Sinus node function and ventricular repolarization during exercise stress test in long QT syndrome patients with KvLQT1 and HERG potassium channel defects

Swan, Heikki; Viitasalo, Matti; Piippo, Kirsi; Laitinen, Päivi; Kontula, Kimmo; Toivonen, Lauri

doi:10.1016/s0735-1097(99)00255-7

Cited by 175 publications

(119 citation statements)

References 24 publications

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“…However, no prior data demonstrate a clear primary autonomic abnormality in patients with LQTS. Examination of earlier studies documenting resting heart rate suggest a tendency toward slower heart rate in patients with LQTS, 6 although this has not been previously confirmed. Our data suggest that the slower heart rate observed previously in children Ͻ3 years of age with LQTS 16 seems to be present even in adults, when these measurements are obtained in resting undisturbed conditions and compared with closely matched control subjects.…”

Section: Discussionmentioning

confidence: 88%

Sympathetic Nerve Activity in the Congenital Long-QT Syndrome

et al. 2003

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Background-Patients with congenital long-QT syndrome (LQTS) are susceptible to life-threatening arrhythmias. The sympathetic nervous system may have an important triggering role for cardiovascular events in LQTS. We therefore examined measurements of sympathetic neural traffic in patients with LQTS and matched control subjects. Methods and Results-Twelve patients with congenital LQTS and 12 healthy volunteers matched for age, sex, and body mass index were studied. Heart rate, respiration, blood pressure, and sympathetic nerve activity to the skeletal muscle blood vessels (muscle sympathetic nerve activity) and to the skin (skin sympathetic nerve activity) were monitored and recorded continuously. Resting heart rate (P‫,)30.0؍‬ muscle sympathetic nerve activity burst rate (Pϭ0.008), and burst incidence (Pϭ0.02) were lower in patients with LQTS than in control subjects. However, skin sympathetic nerve activity was very similar in patients with LQTS and control subjects. Spectral analysis of RR variability showed a decreased low-frequency component, an increased high-frequency component, and a decrease in the ratio of the low-frequency component to the high-frequency component in patients with LQTS (Pϭ0.01). Conclusions-LQTS is associated with a selective reduction in sympathetic drive to muscle blood vessels and perhaps also to the heart.

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Section: Discussionmentioning

confidence: 88%

Sympathetic Nerve Activity in the Congenital Long-QT Syndrome

et al. 2003

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“…Western blot analyses of WT hERG overexpression in several systems, including HEK-293 cells, have shown two protein bands at 135 kDa (immature) and 155 kDa (mature) that represent posttranslational core and complex glycosylation of hERG protein, respectively (2,15,19,45). We next transfected the missense mutations, G601S and N470D hERG (12,16,36), that form trafficking-deficient channel proteins when studied in noncardiac mammalian systems (3,16,45). Western blot analysis in the cardiomyocytes showed that G601S and N470D hERG generate 135-kDa protein bands but only weak or no 155-kDa protein bands, indicating that for control conditions these two mutations generate immature protein that then does not undergo normal Golgi processing to the mature protein.…”

Section: Resultsmentioning

confidence: 99%

Properties of WT and mutant hERG K⁺ channels expressed in neonatal mouse cardiomyocytes

Lin

Holzem

Anson

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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Mutations in humanether-a-go-go-related gene 1 (hERG) are linked to long QT syndrome type 2 (LQT2). hERG encodes the pore-forming ␣-subunits that coassemble to form rapidly activating delayed rectifier K ϩ current in the heart. LQT2-linked missense mutations have been extensively studied in noncardiac heterologous expression systems, where biogenic (protein trafficking) and biophysical (gating and permeation) abnormalities have been postulated to underlie the loss-of-function phenotype associated with LQT2 channels. Little is known about the properties of LQT2-linked hERG channel proteins in native cardiomyocyte systems. In this study, we expressed wild-type (WT) hERG and three LQT2-linked mutations in neonatal mouse cardiomyocytes and studied their electrophysiological and biochemical properties. Compared with WT hERG channels, the LQT2 missense mutations G601S and N470D hERG exhibited altered protein trafficking and underwent pharmacological correction, and N470D hERG channels gated at more negative voltages. The ⌬Y475 hERG deletion mutation trafficked similar to WT hERG channels, gated at more negative voltages, and had rapid deactivation kinetics, and these properties were confirmed in both neonatal mouse cardiomyocyte and human embryonic kidney (HEK)-293 cell expression systems. Differences between the cardiomyocytes and HEK-293 cell expression systems were that hERG current densities were reduced 10-fold and deactivation kinetics were accelerated 1.5-to 2-fold in neonatal mouse cardiomyocytes. An important finding of this work is that pharmacological correction of trafficking-deficient LQT2 mutations, as a potential innovative approach to therapy, is possible in native cardiac tissue.

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“…50 Both of these techniques can aid clinicians in distinguishing LQT1 from LQT2 patients. Studies have also shown differential response of LQT1, 2, and 3 patients to epinephrine infusion.…”

Section: Phenotypic Ascertainment: Other Diagnostic Testsmentioning

confidence: 99%

The long QT syndrome family of cardiac ion channelopathies: A HuGE review

Modell

Lehmann

2006

Genetics in Medicine

146

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Long QT syndrome (LQTS) refers to a group of "channelopathies"-disorders that affect cardiac ion channels. The "family" concept of syndromes has been applied to the multiple LQTS genotypes, LQT1-8, which exhibit converging mechanisms leading to QT prolongation and slowed ventricular repolarization. The 470ϩ allelic mutations induce loss-of-function in the passage of mainly K ϩ ions, and gain-of-function in the passage of Na ϩ ions through their respective ion channels. Resultant early after depolarizations can lead to a polymorphic form of ventricular tachycardia known as torsade de pointes, resulting in syncope, sudden cardiac death, or near-death (i.e., cardiac arrest aborted either spontaneously or with external defibrillation). LQTS may be either congenital or acquired. The genetic epidemiology of both forms can vary with subpopulation depending on the allele, but as a whole, LQTS appears in every corner of the globe. Many polymorphisms, such as HERG P448R and A915V in Asians, and SCN5A

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Sinus node function and ventricular repolarization during exercise stress test in long QT syndrome patients with KvLQT1 and HERG potassium channel defects

Cited by 175 publications

References 24 publications

Sympathetic Nerve Activity in the Congenital Long-QT Syndrome

Sympathetic Nerve Activity in the Congenital Long-QT Syndrome

Properties of WT and mutant hERG K⁺ channels expressed in neonatal mouse cardiomyocytes

The long QT syndrome family of cardiac ion channelopathies: A HuGE review

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Sinus node function and ventricular repolarization during exercise stress test in long QT syndrome patients with KvLQT1 and HERG potassium channel defects

Cited by 175 publications

References 24 publications

Sympathetic Nerve Activity in the Congenital Long-QT Syndrome

Sympathetic Nerve Activity in the Congenital Long-QT Syndrome

Properties of WT and mutant hERG K+ channels expressed in neonatal mouse cardiomyocytes

The long QT syndrome family of cardiac ion channelopathies: A HuGE review

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Product

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Properties of WT and mutant hERG K⁺ channels expressed in neonatal mouse cardiomyocytes