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Effects of human atrial ionic remodelling by ?-blocker therapy on mechanisms of atrial fibrillation: a computer simulation.

ABSTRACT: Atrial anti-arrhythmic effects of ?-adrenoceptor antagonists (?-blockers) may involve both a suppression of pro-arrhythmic effects of catecholamines, and an adaptational electrophysiological response to chronic ?-blocker use; so-called 'pharmacological remodelling'. In human atrium, such remodelling decreases the transient outward (Ito) and inward rectifier (IK1) K(+) currents, and increases the cellular action potential duration (APD) and effective refractory period (ERP). However, the consequences of these changes on mechanisms of genesis and maintenance of atrial fibrillation (AF) are unknown. Using mathematical modelling, we tested the hypothesis that the long-term adaptational decrease in human atrial Ito and IK1 caused by chronic ?-blocker therapy, i.e. independent of acute electrophysiological effects of ?-blockers, in an otherwise un-remodelled atrium, could suppress AF.Contemporarily, biophysically detailed human atrial cell and tissue models were used to investigate effects of the ?-blocker-based pharmacological remodelling. Chronic ?-blockade remodelling prolonged atrial cell APD and ERP. The incidence of small amplitude APD alternans in the CRN model was reduced. At the 1D tissue level, ?-blocker remodelling decreased the maximum pacing rate at which APs could be conducted. At the three-dimensional organ level, ?-blocker remodelling reduced the life span of re-entry scroll waves.This study improves our understanding of the electrophysiological mechanisms of AF suppression by chronic ?-blocker therapy. Atrial fibrillation suppression may involve a reduced propensity for maintenance of re-entrant excitation waves, as a consequence of increased APD and ERP.

SUBMITTER: Kharche SR

PROVIDER: S-EPMC4640177 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Effects of human atrial ionic remodelling by β-blocker therapy on mechanisms of atrial fibrillation: a computer simulation.

Kharche Sanjay R SR Stary Tomas T Colman Michael A MA Biktasheva Irina V IV Workman Antony J AJ Rankin Andrew C AC Holden Arun V AV Zhang Henggui H

Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology 20140801 10

<h4>Aims</h4>Atrial anti-arrhythmic effects of β-adrenoceptor antagonists (β-blockers) may involve both a suppression of pro-arrhythmic effects of catecholamines, and an adaptational electrophysiological response to chronic β-blocker use; so-called 'pharmacological remodelling'. In human atrium, such remodelling decreases the transient outward (Ito) and inward rectifier (IK1) K(+) currents, and increases the cellular action potential duration (APD) and effective refractory period (ERP). However, ...[more]

PMID: 25085203

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Project description:AIMS:Autonomic dysfunction can promote atrial fibrillation (AF) and results from AF-related remodelling. N-type Ca2+-channels (NTCCs) at sympathetic nerve terminals mediate Ca2+-entry that triggers neurotransmitter release. AF-associated remodelling plays an important role in AF pathophysiology but the effects of NTCC inhibition on such remodelling is unknown. Here, we investigated the ability of a clinically available Ca2+-channel blocker (CCB) with NTCC-blocking activity to suppress the arrhythmogenic effects of AF-promoting remodelling in dogs. METHODS AND RESULTS:Mongrel dogs were kept in AF by right atrial tachypacing at 600 bpm. Four groups were studied under short-term AF (7 days): (i) Shams, instrumented but without tachypacing (n = 5); (ii) a placebo group, tachypaced while receiving placebo (n = 6); (iii) a control tachypacing group receiving nifedipine (10 mg orally twice-daily; n = 5), an L-type CCB; and (iv) a cilnidipine group, subjected to tachypacing and treatment with cilnidipine (10 mg orally twice-daily; n = 7), an N-/L-type CCB. With cilnidipine therapy, dogs with 1-week AF showed significantly reduced autonomic changes reflected by heart rate variability (decreases in RMSSD and pNN50) and plasma norepinephrine concentrations. In addition, cilnidipine-treated dogs had decreased extracellular matrix gene expression vs. nifedipine-dogs. As in previous work, atrial fibrosis had not yet developed after 1-week AF, so three additional groups were studied under longer-term AF (21 days): (i) Shams, instrumented without tachypacing or drug therapy (n = 8); (ii) a placebo group, tachypaced while receiving placebo (n = 8); (iii) a cilnidipine group, subjected to tachypacing during treatment with cilnidipine (10 mg twice-daily; n = 8). Cilnidipine attenuated 3-week AF effects on AF duration and atrial conduction, and suppressed AF-induced increases in fibrous-tissue content, decreases in connexin-43 expression and reductions in sodium-channel expression. CONCLUSIONS:Cilnidipine, a commercially available NTCC-blocking drug, prevents AF-induced autonomic, electrical and structural remodelling, along with associated AF promotion.

