Academic literature on the topic 'Atrial electrical remodeling'

Background/Aims: Angiotensin II receptor blockers (ARBs) have been proved to be effective in preventing atrial structural and electrical remodelinq in atrial fibrillation (AF). Previous studies have shown that parasympathetic remodeling plays an important role in AF. However, the effects of ARBs on atrial parasympathetic remodeling in AF and the underlying mechanisms are still unknown. Methods: Canines were divided into sham-operated, pacing and valsartan + pacing groups. Rats and HL-1 cardiomyocytes were divided into control, angiotensin II (Ang II) and Ang II + valsartan groups, respectively. Atrial parasympathetic remodeling was quantified by immunocytochemical staining with anti-choline acetyltransferase (ChAT) antibody. Western blot was used to analysis the protein expression of neurturin. Results: Both inducibility and duration were increased in chronic atrial rapid-pacing canine model, which was significantly inhibited by the treatment with valsartan. The density of ChAT-positive nerves and the protein level of neurturin in the atria of pacing canines were both increased than those in sham-operated canines. Ang II treatment not only induced atrial parasympathetic remodeling in rats, but also up-regulated the protein expression of neurturin. Valsartan significantly prevented atrial parasympathetic remodeling, and suppressed the protein expression of neurturin. Meanwhile, valsartan inhibited Ang II -induced up-regulation of neurturin and MAPKs in cultured cardiac myocytes. Inhibition of MAPKs dramatically attenuated neurturin up-regulation induced by Ang II. Conclusion: Parasympathetic remodeling was present in animals subjected to rapid pacing or Ang II infusion, which was mediated by MAPKs/neurturin pathway. Valsartan is able to prevent atrial parasympathetic remodeling and the occurrence of AF via inhibiting MAPKs/neurturin pathway.

Atrial fibrillation is the most common arrhythmia in adults. In addition to the well-known cardiovascular risk factors, the role of genetic factors in the pathogenesis of atrial fibrillation is emphasized. MicroRNAs are a group of small, endogenous, single-stranded, non-coding RNAs, 20-22 nucleotides long, whose task is to regu­late gene expression at the post-transcriptional level. Changes in the expression of microRNAs in circulating blood and tissues lead to the development of cardiovascular diseases, including atrial fibrillation, leading to the remodeling of the heart muscle. Different types of remodeling, such as electrical remodelling, struc­tural remodeling, autonomic nerve remodelling, calcium handling abnormalities and single nucleotide polymorphisms in microRNA and related genes are responsible for the development and maintenance of atrial fibrillation. This paper presents the most important microRNAs that regulate genes that influence atrial fibrillation and thus may induce arrhythmia.

Several animal models of atrial fibrillation (AF) have been developed that demonstrate either atrial structural remodeling or atrial electrical remodeling, but the characteristics and spatiotemporal organization of the AF between the models have not been compared. Thirty-nine dogs were divided into five groups: rapid atrial pacing (RAP), chronic mitral regurgitation (MR), congestive heart failure (CHF), methylcholine (Meth), and control. Right and left atria (RA and LA, respectively) were simultaneously mapped during episodes of AF in each animal using high-density (240 electrodes) epicardial arrays. Multiple 30-s AF epochs were recorded in each dog. Fast Fourier transform was calculated every 1 s over a sliding 2-s window, and dominant frequency (DF) was determined. Stable, discrete, high-frequency areas were seen in none of the RAP or control dogs, four of nine MR dogs, four of six CHF dogs, and seven of nine Meth dogs in either the RA or LA or both. Average DFs in the Meth model were significantly greater than in all other models in both LA and RA except LA DFs in the RAP model. The RAP model was the only one with a consistent LA-to-RA DF gradient (9.5 ± 0.2 vs. 8.3 ± 0.3 Hz, P < 0.00005). The Meth model had a higher spatial and temporal variance of DFs and lower measured organization levels compared with the other AF models, and it was the only model to show a linear relationship between the highest DF and dispersion ( R2 = 0.86). These data indicate that structural remodeling of atria (models known to have predominantly altered conduction) leads to an AF characterized by a stable high-frequency area, whereas electrical remodeling of atria (models known to have predominantly shortened refractoriness without significant conduction abnormalities) leads to an AF characterized by multiple high-frequency areas and multiple wavelets.

