Manifestations of left ventricular dysfunction and arrhythmia in patients with chronic hypoparathyroidism and pseudohypoparathyroidism: a preliminary study.

BACKGROUND: Cardiac damage triggered by severe hypocalcemia is well known. However, the role of chronic hypoparathyroidism (HP) and pseudohypoparathyroidism (PHP) in cardiac health is still unclear. We investigated the effect of chronic HP and PHP on cardiac structure and conductive function in patients compiling with treatment. METHODS: The study included 18 patients with HP and eight with PHP aged 45.4 ± 15.4 and 22.1 ± 6.4 years, respectively with a previously regular follow-up. In addition, 26 age- and sex-matched healthy controls were included. General characteristics and biochemical indices were recorded. Cardiac function and structure were assessed by estimation of myocardial enzymes, B-type natriuretic peptide (BNP), and echocardiography. The 12-lead electrocardiogram and 24-h Holter electrocardiography were performed to evaluate the conductive function. RESULTS: Levels of serum calcium in HP and PHP were 2.05 ± 0.16 mmol/L and 2.25 ± 0.19 mmol/L, respectively. The levels of myocardial enzyme and BNP were within the normal range. Adjusting for age at evaluation and body mass index, all M-mode measurements, left ventricular mass (LVM), LVM index (LVMI) and relative wall thickness (RWT) were comparable between patients and controls. Prolongation of corrected QT (QTc) intervals occurred in 52.6% (10/19) of patients, and 6.7% (1/15) of patients manifested more than 100 episodes of supraventricular and ventricular extrasystoles, as well as supraventricular tachycardia. None of the above arrhythmias was related to a severe clinical event. CONCLUSIONS: From this pilot study, patients diagnosed with HP and PHP and well-controlled serum calcium levels manifested normal cardiac morphology and ventricular function, except for prolonged QTc intervals, and a small percentage of mild arrhythmias needing further investigation.

Sinus node-like pacemaker mechanisms regulate ectopic pacemaker activity in the adult rat atrioventricular ring.

In adult mammalian hearts, atrioventricular rings (AVRs) surround the atrial orifices of atrioventricular valves and are hotbed of ectopic activity in patients with focal atrial tachycardia. Experimental data offering mechanistic insights into initiation and maintenance of ectopic foci is lacking. We aimed to characterise AVRs in structurally normal rat hearts, identify arrhythmia predisposition and investigate mechanisms underlying arrhythmogenicity. Extracellular potential mapping and intracellular action potential recording techniques were used for electrophysiology, qPCR for gene and, Western blot and immunohistochemistry for protein expression. Conditions favouring ectopic foci were assessed by simulations. In right atrial preparations, sinus node (SN) was dominant and AVRs displayed 1:1 impulse conduction. Detaching SN unmasked ectopic pacemaking in AVRs and pacemaker action potentials were SN-like. Blocking pacemaker current If, and disrupting intracellular Ca2+ release, prolonged spontaneous cycle length in AVRs, indicating a role for SN-like pacemaker mechanisms. AVRs labelled positive for HCN4, and SERCA2a was comparable to SN. Pacemaking was potentiated by isoproterenol and abolished with carbachol and AVRs had abundant sympathetic nerve endings. ß2-adrenergic and M2-muscarinic receptor mRNA and ß2-receptor protein were comparable to SN. In computer simulations of a sick SN, ectopic foci in AVR were unmasked, causing transient suppression of SN pacemaking.

Noninvasive light emitting diode therapy: A novel approach for postinfarction ventricular arrhythmias and neuroimmune modulation.

