AimsClinical observations in patients with long QT syndrome carrying sodium channel mutations (LQT3) suggest that bradycardia caused by parasympathetic stimulation may provoke torsades de pointes (TdP). β-Adrenoceptor blockers appear less effective in LQT3 than in other forms of the disease.Methods and resultsWe studied effects of autonomic modulation on arrhythmias in vivo and in vitro and quantified sympathetic innervation by autoradiography in heterozygous mice with a knock-in deletion (ΔKPQ) in the Scn5a gene coding for the cardiac sodium channel and increased late sodium current (LQT3 mice). Cholinergic stimulation by carbachol provoked bigemini and TdP in freely roaming LQT3 mice. No arrhythmias were provoked by physical stress, mental stress, isoproterenol, or atropine. In isolated, beating hearts, carbachol did not prolong action potentials per se, but caused bradycardia and rate-dependent action potential prolongation. The muscarinic inhibitor AFDX116 prevented effects of carbachol on heart rate and arrhythmias. β-Adrenoceptor stimulation suppressed arrhythmias, shortened rate-corrected action potential duration, increased rate, and minimized difference in late sodium current between genotypes. β-Adrenoceptor density was reduced in LQT3 hearts. Acute β-adrenoceptor blockade by esmolol, propranolol or chronic propranolol in vivo did not suppress arrhythmias. Chronic flecainide pre-treatment prevented arrhythmias (all P < 0.05).ConclusionCholinergic stimulation provokes arrhythmias in this model of LQT3 by triggering bradycardia. β-Adrenoceptor density is reduced, and β-adrenoceptor blockade does not prevent arrhythmias. Sodium channel blockade and β-adrenoceptor stimulation suppress arrhythmias by shortening repolarization and minimizing difference in late sodium current.

. Altered sinus nodal and atrioventricular nodal function in freely moving mice overexpressing the A1 adenosine receptor. Am J Physiol Heart Circ Physiol 285: H145-H153, 2003. First published March 13, 2003 10.1152/ ajpheart.01036.2002To investigate whether altered function of adenosine receptors could contribute to sinus node or atrioventricular (AV) nodal dysfunction in conscious mammals, we studied transgenic (TG) mice with cardiac-specific overexpression of the A 1 adenosine receptor (A1AR). A Holter ECG was recorded in seven freely moving littermate pairs of mice during normal activity, exercise (5 min of swimming), and 1 h after exercise. TG mice had lower maximal heart rates (HR) than wild-type (WT) mice (normal activity: 437 Ϯ 18 vs. 522 Ϯ 24 beats/min, P Ͻ 0.05; exercise: 650 Ϯ 13 vs. 765 Ϯ 28 beats/min, P Ͻ 0.05; 1 h after exercise: 588 Ϯ 18 vs. 720 Ϯ 12 beats/min, P Ͻ 0.05; all values are means Ϯ SE). Mean HR was lower during exercise (589 Ϯ 16 vs. 698 Ϯ 34 beats/min, P Ͻ 0.05) and after exercise (495 Ϯ 16 vs. 592 Ϯ 27 beats/min, P Ͻ 0.05). Minimal HR was not different between genotypes. HR variability (SD of RR intervals) was reduced by 30% (P Ͻ 0.05) in TG compared with WT mice. Pertussis toxin (n ϭ 4 pairs, 150 g/kg ip) reversed bradycardia after 48 h. TG mice showed first-degree AV nodal block (PQ interval: 42 Ϯ 2 vs. 37 Ϯ 2 ms, P Ͻ 0.05), which was diminished but not abolished by pertussis toxin. Isolated Langendorffperfused TG hearts developed spontaneous atrial arrhythmias (3 of 6 TG mice vs. 0 of 9 WT mice, P Ͻ 0.05). In conclusion, A 1AR regulate sinus nodal and AV nodal function in the mammalian heart in vivo. Enhanced expression of A 1AR causes sinus nodal and AV nodal dysfunction and supraventricular arrhythmias. heart rate regulation; autonomous nervous system; heart rate variability; sinus node dysfunction; atrioventricular block; atrial fibrillation

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Objective-An increased expression of adenosine receptors is a promising target for gene therapy aimed at protecting the myocardium against ischemic damage, but may alter cardiac electrophysiology. We therefore studied the effects of heart-directed overexpression of A 3 adenosine receptors (A 3 ARs) at different gene doses on sinus and atrio-ventricular (AV) nodal function in mice.Methods and results-Mice with heart-specific overexpression of A 3 AR at high ( ) or low ( ) levels and their wild-type littermates were studied. Telemetric electrocardiogram (ECG) recordings in adult freely moving mice showed profound sinus bradycardia resulting in either ventricular escape rhythms or an incessant bradycardia-tachycardia syndrome (minimal heart rate 217 ±25*; WT 406 ±21 beats/min, all values as mean ±S.E.M., n = 7 per genotype, *p < 0.05). Exercise attenuated bradycardia in mice (maximal heart rate 650 ±13*; WT 796 ±13 beats/min) and first-degree AV nodal block was present (PQ interval 36 ±4*; WT 23 ±5 ms). Isolated hearts showed complete heart block (10/17 * vs. 1/17 WT). Atrial bradycardia and AV block were already present 3 weeks after birth. Doppler echocardiography revealed atrial dysfunction and progressive atrial enlargement that was moderate at 3 and 8 weeks, and progressed at 12 and 21 weeks of age (all p < 0.05 vs. WT). Atrial contractility and sarcoendoplasmic Ca 2 + ATPase (SERCA) 2a protein expression were reduced in isolated left atria at the age of 14 weeks. Fibrosis was present in left atria at 14 weeks, but not at 5 weeks of age. mice had first-degree AV block without arrhythmias or structural changes. Conclusions-Heart-directed