR Ca2+ release may vary regionally within the normal and diseased heart, left ventricular transmural expression and activity of ...
journal_title：Journal of molecular and cellular cardiology
pub_type： 杂志文章
doi：10.1016/j.yjmcc.2005.04.005
更新日期：2005-08-01 00:00:00
abstract：:Lack of endothelial nitric oxide synthase (eNOS) may affect the sensitivity of cyclic GMP signaling through soluble guanylyl cyclase (sGC). We hypothesized that in eNOS knockout (eNOS-/-) mice, stimulation of guanylyl cyclase would have enhanced effects inhibiting cardiac contraction. We measured cell shortening and c...
journal_title：Journal of molecular and cellular cardiology
pub_type： 杂志文章
doi：10.1016/j.yjmcc.2005.08.008
更新日期：2005-12-01 00:00:00
abstract：:In addition to the well-known reduction in the maximal rate of rise the antiarrhythmic agent, lidocaine, also produces a shortening in the duration of the normal ventricular action potential. The voltage-dependent currents carried by Na, Ca and K ions were examined in the absence and presence of lidocaine, in order to...
journal_title：Journal of molecular and cellular cardiology
pub_type： 杂志文章
doi：10.1016/s0022-2828(88)80117-2
更新日期：1988-07-01 00:00:00
abstract：:Basal levels of cyclic adenosine monophosphate (cAMP) were measured in embryonic chick hearts at various times during development. Basal cAMP was highest on incubation day 5 and decreased throughout the remaining incubation period. Cyclic AMP could not be stimulated above basal level by intravenous in ovo administrati...
journal_title：Journal of molecular and cellular cardiology
pub_type： 杂志文章
doi：10.1016/s0022-2828(86)80957-9
更新日期：1986-08-01 00:00:00
abstract：:The ability of cells in anoxic-perfused hearts to withstand two types of physical stresses (stretching and swelling), in the absence of reoxygenation was determined. Isolated rat hearts were perfused for 20, 40, or 60 mins with anoxic buffer after which hearts were either reoxygenated for 20 mins or exposed for 15 s t...
journal_title：Journal of molecular and cellular cardiology
pub_type： 杂志文章
doi：10.1016/s0022-2828(87)80353-x
更新日期：1987-11-01 00:00:00
abstract：:The heart responds to increased haemodynamic load with growth of the ventricles. The rise in ventricle mass is due to increasing mass of the myocytes and proliferation of fibroblasts and smooth muscle cells. The accompanying adaptation and remodelling of the interstitium, e.g. production and composition of the extrace...
journal_title：Journal of molecular and cellular cardiology
pub_type： 杂志文章
doi：10.1006/jmcc.1996.0280
更新日期：1997-01-01 00:00:00
abstract：:Cardiotrophin-1 (CT-1) is a heart-targeting cytokine that is increased in the metabolic syndrome due to overexpression in the adipocytes. The effects of CT-1 on cardiomyocyte substrate metabolism remain unknown. We therefore determined the effects of CT-1 on basal and stimulated glucose transport in cardiomyocytes exp...
journal_title：Journal of molecular and cellular cardiology
pub_type： 杂志文章
doi：10.1016/j.yjmcc.2012.12.015
更新日期：2013-03-01 00:00:00
abstract：BACKGROUND:Cardiac injury, as measured by troponin elevation, has been reported among hospitalized coronavirus disease 2019 (COVID-19) patients and portends a poor prognosis. However, how the dynamics of troponin elevation interplay with inflammation and coagulation biomarkers over time is unknown. We assessed longitud...
journal_title：Journal of molecular and cellular cardiology
pub_type： 杂志文章
doi：10.1016/j.yjmcc.2020.08.008
更新日期：2020-10-01 00:00:00
abstract：:To determine whether catecholamines produce alterations in myocardial myosin-actin cycling kinetics, we investigated the effects of isoproterenol upon mechanical characteristics of constantly activated heart muscle thought to reflect crossbridge behavior. In isolated rabbit right ventricular papillary muscles in bariu...
journal_title：Journal of molecular and cellular cardiology
pub_type： 杂志文章
doi：10.1016/s0022-2828(88)80133-0
更新日期：1988-05-01 00:00:00
abstract：:Nitric oxide, which is produced endogenously within cardiac myocytes by three distinct isoforms of nitric oxide synthase, is a key regulator of myocardial function. This review will focus on the regulation of myocardial function by each nitric oxide synthase isoform during health and disease, with a specific emphasis ...
journal_title：Journal of molecular and cellular cardiology
pub_type： 杂志文章,评审
doi：10.1016/j.yjmcc.2008.07.015
更新日期：2008-11-01 00:00:00
abstract：:23Na and 31P NMR spectroscopy were used to follow intracellular [Na+] ([Na+]i) and energy metabolism in isolated, perfused rat hearts. During 30 min of Ca(2+)-free perfusion no significant change in [Na+]i could be detected, but during a subsequent 45 min period of ischemia [Na+]i rose significantly as expected, from ...