BACKGROUND: Sympathetic neural activation plays a key role in the incidence and maintenance of acute myocardial infarction (AMI) induced ventricular arrhythmia (VA). Furthermore, previous studies showed that AMI might induce microglia and sympathetic activation and that microglial activation might contribute to sympathetic activation. Recently, studies showed that light emitting diode (LED) therapy might attenuate microglial activation. Therefore, we hypothesized that LED therapy might reduce AMI-induced VA by attenuating microglia and sympathetic activation. METHODS: Thirty anesthetized rats were randomly divided into three groups: the Control group (n = 6), AMI group (n = 12), and AMI + LED group (n = 12). Electrocardiogram (ECG) and left stellate ganglion (LSG) neural activity were continuously recorded. The incidence of VAs was recorded during the first hour after AMI. Furthermore, we sampled the brain and myocardium tissue of the different groups to examine the microglial activation and expression of nerve growth factor (NGF), interleukin-18 (IL-18), and IL-1ß, respectively. RESULTS: Compared to the AMI group, LED therapy significantly reduced the incidence of AMI-induced VAs (ventricular premature beats [VPB] number: 85.08 ± 13.91 vs 27.5 ± 9.168, P < .01; nonsustained ventricular tachycardia (nSVT) duration: 34.39 ± 8.562 vs 9.005 ± 3.442, P < .05; nSVT number: 18.92 ± 4.52 vs 7.583 ± 3.019, P < .05; incidence rate of SVT/VF: 58.33% vs. 8.33%, P < .05) and reduced the LSG neural activity (P < .01) in the AMI + LED group. Furthermore, LED significantly attenuated microglial activation and reduced IL-18, IL-1ß, and NGF expression in the peri-infarct myocardium. CONCLUSION: LED therapy may protect against AMI-induced VAs by suppressing sympathetic neural activity and the inflammatory response.

The relationship between blood glucose and nocturnal supraventricular tachycardia attacks in non-diabetic patients.

PURPOSE: Decrease in the blood glucose level may trigger the tachycardia or bradycardia because it has an arrhythmogenic effect on the heart. Our purpose in this study was to investigate whether the blood glucose level has an effect on patients who attended to the hospital with nocturnal supraventricular tachycardia (SVT). METHODS: We included 151 patients in our study who have SVT history. Plasma glucose levels which were taken during night hours, electrolytes, and 12 lead electrocardiography were evaluated. RESULTS: There were 105 patients without nocturnal SVT attack and 46 patients with nocturnal SVT attack. Patients with nocturnal SVT attack, blood glucose level, potassium, calcium, and hemoglobin levels were significantly lower, hs-CRP was significantly higher, basal cycle length (BCL) was significantly short, and QT interval was significantly longer. It was found that blood glucose (O.R. = 0.904, 95% GA 0.828-0.986, p = 0.023) and potassium levels (O.R. = 0.128, 95% GA 0.029-0.561, p = 0.006) and basal cycle length (BCL) (O.R. 0.988, 95% GA, 0.980-0.996, p = 0.005) values were in independently correlated with nocturnal SVT attacks. CONCLUSION: The decrease in blood glucose level of the patients who are being followed with SVT diagnosis might trigger the nocturnal SVT attacks.

Optogenetic termination of atrial fibrillation in mice.

Aims: The primary goal in the treatment of symptomatic atrial fibrillation/flutter (AF) is to restore sinus rhythm by cardioversion. Electrical shocks are highly effective, but have to be applied under analgo-sedation and can further harm the heart. In order to develop a novel pain-free and less harmful approach, we explored herein the optogenetic cardioversion by light-induced depolarization. Methods and results: Hearts from mice expressing Channelrhodopsin-2 (ChR2) and the AF-promoting loss-of-function Connexin 40 Ala96Ser mutation were explanted and perfused with low K+ Tyrode's solution and an atrial KATP-channel activator. This new protocol shortened atrial refractoriness as well as slowed atrial conduction and thereby enabled the induction of sustained AF. AF episodes could be terminated by epicardial illumination of the atria with focussed blue light (470 nm, 0.4 mW/mm2) with an efficacy of ∼97% (n = 17 hearts). In > 80% of cases, light directly terminated the AF episode with onset of illumination. Because similar illumination intensity was able to locally inhibit atrial activity, we propose that a light-induced block of electrical activity is responsible for reliable AF termination. The success rate was strongly depending on the illuminated area, applied light intensity and duration of illumination. Importantly, we were also able to demonstrate optogenetic termination of AF in vivo, using epicardial illumination through the open chest (n = 3 hearts). To point towards a translational potential, we systemically injected an adeno-associated virus to express ChR2 in wild type hearts. After 6-8 months, we found robust ChR2 expression in the atria, enabling light-mediated AF termination in six of seven mice tested. Conclusion: We provide the first evidence for optogenetic termination of atrial tachyarrhythmia in intact hearts from transgenic as well as wild type mice ex and in vivo. Thus, this report could lay the foundation for the development of implantable devices for pain-free termination of AF.

New-onset, postoperative tachyarrhythmias in critically ill surgical patients.

