Effects of verapamil on atrial fibrillation and its electrophysiological determinants in dogs

Background: Atrial tachycardia-induced remodeling promotes the occurrence and maintenance of atrial fibrillation (AF) and decreases L-type Ca2+ current. There is also a clinical suggestion that acute L-type Ca2 channel blockade can promote AF, consistent with an AF promoting effect of Ca2+ channel inhibition. Methods: To evaluate the potential mechanisms of AF promotion by Ca2+ channel blockers, we administered verapamil to morphine-chloralose anesthetized dogs. Diltiazem was used as a comparison drug and autonomic blockade with atropine and nadolol was applied in some experiments. Epicardial mapping with 240 epicardial electrodes was used to evaluate activation during AF. Results: Verapamil caused AF promotion in six dogs, increasing mean duration of AF induced by burst pacing, from 8±4 s (mean±S.E.) to 95±39 s (P<0.01 vs. control) at a loading dose of 0.1 mg/kg and 228±101 s (P<0.0005 vs. control) at a dose of 0.2 mg/kg. Underlying electrophysiological mechanisms were studied in detail in five additional dogs under control conditions and in the presence of the higher dose of verapamil. In these experiments, verapamil shortened mean effective refractory period (ERP) from 122±5 to 114±4 ms (P<0.02) at a cycle length of 300 ms, decreased ERP heterogeneity (from 15±1 to 10±1%, P<0.05), heterogeneously accelerated atrial conduction and decreased the cycle length of AF (94±4 to 84±3 ms, P<0.005). Diltiazem did not affect ERP, AF cycle length or AF duration, but produced conduction acceleration similar to that caused by verapamil (n = 5). In the presence of autonomic blockade, verapamil failed to promote AF and increased, rather than decreasing, refractoriness. Neither verapamil nor diltiazem affected atrial conduction in the presence of autonomic blockade. Epicardial mapping suggested that verapamil promoted AF by increasing the number of simultaneous wavefronts reflected by separate zones of reactivation in each cycle. Conclusions: Verapamil promotes AF in normal dogs by promoting multiple circuit reentry, an effect dependent on intact autonomic tone and not shared by diltiaze

Differential efficacy of L- and T-type calcium channel blockers in preventing tachycardia-induced atrial remodeling in dogs

Background: Tachycardia-induced remodeling likely plays an important role in atrial fibrillation (AF) maintenance and recurrence after cardioversion, and Ca2+ overload may be an important mediator. This study was designed to evaluate the relative efficacies of selective T-type (mibefradil) and L-type (diltiazem) Ca2+-channel blockers in preventing tachycardia-induced atrial remodeling. Methods: Dogs were given daily doses of mibefradil (100 mg), diltiazem (240 mg) or placebo in a blinded fashion, beginning 4 days before and continuing through a 7-day period of atrial pacing at 400 bpm. An electrophysiological study was then performed to assess changes in refractoriness, refractoriness heterogeneity and AF duration. Results: Mean duration of burst-pacing induced AF was similar in placebo (567±203 s) and diltiazem-treated (963±280 s, P = NS) animals, but was much less in mibefradil-treated dogs (3.6±0.9 s, P<0.002) and non-paced controls (6.6±2.7 s). In contrast to mibefradil, diltiazem did not alter tachycardia-induced refractoriness abbreviation or heterogeneity. To exclude inadequate dosing as an explanation for diltiazem's inefficacy, we studied an additional group of dogs treated with 720 mg/day of diltiazem, and again noted no protective effect. Acute intravenous administration of diltiazem to control dogs failed to alter atrial refractoriness or AF duration, excluding a masking of remodeling suppression by offsetting profibrillatory effects of the drug. Conclusions: Whereas the selective T-type Ca2+-channel blocker mibefradil protects against atrial remodeling caused by 7-day atrial tachycardia, the selective L-type blocker diltiazem is without effect. These findings are potentially important for understanding the mechanisms and prevention of clinically-relevant atrial-tachycardia-induced remodelin

Role of the Autonomic Nervous System in Atrial Fibrillation: Pathophysiology and Therapy