journal_title：Journal of molecular and cellular cardiology
pub_type： 杂志文章
doi：10.1006/jmcc.1997.0578
更新日期：1998-01-01 00:00:00
abstract：:Fluorescein isothiocyanate-conjugated lectins (FTC-lectins) have been used to study the occurrence and the distribution of their receptors in the coating of mouse myocardial cells throughout their differentiation (from 10 days post-coitum to the adult stage). FTC-Con A, -WGA and -PNA specifically inhibited by alpha-ma...
journal_title：Journal of molecular and cellular cardiology
pub_type： 杂志文章
doi：10.1016/0022-2828(83)90285-7
更新日期：1983-02-01 00:00:00
abstract：:Myocardial infarction (MI) is one of the leading causes of morbidity and mortality world-wide. Whether endogenous repair and regenerative ability could be augmented by drug administration is an important issue for generation of novel therapeutic approach. Recently it was reported that in mice pretreated with thymosin ...
journal_title：Journal of molecular and cellular cardiology
pub_type： 杂志文章
doi：10.1016/j.yjmcc.2011.08.020
更新日期：2012-01-01 00:00:00
abstract：:The protection of ischemic preconditioning (PC) appears to be triggered by activation of receptors which couple to protein kinase C (PKC) during the brief ischemia. Previous experiments, however, suggest that phosphorylation of PKC's substrates is not required for the myocytes to enter the preconditioned state. Becaus...
journal_title：Journal of molecular and cellular cardiology
pub_type： 杂志文章
doi：10.1006/jmcc.1996.0344
更新日期：1997-03-01 00:00:00
abstract：:Cardiac arrhythmias are one of the main causes of death worldwide. Several studies have shown that inflammation plays a key role in different cardiac diseases and Toll-like receptors (TLRs) seem to be involved in cardiac complications. In the present study, we investigated whether the activation of TLR4 induces cardia...
journal_title：Journal of molecular and cellular cardiology
pub_type： 杂志文章
doi：10.1016/j.yjmcc.2014.08.012
更新日期：2014-11-01 00:00:00
abstract：:Previous work on the rat heart has demonstrated an age-related reduction in catecholamines and a decline in myocardial cell sensitivity to catecholamines in vitro. We used ultrastructural cytochemical techniques to label noradrenergic vesicles of the sympathetic nerve terminals of the rat heart atrium, and addressed t...
journal_title：Journal of molecular and cellular cardiology
pub_type： 杂志文章
doi：10.1016/0022-2828(83)90284-5
更新日期：1983-02-01 00:00:00
abstract：RATIONALE:How ischemic postconditioning can inhibit opening of the mitochondrial permeability transition pore (PTP) and subsequent cardiac myocytes death at reperfusion remains unknown. Recent studies have suggested that de-acetylation of cyclophilin D (CyPD) by sirtuin 3 (SIRT3) can modulate its binding to the PTP. O...
journal_title：Journal of molecular and cellular cardiology
pub_type： 杂志文章
doi：10.1016/j.yjmcc.2015.03.017
更新日期：2015-07-01 00:00:00
abstract：:Coronary blood flow is tightly adjusted to the oxygen requirements of the myocardium. The underlying control mechanisms keep coronary venous pO(2) at a rather constant level around 20mm Hg under a variety of physiological conditions. Because coronary flow may increase more than 5-fold during exercise without any signs...
journal_title：Journal of molecular and cellular cardiology
pub_type： 杂志文章,评审
doi：10.1016/j.yjmcc.2011.10.001
更新日期：2012-04-01 00:00:00
abstract：:Duchenne Muscular Dystrophy (DMD) cardiomyopathy is a progressive lethal disease caused by the lack of the dystrophin protein in the heart. The most widely used animal model of DMD is the dystrophin-deficient mdx mouse; however, these mice exhibit a mild dystrophic phenotype with heart failure only late in life. In co...
journal_title：Journal of molecular and cellular cardiology
pub_type： 杂志文章
doi：10.1016/j.yjmcc.2017.06.004
更新日期：2017-07-01 00:00:00
abstract：:Congenital heart block (CHB) affects offspring of mothers with autoantibodies (positive IgG) to intracellular SSA/Ro and SSB/La ribonucleoproteins and is associated with high morbidity and mortality. Here, we show that maternal anti-Ro/La antibodies immunoreact with human fetal cardiomyocyte sarcolemma, recognize huma...