Increasing evidence indicates systemic inflammation as a new potential cause of acquired LQTS and Torsade de Pointes and a strong predictor of Atrial Fibrillation, via cytokine-mediated changes in cardiomyocyte ion channels and in gap-junction. We hypothesised that systemic inflammation may represent a novel risk factor contributing to TdP development in the general population and can promotes atrial electric remodelling in-vivo, as a result of cytokine-mediated changes in connexins expression. For this reason, two population studies have been designed to confirm these hypotheses. In the first study, forty consecutive patients who experienced TdP (TdP cohort) were consecutively enrolled and circulating levels of C-reactive protein and proinflammatory cytokines (IL-6, TNFα and IL-1) were compared with patients with active rheumatoid arthritis (RA), comorbidity or healthy controls. An additional 46 patients with different inflammatory conditions and elevated CRP (inflammatory cohort) were prospectively enrolled, and corrected QT and cytokine levels were measured during active disease and after a CRP decrease of >75% subsequent to therapy. In the TdP cohort, 80% of patients showed elevated CRP levels (median: ~3 mg/dL). In these subjects, IL-6 was ~15–20 times higher than in controls, and comparable to RA patients. In the inflammatory cohort, where QTc prolongation was common, CRP reduction was associated with IL-6 level decrease and significant QTc shortening. In the second study, fifty-four patients with different inflammatory diseases and elevated C-reactive protein (CRP) levels were prospectively enrolled, and electrocardiographic P-wave dispersion indices, pro-inflammatory cytokine levels (IL-6, TNFα, IL-1), and connexin expression (connexin40, connexin43) were measured during active disease and after reducing CRP by >75%. In addition, peripheral blood mononuclear cells (PBMC) and atrial tissue specimens from 12 patients undergoing cardiac surgery were evaluated for atrial and circulating mRNA levels of connexins. In patients with active inflammatory diseases, P-wave dispersion indices are increased, but rapidly decreased within days when CRP normalizes and IL-6 levels decline. In inflammatory disease patients both P-wave dispersion indices and IL-6 changes are inversely associated with circulating connexins levels, and a positive correlation between connexins expression in PBMC and atrial tissue was demonstrated. Moreover, in-vitro incubation of mouse atrial cardiomyocytes with IL-6 significantly reduces connexins expression. The data are first to show that systemic inflammation via elevated IL-6 levels may represent a novel QT-prolonging risk factor contributing to TdP occurrence. Furthermore, these data suggest that regardless of specific aetiology and organ localization, systemic inflammatory activation, via elevation of IL-6 levels, rapidly induces atrial electrical remodelling by down-regulating cardiac connexins.

Background: Obstructive sleep apnea (OSA) has been associated with atrial enlargement in response to high arterial and pulmonary pressures and increased sympathetic tone. Continuous positive airway pressure (CPAP) is the gold standard treatment for OSA; its impact on atrial electrical remodeling has not been investigated however. Signal-averaged p-wave (SAPW) is a non-invasive quantitative method to determine p-wave duration, an accepted marker for atrial electrical remodeling. The objective was to determine whether CPAP induces reverse atrial electrical remodeling in patients with severe OSA. Methods: Prospective study in consecutive patients attending the Sleep Clinic at Kingston General Hospital. All patients underwent full polysomnography. OSA-negative and severe OSA were defined as apnea-hypopnea index (AHI) < 5 events/hour and AHI ≥ 30 events/hour, respectively. In severe OSA patients, SAPW was determined pre- and post-intervention with CPAP for 4 - 6 weeks. In OSA-negative controls, SAPW was recorded at baseline and 4 - 6 weeks thereafter without any intervention. Results: A total of 19 severe OSA patients and 10 controls were included in the analysis. Mean AHI and minimum O2 saturation were 41.4 ± 10.1 events/hour and 80.5 ± 6.5% in severe OSA patients and 2.8 ± 1.2 events/hour and 91.4 ± 2.1% in controls. Baseline BMI was different between severe OSA patients and controls (34.3 ± 5.4 vs 26.6 ± 4.6 kg/m2; p < 0.001). At baseline, severe OSA patients had a greater SAPW duration than controls (131.9 ± 10.4 vs 122.8 ± 10.5 ms; p = 0.02). After CPAP intervention, there was a significant reduction of SAPW duration in severe OSA (131.9 ± 10.4 to 126.2 ± 8.8 ms; p < 0.001). In controls, SAPW duration did not change within 4 - 6 weeks. Conclusion: CPAP induced reverse atrial electrical remodeling in patients with severe OSA as represented by a significant reduction in SAPW duration.
Thesis (Master, Physiology) -- Queen's University, 2011-07-29 12:53:09.134

