Role In Atrial Fibrillation Research Articles

Endogenous VIP May Contribute to Vagally Induced Electrophysiological Changes in Canine Atria

Background: There has been increasing evidence that complex interactions among the various components of intracardiac neural network play an important role in atrial fibrillation (AF). Perfusion of vasoactive intestine polypeptide (VIP), a neural polypeptide, co-released with acetylcholine from intrinsic cardiac neurons during vagal stimulation, was shown to shorten the action potential duration (APD), decrease the intraatrial conduction velocity (CV), and promote induction of AF. However, the effect of endogenous VIP remains unclear. Methods: In 6 isolated arterially perfused canine left atria, high-resolution optical mapping techniques with di-4-ANEPPS and blebbistatin were used to measure APD and CV during fat-pad ganglion plexus stimulation (GPS, 30Hz, 10.2±2.3Volt validated with blockage of atrioventricular conduction), at during H9935, a VIP antagonist (1 μM) perfusion. The atria were paced at 200beats per minute. Metoprolol (1.8μM) was used to block the sympathetic effects. Results: Average APD was shorter (21%) during GPS compared to the baseline (100±8ms vs. 126±7ms, p<0.05), and average CV was slower than baseline (87±10cm/sec vs. 103±13cm/sec, p<0.05), which recovered within 2 min (APD: 128±8ms, p<0.05; CV: 105±13cm/sec, p<0.05). With H9335, the APD shortening effect (17%) of GPS persisted (GPS, 105±14ms, vs. 127±8ms at baseline and 125±10ms after recovery, p<0.05) with a trend towards being less pronounced as compared to GPS effect without H9335 (−18±6ms vs. −29±3ms, p=0.07). However, the GPS-induced CV slowing was abolished by H9335 (97±14cm/sec, vs. 103±15cm/sec at baseline and 101±16cm/sec after recovery, p=0.23). The effects of endogenous VIP were eliminated by atropine during GPS, indicating VIP release from intrinsic cardiac neurons may be mediated by muscarinic recpetors. Conclusion: Neuronally released VIP could contribute vagal effects and is primarily responsible for CV slowing during GPS. Neuronal release of VIP is likely mediated by muscarinic receptors in the intrinsic cardiac neurons.

VIP Enhances Acetylcholine-Activated Potassium Current via a cAMP/PKA Transduction Pathway

Background: Recent studies have indicated that various components of cardiac nerve network may play important role in atrial fibrillation (AF). Vagal stimulation shortens atrial effective refractory period, predominantly via the activation of the acetylcholine-activated potassium channel (IKACh) that shortens action potential duration and increases the vulnerability to AF. Vasoactive intestine polypeptide (VIP), a neural polypeptide co-released with acetylcholine (ACh) largely from intrinsic cardiac neurons during vagal stimulation, was shown to contribute to the vulnerability to AF. However, the underlying mechanism remains unclear. The aim of this study is to investigate the effect of VIP on IKACh in the presence of ACh in rat atrial myocytes.Methods: The effects of VIP on IKACh in isolated adult rat atrial myocytes were investigated with voltage patch-clamp recording techniques. IKACh were recorded as an inwardly rectifying current activated by muscarinic agonist carbachol (CCH, 1μM). Furthermore, the post-synaptic signal pathway was investigated with Rp-cAMP (10 μM), a competitive antagonist of cyclic AMP (cAMP), H-89 (0.1μM), PKA inhibitor, and forskolin (0.1μM), an activator of adenylyl cyclase.Results: VIP (1μM) potentiates IKACh at a holding potential of −115 mV (VIP: −19.34 ± 5.22 pA/pF, n=12, vs. baseline: −15.85 ± 2.66 pA/pF, n=14, p<0.05). The enhancement of IKACh by VIP could be mitigated by Rp-cAMP (VIP plus Rp-cAMP: −8.24 ± 1.44 pA/pF n= 6; p<0.05 vs. baseline), and could be inhibited by H-89 (VIP plus H-89: −13.41 ± 2.95 pA/pF n=6; p=0.59 vs. baseline). Furthermore, these enhancements could be mimicked by an activator of adenylyl cyclase, forskolin (−27.35 ± 4.82pA/pF n= 5; p<0.01 vs. baseline).Conclusion: VIP enhanced IKACh in atrial myocytes which might contribute to vagal-induced APD shortening and is likely mediated by a cAMP-PKA dependent pathway.

