Abstract：
:Long QT syndrome is a potentially life-threatening disease characterized by delayed repolarization of cardiomyocytes, QT interval prolongation in the electrocardiogram, and a high risk for sudden cardiac death caused by ventricular arrhythmia. The genetic type 3 of this syndrome (LQT3) is caused by gain-of-function mutations in the SCN5A cardiac sodium channel gene which mediates the fast Nav1.5 current during action potential initiation. Here, we report the analysis of LQT3 human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). These were generated from a patient with a heterozygous p.R1644H mutation in SCN5A known to interfere with fast channel inactivation. LQT3 hiPSC-CMs recapitulated pathognomonic electrophysiological features of the disease, such as an accelerated recovery from inactivation of sodium currents as well as action potential prolongation, especially at low stimulation rates. In addition, unlike previously described LQT3 hiPSC models, we observed a high incidence of early after depolarizations (EADs) which is a trigger mechanism for arrhythmia in LQT3. Administration of specific sodium channel inhibitors was found to shorten action and field potential durations specifically in LQT3 hiPSC-CMs and antagonized EADs in a dose-dependent manner. These findings were in full agreement with the pharmacological response profile of the underlying patient and of other patients from the same family. Thus, our data demonstrate the utility of patient-specific LQT3 hiPSCs for assessing pharmacological responses to putative drugs and for improving treatment efficacies.
journal_name
Basic Res Cardioljournal_title
Basic research in cardiologyauthors
Malan D,Zhang M,Stallmeyer B,Müller J,Fleischmann BK,Schulze-Bahr E,Sasse P,Greber Bdoi
10.1007/s00395-016-0530-0subject
Has Abstractpub_date
2016-03-01 00:00:00pages
14issue
2eissn
0300-8428issn
1435-1803pii
10.1007/s00395-016-0530-0journal_volume
111pub_type
杂志文章abstract：:Diseases accompanied by severe cardiac impairment like sepsis and chronic uremia are frequently linked to an increase in cytokine release. In order to investigate possible toxic effects of the immune mediators on myocardial cells, we studied the contractility of cardiac myocytes and the de novo formation of stress pro...
journal_title：Basic research in cardiology
pub_type： 杂志文章
doi：10.1007/BF00795385
更新日期：1992-01-01 00:00:00
abstract：:Short repeated cycles of peripheral ischemia/reperfusion (I/R) can protect distant organs from subsequent prolonged I/R injury; a phenomenon known as remote ischemic preconditioning (RIPC). A RIPC-mediated release of humoral factors might play a key role in this protection and vascular endothelial cells are potential ...
journal_title：Basic research in cardiology
pub_type： 杂志文章
doi：10.1007/s00395-015-0474-9
更新日期：2015-03-01 00:00:00
abstract：:In order to clarify the genesis of the characteristic pressure and flow pulse contours of the common carotid artery of man, at first transcutaneous pulse recordings were carried out on healthy resting subjects during breathing of room air and of a mixture of 95% O2 and 5% CO2 (Carbogen). The latter was used to cause v...
journal_title：Basic research in cardiology
pub_type： 杂志文章
doi：10.1007/BF01907041
更新日期：1977-11-01 00:00:00
abstract：:Delta-opioid receptors are known to participate in the protection found following ischemic preconditioning (IPC), but the role of kappa-receptors in IPC is currently controversial. Langendorff-perfused rat hearts received 35 min regional ischemia and 2 h reperfusion. PC (2 cycles 5 min global ischemia) substantially r...
journal_title：Basic research in cardiology
pub_type： 杂志文章
doi：10.1007/s003950050001
更新日期：2000-02-01 00:00:00
abstract：:The cardiac hormone atrial natriuretic peptide (ANP) regulates systemic and pulmonary arterial blood pressure by activation of its cyclic GMP-producing guanylyl cyclase-A (GC-A) receptor. In the lung, these hypotensive effects were mainly attributed to smooth muscle-mediated vasodilatation. It is unknown whether pulmo...