Autonomic nervous system activation can induce significant and heterogeneous changes of atrial electrophysiology and induce atrial tachyarrhythmias, including atrial tachycardia (AT) and atrial fibrillation (AF). The importance of the autonomic nervous system in atrial arrhythmogenesis is also supported by circadian variation in the incidence of symptomatic AF in humans. Methods that reduce autonomic innervation or outflow have been shown to reduce the incidence of spontaneous or induced atrial arrhythmias, suggesting that neuromodulation may be helpful in controlling AF. In this review we focus on the relationship between the autonomic nervous system and the pathophysiology of AF, and the potential benefit and limitations of neuromodulation in the management of this arrhythmia. We conclude that autonomic nerve activity plays an important role in the initiation and maintenance of AF, and modulating autonomic nerve function may contribute to AF control. Potential therapeutic applications include ganglionated plexus ablation, renal sympathetic denervation, cervical vagal nerve stimulation, baroreflex stimulation, cutaneous stimulation, novel drug approaches and biological therapies. While the role of the autonomic nervous system has long been recognized, new science and new technologies promise exciting prospects for the future

Electrophysiological effects of 5-hydroxytryptamine on isolated human atrial myocytes, and the influence of chronic beta-adrenoceptor blockade

&lt;b&gt;1.&lt;/b&gt; 5-Hydroxytryptamine (5-HT) has been postulated to play a proarrhythmic role in the human atria via stimulation of 5-HT&lt;sub&gt;4&lt;/sub&gt; receptors. &lt;b&gt;2.&lt;/b&gt; The aims of this study were to examine the effects of 5-HT on the L-type Ca&lt;sup&gt;2+&lt;/sup&gt; current (&lt;i&gt;I&lt;/i&gt;&lt;sub&gt;CaL&lt;/sub&gt;) action potential duration (APD), the effective refractory period (ERP) and arrhythmic activity in human atrial cells, and to assess the effects of prior treatment with &#946;-adrenoceptor antagonists. &lt;b&gt;3.&lt;/b&gt; Isolated myocytes, from the right atrial appendage of 27 consenting patients undergoing cardiac surgery who were in sinus rhythm, were studied using the whole-cell perforated patch-clamp technique at 37&#186;C. &lt;b&gt;4.&lt;/b&gt; 5-HT (1 n-10 &#956;M) caused a concentration-dependent increase in &lt;i&gt;I&lt;/i&gt;&lt;sub&gt;CaL&lt;/sub&gt;, which was potentiated in cells from &#946;-blocked (maximum response to 5-HT, E&lt;sub&gt;max&lt;/sub&gt;=299&#177;12% increase above control) compared to non-&#946;-blocked patients (E&lt;sub&gt;max&lt;/sub&gt;=220&#177;6%, P&#60;0.05), but with no change in either the potency (log EC&lt;sub&gt;50&lt;/sub&gt;: -7.09&#177;0.07 vs -7.26&#177;0.06) or Hill coefficient (&lt;i&gt;n&lt;/i&gt;&lt;sub&gt;H&lt;/sub&gt;: 1.5&#177;0.6 vs 1.5&#177;0.3) of the 5-HT concentration-response curve. &lt;b&gt;5.&lt;/b&gt; 5-HT (10 &#956;M) produced a greater increase in the APD at 50% repolarisation (APD50) in cells from &#946;-blocked patients (of 37&#177;10 ms, i.e. 589&#177;197%) vs non-&#946;-blocked patients (of 10&#177;4 ms, i.e. 157&#177;54%; P&#60;0.05). Both the APD&lt;sub&gt;90&lt;/sub&gt; and the ERP were unaffected by 5-HT. &lt;b&gt;6.&lt;/b&gt; Arrhythmic activity was observed in response to 5-HT in five of 17 cells (29%) studied from &#946;-blocked, compared to zero of 16 cells from the non-&#946;-blocked patients (P&#60;0.05). &lt;b&gt;7.&lt;/b&gt; In summary, the 5-HT-induced increase in calcium current was associated with a prolonged early plateau phase of repolarisation, but not late repolarisation or refractoriness, and the enhancement of these effects by chronic &#946;-adrenoceptor blockade was associated with arrhythmic potential

Rate-dependency of action potential duration and refractoriness in isolated myocytes from the rabbit AV node and atrium