Abstract 9345: CaMKII Integrates Oxidative Stress and Calcium Signaling in Atrial Fibrillation

Introduction: Emerging evidence suggests that abnormal calcium (Ca 2+ ) signaling and oxidative stress play an important role in Atrial Fibrillation (AF). We hypothesized that oxidative activation of CaMKII leads to increased sarcoplasmic reticulum (SR) Ca 2+ release and delayed afterdepolarizations (DAD) to cause AF. Methods: We established a mouse model of AF by implanting subcutaneous angiotensin II (Ang II) eluting osmotic pumps for three weeks followed by in vivo right atrial burst pacing. We measured oxidized CaMKII (ox-CaMKII) in atria from Ang II infused mice and from patients in AF or sinus rhythm. We developed ox-CaMKII resistant knock-in mice by replacing key methionines (281/282) with valines (MM-VV) in the predominant myocardial isoform (CaMKIIδ) and mice with transgenic myocardial expression of methionine sulfoxide reductase A (MsrA), an enzyme that reduces ox-CaMKII, to test if ox-CaMKII was required for AF promoted by Ang II. Results: ox-CaMKII is elevated in atrial tissue from patients with AF and from mice infused with Ang II compared to patients in sinus rhythm or mice infused with saline. Mice treated with Ang II are highly susceptible to AF, while AF was rarely induced in saline infused mice. MM-VV mice and MsrA transgenic mice were resistant to AF and did not show increased ox-CaMKII after Ang II infusion. Atrial myocytes from Ang II treated wild type mice showed significantly increased DADs and SR Ca 2+ sparks compared to saline treated controls. Ang II treatment did not increase calcium sparks in MM-VV mice. Conclusions: Oxidative activation of CaMKII is an important molecular pathway for AF and strategies that decrease the level of ox-CaMKII can prevent AF.

Use of Computed Tomography to Identify Atrial Fibrillation Associated Differences in Left Atrial Wall Thickness and Density

Left atrial (LA) tissue characteristics may play an important role in atrial fibrillation (AF) induction and perpetuation. Although frequently used in clinical practice, computed tomography (CT) has not been employed to describe differences in LA wall properties between AF patients and controls. We sought to noninvasively characterize AF-associated differences in LA tissue using CT. CT images of the LA were obtained in 98 consecutive patients undergoing AF ablation and in 89 controls. A custom software algorithm was used to measure wall thickness and density in four prespecified regions of the LA. On average, LA walls were thinner (-15.5%, 95% confidence interval [CI] -23.2 to -7.8%, P < 0.001) and demonstrated significantly lower density (-19.7 Hounsfield Units [HU], 95% CI -27.0 to -12.5 HU, P < 0.001) in AF patients compared to controls. In linear mixed models adjusting for demographics, clinical variables, and other CT measurements, the average LA, interatrial septum, LA appendage, and anterior walls remained significantly thinner in AF patients. After adjusting for the same potential confounders, history of AF was associated with reduced density in the LA anterior wall and increased density below the right inferior pulmonary vein and in the LA appendage. Application of an automated measurement algorithm to CT imaging of the atrium identified significant thinning of the LA wall and regional alterations in tissue density in patients with a history of AF. These findings suggest differences in LA tissue composition can be noninvasively identified and quantified using CT.