Tachyarrhythmias in critically ill surgical patients can have varying effects, from minimal consequence to lifetime sequelae. Atrial fibrillation can be common in the post-operative period, often a result of fluctuations in volume status and electrolyte derangements. While there is extensive literature regarding the critically ill medical or cardiac patient, there is less focusing on the critically ill surgical or trauma patient. More specifically, there is minimal regarding tachyarrhythmias in burn patients. The latter population tends to have frequent and wide variations in volume status given initial resuscitation and after major excisions, concomitant with acute blood loss anemia, which can contribute to cardiac disturbances. A literature review was conducted to investigate the incidence and consequences of tachyarrhythmias in critically ill surgical and trauma patients, with a focus on the burn population. While some similarities and conclusions can be drawn between these surgical populations, further inquiry into the unique burn patient is necessary.

Angiotensin-(1-7) prevents atrial tachycardia induced-heat shock protein 27 expression.

OBJECTIVE: We aimed to investigate the effects of angiotensin-(1-7) [Ang-(1-7)] on heat-shock protein 27 (HSP27) in a canine model of induced tachycardia. METHODS: Eighteen dogs were randomized into three equal treatment groups: sham, pacing and pacing+Ang-(1-7) group. The dogs in the last two groups were subjected to 2weeks of rapid atrial pacing (500bpm). The effects of Ang-(1-7) on HSP27 were assessed by real-time polymerase chain reaction and western blot. RESULTS: The expression levels of atrial HSP27 mRNA and protein were significantly (P<0.05) higher for the pacing group than the sham group and significantly (P<0.05) lower for the pacing+Ang-(1-7) group than the pacing group. There was no significant difference between the HSP27 expression levels in the right and left atria among all three groups. CONCLUSIONS: Our findings suggest that the overexpression of HSP27 may possibly be occurring as an adaptive response that allows atrial tissues to cope with rapid atrial pacing, and an inhibiting effect of Ang-(1-7) on atrial remodeling may be one of the mechanisms responsible for the attenuation of HSP27 up-regulation induced by rapid pacing.

Cilostazol Prevents Atrial Structural Remodeling through the MEK/ERK Pathway in a Canine Model of Atrial Tachycardia.

OBJECTIVES: Atrial fibrillation (AF) is the most common sustained arrhythmia in clinical practice. Atrial structural remodeling (ASR), particularly atrial fibrosis, is an important contributor to the AF substrate. This study aimed to investigate the preventive effects of the phosphodiesterase 3 inhibitor cilostazol on ASR and its potential molecular mechanisms in a canine model of rapid atrial pacing (RAP). METHODS: Thirty dogs were assigned to sham (Sham), paced/ no treatment (Paced) and paced + cilostazol 5 mg/kg/day (Paced + cilo) groups, with 10 dogs in each group. RAP at 500 beats/min was maintained for 2 weeks, while the Sham group was instrumented without pacing. Cilostazol was provided orally during pacing. Western blotting, RT-PCR and pathology were used to assess ASR. RESULTS: Cilostazol attenuated atrial interstitial fibrosis and structural remodeling in canines with RAP. MEK/ERK transduction pathway gene expression was upregulated in the Paced group compared with the Sham group. Cilostazol markedly alleviated these changes in the MEK/ERK pathway. Transforming growth factor-ß1 protein expression in the Paced group was significantly higher than in the Sham group (p < 0.01), and was significantly reduced by cilostazol (p < 0.01). CONCLUSIONS: Our findings suggest that cilostazol is beneficial for prevention and treatment in atrial tachycardia-induced ASR in a canine model of RAP.

Effect of irbesartan on development of atrial fibrosis and atrial fibrillation in a canine atrial tachycardia model with left ventricular dysfunction, association with p53.

