Abstract:
:The QT interval, a global index of ventricular repolarization, varies among individuals and is influenced by diverse physiologic and pathophysiologic stimuli such as gender, age, heart rate, electrolyte concentrations, concomitant cardiac disease, and other diseases such as diabetes. Many drugs produce a small but reproducible effect on QT interval but in rare instances this is exaggerated and marked QT prolongation can provoke the polymorphic ventricular tachycardia 'torsades de pointes', which can cause syncope or sudden cardiac death. The generally accepted common mechanism whereby drugs prolong QT is block of a key repolarizing potassium current in heart, IKr, generated by expression of KCNH2, also known as HERG. Thus, evaluation of the potential that a new drug entity may cause torsades de pointes has relied on exposure of normal volunteers or patients to drug at usual and high concentrations, and on assessment of IKr block in vitro. More recent work, focusing on anticancer drugs with QT prolonging liability, is defining new pathways whereby drugs can prolong QT. Notably, the in vitro effects of some tyrosine kinase inhibitors to prolong cardiac action potentials (the cellular correlate of QT) can be rescued by intracellular phosphatidylinositol 3,4,5-trisphosphate, the downstream effector of phosphoinositide 3-kinase. This finding supports a role for inhibition of this enzyme, either directly or by inhibition of upstream kinases, to prolong QT through mechanisms that are being worked out, but include enhanced inward 'late' sodium current during the plateau of the action potential. The definition of non-IKr-dependent pathways to QT prolongation will be important for assessing risk, not only with anticancer therapies but also with other QT prolonging drugs and for generating a refined understanding how variable activity of intracellular signalling systems can modulate QT and associated arrhythmia risk.
journal_name
Cardiovasc Resjournal_title
Cardiovascular researchauthors
Roden DMdoi
10.1093/cvr/cvz013subject
Has Abstractpub_date
2019-04-15 00:00:00pages
895-903issue
5eissn
0008-6363issn
1755-3245pii
5299452journal_volume
115pub_type
杂志文章,评审abstract::This study is the first report describing the sequence of biochemical alterations of myocardium during the progression of naturally occurring hypertrophy in spontaneously hypertensive rats (SHRs) and then with its reversal by alpha-methyldopa therapy. Changes in DNA, RNA, hydroxyproline, as well as incorporation of 14...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/10.2.254
更新日期:1976-03-01 00:00:00
abstract:OBJECTIVE:The aim was to test the hypothesis that A1 receptor mediated cardioprotection by endogenous adenosine is exerted during ischaemia rather than reperfusion. METHODS:Anaesthetised open chest rabbits were subjected to 30 min regional ischaemia and 120 min reperfusion, and randomised to one of six groups: group I...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/28.2.270
更新日期:1994-02-01 00:00:00
abstract:AIMS:The channel function of the cardiac ryanodine receptor (RyR2) is modulated by calmodulin (CaM). However, the involvement of CaM in aberrant Ca(2+) release in diseased hearts remains unclear. Here, we investigated the pathogenic role of defective CaM binding to the RyR2 in the channel dysfunction associated with he...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvs271
更新日期:2012-12-01 00:00:00
abstract:OBJECTIVE:Matrix metalloproteinases (MMPs) cause extracellular matrix degradation and may be involved in the rupture of atherosclerotic plaques by degrading fibrous cap, resulting in the intravascular thrombus formation. Here we examined whether local overexpression of MMP-9 alters the characteristics of arteriosclerot...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(02)00710-1
更新日期:2003-02-01 00:00:00
abstract::Functional studies in extrarenal non-epithelial cells such as smooth muscle cells and easily accessible human lymphocytes have demonstrated that aldosterone not only produces classical genomic effects, but also rapid non-genomic effects on transmembrane electrolyte movements. These involve the activation of the Na+/H+...
journal_title:Cardiovascular research
pub_type: 杂志文章,评审
doi:
更新日期:1995-02-01 00:00:00
abstract::Nitric oxide (NO) is a highly reactive, free radical signalling molecule that is constitutively released in cardiomyocytes by both the endothelial and neuronal isoforms of nitric oxide synthase (eNOS and nNOS, respectively). There are increasing data indicating that NO modulates various proteins involved in excitation...