During atrial fibrillation, ventricular rate is determined by atrioventricular nodal (AVN) conduction, which in part is dependent upon the refractoriness of single AVN cells. The aims of this study were to investigate the rate-dependency of the action potential duration (APD) and effective refractory period (ERP) in single myocytes isolated from the AV node and atrium of rabbit hearts, using whole cell patch clamping, and to determine the contribution of the 4-aminopyridine (4-AP)-sensitive current, ITO1to these relationships in the two cell types. AVN cells had a more positive maximum diastolic potential (-60&#177;1 v-71&#177;2 mV), lower Vmax(8&#177;2 v 144&#177;17 V/s) and higher input resistance [420&#177;46 v 65&#177;7 MOHgr (mean±s.eP&#60;0.05n=9–33)], respectively, than atrial myocytes. Stepwise increases in rate from 75 beats/min caused activation failure and Wenckebach periodicity in AVN cells (at around 400 beats/min), but 1:1 activation in atrial cells (at up to 600 beats/min). Rate reduction from 300 to 75 beats/min shortened the ERP in both cell types (from 155&#177;7 to 135&#177;11 ms in AVN cells [P&#60;0.05, n=6] and from 130±8 to 106&#177;7 ms in atrial cells [P&#60;0.05, n=10]). Rate increase from 300 to 480 and 600 beats/min shortened ERP in atrial cells, by 12&#177;4% (n=8) and 26&#177;7% (n=7), respectively (P&#60;0.05). By contrast, AVN ERP did not shorten at rates &#62;300 beats/min. In atrial cells, rate reduction to 75 beats/min caused marked shortening of APD50(from 51&#177;6 to 29&#177;6 ms, P&#60;0.05). 4-AP (1 mm) significantly prolonged atrial APD50at 75 beats/min (P&#60;0.05, n=7), but not at 300 or 400 beats/min. In AVN cells, in contrast, there was less effect of rate change on APD, and 4-AP did not alter APD50at any rate. 4-AP also did not affect APD90or ERP in either cell type. In conclusion, a lack of ERP-shortening at high rates in rabbit single AVN cells may contribute to ventricular rate control. ITO1contributed to the APD50rate relation in atrial, but not AVN cells and did not contribute to the ERP rate relation in either cell type

Exponential distribution of long heart beat intervals during atrial fibrillation and their relevance for white noise behaviour in power spectrum

The statistical properties of heart beat intervals of 130 long-term surface electrocardiogram recordings during atrial fibrillation (AF) are investigated. We find that the distribution of interbeat intervals exhibits a characteristic exponential tail, which is absent during sinus rhythm, as tested in a corresponding control study with 72 healthy persons. The rate of the exponential decay lies in the range 3-12 Hz and shows diurnal variations. It equals, up to statistical uncertainties, the level of the previously uncovered white noise part in the power spectrum, which is also characteristic for AF. The overall statistical features can be described by decomposing the intervals into two statistically independent times, where the first one is associated with a correlated process with 1/f noise characteristics, while the second one belongs to an uncorrelated process and is responsible for the exponential tail. It is suggested to use the rate of the exponential decay as a further parameter for a better classification of AF and for the medical diagnosis. The relevance of the findings with respect to a general understanding of AF is pointed out

Do physicians correctly calculate thromboembolic risk scores?: a comparison of concordance between manual and computer‐based calculation of CHADS2 and CHA2DS2‐VASc scores

[Abstract] BACKGROUND: Clinical risk scores, CHADS2 and CHA2 DS2 -VASc scores, are the established tools for assessing stroke risk in patients with atrial fibrillation (AF). AIM: The aim of this study is to assess concordance between manual and computer-based calculation of CHADS2 and CHA2 DS2 -VASc scores, as well as to analyse the patient categories using CHADS2 and the potential improvement on stroke risk stratification with CHA2 DS2 -VASc score. METHODS: We linked data from Atrial Fibrillation Spanish registry FANTASIIA. Between June 2013 and March 2014, 1318 consecutive outpatients were recruited. We explore the concordance between manual scoring and computer-based calculation. We compare the distribution of embolic risk of patients using both CHADS2 and CHA2 DS2 -VASc scores RESULTS: The mean age was 73.8 ± 9.4 years, and 758 (57.5%) were male. For CHADS2 score, concordance between manual scoring and computer-based calculation was 92.5%, whereas for CHA2 DS2 -VASc score was 96.4%. In CHADS2 score, 6.37% of patients with AF changed indication on antithrombotic therapy (3.49% of patients with no treatment changed to need antithrombotic treatment and 2.88% of patients otherwise). Using CHA2 DS2 -VASc score, only 0.45% of patients with AF needed to change in the recommendation of antithrombotic therapy. CONCLUSION: We have found a strong concordance between manual and computer-based score calculation of both CHADS2 and CHA2 DS2 -VASc risk scores with minimal changes in anticoagulation recommendations. The use of CHA2 DS2 -VASc score significantly improves classification of AF patients at low and intermediate risk of stroke into higher grade of thromboembolic score. Moreover, CHA2 DS2 -VASc score could identify 'truly low risk' patients compared with CHADS2 score