Effects of ganglionated plexi ablation on ventricular electrophysiological properties in normal hearts and after acute myocardial ischemia

BackgroundGanglionated plexi (GP) ablation has been shown to play an important role in atrial fibrillation (AF) initiation and maintenance. Also, GP ablation increases chances for prevention of AF recurrence. This study investigated the effects of GP ablation on ventricular electrophysiological properties in normal dog hearts and after acute myocardial ischemia (AMI). MethodsFifty anesthetized dogs were assigned into normal heart group (n=16) and AMI heart group (n=34). Ventricular dynamic restitution, effective refractory period (ERP), electrical alternans and ventricular fibrillation threshold (VFT) were measured before and after GP ablation in the normal heart group. In the AMI heart group, the incidence of ventricular arrhythmias and VFT were determined. ResultsIn the normal heart group, GP ablation significantly prolonged ERP, facilitated electrical alternans but did not increase ERP dispersion, the slope of restitution curves and its spatial dispersion. Also, GP ablation did not cause significant change of VFT. In the AMI heart group, the incidence of ventricular arrhythmias after GP ablation was significantly higher than that in the control group or the GP plus stellate ganglion (SG) ablation group (P<0.05). Spontaneous VF occurred in 8/12, 1/10 and 2/12 dogs in the GP ablation group, the GP plus SG ablation group and the control group, respectively (P<0.05). VFT in the GP ablation group showed a decreased trend though a significant difference was not achieved compared with the control or the GP plus SG ablation group. ConclusionsGP ablation increases the risk of ventricular arrhythmias in the AMI heart compared to the normal heart.

Transient Receptor Potential Canonical-3 Channel–Dependent Fibroblast Regulation in Atrial Fibrillation

Fibroblast proliferation and differentiation are central in atrial fibrillation (AF)-promoting remodeling. Here, we investigated fibroblast regulation by Ca(2+)-permeable transient receptor potential canonical-3 (TRPC3) channels. Freshly isolated rat cardiac fibroblasts abundantly expressed TRPC3 and had appreciable nonselective cation currents (I(NSC)) sensitive to a selective TPRC3 channel blocker, pyrazole-3 (3 μmol/L). Pyrazole-3 suppressed angiotensin II-induced Ca(2+) influx, proliferation, and α-smooth muscle actin protein expression in fibroblasts. Ca(2+) removal and TRPC3 blockade suppressed extracellular signal-regulated kinase phosphorylation, and extracellular signal-regulated kinase phosphorylation inhibition reduced fibroblast proliferation. TRPC3 expression was upregulated in atria from AF patients, goats with electrically maintained AF, and dogs with tachypacing-induced heart failure. TRPC3 knockdown (based on short hairpin RNA [shRNA]) decreased canine atrial fibroblast proliferation. In left atrial fibroblasts freshly isolated from dogs kept in AF for 1 week by atrial tachypacing, TRPC3 protein expression, currents, extracellular signal-regulated kinase phosphorylation, and extracellular matrix gene expression were all significantly increased. In cultured left atrial fibroblasts from AF dogs, proliferation rates, α-smooth muscle actin expression, and extracellular signal-regulated kinase phosphorylation were increased and were suppressed by pyrazole-3. MicroRNA-26 was downregulated in canine AF atria; experimental microRNA-26 knockdown reproduced AF-induced TRPC3 upregulation and fibroblast activation. MicroRNA-26 has NFAT (nuclear factor of activated T cells) binding sites in the 5' promoter region. NFAT activation increased in AF fibroblasts, and NFAT negatively regulated microRNA-26 transcription. In vivo pyrazole-3 administration suppressed AF while decreasing fibroblast proliferation and extracellular matrix gene expression. TRPC3 channels regulate cardiac fibroblast proliferation and differentiation, likely by controlling the Ca(2+) influx that activates extracellular signal-regulated kinase signaling. AF increases TRPC3 channel expression by causing NFAT-mediated downregulation of microRNA-26 and causes TRPC3-dependent enhancement of fibroblast proliferation and differentiation. In vivo, TRPC3 blockade prevents AF substrate development in a dog model of electrically maintained AF. TRPC3 likely plays an important role in AF by promoting fibroblast pathophysiology and is a novel potential therapeutic target.

