Adenosine can be released from the heart and may stimulate four different cardiac adenosine receptors. A receptor subtype that couples to the generation of cyclic adenosine monophosphate (cAMP) is ...the A
2A
-adenosine receptor (A
2A
-AR). To better understand its role in cardiac function, we studied mechanical and electrophysiological effects in transgenic mice that overexpress the human A
2A
-AR in cardiomyocytes (A
2A
-TG). We used isolated preparations from the left atrium, the right atrium, isolated perfused hearts with surface electrocardiogram (ECG) recording, and surface body ECG recordings of living mice. The hypothesized arrhythmogenic effects of transgenicity per se and A
2A
-AR stimulation were studied. We noted an increase in the incidence of supraventricular and ventricular arrhythmias under these conditions in A
2A
-TG. Moreover, we noted that the A
2A
-AR agonist CGS 21680 exerted positive inotropic effect in isolated human electrically driven (1 Hz) right atrial trabeculae carneae. We conclude that A
2A
-ARs are functional not only in A
2A
-TG but also in isolated human atrial preparations. A
2A
-ARs in A
2A
-TG per se and their stimulation can lead to cardiac arrhythmias not only in isolated cardiac preparations from A
2A
-TG but also in living A
2A
-TG.
Patients with long QT syndrome (LQTS) are at increased risk not only for ventricular arrhythmias but also for atrial pathology including atrial fibrillation (AF). Some patients with "lone" AF carry ...Na(+)-channel mutations.
The purpose of this study was to determine the mechanisms underlying atrial pathology in LQTS.
In mice with a heterozygous knock-in long QT syndrome type 3 (LQT3) mutant of the cardiac Na(+) channel (ΔKPQ-SCN5A) and wild-type (WT) littermates, atrial size, function, and electrophysiologic parameters were measured in intact Langendorff-perfused hearts, and histologic analysis was performed.
Atrial action potential duration, effective refractory period, cycle length, and PQ interval were prolonged in ΔKPQ-SCN5A hearts (all P < .05). Flecainide (1 μM) reversed atrial action potential duration prolongation and induced postrepolarization refractoriness (P < .05). Arrhythmias were infrequent during regular rapid atrial rate in both WT and ΔKPQ-SCN5A but were inducible in 15 (38%) of 40 ΔKPQ-SCN5A and 8 (29%) of 28 WT mice upon extrastimulation. Pacing protocols generating rapid alterations in rate provoked atrial extrasystoles and arrhythmias in 6 (66%) of 9 ΔKPQ-SCN5A but in 0 (0%) of 6 WT mice (P < .05). Atrial diameter was increased by nearly 10% in ΔKPQ-SCN5A mice > 5 months old without increase in fibrotic tissue.
Murine hearts bearing an LQT3 mutation show abnormalities in atrial electrophysiology and subtle changes in atrial dimension, including an atrial arrhythmogenic phenotype on provocation. These results support clinical data suggesting that LQTS mutations can cause atrial pathology and arrhythmogenesis and indicate that murine sodium channel LQTS models may be useful for exploring underlying mechanisms.
Aims Clinical 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 results We 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). Conclusion Cholinergic 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.
1 Department of Cardiology and Angiology and
2 Institute for Pharmacology and Toxicology, University
Hospital Münster, D-48129 Münster;
3 Institute for Pathology, University of Essen, D-45122
Essen, ...Germany; and 4 Department of Pediatrics and
Cardiovascular Research Center, University of Virginia, Charlottesville,
Virginia 22908-1356
Submitted 2 December 2002
; accepted in final form 2 February 2003
To 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 (A 1 AR). 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 ± 18 vs. 522 ± 24 beats/min, P < 0.05; exercise:
650 ± 13 vs. 765 ± 28 beats/min, P < 0.05; 1 h after
exercise: 588 ± 18 vs. 720 ± 12 beats/min, P < 0.05;
all values are means ± SE). Mean HR was lower during exercise (589
± 16 vs. 698 ± 34 beats/min, P < 0.05) and after
exercise (495 ± 16 vs. 592 ± 27 beats/min, P <
0.05). Minimal HR was not different between genotypes. HR variability (SD of
RR intervals) was reduced by 30% ( P < 0.05) in TG compared with WT
mice. Pertussis toxin ( n = 4 pairs, 150 µg/kg ip) reversed
bradycardia after 48 h. TG mice showed first-degree AV nodal block (PQ
interval: 42 ± 2 vs. 37 ± 2 ms, P < 0.05), which was
diminished but not abolished by pertussis toxin. Isolated Langendorff-perfused
TG hearts developed spontaneous atrial arrhythmias (3 of 6 TG mice vs. 0 of 9
WT mice, P < 0.05). In conclusion, A 1 AR regulate sinus
nodal and AV nodal function in the mammalian heart in vivo. Enhanced
expression of A 1 AR 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
Address for reprint requests and other correspondence: P. Kirchhof,
Medizinische Klinik C, Kardiologie und Angiologie, Universitätsklinikum
Münster, Albert-Schweitzer-Strasse 33, D-48129 Münster, Germany
(E-mail:
kirchhp{at}uni-muenster.de ).