Effects of an angiotensin II receptor blocker, irbesartan (IRB), on the development of atrial fibrosis and atrial fibrillation (AF) were assessed in a canine model of atrial tachycardia remodeling (ATR) with left ventricular dysfunction, together with its possible association with involvement of p53. Atrial tachypacing (400 bpm for 4 weeks) was used to induce ATR in beagles treated with placebo (ATR-dogs, n = 6) or irbesartan (IRB-dogs, n = 5). Non-paced sham dogs served as control (Control-dogs, n = 4). ATR- and IRB-dogs developed tachycardia-induced left ventricular dysfunction. Atrial effective refractory period (AERP) shortened (83 ± 5 ms, p < 0.05), inter-atrial conduction time prolonged (72 ± 2 ms, p < 0.05), and AF duration increased (29 ± 5 s, p < 0.05 vs. baseline) after 4 weeks in ATR-dogs. ATR-dogs also had a larger area of atrial fibrous tissue (5.2 ± 0.5 %, p < 0.05 vs. Control). All these changes, except for AERP, were attenuated in IRB-dogs (92 ± 3 ms, 56 ± 3 ms, 9 ± 5 s, and 2.5 ± 0.7 %, respectively; p < 0.05 vs. ATR for each). In ATR-dogs, p53 expression in the left atrium decreased by 42 % compared with Control-dogs (p < 0.05); however, it was highly expressed in IRB-dogs (+89 % vs. ATR). Transforming growth factor (TGF)-ß1 expression was enhanced in ATR-dogs (p < 0.05 vs. Control) but reduced in IRB-dogs (p < 0.05 vs. ATR). Irbesartan suppresses atrial fibrosis and AF development in a canine ATR model with left ventricular dysfunction in association with p53.

Potential Role of Regulator of G-Protein Signaling 5 in the Protection of Vagal-Related Bradycardia and Atrial Tachyarrhythmia.

BACKGROUND: The regulator of G-protein signaling 5 (Rgs5), which functions as the regulator of G-protein-coupled receptor (GPCR) including muscarinic receptors, has a potential effect on atrial muscarinic receptor-activated IKA ch current. METHODS AND RESULTS: In the present study, hearts of Rgs5 knockout (KO) mice had decreased low-frequency/high-frequency ratio in spectral measures of heart rate variability. Loss of Rgs5 provoked dramatically exaggerated bradycardia and significantly (P<0.05) prolonged sinus nodal recovery time in response to carbachol (0.1 mg/kg, intraperitoneally). Compared to those from wild-type (WT) mice, Langendorff perfused hearts from Rgs5 KO mice had significantly (P<0.01) abbreviated atrial effective refractory periods and increased dominant frequency after administration of acetylcholine (ACh; 1 µmol/L). In addition, whole patch clamp analyses of single atrial myocytes revealed that the ACh-regulated potassium current (IKA ch) was significant increased in the time course of activation and deactivation (P<0.01) in Rgs5 KO, compared to those in WT, mice. To further determine the effect of Rgs5, transgenic mice with cardiac-specific overexpression of human Rgs5 were found to be resistant to ACh-related effects in bradycardia, atrial electrophysiology, and atrial tachyarrhythmia (AT). CONCLUSION: The results of this study indicate that, as a critical regulator of parasympathetic activation in the heart, Rgs5 prevents vagal-related bradycardia and AT through negatively regulating the IKA ch current.

[Ventricular and supraventricular arrhythmias in women]. / Nadkomorowe i komorowe zaburzenia rytmu--skala problemu u kobiet.

There are few gender-related differences in electrophysiology regarding occurrence, clinical symptoms and prognosis of arrhythmias. Women tend to have higher incidence of sinus tachycardia and atrio-ventricular nodal re-entry tachycardia. Atrial fibrillation is more frequent among men, but women have worse prognosis as their mortality is higher, "rhythm control" strategy is less favorable and the thromboembolic risk is greater. Ventricular arrhythmias are less common in women and their significance is smaller. As women have longer QTc interval and torsade de pointes is typical women's arrhythmia, physicians must be very careful ordering QT-elongating drugs. Coronary heart disease (CHD) is seldom background for ventricular tachycardia and women with CHD and arrhythmias have better prognosis than men. Sex hormones play important role in women's electrophysiology. Pregnancy increase risk of supraventricular tachycardia and decrease occurrence of torsade de pointes.

Characterization of thrombogenic, endothelial and inflammatory markers in supraventricular tachycardia: a study in patients with structurally normal hearts.