Atrial fibrillation is the most common sustained arrhythmia; however, its mechanism is not well understood. Several conditions such as valvular disease, heart failure, and hypertension predispose to atrial fibrillation. Identifying the electrophysiological substrate in these clinical conditions would yield insight into the mechanism of atrial fibrillation and aid in developing strategies to prevent or cure it. Rheumatic mitral stenosis is associated with high prevalence of atrial fibrillation. While atrial stretch itself may be adequate to explain the occurrence of atrial fibrillation in this population, it is not known if the disease process would remodel the atria so as to increase its propensity. Chapters 2 and 3 present the results of the studies evaluating the substrate for atrial fibrillation in both the left and right atria in rheumatic mitral stenosis. These studies have demonstrated extensive conduction abnormalities both regional and site specific associated with low voltage area and scar. Despite the prolonged atrial refractoriness, the propensity for atrial fibrillation was increased; lending support to the theory that structural remodelling associated with conduction abnormalities plays a greater role in the substrate predisposing to atrial fibrillation. Chapters 4 and 5 present the results of the studies evaluating the immediate effects of chronic atrial stretch reversal on the atrial electrical remodelling. These studies demonstrated that immediately after percutaneous mitral commissurotomy there was decrease in P wave duration, improvement in site specific conduction delay and conduction velocity associated with increase in the voltage. However, there was no change in atrial refractoriness. Chapter 6 studies the substrate long-term after reduction of stretch. There was further increase in conduction velocity and voltage associated with decrease in atrial refractoriness and conduction delay across the crista terminalis. These observations suggest that strategies aimed at reducing atrial stretch in different disease conditions would potentially decrease the burden or prevent atrial fibrillation. There is mounting evidence of the effect of stretch on the atria; however, the effect of stretch on the triggers of atrial fibrillation has not been evaluated before. Chapter 7 and 8 present the results of the study examining the effect of acute and chronic stretch on human pulmonary veins. Simultaneous pacing of the right ventricle and pulmonary vein induced acute stretch. The effect of chronic stretch was evaluated in patients with mitral stenosis. The atrial refractoriness was abbreviated in acute stretch while it was prolonged in the chronic form. Nevertheless, both resulted in marked pulmonary vein conduction abnormalities that were pronounced with chronic stretch and extra-stimuli. Additionally, structural remodelling was seen with chronic stretch. These abnormalities implicate stretch in the milieu for re-entry and pulmonary vein arrhythmogenesis in conditions predisposed to atrial fibrillation. In summary, this thesis has evaluated the effects of stretch on the substrate and triggers of atrial fibrillation. It provides evidence for the importance of structural changes and the associated abnormalities in conduction in predisposing to atrial fibrillation. These observations may be important in the development of tools to treat, cure and prevent atrial fibrillation.
Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2008