journal_title：Basic research in cardiology
pub_type： 杂志文章
doi：10.1007/s00395-016-0541-x
更新日期：2016-03-01 00:00:00
abstract：:Pressure-overloaded cardiac hypertrophy was induced by abdominal aortic constriction in 10-week-old male Wistar rats. 24-26 weeks after aortic constriction, the hearts were excised and a myocardial mechanical study was performed using isolated left ventricular papillary muscles. There was no significant difference in ...
journal_title：Basic research in cardiology
pub_type： 杂志文章
doi：10.1007/BF01907024
更新日期：1987-07-01 00:00:00
abstract：:The role of the cardiac current Ik1 in arrhythmogenesis remains highly controversal. To gain further insights into the mechanisms of IK1 involvement in cardiac excitability, we studied the susceptibility of transgenic mice with altered IK1 to arrhythmia during various pharmacological and physiological challenges. Arrh...
journal_title：Basic research in cardiology
pub_type： 杂志文章
doi：10.1007/s00395-007-0659-y
更新日期：2007-09-01 00:00:00
abstract：:Nitroglycerin (GTN) and other organic nitrates are widely used vasodilators. Their side effects are development of nitrate tolerance and endothelial dysfunction. Given the potential of GTN to induce nitro-oxidative stress, we investigated the interaction between nitro-oxidative DNA damage and vascular dysfunction in e...
journal_title：Basic research in cardiology
pub_type： 杂志文章
doi：10.1007/s00395-016-0571-4
更新日期：2016-07-01 00:00:00
abstract：:We have examined the sodium-calcium exchange stoichiometry in Langendorff-perfused rabbit hearts using gamma-emitting tracers under conditions of sodium pump inhibition. Following a 60-min perfusion with 10(-5) acetylstrophanthidin, and extracellular concentrations [Na]o = 70 mM and [Ca]o = 300 microM, intracellular s...
journal_title：Basic research in cardiology
pub_type： 杂志文章
doi：10.1007/BF01907365
更新日期：1988-05-01 00:00:00
abstract：:Rat hearts were exposed and injured locally by direct cryoapplication. The hearts were examined 2, 4, 20 and 48 hours, 7 and 12 days later. In the first 48 hours mast cell and polymorphonuclear (mainly eosinophilic) granulocyte infiltration was followed by proliferation of mononuclear phagocytic and fibroblastic cells...
journal_title：Basic research in cardiology
pub_type： 杂志文章
doi：10.1007/BF01907742
更新日期：1979-05-01 00:00:00
abstract：:Cardiovascular cell therapy offers the first real potential to treat the underlying injuries associated with cardiac and vascular disease. By delivering appropriate exogenous cells to an injury site, the potential exists to mitigate injury or even to begin to reverse damage. Based on their inordinate pre-clinical prom...
journal_title：Basic research in cardiology
pub_type： 杂志文章,评审
doi：10.1007/s00395-004-0558-z
更新日期：2005-11-01 00:00:00
abstract：:At 36 degrees C and 2 mM [Ca2+]o, single guinea-pig ventricular myocytes were voltage clamped with patch electrodes. When paired pulsing had potentiated the contraction to the maximum, the cells were shock-frozen for electron probe microanalysis (EPMA). Shock-freezing was timed at the end of diastole (-80 mV) or at di...
journal_title：Basic research in cardiology
pub_type： 杂志文章
doi：10.1007/978-3-662-30769-4_9
更新日期：1991-01-01 00:00:00
abstract：:The renin angiotensin system and endothelium-derived vasoactive substances are both important regulators of vascular tone. Recent evidence suggests that the two systems may be tightly interconnected and drugs interfering with one system may also affect the other. Beside the circulating renin angiotensin system, a vasc...