journal_title:Cardiovascular research
pub_type: 杂志文章,评审
doi:10.1093/cvr/cvm012
更新日期:2008-01-15 00:00:00
abstract:AIMS:Baicalin is the major component found in Scutellaria baicalensis root, a widely used herb in traditional Chinese medicine. Although it has been used for thousands of years to treat stroke, the mechanisms of action of S. baicalensis have not been clearly elucidated. In this report, we studied the modulation of angi...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvq296
更新日期:2011-02-01 00:00:00
abstract:OBJECTIVE:Heart failure is associated with reduced function of sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA2a) but increased function of sarcolemmal Na+/Ca2+ exchanger (NCX), leading to decreased SR Ca2+ content and loss of frequency-potentiation of contractile force. We reported that SERCA2a-overexpression in transg...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/j.cardiores.2005.05.006
更新日期:2005-09-01 00:00:00
abstract:AIMS:The P2Y12 antagonist ticagrelor reduces mortality in patients with acute coronary syndrome (ACS), compared with clopidogrel, and the mechanisms underlying this effect are not clearly understood. Arterial thrombosis is the key event in ACS; however, direct vascular effects of either ticagrelor or clopidogrel with f...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvw233
更新日期:2017-01-01 00:00:00
abstract:AIMS:Expression of extracellular matrix protein CCN1 is induced in end-stage ischaemic cardiomyopathy in humans, and after cardiac ischaemia and reperfusion in experimental animal models. Despite its well-documented angiogenic activities, CCN1 increases the cytotoxicities of the tumour necrosis factor family cytokines,...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvt001
更新日期:2013-04-01 00:00:00
abstract:OBJECTIVE:The mechanism of the protective effect of ischaemic preconditioning in the myocardium is not yet known. The aim of this study was to test the hypothesis that endogenous myocardial catecholamines may be mediators of preconditioning. METHODS:To test whether endogenous catecholamines are involved in preconditio...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:
更新日期:1995-01-01 00:00:00
abstract::The structural nature of fibrillar collagen involved in the replacement fibrosis which accompanies discrete areas of cell necrosis remains uncertain, as does its influence on the diastolic and systolic stiffness of the intact myocardium. This study, using 15 micron diameter microsphere embolisation of the rat myocardi...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/23.8.655
更新日期:1989-08-01 00:00:00
abstract:STUDY OBJECTIVE:The aim was to record diastolic transmitral pressure gradients at high sensitivity to quantitate the effect on transmitral pressure gradients of changing the heart rate. DESIGN:Diastolic left atrial and left ventricular pressures were recorded at high sensitivity (40 mm Hg = 10 mm recorded deflection) ...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/24.7.560
更新日期:1990-07-01 00:00:00
abstract::The effect of circulation time on plasma high density lipoprotein cholesterol concentrations was investigated in 20 male Wistar rats injected with alcohol, stressed with lighting, or fed a high fat diet. Circulation time was measured during anaesthesia with a computerised dichromatic earpiece densitometer. Indocyanine...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/22.5.368
更新日期:1988-05-01 00:00:00
abstract:STUDY OBJECTIVE:The aim of the study was to determine whether the deleterious effects of anaesthesia on cardiac muscle function were due to disturbance of protein synthesis. Comparative investigations were made on anaerobic and aerobic skeletal muscles, and plasma insulin and growth hormone levels were also measured to...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/25.4.314
更新日期:1991-04-01 00:00:00
abstract::Since increases in blood pressure may be effectively controlled by hydraulic feedback by reducing the venous return through the inferior vena cava in proportion to the blood pressure this principle was applied using a totally implantable extravascular system consisting of a periaortic blood pressure sensor and a peric...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/21.5.337
更新日期:1987-05-01 00:00:00
abstract:OBJECTIVE:The aim was to characterise the influence of a decrease in transsarcolemmal calcium influx on the calcium content of the sarcoplasmic reticulum and on the force of postrest contraction, which is largely activated by calcium released from the sarcoplasmic reticulum. METHODS:Isometric force of postrest contrac...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/27.5.801
更新日期:1993-05-01 00:00:00
abstract::Microelectrode recordings of skin nerve sympathetic activity were made in the median nerve supplying the right hand of nine patients with Raynaud's phenomenon and 10 control subjects. With subjects warmed up (finger temperature 33 to 34 degrees C) different manoeuvres were used to evoke strong, single sympathetic burs...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/19.5.249