博士
國立臺灣大學
臨床醫學研究所
95
The aim of the present doctoral thesis is to investigate the detailed molecular mechanism by which angiotensin II (AngII) is involved in the pathegenesis of atrial fibrillation (AF). Recently, it has been shown that local atrial rennin-angiotensin system (RAS) is activated with increased tissue AngII level during AF. AngII activates the downstream mitogen-activated protein kinase pathway (MAPK) signaling pathways, resulting in atrial structural remodeling. AngII is also involved in atrial electrical remodeling, and it has also been shown that blockage of endogenous AngII prevents rapid-pacing induced shortening of atrial effective refractory period (AERP). In our previous study, we first demonstrated the genetic association between RAS genetic variations and the development of AF. In the present study, we further increased the sample size of our genetic association study to more than 2 fold, and have found more significant results. We also showed that RAS genetic variations and gene-gene interactions among RAS genes were also associated with the development of various cardiovascular diseases, including hypertension and coronary artery disease, in addition to AF. Because the molecular mechanisms by which AngII is involved in the pathogenesis of hypertension or coronary artery disease are well known, the following study subjects were focusing on the molecular mechanisms by which AngII is involved in the pathogenesis of AF, with emphases on the structural and electrical remodelings. Regarding AngII and structural remodeling, we used a rapid-pacing porcine AF model. AF was induced by atrial pacing at 600/min in adult pigs. Significant structural and inflammatory changes were noted in the AF pigs. Although atrial tissue angiotensin II level was elevated in the AF pigs, the MAPK pathways were not activated. However, signal transducers and activators of transcription-1 (STAT1) and STAT3 were activated with increased STAT3 nuclear translocation in the AF pigs. Membrane translocation and activation of Rac1 was also noted. Furthermore, in cultured atrial myocytes and fibroblasts, angiotensin II activated STAT3 through a Rac1-dependent mechanism, which was inhibited by dominant negative Rac1, losartan and simvastatin. We found that the STATs pathways, but not the MAPKs, were activated by angiotensin II and might contribute to structural and inflammatory changes in AF. The activation of STAT3 was dependent on Rac1 and was blocked by losartan and simvastatin. Regarding AngII and electrical remodeling, we investigated whether AngII modulates L-type calcium channel (LCC) current through transcriptional regulation, using a murine atrial HL-1 cells model. AngII increased LCC α1C subunit mRNA and protein levels and LCC current density, which resulted in an augmented calcium transient. AngII significantly increased promoter activity of LCC α1C subunit gene in a concentration- and time-dependent manner. Truncation and mutational analysis of the LCC α1C subunit gene promoter showed that cAMP response element (CRE)(-1853 to –1845) was an important cis-element in Ang II-induced LCC α1C subunit gene expression. AngII induced serine 133 phosphorylation of CRE binding protein (CREB), binding of CREB to CRE, and increase of LCC α1C subunit gene promoter activity through a protein kinase C (PKC)/NADPH oxidase/reactive oxygen species (ROS) dependent pathway, which was blocked by the AngII type 1 receptor blocker losartan and the antioxidant simvastatin. In summary, Ang II increases LCC α1C subunit expression, LCC current density, and amplitude of the calcium transient in atrial myocytes. AngII-induced LCC α1C subunit expression was PKC-, ROS-, and CREB-dependent, and was blocked by losartan and simvastatin. Why local atrial tissue angiotensin II (AngII) production is up-regulated during atrial fibrillation (AF)? It is possible that atrial myocytes express all the components of renin-angiotensin system (RAS), and AF or rapid depolarization per se could increase AngII production by up-regulating the expressions of components of RAS. Again, we used porcine and cellular models to prove this hypothesis. In the cell model, AF was simulated in the cultured murine atrial HL-1 cells by rapid field pacing (RES)(1.0 V/cm, 10 Hz). AngII concentration was measured by ELISA, and expressions of angiotensin converting enzyme (ACE), chymase, angiotensinogen (AGT), renin, AngII type 1 receptor (AT1R) and type 2 receptor (AT2R) were measured by immnunoblotting. In the porcine model, atrial tissue AngII, ACE, chymase and AGT were up-regulated in the AF pigs, but renin was down-regulated. AT1R was up-regulated in the left atria, but down-regulated in the right atria. AT2R was up-regulated in both left atria and right atria. In the cellular model, RES induced a similar pattern of expressions of RAS components, and increased AngII concentrations in the mediums and cellular extracts. RES induced AngII production was attenuated by ACEI Enalapril and chymase inhibitor chymostatin. These results suggest that combination of ACEI and chymase inhibitor prevents rapid-depolarization induced AngII production and atrial structural remodeling. Regarding clinical studies, to evaluate whether echocardiography could be used to evaluate atrial volume and function that may be related to atrial structural remodeling, we first designed a study to evaluate the left atrial (LA) volume, and LA systolic (contractile) and diastolic (expansion) functions in different stages of hypertension with or without atrial fibrillation, as well as the effects of good blood pressure control. This was a prospective observational study. Individuals including 22 normotensive controls, 23 patients with mild hypertension (MH), 20 with severe hypertension (SH), and 17 with both hypertension and paroxysmal atrial fibrillation (AH) were recruited for paired echocardiography studies at baseline and 6 months after medical control of hypertension. We found that with increasing severity of hypertension, LV diastolic function deteriorated progressively from controls, MH, SH, to AH patients. LA expansion index was reduced in parallel. LA expansion index was correlated positively with LV E’/A’ ratio and inversely with LV E/E’ ratio. Significant improvement of LV diastolic function and LA expansion index preceded the reduction of LA volume after 6 months of effective blood pressure control. In summary, with progressive LV diastolic dysfunction in different stages of hypertension, there was a corresponding deterioration in LA expansion or diastolic function, which preceded changes in LA volume and LA contractile function. Recently there is increasing evidence that AF is an inflammatory disease. It has also been shown that statin is a potent anti-inflammatory agent. Furthermore, in the above studies, we have showed that statin blocked AngII signaling pathways, which play important roles in atrial structural and electrical remodeling. Therefore, we hypothesized that statin therapy may provide an effective treatment strategy for AF. We conducted a prospective randomzed clinical study to test the efficacy of atorvastatin in the treatment of paroxysmal AF (PAF). We chose patients who have received implantation of a pacemaker. By pacemaker interrogation, we could accurately detect the first attack of AF to see the effect of atorvastatin to prevent AF attack. Fifty-two patients (23 males, 70±13 years old) were randomized to the statin group and 54 (25 males, 72±13 years old) to the control group. Around 70 % of the patients had SSS and the remaining AVB. Around 75 % of the patients had underwent implantation of a dual chamber pacemaker (DDD[R]), and the remaining single chamber PM (AAI[R]). Three patients did not complete the follow-up and the other patients completed the followed-up for one year. Significant atrial high rate episode (AHE)(rate>180/min and duration≧10 min) occurred in 3 of 50 patients (6.0%) in the statin group, and 10 of 53 patients (18.9%)(OR=0.27; 95% confidence interval [CI] 0.05-0.96, p=0.03) in the control group. Patients in the non-statin group were more likely to develop significant AHE that those in the statin group (log-rank p=0.028). The present study clearly and accurately demonstrated the efficacy of atorvastatin to prevent the occurrence of AF in patients with bradycardia. The possible molecular mechanisms warrant further studies. In conclusions, the present doctoral thesis combined genetic association studies, molecular studies and clinical studies to demonstrate how AngII is involved in the pathogeneses of atrial structural and electrical remodeling, which are important substrates of AF. We first showed the association between RAS genetic variants and the development of AF. Second, we further investigated the possible molecular mechanisms by which AngII is involved in the pathogeneses of atrial structural and electrical remodelings. Third, we found that echocardiography was a useful tool to non-invasively evaluate atrial volume and function, which could serve as a clinical surrogate to represent atrial structural remodeling. Finally, we performed a prospective and randomized clinical trial showing a decrease of AF by statin, which has been shown to block AngII signaling pathways in the former basic molecular studies.