Remodelling of human atrial K+ currents but not ion channel expression by chronic β-blockade

Chronic β-adrenoceptor antagonist (β-blocker) treatment in patients is associated with a potentially anti-arrhythmic prolongation of the atrial action potential duration (APD), which may involve remodelling of repolarising K+ currents. The aim of this study was to investigate the effects of chronic β-blockade on transient outward, sustained and inward rectifier K+ currents (ITO, IKSUS and IK1) in human atrial myocytes and on the expression of underlying ion channel subunits. Ion currents were recorded from human right atrial isolated myocytes using the whole-cell-patch clamp technique. Tissue mRNA and protein levels were measured using real time RT-PCR and Western blotting. Chronic β-blockade was associated with a 41% reduction in ITO density: 9.3 ± 0.8 (30 myocytes, 15 patients) vs 15.7 ± 1.1 pA/pF (32, 14), p &#60; 0.05; without affecting its voltage-, time- or rate dependence. IK1 was reduced by 34% at −120 mV (p &#60; 0.05). Neither IKSUS, nor its increase by acute β-stimulation with isoprenaline, was affected by chronic β-blockade. Mathematical modelling suggested that the combination of ITO- and IK1-decrease could result in a 28% increase in APD90. Chronic β-blockade did not alter mRNA or protein expression of the ITO pore-forming subunit, Kv4.3, or mRNA expression of the accessory subunits KChIP2, KChAP, Kvβ1, Kvβ2 or frequenin. There was no reduction in mRNA expression of Kir2.1 or TWIK to account for the reduction in IK1. A reduction in atrial ITO and IK1 associated with chronic β-blocker treatment in patients may contribute to the associated action potential prolongation, and this cannot be explained by a reduction in expression of associated ion channel subunits

Multiple Potential Molecular Contributors to Atrial Hypocontractility Caused by Atrial Tachycardia Remodeling in Dogs

Background-Atrial fibrillation impairs atrial contractility, inducing atrial stunning that promotes thromboembolic stroke. Action potential (AP)-prolonging drugs are reported to normalize atrial hypocontractility caused by atrial tachycardia remodeling (ATR). Here, we addressed the role of AP duration (APD) changes in ATR-induced hypocontractility. Methods and Results-ATR (7-day tachypacing) decreased APD (perforated patch recording) by approximate to 50%, atrial contractility (echocardiography, cardiomyocyte video edge detection), and [Ca2+](i) transients. ATR AP waveforms suppressed [Ca2+](i) transients and cell shortening of control cardiomyocytes; whereas control AP waveforms improved [Ca2+](i) transients and cell shortening in ATR cells. However, ATR cardiomyocytes clamped with the same control AP waveform had approximate to 60% smaller [Ca2+](i) transients and cell shortening than control cells. We therefore sought additional mechanisms of contractile impairment. Whole-cell voltage clamp revealed reduced I-CaL; I-CaL inhibition superimposed on ATR APs further suppressed [Ca2+](i) transients in control cells. Confocal microscopy indicated ATR-impaired propagation of the Ca2+ release signal to the cell center in association with loss of t-tubular structures. Myofilament function studies in skinned permeabilized cardiomyocytes showed altered Ca2+ sensitivity and force redevelopment in ATR, possibly due to hypophosphorylation of myosin-binding protein C and myosin light-chain protein 2a (immunoblot). Hypophosphorylation was related to multiple phosphorylation system abnormalities where protein kinase A regulatory subunits were downregulated, whereas autophosphorylation and expression of Ca2+-calmodulin-dependent protein kinase II delta and protein phosphatase 1 activity were enhanced. Recovery of [Ca2+](i) transients and cell shortening occurred in parallel after ATR cessation. Conclusions-Shortening of APD contributes to hypocontractility induced by 1-week ATR but accounts for it only partially. Additional contractility-suppressing mechanisms include I-CaL current reduction, impaired subcellular Ca2+ signal transmission, and altered myofilament function associated with abnormal myosin and myosin-associated protein phosphorylation. The complex mechanistic basis of the atrial hypocontractility associated with AF argues for upstream therapeutic targeting rather than interventions directed toward specific downstream pathophysiological derangements. (Circ Arrhythm Electrophysiol. 2010;3:530-541.