journal_title：Journal of molecular and cellular cardiology
pub_type： 杂志文章
doi：10.1006/jmcc.2001.1379
更新日期：2001-06-01 00:00:00
abstract：:α-Keto acids (α-KAs) are not just metabolic intermediates but are also powerful modulators of different cellular pathways. Here, we tested the hypothesis that α-KA concentrations are regulated by complex II (succinate dehydrogenase=SDH), which represents an intersection between the mitochondrial respiratory chain for ...
journal_title：Journal of molecular and cellular cardiology
pub_type： 杂志文章
doi：10.1016/j.yjmcc.2010.09.023
更新日期：2010-12-01 00:00:00
abstract：:Cardioprotection and preconditioning mediated via G-protein-coupled receptors may be lost or impaired with advancing age, limiting ischemic tolerance and the ability to pharmacologically protect older hearts from ischemic injury. Our preliminary findings indicated a loss of delta-opioid receptor-mediated protection in...
journal_title：Journal of molecular and cellular cardiology
pub_type： 杂志文章
doi：10.1016/j.yjmcc.2007.02.011
更新日期：2007-05-01 00:00:00
abstract：:In this study, calcium overload during reperfusion and the severity of morphologically evident ischemic myocardial injury were compared in hypertrophied and normal hearts. Hypertrophied hearts isolated from rats where a clip had been placed on the proximal thoracic aorta for 6 weeks were compared to those from sham-op...
journal_title：Journal of molecular and cellular cardiology
pub_type： 杂志文章
doi：10.1006/jmcc.1994.1175
更新日期：1994-12-01 00:00:00
abstract：:Patients with chronic coronary artery disease may exhibit chronically depressed regional myocardial function, which can be reversed by revascularization. This was called hibernating myocardium, since it was thought that myocardial blood flow was also chronically reduced and since animals during true hibernation are th...
journal_title：Journal of molecular and cellular cardiology
pub_type： 杂志文章
doi：10.1016/s0022-2828(03)00174-3
更新日期：2003-08-01 00:00:00
abstract：:Reoxygenation of isolated rat cardiac myocytes following a period of hypoxia and substrate deprivation resulted in a 1.5-2-fold increase in the total Ca2+ content which could be inhibited by 1 microM antimycin A or ruthenium red (50% inhibition at 2.5 microM). This increase in Ca2+ content was not accompanied by any r...
journal_title：Journal of molecular and cellular cardiology
pub_type： 杂志文章
doi：10.1016/0022-2828(89)90795-5
更新日期：1989-10-01 00:00:00
abstract：:Increasing heart rate enhances cardiac contractility (force frequency relationship, FFR) and accelerates cardiac relaxation (frequency-dependent acceleration of relaxation, FDAR). The positive FFR together with FDAR promotes rapid filling and ejection of blood from the left ventricle (LV) at higher heart rates. Recent...
journal_title：Journal of molecular and cellular cardiology
pub_type： 杂志文章
doi：10.1016/j.yjmcc.2012.06.019
更新日期：2012-09-01 00:00:00
abstract：:Modification of gene expression in pulmonary arterial smooth muscle cells (PASMCs) could be a valuable tool for investigating the role of specific gene products in normal and pathological PASMC growth, and a novel potential therapy for pulmonary vascular diseases. To examine the direct role of fosB protein in PASMC gr...
journal_title：Journal of molecular and cellular cardiology
pub_type： 杂志文章
doi：10.1006/jmcc.1996.0160
更新日期：1996-08-01 00:00:00
abstract：:Structural and morphological changes of the cardiovascular systems (cardiovascular remodeling) are a major clinical outcome of cardiovascular diseases. Many lines of evidences have implied that transfiguration of reduction/oxidation (redox) homeostasis due to excess production of reactive oxygen species (ROS) and/or R...
journal_title：Journal of molecular and cellular cardiology
pub_type： 杂志文章,评审
doi：10.1016/j.yjmcc.2014.02.003
更新日期：2014-08-01 00:00:00
abstract：:Recent data indicates that DJ-1 plays a role in the cellular response to stress. Here, we aimed to examine the underlying molecular mechanisms mediating the actions of DJ-1 in the heart following myocardial ischemia-reperfusion (I/R) injury. In response to I/R injury, DJ-1 KO mice displayed increased areas of infarcti...
journal_title：Journal of molecular and cellular cardiology
pub_type： 杂志文章
doi：10.1016/j.yjmcc.2016.04.008
更新日期：2016-08-01 00:00:00
abstract：:Carnitine, certain of its derivatives, and the amino acid metabolite, taurine, when administered independently in prior studies have been shown to improve cardiac mechanic and/or metabolism. The purpose of these studies is to test a new compound, propionylcarnitine taurine (PCT), which potentially combines these actio...
journal_title：Journal of molecular and cellular cardiology
pub_type： 杂志文章
doi：10.1016/s0022-2828(88)80179-2
更新日期：1988-01-01 00:00:00