journal_title：Basic research in cardiology
pub_type： 杂志文章,评审
doi：10.1007/978-3-642-72497-8_2
更新日期：1993-01-01 00:00:00
abstract：:The effects of 3 hours of ischemia and 1 hour of reperfusion on biochemical, physiological and ultrastructural parameters were studied in 12 dogs. In the ischemic subendocardium without reperfusion, mitochondrial losses of adenine (ATP + ADP + AMP) and pyridine (NAD + NADH) nucleotides far exceeded those observed in w...
journal_title：Basic research in cardiology
pub_type： 杂志文章
doi：10.1007/BF01908307
更新日期：1984-03-01 00:00:00
abstract：:The purpose of this study was to determine the effects of bradykinin (BK), substance P (SP) and histamine on plasma exudation in the skin of conscious dogs with and without pacing-induced heart failure. We also determined the role tissue angiotensin I-converting enzyme (ACE) and neutral endopeptidase (NEP) play in mod...
journal_title：Basic research in cardiology
pub_type： 杂志文章
doi：10.1007/BF00788284
更新日期：1994-09-01 00:00:00
abstract：:The effects of the potassium channel openers (KCO), cromakalim or pinacidil, were evaluated in an anesthetized porcine model of pacing- and ischemia-induced ventricular fibrillation (VF). Hearts were paced at 180 bpm and the left anterior descending coronary artery was occluded until VF was induced. Reproducible times...
journal_title：Basic research in cardiology
pub_type： 杂志文章
doi：10.1007/BF00788735
更新日期：1994-03-01 00:00:00
abstract：:Acute ischemia is a well-known inductor of extracellular matrix (ECM) remodeling, which leads to the development of congestive heart failure and is associated with left ventricular dilatation. Here we investigate the timecourse of ECM processing with release of endostatin (ES) and other low-molecular-weight fragments ...
journal_title：Basic research in cardiology
pub_type： 杂志文章
doi：10.1007/s00395-009-0013-7
更新日期：2009-09-01 00:00:00
abstract：:We tested the hypotheses that myocardial infarction in mice would lead to progressively worsening heart failure 12-18 weeks later and that exercise testing would provide a suitable means to evaluate left ventricular function sequentially. C57BL/6 mice (n = 69) underwent left coronary artery ligation (n = 50) or thorac...
journal_title：Basic research in cardiology
pub_type： 杂志文章
doi：10.1007/s003950200013
更新日期：2002-05-01 00:00:00
abstract：:The pathogenesis of atherosclerosis is a multifactorial process. A possible anti-atherosclerotic drug should therefore interfere with different targets that are important during the development of an atherosclerotic lesion. Two of the early events are the activated migration and proliferation of arterial smooth muscle...
journal_title：Basic research in cardiology
pub_type： 杂志文章
doi：10.1007/BF01907976
更新日期：1989-05-01 00:00:00
abstract：:Atherosclerotic plaque rupture is the key event in the pathogenesis of acute coronary syndromes and it also occurs during coronary interventions. Atherosclerotic plaque rupture does not always result in complete thrombotic occlusion of the epicardial coronary artery with subsequent impending myocardial infarction, but...
journal_title：Basic research in cardiology
pub_type： 杂志文章,评审
doi：10.1007/s00395-006-0616-1
更新日期：2006-09-01 00:00:00
abstract：:Ventricular remodeling following nonfatal myocardial infarction includes an excentric hypertrophy of the surviving myocardium, associated with hemodynamic overload. Disseminated cardiomyocyte apoptosis and phenotype changes of the surviving myocardium, such as a labile calcium homeostasis of the hypertrophied cardiomy...
journal_title：Basic research in cardiology
pub_type： 杂志文章,评审
doi：10.1007/s003950050228
更新日期：1998-01-01 00:00:00
abstract：BACKGROUND:Reopening of the infarct-related coronary artery is the treatment of choice in the clinical setting of acute myocardial infarction. Nevertheless the removal of the total occlusion obtained either by thrombolysis or by primary angioplasty is followed by the ischemia/reperfusion sequelae. One of many proposed ...
