IKr and IKs remodeling differentially affects QT interval prolongation and dynamic adaptation to heart rate acceleration in bradycardic rabbits

Suto, Fumiaki; Zhu, Wei; Chan, Alice; Gross, Gil J.

doi:10.1152/ajpheart.00932.2006

Cited by 8 publications

(5 citation statements)

References 30 publications

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“…This is believed to be the result of a downregulation of I Ks and of the general b-receptor density. 34,35 In line with these findings, we observed that the b-receptor response on stimulation with Iso differentially affected the adaptation of HR and QT. The in vivo infusion of Iso showed an unaltered response of HR to 1 mg$kg −1 $min −1 between control and tachypaced but a significantly attenuated QT shortening and shortened DI in tachypaced, indicating a preserved effect of b-adrenergic stimulation on HR, whereas the response of QT shortening was attenuated due to a reduced repolarization reserve in tachypaced compared with control.…”

Section: Attenuated Response To B-adrenergic Stimulationsupporting

confidence: 85%

Attenuated Ventricular β-Adrenergic Response and Reduced Repolarization Reserve in a Rabbit Model of Chronic Heart Failure

Nissen

Thomsen²,

Bentzen³

et al. 2012

Journal of Cardiovascular Pharmacology

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Animal models of pacing-induced heart failure (HF) are often associated with high acute mortality secondary to high pacing frequencies. The present study therefore exploits lower-frequency left ventricular pacing (300 beats per minute) in rabbits for 11 weeks to produce chronic HF with low acute mortality but profound structural, functional, and electrical remodeling and compare with nonpaced controls. Pacing increased heart weight/body weight ratio and decreased left ventricular fractional shortening in tachypaced only. Electrocardiogram recordings during sinus rhythm revealed QTc prolongation in paced animals. Ventricular arrhythmias or sudden death was not observed. Isoproterenol increased heart rate similarly in both groups but showed a blunted QT-shortening effect in tachypaced rabbits compared with controls. Langendorff experiments revealed significant monophasic action potential duration prolongation in tachypaced hearts and reduced contractility at cycle lengths from 400 to 250 ms. Hyperkalemia caused monophasic action potential duration shortening in controls, whereas crossover was seen in tachypaced with monophasic action potential duration prolongation at short cycle length. Hypokalemia prolonged monophasic action potential duration and increased short-term variability of repolarization in tachypaced hearts. A blunted monophasic action potential duration response was observed ex vivo in tachypaced hearts after isoproterenol. The HF rabbits showed structural, functional, and electrical remodeling but very low mortality. Isokalemic and hyperkalemic responses indicate downregulation of functional IKs. Increased short-term variability during hypokalemia unmasks a reduced repolarization reserve.

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Section: Attenuated Response To B-adrenergic Stimulationsupporting

confidence: 85%

Attenuated Ventricular β-Adrenergic Response and Reduced Repolarization Reserve in a Rabbit Model of Chronic Heart Failure

Nissen

Thomsen²,

Bentzen³

et al. 2012

Journal of Cardiovascular Pharmacology

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“…I Ks appears to be most important during physical exertion or other contexts when β–adrenergic stimulation increases I K s density to compensate for higher heart rates. At other times, I Kr (generated by hERG, which is regulated in vivo by KCNE1 and KCNE2) is probably dominant in human ventricles 87,88 .…”

Section: Physiological Roles For Kcne1: the Heart And Inner Earmentioning

confidence: 99%

KCNE1 and KCNE3: The yin and yang of voltage-gated K+ channel regulation

Abbott

2016

Gene

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The human KCNE gene family comprises five genes encoding single transmembrane-spanning ion channel regulatory subunits. The primary function of KCNE genes appears to be regulation of voltage-gated potassium (Kv) channels, and the best-understood KCNE complexes are with the KCNQ1 Kv α subunit. Here, we review the often opposite effects of KCNE1 and KCNE3 on Kv channel biology, with an emphasis on regulation of KCNQ1. Slow-activating IKs channel complexes formed by KCNQ1 and KCNE1 are essential for human ventricular myocyte repolarization, while constitutively active KCNQ1-KCNE3 channels are important in the intestine. Inherited sequence variants in human KCNE1 and KCNE3 cause cardiac arrhythmias but by different mechanisms, and each is important for hearing in unique ways. Because of their contrasting effects on KCNQ1 function, KCNE1 and KCNE3 have proved an invaluable tool in the mechanistic understanding of how channel gating can be manipulated, and each may also provide a window into novel insights and new therapeutic opportunities in K+ channel pharmacology. Finally, findings from studies of Kcne1−/− and Kcne3−/− mouse lines serve to illustrate the complexity of KCNE biology and KCNE-linked disease states.

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“…Abnormal QT adaptation abnormalities have been associated with higher mortality (15) and ventricular fibrillation (34). Autonomic nervous system modulation and the slow-activating delayed rectifier I Ks current have been shown to affect QT adaptation (32,33); however, other factors may be involved. It is our hypothesis that the rapid decrease in pK during recovery following exercise may modulate the QT adaptation to heart rate recovery.…”

Section: Tran Ct Bundgaard H Ladefoged Sd Haunsø S Kjeldsen Kmentioning

confidence: 99%

Potassium dynamics are attenuated in hyperkalemia and a determinant of QT adaptation in exercising hemodialysis patients

Tran

Bundgaard

Ladefoged

et al. 2013

Journal of Applied Physiology

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Disturbances in plasma potassium concentration (pK) are well known risk factors for the development of cardiac arrhythmia. The aims of the present study were to evaluate the effect of hemodialysis on exercise pK dynamics and QT hysteresis, and whether QT hysteresis is associated with the pK decrease following exercise. Twenty-two end-stage renal disease patients exercised on a cycle ergometer with incremental work load before and after hemodialysis. ECG was recorded and pK was measured during exercise and recovery. During exercise, pK increased from 5.1 ± 0.2 to 6.1 ± 0.2 mM (mean ± SE; P < 0.0001) before hemodialysis and from 3.8 ± 0.1 to 5.1 ± 0.1 mM (P < 0.0001) after hemodialysis. After 2 min of recovery, pK had decreased to 5.0 ± 0.2 mM and 4.1 ± 0.1 mM (P < 0.0001) before and after hemodialysis, respectively. pK increase during exercise was accentuated after hemodialysis. The pK increase was negatively linearly correlated with pK before exercise (β = -0.21, R(2) = 0.23, P = 0.001). QT hysteresis was negatively linearly correlated with the decrease in pK during recovery (β = -28 ms/mM, R(2) = 0.36, P = 0.006). Thus, during recovery, low pK was associated with relatively longer QT interval. In conclusion, new major findings are an accentuated increase in pK during exercise after hemodialysis, an attenuated increase in pK in hyperkalemia, and an association between pK and QT interval adaptation during recovery. The acute pK shift after exercise may modulate QT interval adaptation and trigger cardiac arrhythmias.

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I_Kr and I_Ks remodeling differentially affects QT interval prolongation and dynamic adaptation to heart rate acceleration in bradycardic rabbits

Cited by 8 publications

References 30 publications

Attenuated Ventricular β-Adrenergic Response and Reduced Repolarization Reserve in a Rabbit Model of Chronic Heart Failure

Attenuated Ventricular β-Adrenergic Response and Reduced Repolarization Reserve in a Rabbit Model of Chronic Heart Failure

KCNE1 and KCNE3: The yin and yang of voltage-gated K+ channel regulation

Potassium dynamics are attenuated in hyperkalemia and a determinant of QT adaptation in exercising hemodialysis patients

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