A review of the epidemiological profile of patients with atrial fibrillation and heart failure

Heart failure (HF) and atrial fibrillation (AF) are cardiovascular diseases that have a continuously increasing prevelance and both often coexist. The presence of AF in HF patients has been reported as being between 10 and 50% depending on the different study settings. AF patients have a different clinical profile: they are older, with more severe HF and comorbidities than those without AF. Despite this poor clinical profile, observational studies report a lower use of the recommended treatments such as angiotensin-converting enzyme inhibitors and β-blockers. Clinical trials using antiarrhythmic drugs for rhythm control have failed to demonstrate the clinical advantage of a rhythm control approach over one for rate control. The prognostic role of AF in HF remains controversial, while the impact of new AF has been shown to be associated with an adverse outcome.

Protective role of simvastatin on isolated rabbit atrioventricular node during experimental atrial fibrillation model: role in rate control of ventricular beats

The purpose of the present study was to determine (1) whether simvastatin (SV) modifies the rate-dependent conduction time and refractoriness of the atrioventricular (AV) node and (2) how it can change the protective mechanism of the AV node during atrial fibrillation (AF). Predefined stimulation protocols were applied to detect the electrophysiological parameters of the AV node, including atrial-His conduction time, effective refractory period (ERP), functional refractory period (FRP), concealed conduction, excitable index, and fatigue in two groups of isolated, perfused rabbit AV nodal preparations (N=16). The stimulation protocols (fatigue, recovery) were carried out during control and in the presence of SV (0.5, 0.8, 3, and 10 μM). Simulated AF was executed in a separate group (N=8), and specific indexes, including H-H mean, zone of concealment (ZOC), and concealed beats were recorded. SV, in a concentration-dependent manner, prolonged ERP, FRP, and Wenckebach cycle lengths. It (10 μM) significantly increased fatigue and the excitable index. In addition, SV elicited prolongation of ZOC and H-H mean at 3 and 10 μM. SV-evoked prolongation of nodal refractoriness and concealed conduction caused rate-dependent ventricular slowing effects during AF. The ability of simvastatin to decrease the excitable gap by its heterogeneous effects on nodal dual pathways proposes its protective role in AF.

Increased risk of cognitive and functional decline in patients with atrial fibrillation: results of the ONTARGET and TRANSCEND studies

The role of atrial fibrillation in cognitive impairment and dementia, independent of stroke, is uncertain. We sought to determine the association of atrial fibrillation with cognitive and physical impairment in a large group of patients at high cardiovascular risk. We conducted a post-hoc analysis of two randomized controlled trials involving 31,546 patients, the aims of which were to evaluate the efficacy of treatment with ramipril plus telmisartan (ONTARGET) or telmisartan alone (TRANSCEND) in reducing cardiovascular disease. We evaluated the cognitive function of participants at baseline and after two and five years using the Mini-Mental State Examination (MMSE). In addition, we recorded incident dementia, loss of independence in activities of daily living and admission to long-term care facilities. We used a Cox regression model adjusting for main confounders to determine the association between atrial fibrillation and our primary outcomes: a decrease of three or more points in MMSE score, incident dementia, loss of independence in performing activities of daily living and admission to long-term care. We enrolled 31,506 participants for whom complete information on atrial fibrillation was available, 70.4% of whom were men. The mean age of participants was 66.5 years, and the mean baseline MMSE score was 27.7 (standard deviation 2.9) points. At baseline, 1016 participants (3.3%) had atrial fibrillation, with the condition developing in an additional 2052 participants (6.5%) during a median follow-up of 56 months. Atrial fibrillation was associated with an increased risk of cognitive decline (hazard ratio [HR] 1.14, 95% confidence interval [CI] 1.03-1.26), new dementia (HR 1.30, 95% CI 1.14-1.49), loss of independence in performing activities of daily living (HR 1.35, 95% CI 1.19-1.54) and admission to long-term care facilities (HR 1.53, 95% CI 1.31-1.79). Results were consistent among participants with and without stroke or receiving antihypertensive drugs. Cognitive and functional decline are important consequences of atrial fibrillation, even in the absence of overt stroke.