Patients with atrial fibrillation (AF) are at an increased risk of thromboembolism and stroke primarily from the development of thrombi within the left atrium. Pathological changes in blood constituents and atrial endothelial damage promote left atrial thrombus formation. It is not known whether factors predisposing to left atrial thrombus formation in AF are disease specific or also evident within the normal heart. The present study examined whether there are differences in platelet reactivity, endothelial function and inflammation in blood samples obtained from intracardiac and peripheral sites in subjects within structurally normal hearts. Sixteen patients with diagnosed left-sided supraventricular tachycardia (SVT) undergoing a routine elective electrophysiological study and ablation were investigated. Blood samples were taken simultaneously from the femoral vein, right atrium and left atrium, immediately following trans-septal puncture and prior to heparin bolus administration. Between peripheral and atrial sample sites, patients with SVT showed no change in platelet reactivity or aggregation (P-selectin (CD62P) P = 0.91; platelet-derived soluble CD40 ligand P = 0.9), thrombus formation (thrombin-antithrombin complex; P = 0.55), endothelial function (von Willebrand factor P = 0.75; asymmetric dimethylarginine (ADMA) P = 0.97; nitric oxide P = 0.61), or inflammation (vascular cell adhesion molecule-1 P = 0.59; intercellular adhesion molecule-1 (ICAM-1) P = 0.69). However, SVT patients had lower ADMA and ICAM-1 levels than AF patients. The present study demonstrates, for the first time, that SVT subjects with structurally normal hearts have consistent haemostatic function between atrial and peripheral sites. These results suggest that the atria of SVT patients do not contain predisposing thrombogenic, endothelial or inflammatory factors that promote and/or initiate thrombus formation.

The role of Interleukin-6, its -174 G>C polymorphism and C-reactive protein in idiopathic cardiac arrhythmias in children.

UNLABELLED: ABSTRACT Purpose: Knowledge about the role of inflammation in the pathogenesis of arrhythmias in children is limited. Several studies have suggested a relationship between plasma IL-6 levels and/or the -174G>C IL-6 gene polymorphism and atrial fibrillation in adults. Our present study was performed to investigate whether serum IL-6, -174G>C IL-6 polymorphism and C-reactive protein (CRP) are associated with arrhythmias of unknown origin in children. METHODS: The study included 126 children diagnosed with supraventricular or ventricular arrhythmia. Patients with congenital heart defects as well as arrhythmias of known origin were excluded from the study. The control group comprised 37 healthy children. The 24 hour Holter electrocardiography monitoring was performed. Serum IL-6, -174 GC IL-6 polymorphism and CRP concentrations were measured on admission. RESULTS: There were no differences in IL-6, CRP and -174 G>C IL-6 genotype distribution between the control and patient groups. No significant differences in IL-6, CRP and -174 G>C IL-6 genotypes were observed between children with supraventricular or ventricular arrhythmias. The severity of arrhythmias showed also no associations with IL-6, CRP or -174 G>C IL-6 genotypes. CONCLUSION: The results suggest that idiopathic cardiac arrhythmias of unknown origin in children are not associated with selected pro-inflammatory markers of infections i.e. elevated IL-6, CRP or -174 G>C IL-6 polymorphism. This new information can effectively reduce the total financial cost of unnecessary diagnosis and treatment of children affected by cardiac arrhythmias.

Transforming growth factor-ß and oxidative stress mediate tachycardia-induced cellular remodelling in cultured atrial-derived myocytes.

AIMS: Atrial fibrillation (AF), a common tachyarrhythmia in clinical practice, is associated with increased oxidative stress. Structural remodelling in atrial myocytes, including myofibril degradation, is an important characteristic of AF. However, the mechanism underlying AF-induced cellular structural remodelling remains unclear. The aim of this study was to investigate the role of oxidative stress and related factors in tachycardia-induced atrial structural remodelling. METHODS AND RESULTS: Cultured atrial-derived myocytes (HL-1 cell line) were subjected to electrical stimulation. Immunofluorescence and immunoblotting were used to evaluate oxidative stress, myofibril degradation, and transforming growth factor-ß (TGF-ß) expression. Tachypacing in HL-1 cells induced TGF-ß expression, pronounced oxidative stress including up-regulation of NADPH oxidases (Nox2/4), and myofibril degradation. Oxidative stress scavenger, NADPH oxidase inhibitors, and small-interfering RNAs for Nox2/4 blocked tachypacing-induced myofibril degradation, suggesting that Nox-derived oxidative stress may lead to tachycardia-induced myofibril degradation. Blockade of TGF-ß signalling by neutralizing TGF-ß antibodies attenuated myofibril loss in response to tachypacing, implicating autocrine and/or paracrine roles for TGF-ß in such effects. Tachypacing also induced the activation of p-Smad3 (an effective mediator of TGF-ß) and small-interfering RNAs for Nox2/4 attenuated its activation, supporting a crosstalk between both signalling pathways. Furthermore, TGF-ß expression, oxidative stress, and myofibril loss were greater in the atria of patients with AF than those with sinus rhythm. CONCLUSIONS: Rapid activation in atrial myocytes promotes myofibril degradation through autocrine/paracrine TGF-ß signalling and increased oxidative stress. These findings provide an important mechanistic insight into AF-related structural remodelling.

