Attenuated ventricular β-adrenergic response and reduced repolarization reserve in a rabbit model of chronic heart failure

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Jakob Dahl Nissen, Morten Bækgaard Thomsen, Bo Hjorth Bentzen, Jonas Goldin Diness, Thomas Goldin Diness, Thomas Jespersen, Morten Grunnet

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.
OriginalsprogEngelsk
TidsskriftJournal of Cardiovascular Pharmacology
Vol/bind59
Udgave nummer2
Sider (fra-til)142-150
Antal sider9
ISSN0160-2446
DOI
StatusUdgivet - 2012

ID: 37726393