The term ‘athlete’s heart’ refers to the structural, functional, and electrical adaptations that occur as a result of habitual exercise training. It is characterized by an increase of the internal chamber dimensions and wall thickness of both atria and ventricles. The athlete’s right ventricle also undergoes structural, functional, and electrical remodelling as a result of intense exercise training. Some research suggests that the haemodynamic stress of intense exercise is greater for the right heart and, as a result, right heart remodelling is slightly more profound when compared with the left heart. Echocardiography is the primary tool for the assessment of morphological and functional features of athlete’s heart and facilitates differentiation between physiological and pathological LV hypertrophy. Doppler myocardial and strain imaging can give additional information to the standard indices of global systolic and diastolic function and in selected cases cardiac magnetic resonance imaging may help in the diagnosis of specific myocardial diseases among athletes such as hypertrophic cardiomyopathy, dilated cardiomyopathy, or arrhythmogenic right ventricular cardiomyopathy.

The atria serve a combination of reservoir, sensor, and neuroendocrine roles that help the heart to adapt to variations in blood volume, heart rate, and ventricular filling. When stressed by high-rate activity or increased haemodynamic load (due to hypertension, valve disease, or heart failure), the atria respond with increased oxidant production (oxidative stress) that promotes transcriptional changes that reversibly remodel electromechanical activity, with shortened action potential duration and effective refractory period, slowed and heterogeneous conduction, and impaired contractility. When the stresses persistent, the atria undergo persistent structural changes including chamber dilatation and increased interstitial fibrosis. The combination of electrical and structural remodelling leads to increased risk and persistence of atrial fibrillation and stroke. Accumulation of dysfunctional proteins that are normally recycled by the proteasome may contribute to the susceptibility to development of atrial fibrillation. Changes in ion channel expression are most often associated with the development of persistent atrial fibrillation. While many atrial fibrillation therapies have focused on targeting of atrial ion channels, efforts to target atrial proteostasis may have promise as a therapeutic atrial fibrillation treatment or prevention strategy.

Sinus node disease is the commonest bradyarrhythmia, often presenting as syncope or exercise limitation and is an important reason for pacemaker implantation. It is usually idiopathic and a disease of ageing with a peak incidence in the seventh decade of life, but may develop secondary to other conditions including heart failure and chronic endurance exercise. The detailed pathophysiology of sinus node disease remains unknown, studies have found evidence of widespread atrial electrical remodelling, and contemporary research suggests that cellular electrical and fibrotic changes may be important mediators of this remodelling. There is an important association between sinus node disease and atrial fibrillation, and the two arrhythmias often coexist, but the nature of this interaction remains a source of debate. This chapter will summarize the current understanding of the natural history and pathophysiology of sinus node disease, with a focus on remodelling and including discussion of theories that may explain the development of coexistent atrial arrhythmia in these patients.