[Metabolic syndrome impact on arrhythmias genesis in elderly women].

The article discusses the data of a study aimed at the impact of the metabolic syndrome on arrhythmias in elderly women. Analysis of the data showed that supraventricular arrhythmias were detected in most part of elderly women, ventricular arrhythmias a few less. The share of prognostically unfavorable arrhythmias is small, but they develop linked to the metabolic changes, and dangerous ventricular arrhythmias and atrial fibrillation develop more often in patients with metabolic syndrome.

Prognostic significance of cardiac troponin I levels in hospitalized patients presenting with supraventricular tachycardia.

Although cardiac troponin I (cTnI) elevation in patients presenting to the hospital with supraventricular tachycardia (SVT) is well recognized, the prevalence, predictors, and prognostic significance of cTnI elevation associated with SVT presentation are not known. We screened records of all patients presenting to 2 hospitals over a 4-year period with the diagnosis of SVT confirmed by 12-lead electrocardiogram, and who had at least 1 measured cTnI level and at least 1 year of follow-up after discharge. The primary endpoint was the occurrence of 1 of the following outcomes: death, myocardial infarction, or cardiovascular rehospitalization. Seventy-eight patients met the study criteria (54% female; mean age, 62.2 +/- 15.8 yr), and 29 patients (37.2%) had an elevated cTnI level of > or =0.06 ng/mL (range, 0.06-7.78 ng/mL). Univariate predictors of elevated cTnI included left ventricular ejection fraction (LVEF) <50%, renal dysfunction, ST-segment depression or left bundle branch block on the electrocardiogram, and moderate or severe regurgitation of any cardiac valve. Predictors of elevated cTnI after multivariate analysis included peak heart rate during SVT (per 15 bpm) (odds ratio [OR], 1.58; 95% confidence interval [CI], 1.01-2.46; p = 0.04) and LVEF <50% (OR, 6.12; 95% CI, 1.40-26.7; p = 0.02). After multivariable adjustment, the presence of elevated cTnI with SVT was associated with increased risk of the primary endpoint of death, myocardial infarction, or cardiovascular rehospitalization (hazard ratio [HR], 3.67; 95% CI, 1.22-11.1; p = 0.02). Mild elevation of cTnI is common in patients presenting to the hospital with SVT, and is associated with increased risk of future cardiovascular events. Further study is needed to determine the mechanisms of SVT-related cTnI elevation and its association with elevated cardiovascular risk.

A slowly inactivating sodium current contributes to spontaneous diastolic depolarization of atrial myocytes.

Diastolic depolarization (DD) of atrial myocytes can lead to spontaneous action potentials (APs) and, potentially, atrial tachyarrhythmias. This study examined the hypotheses that 1) a slowly inactivating component of the Na(+) current (referred to as late I(Na)) may contribute to DD and initiate AP firing and that 2) blocking late I(Na) will reduce spontaneous and induced firing of APs by atrial myocytes. Guinea pig atrial myocytes without or with DD and spontaneous AP firing were studied using the whole cell patch-clamp technique. In experiments using cells with a stable resting membrane potential (no spontaneous DD or firing), hydrogen peroxide (H(2)O(2), 50 micromol/l) caused DD and AP firing. The H(2)O(2)-induced activity was suppressed by the late I(Na) inhibitors tetrodotoxin (TTX, 1 micromol/l) and ranolazine (5 micromol/l). In cells with DD but no spontaneous APs, the late I(Na) enhancer anemone toxin II (ATX-II, 10 nmol/l) accelerated DD and induced APs. In cells with DD and spontaneous AP firing, TTX and ranolazine (both, 1 micromol/l) significantly reduced the slope of DD by 81 +/- 12% and 75 +/- 11% and the frequency of spontaneous firing by 70 +/- 15% and 74 +/- 9%, respectively. Ramp voltage-clamp simulating DD elicited a slow inward current. TTX at 1, 3, and 10 micromol/l inhibited this current by 41 +/- 4%, 73 +/- 2%, and 91 +/- 1%, respectively, suggesting that a slowly inactivating I(Na) underlies the DD. ATX-II and H(2)O(2) increased the amplitude of this current, and the effects of ATX-II and H(2)O(2) were attenuated by ranolazine or TTX. In conclusion, late I(Na) can contribute to the DD of atrial myocytes and the inhibition of this current suppresses atrial DD and spontaneous APs.