Despite recent progress in the understanding of cardiac ion channel function and its role in inherited forms of ventricular arrhythmias, the molecular basis of cardiac conduction disorders often ...remains unresolved. We aimed to elucidate the genetic background of familial atrioventricular block (AVB) using a whole exome sequencing (WES) approach. In monozygotic twins with a third-degree AVB and in another, unrelated family with first-degree AVB, we identified a heterozygous nonsense mutation in the POPDC2 gene causing a premature stop at position 188 (POPDC2W188⁎), deleting parts of its cAMP binding-domain. Popeye-domain containing (POPDC) proteins are predominantly expressed in the skeletal muscle and the heart, with particularly high expression of POPDC2 in the sinoatrial node of the mouse. We now show by quantitative PCR experiments that in the human heart the POPDC-modulated two-pore domain potassium (K2P) channel TREK-1 is preferentially expressed in the atrioventricular node. Co-expression studies in Xenopus oocytes revealed that POPDC2W188⁎ causes a loss-of-function with impaired TREK-1 modulation. Consistent with the high expression level of POPDC2 in the murine sinoatrial node, POPDC2W188⁎ knock-in mice displayed stress-induced sinus bradycardia and pauses, a phenotype that was previously also reported for POPDC2 and TREK-1 knock-out mice. We propose that the POPDC2W188⁎ loss-of-function mutation contributes to AVB pathogenesis by an aberrant modulation of TREK-1, highlighting that POPDC2 represents a novel arrhythmia gene for cardiac conduction disorders.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
ABSTRACT
Hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels encode neuronal and cardiac pace maker currents. The composition of pacemaker channel complexes in different tissues is ...poorly understood, and the presence of additional HCN modulating subunits was speculated. Here we show that vesicle‐associated membrane protein‐associated protein B (VAPB), previously associated with a familial form of amyotrophic lateral sclerosis 8, is an essential HCN1 and HCN2 modulator. VAPB significantly increases HCN2 currents and surface expression and has a maj or influence on the dendritic neuronal distribution of HCN2. Severe cardiac bradycardias in VAPB‐deficient zebrafish and VAPB−/− mice highlight that VAPB physiologically serves to increase cardiac pacemaker currents. An altered T‐wave morphology observed in the ECGs of VAPB−/− mice supports the recently proposed role of HCN channels for ventricular repolarization. The critical function of VAPB in native pacemaker channel complexes will be relevant for our understanding of cardiac arrhythmias and epilepsies, and provides an unexpected link between these diseases and amyotrophic lateral sclerosis.—Silbernagel, N., Walecki, M., Schäfer, M.‐K. H., Kessler, M., Zobeiri, M., Rinné, S., Kiper, A. K., Komadowski, M. A., Vowinkel, K. S., Wemhöner, K., Fortmüller, L., Schewe, M., Dolga, A. M., Scekic‐Zahirovic, J., Matschke, L. A., Culmsee, C., Baukrowitz, T., Monassier, L., Ullrich, N. D., Dupuis, L., Just, S., Budde, T., Fabritz, L., Decher, N. The VAMP‐associated protein VAPB is required for cardiac and neuronal pacemaker channel function. 32, 6159–6173 (2018). www.fasebj.org
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy and a leading cause of sudden cardiac death in a young population. ARVC is especially common in young athletes. ...Mutations in different desmosomal genes have been identified causing dysfunctional cell–cell contacts. Reduced myocardial expression of plakoglobin in cell–cell contact complexes appears to associate with disease manifestation in patients harbouring mutations within other cell–cell contact genes. Experimental data suggest that preload reduction may be a simple and effective intervention to prevent disease progression and ventricular arrhythmias in ARVC. This review discusses the potential effects of this innovative approach and describes the design of the first controlled trial of preload-reducing therapy in patients with ARVC.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The concept of mechano-electrical feedback was derived from the observation that a short stretch applied to the beating heart can invoke an electrical response in the form of an afterdepolarization ...or a premature ventricular beat. More recent work has identified stretch-activated channels whose specific inhibition might help to treat atrial fibrillation in the near future. But the interaction between electrical and mechanical function of the heart is a continuum from short-term (within milliseconds) to long-term (within weeks or months) effects. The long-term effects of pressure overload have been well-described on the molecular and cellular level, and substances that interact with these processes are used in clinical routine in the care of patients with cardiac hypertrophy and heart failure. These treatments help to prevent lethal arrhythmias (sudden death) and potentially atrial fibrillation. The intermediate interaction between mechanical and electrical function of the heart is less well-understood. Several recently identified regulatory mechanisms may provide novel antiarrhythmic targets associated with the “intermediate” response of the myocardium to stretch.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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.
Mice with heart-specific overexpression of A(3)AR at high (A(3)(high)) or low (A(3)(low)) levels and their wild-type littermates were studied. Telemetric electrocardiogram (ECG) recordings in adult freely moving A(3)(high) mice showed profound sinus bradycardia resulting in either ventricular escape rhythms or an incessant bradycardia-tachycardia syndrome (minimal heart rate A(3)(high) 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 A(3)(high) mice (maximal heart rate A(3)(high) 650+/-13*; WT 796+/-13 beats/min) and first-degree AV nodal block was present (PQ interval A(3)(high) 36+/-4*; WT 23+/-5 ms). Isolated hearts showed complete heart block (10/17 A(3)(high)* 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 A(3)(high) atria at the age of 14 weeks. Fibrosis was present in left A(3)(high) atria at 14 weeks, but not at 5 weeks of age. A(3)(low) mice had first-degree AV block without arrhythmias or structural changes.
Heart-directed overexpression of A(3)AR resulted in gene dose-dependent AV block and pronounced sinus nodal dysfunction in vivo. Profound bradycardia heralded atrial and ventricular dilatation, dysfunction, and fibrosis. In contrast to A(1) adenosine receptors (A(1)AR), the effects of A(3)AR overexpression were attenuated during exercise. This may have implications for the physiology of sinus nodal regulation and for therapeutic attempts to increase the expression of adenosine receptors.
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