MiRNAs and cardiac arrhythmogenesis: role in atrial fibrillation

BackgroundAtrial fibrillation (AF) is a highly prevalent condition associated with pronounced morbidity, mortality, and socioeconomic burden. A characteristic of both clinical and experimental AF is atrial electric remodelling associated with...

Pulmonary vein variants predispose to atrial fibrillation: a case-control study using multislice contrast-enhanced computed tomography

Pulmonary veins (PV) play a pivotal role in atrial fibrillation (AF). Anatomical variants of PV have been described and related to a higher arrhythmogenic potential. The aim of this study was to compare the prevalence of PV variants and diameters of PV ostia in AF patients and controls. Variants of PV were defined as right or left common ostia (RCO, LCO), a right middle or right top PV . A long common trunk (LCT) was defined as an LCO with a distance to the first branching ≥ 10 mm. Multislice contrast-enhanced thoracic computed tomography was performed prior to AF ablation in 166 consecutive patients, 47.6% with paroxysmal, 52.4% with persistent AF, as well as in a sex- and age-matched control group without AF, for non-cardiological indications. Images were evaluated by two independent observers. The mean age was 59 ± 10 years, 108 were men (65.1%). A higher prevalence of LCO was found in the AF group: 33.7 vs. 19.9% (P= 0.004), odds ratio (OR) 2.1; 15.4% in patients vs. 10.2% in controls had an LCT (P= 0.14). No differences in other PV variants were found. The ostial diameters were greater in AF-patients (P< 0.001). To the best of our knowledge, the present study shows for the first time a higher prevalence of an LCO in patients with AF as compared with controls, with an OR of 2.1. This suggests a pre-disposing role of LCO in the development of AF.

Is Pitx2 Growing Up?

In this issue of Circulation: Cardiovascular Genetics , Kirchhof et al1 present an interesting study on the expression of the developmental transcription factor Pitx2c in adult heart and its potential role in atrial fibrillation (AF). AF is the most common sustained cardiac arrhythmia, with a prevalence that increases with age and affects 1% to 2% of the general population.2 Despite recent advances in AF research, underlying pathophysiologic mechanisms are not fully understood. In general, initiation and perpetuation of AF needs a trigger for its onset and a vulnerable substrate for its maintenance.3 Focal ectopic activity can act as a trigger to initiate AF on the basis of a single- or multiple-circuit reentry.4 Especially, cardiomyocyte sleeves around the pulmonary veins have been shown as an origin of focal activity.5 Underlying mechanisms are early and delayed after depolarizations as a result of disturbances in depolarizing inward (Na+ or Ca2+) or repolarizing outward (K+) currents.6 Article see p 123 Once initiated, AF itself induces structural and electric remodeling, which stabilizes reentry and AF maintenance.6 Structural remodeling due to signaling through angiotensin, profibrotic cytokines like transforming growth factor-β, or microRNAs leads to upregulation of extracellular matrix proteins (eg, collagen) and downregulation of matrix-degrading enzymes (eg, matrix metalloproteinase), resulting in progressive atrial fibrosis. Electric remodeling is caused by expressional changes in ion channel subunits. AF induces calcium overload and increases activity of protein phosphatases, leading to downregulation of depolarizing L-type calcium channels and upregulation of repolarizing potassium channels. Measurable substrate of these changes in atrial electric properties is the shortening of action potential duration (APD), leading to shortening of refractory period and enabling reentry mechanisms. In most cases, therefore, AF is self-terminating (paroxysmal) in the beginning, developing to more sustained forms (persistent and permanent) over …