Diabetes and thyroid hormones affect connexin-43 and PKC-epsilon expression in rat heart atria.

We have examined the changes of intercellular electrical coupling protein connexin-43 (Cx43) and of PKC-epsilon in heart atria of diabetic rats and/or after the treatment with triiodothyronine (T(3)). Diabetes was induced in Wistar-Kyoto rats by streptozotocin (50 mg/kg, i.v.) and atria were examined after 5 (acute stage) and 10 (chronic stage) weeks. T(3) (10 microg/100 g/day) was applied via a gastric tube for the last 10 days prior to the end of the experiments to non-diabetic and to the half of diabetic rats. Expression and phosphorylated status of Cx43, as well as expression of PKC-epsilon, were analyzed by Western blots using mouse monoclonal anti-Cx43 and rabbit polyclonal anti-PKC-epsilon antibodies. We found that the Cx43 expression was significantly increased after the treatment with T(3) and in the acute diabetes. Both in diabetes and after T(3) treatment the phosphorylation of Cx43 isoforms was markedly suppressed compared to the non-diabetic and T(3)-untreated controls. Such a down-regulation was less pronounced in diabetic rats after the T(3)-treatment. The expression of atrial PKC-epsilon was increased in diabetic rats. This increase was suppressed after T(3) administration and the expression was decreased in T(3)-treated non-diabetic rats. We suggest that the reduced Cx43 phosphorylation in diabetic and hyperthyroid rats can deteriorate a cell-to-cell coupling and consequently facilitate a development of atrial tachyarrhythmia in diabetic or hyperthyroid animals.

Cellular signaling underlying atrial tachycardia remodeling of L-type calcium current.

Atrial tachycardia (AT) downregulates L-type Ca(2+) current (I(CaL)) and causes atrial fibrillation-promoting electric remodeling. This study assessed potential underlying signal transduction. Cultured adult canine atrial cardiomyocytes were paced at 0, 1, or 3 Hz (P0, P1, P3) for up to 24 hours. Cellular tachypacing (P3) mimicked effects of in vivo AT: decreased I(CaL) and transient outward current (I(to)), unchanged I(CaT), I(Kr), and I(Ks), and reduced action potential duration (APD). I(CaL) was unchanged in P3 at 2 and 8 hours but decreased by 55+/-6% at 24 hours. Tachypacing caused Ca(2+)(i) accumulation in P3 cells at 2 to 8 hours, but, by 24 hours, Ca(2+)i returned to baseline. Ca(v)1.2 mRNA expression was not altered at 2 hours but decreased significantly at 8 and 24 hours (32+/-4% and 48+/-4%, respectively) and protein expression was decreased (47+/-8%) at 24 hours only. Suppressing Ca(2+)(i) increases during tachypacing with the I(CaL) blocker nimodipine or the Ca(2+) chelator BAPTA-AM prevented I(CaL) downregulation. Calcineurin activity increased in P3 at 2 and 8 hours, respectively, returning to baseline at 24 hours. Nuclear factor of activated T cells (NFAT) nuclear translocation was enhanced in P3 cells. Ca(2+)-dependent signaling was probed with inhibitors of Ca(2+)/calmodulin (W-7), calcineurin (FK-506), and NFAT (INCA6): each prevented I(CaL) downregulation. Significant APD reductions ( approximately 30%) at 24 hours in P3 cells were prevented by nimodipine, BAPTA-AM, W-7, or FK-506. Thus, rapid atrial cardiomyocyte activation causes Ca(2+) loading, which activates the Ca(2+)-dependent calmodulin-calcineurin-NFAT system to cause transcriptional downregulation of I(CaL), restoring Ca(2+)i to normal at the cost of APD reduction. These studies elucidate for the first time the molecular feedback mechanisms underlying arrhythmogenic AT remodeling.