TY - JOUR

T1 - Attenuated ventricular β-adrenergic response and reduced repolarization reserve in a rabbit model of chronic heart failure

AU - Nissen, Jakob Dahl

AU - Thomsen, Morten Bækgaard

AU - Bentzen, Bo Hjorth

AU - Diness, Jonas Goldin

AU - Diness, Thomas Goldin

AU - Jespersen, Thomas

AU - Grunnet, Morten

PY - 2012

Y1 - 2012

N2 - 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.

AB - 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.

KW - Action Potentials

KW - Adrenergic beta-Agonists

KW - Animals

KW - Cardiac Pacing, Artificial

KW - Chronic Disease

KW - Disease Models, Animal

KW - Down-Regulation

KW - Electrocardiography

KW - Female

KW - Heart Failure

KW - Heart Rate

KW - Hyperkalemia

KW - Hypokalemia

KW - Isoproterenol

KW - Long QT Syndrome

KW - Myocardial Contraction

KW - Potassium Channels

KW - Rabbits

U2 - 10.1097/FJC.0b013e318238727a

DO - 10.1097/FJC.0b013e318238727a

M3 - Journal article

C2 - 21992969

VL - 59

SP - 142

EP - 150

JO - Journal of Cardiovascular Pharmacology

JF - Journal of Cardiovascular Pharmacology

SN - 0160-2446

IS - 2

ER -