Baseline B‐Type Natriuretic Peptide: A Gender‐Specific Predictor of Procedure‐Outcome in Atrial Fibrillation Patients Undergoing Catheter Ablation

Close association between atrial fibrillation (AF) and brain natriuretic peptide (BNP) has been demonstrated by several studies. Important gender differences exist in AF patients including a higher plasma BNP level in women. Therefore, it is imperative to evaluate the relationship between AF and BNP separately in men and women. This study examined possible gender-specific role of BNP in predicting procedure outcome in AF patients undergoing catheter ablation. The study population included 568 consecutive patients (age 62 ± 10, male 73%, paroxysmal 25%, persistent 38%, and long-standing persistent AF 37%) undergoing AF ablation, who had structurally normal heart and left ventricular ejection fraction ≥45%. Baseline BNP was measured in all. Patients were grouped into "normal" and "high" BNP based on gender-specific cut-off values (<50 and ≥50 pg/mL in males, <100 and ≥ 100 pg/mL in females). Baseline BNP was significantly higher among women than men (126 ± 112 versus 87 ± 99, P = 0.009). At 12 ± 6 month follow-up, 304 of 414 (73%) males and 98 of 154 (64%) females were AF/atrial tachycardia-free off antiarrhythmic drugs (log-rank P = 0.018). In multivariable analysis, BNP remained an independent predictor of AF recurrence (BNP ≥ 50: hazard ratio [HR] 2.54, P = 0.006) in males. No such association was observed among females (BNP ≥ 100: HR 0.79, 95% CI 0.43-1.42; P = 0.426). Baseline BNP was found to be an independent predictor of AF recurrence in male patients undergoing ablation. This correlation between BNP and AF recurrence was not observed in females. Thus, BNP plays a gender-specific prognostic role in AF.

Intracardiac echocardiography for registration of rotational angiography-based left atrial reconstructions: a novel approach integrating two intraprocedural three-dimensional imaging techniques in atrial fibrillation ablation

Image integration of three-dimensional (3D) reconstructions of left atrial (LA) and pulmonary vein (PV) anatomy into electroanatomical mapping (EAM) plays a major role in atrial fibrillation (AF) ablation. Point-by-point EAM is commonly used for registration of imported LA and PV anatomy. We aimed to assess the accuracy of intraprocedural rotational angiography-based LA imaging registered by spatial reconstruction of intracardiac echocardiography (ICE) in patients undergoing AF ablation. Twenty-two patients (11 males, 66 ± 12 years) were studied. Reconstructions of LA and PVs based on rotational angiography were registered by a second 3D reconstruction based on ICE. In a second step, EAM points were added to ICE 3D reconstructions. A 3D image of the LA and PVs was reconstructed in all patients by both imaging modalities. Rotational angiography and ICE-based LA 3D reconstructions took 11.5 ± 5.2 and 20.4 ± 11.2 min, respectively. A total of 17 ± 6 two-dimensional ICE fans were used for spatial reconstruction of ICE. The deviation between the two 3D shells was 2.6 ± 0.5 mm. Integration of 78 ± 58 EAM points into ICE 3D reconstruction did not significantly reduce the deviation to rotational angiography-based reconstructions (2.7 ± 0.6 mm). All PVs were isolated successfully. Intraprocedural 3D reconstruction of LA and PVs for ablation of AF is feasible based on both rotational angiography and ICE. LA reconstructions based on rotational angiography can accurately be registered using 3D ICE shells. Additional EAM does not enhance accuracy. Therefore, registration of rotational angiography-based 3D reconstructions by 3D reconstructions from ICE seems to be an alternative technique to support AF ablation.