更新日期:1985-05-01 00:00:00
abstract:OBJECTIVE:Oxidized low-density lipoproteins (ox-LDL) or their components suppress macrophage inflammatory response by down-regulating cytokine synthesis, nitric oxide synthase and inducible cyclooxygenase (Cox-2). This event is crucial for the pathophysiological process leading to the formation of atherosclerotic plaqu...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(02)00437-6
更新日期:2002-08-01 00:00:00
abstract::Impairment of contractile function and extent of release of several intracellular marker enzymes and DNA were studied in isolated perfused rat hearts after low-flow (0.16 ml . min-1) ischaemia followed by 2 h of reperfusion and after anoxia followed by 2 h of reoxygenation. After varying periods of ischaemia or anoxia...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/18.12.768
更新日期:1984-12-01 00:00:00
abstract:OBJECTIVE:In pigs, the infarct size (IS) reduction achieved by a strong preconditioning stimulus (IPs) of 10 min ischemia and 15 min reperfusion is greater than that by a weaker preconditioning stimulus (IPw) of 3 min ischemia and 15 min reperfusion. The cardioprotection achieved by IPw is completely abolished by block...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(01)00505-3
更新日期:2002-08-15 00:00:00
abstract::The hypothalamic-pituitary-adrenal (HPA) axis, like the sympathetic nervous system and the renin-angiotensin-aldosterone (RAA) system, sustains life in stressful situations by increasing vascular tone and ensuring fuel availability. It also modulates inflammation and tissue repair processes. Untoward cardiovascular ef...
journal_title:Cardiovascular research
pub_type: 杂志文章,评审
doi:10.1016/j.cardiores.2004.07.006
更新日期:2004-11-01 00:00:00
abstract:AIM:Mechanical forces are important regulators of cell and tissue phenotype. We hypothesized that mechanical loading and boundary conditions would influence neovessel activity during angiogenesis. METHODS AND RESULTS:Using an in vitro model of angiogenesis sprouting and a mechanical loading system, we evaluated the ef...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvn055
更新日期:2008-05-01 00:00:00
abstract:OBJECTIVE:To study the effect of cardiac contraction on left coronary artery pressure-flow relations at different vascular volumes and to compare these relations in the beating heart with those in the heart arrested in systole and diastole. METHODS:Maximally vasodilated, Tyrode perfused, rabbit hearts (n = 6) with an ...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(98)00119-9
更新日期:1998-10-01 00:00:00
abstract:AIMS:Our recent work demonstrated that common cardiovascular progenitor cells are characterized and induced by the expression of the transcription factor mesoderm posterior1 (MesP1) in vertebrate embryos and murine embryonic stem cells. As the proliferative potential of stem cell-derived cardiomyocytes is limited, it i...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvr158
更新日期:2011-10-01 00:00:00
abstract:AIMS:Atrial fibrillation (AF) is the most common type of arrhythmia in humans, yet the genetic cause of AF remains elusive. Genome-wide association studies (GWASs) have reported risk variants in four distinct genetic loci, and more recently, a meta-GWAS has further implicated six new loci in AF. However, the functional...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvv207
更新日期:2016-01-01 00:00:00
abstract::When the vagus nerves are stimulated with one burst of pulses per minute, but each burst is placed at a different time in the cardiac cycle, a "vagal effect curve" can be derived which displays the changes in cardiac cycle length (CCL) as a function of the elapsed time from the stimulus. This curve consists of a prima...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/18.2.75
更新日期:1984-02-01 00:00:00
abstract::An isolated working rat heart preparation was used to characterise the temperature-dependency of the anti-ischaemic properties of nifedipine. In this study hearts were subjected to pre-ischaemic infusion with the St Thomas' cardioplegic solution with or without added nifedipine (0.075 mumol X litre-1). Hearts were the...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/19.2.95
更新日期:1985-02-01 00:00:00
abstract:Aims:Atherosclerosis is an inflammatory disease wherein cholesterol-loaded macrophages play a major role. MicroRNAs and microparticles propagate inflammatory pathways and are involved in cardiovascular disease. We aimed to screen and validate circulating microRNAs correlated with atherosclerosis development in humans, ...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvx157
更新日期:2017-11-01 00:00:00
abstract:OBJECTIVE:The aim was to examine the effect of doxorubicin on spontaneous cyclic Ca2+ release from the sarcoplasmic reticulum of skinned fibres, as measured by isometric tension development in EGTA free, Ca2+ free solution. METHODS:Experiments were done on fragments of papillary muscles from the right ventricles of gu...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/26.4.371
更新日期:1992-04-01 00:00:00