journal_title：Basic research in cardiology
pub_type： 杂志文章
doi：10.1007/s003950200049
更新日期：2002-09-01 00:00:00
abstract：:Toxic peroxides result when oxygen radicals react with various peroxidic precursors in tissue or blood. A colorimetric method based on reactions of malondialdehyde (MDA), a key intermediate in the formation of peroxides, has been described in fresh tissues. The present report adapts this assay to measure MDA levels in...
journal_title：Basic research in cardiology
pub_type： 杂志文章
doi：10.1007/BF01910480
更新日期：1984-09-01 00:00:00
abstract：:Ventricular and atrial cardiac muscle cells isolated from the adult rat have been cultured and characterized. Once established in culture these myocytes resemble morphologically their in vivo counterparts except that they are flattened on the surface of the culture flask. These cultured cells possess differentiated ul...
journal_title：Basic research in cardiology
pub_type： 杂志文章
doi：
更新日期：1985-01-01 00:00:00
abstract：:Recent reports indicate that elevating DNA glycosylase/AP lyase repair enzyme activity offers marked cytoprotection in cultured cells and a variety of injury models. In this study, we measured the effect of EndoIII, a fusion protein construct that traffics Endonuclease III, a DNA glycosylase/AP lyase, to the mitochond...
journal_title：Basic research in cardiology
pub_type： 杂志文章
doi：10.1007/s00395-014-0459-0
更新日期：2015-03-01 00:00:00
abstract：:Calcium transport functions of mitochondria and sarcoplasmic reticulum (SR) were studied without prior extraction using isolated rat heart myocytes permeabilized with saponin. Calcium uptake by SR was rapid and its affinity was high in comparison to calcium uptake by mitochondria, which had a higher capacity. The sens...
journal_title：Basic research in cardiology
pub_type： 杂志文章
doi：10.1007/BF01907975
更新日期：1989-05-01 00:00:00
abstract：:Recent studies demonstrated that NADPH oxidase 2 (NOX2) expression in myocardium after ischemia-reperfusion (IR) is significantly upregulated. However, the underlying mechanisms remain unknown. This study aims to determine if nuclear cardiac myosin light chain 2 (MYL2), a well-known regulatory subunit of myosin, funct...
journal_title：Basic research in cardiology
pub_type： 杂志文章
doi：10.1007/s00395-015-0494-5
更新日期：2015-01-01 00:00:00
abstract：:The influence of changes in pre- and afterload, heart frequency and inotropic state on the difference between right ventricular dP/dtmax measured isovolumically and auxotonically has been investigated in canine heart-lung preparations. Isovolumic systoles were obtained by occluding the pulmonary artery during diastole...
journal_title：Basic research in cardiology
pub_type： 杂志文章
doi：10.1007/BF01909767
更新日期：1976-09-01 00:00:00
abstract：:Light in the near-infrared (NIR) region between 700-900 nm can penetrate deep into living tissue, thereby offering a unique opportunity to use near-infrared fluorescence (NIRF) imaging techniques to detect and visualize fluorescent probes in-vivo. In the past few years, many novel NIR fluorescent probes have been desi...
journal_title：Basic research in cardiology
pub_type： 杂志文章,评审
doi：10.1007/s00395-008-0702-7
更新日期：2008-03-01 00:00:00
abstract：:Receptor for advanced glycation end products (RAGE) and connective tissue growth factor (CTGF) play a key role in diabetic myocardial fibrosis, and peroxisome proliferator-activated receptor-gamma (PPAR-gamma) activation has been reported to reduce RAGE and CTGF expression. This study investigated the effects of the P...
journal_title：Basic research in cardiology
pub_type： 杂志文章
doi：10.1007/s00395-009-0071-x
更新日期：2010-05-01 00:00:00