Herzinsuffizienz

Heart failure (HF) is a disease with an increasing prevalence and results in both reduced quality of life and decreased lifespan for patients. Despite improved therapy mortality remains very high. HF is induced by events that lead to reduced function of the heart, e.g. myocardial infarction and increased chronic afterload through arterial hypertension. For compensation to occur, neurohumoral mechanisms temporarily maintain cardiac function. Over time this results in left ventricular remodelling and, by means of a vicious circle, compensated HF becomes symptomatic HF. The myocardium of patients with HF is characterised by a dysfunction in excitation-contraction coupling (ECC), which causes reduced cell contractility due to reduced Ca(2+) transients and SR Ca(2+) load. The Ca(2+)/calmodulin-dependent protein kinase IIδ (CaMKIIδ) plays an important role in the onset of HF. CaMKIIδ phosphorylates several functional key proteins, leads to reduced SR Ca(2+) load and Ca(2+)-transients in HF, acts as an arrhythmogenic protein by increasing late I(Na), and contributes to diastolic dysfunction by accumulation of intracellular Ca(2+). CaMKIIδ also plays an important role in atrial fibrillation. Interestingly, with regard to increased cardiac load, CaMKIIδ is activated in increased afterload but not in preload. The important role of CaMKIIδ in HF implies new therapeutic options to improve HF therapy in the future.

Distinct restitution properties in vagally mediated atrial fibrillation and six-hour rapid pacing-induced atrial fibrillation

The atrial potential duration (APD) restitution has been suggested to play an important role in ventricular fibrillation; however, its role in atrial fibrillation (AF) has not been determined. This study sought to investigate the APD restitution properties in two different AF models: vagally mediated AF and 6-h rapid atrial pacing-induced AF. Twenty anaesthetized open-chest dogs were assigned to Group I, vagally mediated AF (n= 8) or Group II, 6-h rapid atrial pacing-induced AF (n= 12). In both groups, the monophasic APD was subsequently recorded at multiple pulmonary vein and atrial sites. The APD restitution curve was constructed using a dynamic pacing protocol and determined by plotting each APD(90) against the preceding diastolic interval at incremental atrial pacing rates at eight sites. In Group I, vagal stimulation significantly shortened the APD(90), flattened the APD restitution curve (slopes <1), and suppressed the APD alternans at each site, while increasing the AF inducibility and duration (P<0.05 for all). In Group II, 6-h rapid pacing-induced APD shortening steepened the restitution curves (slopes >1), facilitated the APD alternans, and also increased the incidence and duration of AF (P< 0.05 for all). The spatial dispersion of APD restitution was significantly increased in both groups. This study showed distinct atrial APD restitution properties in vagally mediated AF and 6-h rapid pacing-induced AF, indicating specific restitution kinetics in different mechanisms of AF.

Molecular determinants of cardiac fibroblast electrical function and therapeutic implications for atrial fibrillation

Cardiac fibroblasts account for about 75% of all cardiac cells, but because of their small size contribute only ∼10-15% of total cardiac cell volume. They play a crucial role in cardiac pathophysiology. For a long time, it has been recognized that fibroblasts and related cell types are the principal sources of extracellular matrix (ECM) proteins, which organize cardiac cellular architecture. In disease states, fibroblast production of increased quantities of ECM proteins leads to tissue fibrosis, which can impair both mechanical and electrical function of the heart, contributing to heart failure and arrhythmogenesis. Atrial fibrosis is known to play a particularly important role in atrial fibrillation (AF). This review article focuses on recent advances in understanding the molecular electrophysiology of cardiac fibroblasts. Cardiac fibroblasts express a variety of ion channels, in particular voltage-gated K(+) channels and non-selective cation channels of the transient receptor potential (TRP) family. Both K(+) and TRP channels are important determinants of fibroblast function, with TRP channels acting as Ca(2+)-entry pathways that stimulate fibroblast differentiation into secretory myofibroblast phenotypes producing ECM proteins. Fibroblasts can couple to cardiomyocytes and substantially affect their cellular electrical properties, including conduction, resting potential, repolarization, and excitability. Co-cultured preparations of cardiomyocytes and fibroblasts generate arrhythmias by a variety of mechanisms, including spontaneous impulse formation and rotor-driven reentry. In addition, the excess ECM proteins produced by fibroblasts can interrupt cardiomyocyte-bundle continuity, leading to local conduction disturbances and reentrant arrhythmias. A better understanding of the electrical properties of fibroblasts should lead to an improved comprehension of AF pathophysiology and a variety of novel targets for antiarrhythmic intervention.