Project description:Importance:The association between obesity, an established risk factor for atrial fibrillation (AF), and response to antiarrhythmic drugs (AADs) remains unclear. Objective:To test the hypothesis that obesity differentially mediates response to AADs in patients with symptomatic AF and in mice with diet-induced obesity (DIO) and pacing induced AF. Design, Setting, and Participants:An observational cohort study was conducted including 311 patients enrolled in a clinical-genetic registry. Mice fed a high-fat diet for 10 weeks were also evaluated. The study was conducted from January 1, 2018, to June 2, 2019. Main Outcomes and Measures:Symptomatic response was defined as continuation of the same AAD for at least 3 months. Nonresponse was defined as discontinuation of the AAD within 3 months of initiation because of poor symptomatic control of AF necessitating alternative rhythm control therapy. Outcome measures in DIO mice were pacing-induced AF and suppression of AF after 2 weeks of treatment with flecainide acetate or sotalol hydrochloride. Results:A total of 311 patients (mean [SD] age, 65 [12] years; 120 women [38.6%]) met the entry criteria and were treated with a class I or III AAD for symptomatic AF. Nonresponse to class I AADs in patients with obesity was less than in those without obesity (30% [obese] vs 6% [nonobese]; difference, 0.24; 95% CI, 0.11-0.37; P?=?.001). Both groups had similar symptomatic response to a potassium channel blocker AAD. On multivariate analysis, obesity, AAD class (class I vs III AAD [obese] odds ratio [OR], 4.54; 95% Wald CI, 1.84-11.20; P?=?.001), female vs male sex (OR, 2.31; 95% Wald CI, 1.07-4.99; P?=?.03), and hyperthyroidism (OR, 4.95; 95% Wald CI, 1.23-20.00; P?=?.02) were significant indicators of the probability of failure to respond to AADs. Pacing induced AF in 100% of DIO mice vs 30% (P?<?.001) in controls. Furthermore, DIO mice showed a greater reduction in AF burden when treated with sotalol compared with flecainide (85% vs 25%; P?<?.01). Conclusions and Relevance:Results suggest that obesity differentially mediates response to AADs in patients and in mice with AF, possibly reducing the therapeutic effectiveness of sodium channel blockers. These findings may have implications for the management of AF in patients with obesity.

Project description:Background and aimsThis study aimed to histologically validate atrial structural remodelling associated with atrial fibrillation.Methods and resultsPatients undergoing atrial fibrillation ablation and endomyocardial atrial biopsy were included (n = 230; 67 ± 12 years old; 69 women). Electroanatomic mapping was performed during right atrial pacing. Voltage at the biopsy site (Vbiopsy), global left atrial voltage (VGLA), and the proportion of points with fractionated electrograms defined as ≥5 deflections in each electrogram (%Fractionated EGM) were evaluated. SCZtotal was calculated as the total width of slow conduction zones, defined as regions with a conduction velocity of <30 cm/s. Histological factors potentially associated with electroanatomic characteristics were evaluated using multiple linear regression analyses. Ultrastructural features and immune cell infiltration were evaluated by electron microscopy and immunohistochemical staining in 33 and 60 patients, respectively. Fibrosis, intercellular space, myofibrillar loss, and myocardial nuclear density were significantly associated with Vbiopsy (P = .014, P < .001, P < .001, and P = .002, respectively) and VGLA (P = .010, P < .001, P = .001, and P < .001, respectively). The intercellular space was associated with the %Fractionated EGM (P = .001). Fibrosis, intercellular space, and myofibrillar loss were associated with SCZtotal (P = .028, P < .001, and P = .015, respectively). Electron microscopy confirmed plasma components and immature collagen fibrils in the increased intercellular space and myofilament lysis in cardiomyocytes, depending on myofibrillar loss. Among the histological factors, the severity of myofibrillar loss was associated with an increase in macrophage infiltration.ConclusionHistological correlates of atrial structural remodelling were fibrosis, increased intercellular space, myofibrillar loss, and decreased nuclear density. Each histological component was defined using electron microscopy and immunohistochemistry studies.

Project description:AimsAtrial fibrillation (AF) is associated with tachycardia-induced cellular electrophysiology alterations which promote AF chronification and treatment resistance. Development of novel antiarrhythmic therapies is hampered by the absence of scalable experimental human models that reflect AF-associated electrical remodelling. Therefore, we aimed to assess if AF-associated remodelling of cellular electrophysiology can be simulated in human atrial-like cardiomyocytes derived from induced pluripotent stem cells in the presence of retinoic acid (iPSC-aCM), and atrial-engineered human myocardium (aEHM) under short term (24 h) and chronic (7 days) tachypacing (TP).Methods and resultsFirst, 24-h electrical pacing at 3 Hz was used to investigate whether AF-associated remodelling in iPSC-aCM and aEHM would ensue. Compared to controls (24 h, 1 Hz pacing) TP-stimulated iPSC-aCM presented classical hallmarks of AF-associated remodelling: (i) decreased L-type Ca2+ current (ICa,L) and (ii) impaired activation of acetylcholine-activated inward-rectifier K+ current (IK,ACh). This resulted in action potential shortening and an absent response to the M-receptor agonist carbachol in both iPSC-aCM and aEHM subjected to TP. Accordingly, mRNA expression of the channel-subunit Kir3.4 was reduced. Selective IK,ACh blockade with tertiapin reduced basal inward-rectifier K+ current only in iPSC-aCM subjected to TP, thereby unmasking an agonist-independent constitutively active IK,ACh. To allow for long-term TP, we developed iPSC-aCM and aEHM expressing the light-gated ion-channel f-Chrimson. The same hallmarks of AF-associated remodelling were observed after optical-TP. In addition, continuous TP (7 days) led to (i) increased amplitude of inward-rectifier K+ current (IK1), (ii) hyperpolarization of the resting membrane potential, (iii) increased action potential-amplitude and upstroke velocity as well as (iv) reversibly impaired contractile function in aEHM.ConclusionsClassical hallmarks of AF-associated remodelling were mimicked through TP of iPSC-aCM and aEHM. The use of the ultrafast f-Chrimson depolarizing ion channel allowed us to model the time-dependence of AF-associated remodelling in vitro for the first time. The observation of electrical remodelling with associated reversible contractile dysfunction offers a novel platform for human-centric discovery of antiarrhythmic therapies.

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Effects of human atrial ionic remodelling by ?-blocker therapy on mechanisms of atrial fibrillation: a computer simulation.

Publications

Effects of human atrial ionic remodelling by β-blocker therapy on mechanisms of atrial fibrillation: a computer simulation.

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