Renin-angiotensin system–related gene polymorphisms are associated with risk of atrial fibrillation

Renin-angiotensin system (RAS) plays an important role in atrial fibrillation (AF). Recently, many publications have studied the associations between RAS-related gene polymorphisms and AF risk, with inconsistent results. To further evaluate these associations, we carried out a meta-analysis of all the published studies. Electronic searches were used to identify published studies evaluating RAS-related gene polymorphisms and AF risk before April 2009. We extracted data sets and performed meta-analysis with standardized methods. A meta-analysis of 12 publications on association between angiotensin-converting enzyme (ACE insertion/deletion) and AF risk was performed. The pooled relative risk (RR) of allele D versus I was 1.19 (95% CI, 1.07-1.32, P < .01), pooled RR of DD and DI versus II was 1.31(95% CI, 1.09-1.58, P < .01) and 1.06 (95% CI, 0.97-1.16, P = .22) respectively. In subgroup analysis, a stronger association was found in hypertensive population, Western ethnic, lone AF, and patients aged > or = 65 years, with pooled RR of DD versus II was 1.74 (95% CI, 1.39-2.18, P < .01), 1.27 (95% CI, 1.01-1.59, P = .04), 1.53 (95% CI, 1.31-1.78, P < .01) and 1.38 (95% CI, 1.10-1.73, P < .01), respectively. The results suggested an association between ACE insertion/deletion and AF risk. More large-scale studies are warranted to document the conclusive evidence of the effects of the RAS genes on AF risk.

BAS/BSCR16 Time-dependent changes in atrial nitric oxide-redox balance in atrial fibrillation: translational research (from goats to humans)

RationaleOxidative stress has an important role in atrial fibrillation (AF)-induced myocardial remodelling, suggesting that specific oxidases may represent a novel therapeutic target in AF. Here we evaluated how the duration...

Spontaneous and electrically evoked Ca 2+ transients in cardiomyocytes of the rat pulmonary vein

The pulmonary vein is surrounded by an external sleeve of cardiomyocytes that are widely recognised to play an important role in atrial fibrillation. While intracellular Ca 2+ is thought to influence the electrical activity of cardiomyocytes, there have been relatively few studies examining Ca 2+ signalling in these cells. Therefore, using fluo-4 and fluorescence imaging microscopy, we have investigated Ca 2+ signalling in an intact section of the rat pulmonary vein. Under resting conditions cardiomyocytes displayed spontaneous Ca 2+ transients, which were variable in amplitude and had a frequency of 1.6 ± 0.03 Hz. The Ca 2+ transients were asynchronous amongst neighbouring cardiomyocytes and tended to propagate throughout the cell as a wave. Removing extracellular Ca 2+ produced a slight reduction in the amplitude and frequency of the spontaneous Ca 2+ transients; however, ryanodine (20 μM) had a much greater effect on the amplitude and reduced the frequency by 94 ± 2%. Blocking IP 3 receptors with 2-aminoethoxydiphenyl borate (20 μM) also reduced the amplitude and frequency (by 73 ± 11%) of these events, indicating the importance of Ca 2+ release from the SR. Electrical field stimulation of the pulmonary vein produced Ca 2+ transients in cardiomyocytes that were significantly reduced by either voltage-gated Ca 2+ channel blockers or ryanodine.