Role In Atrial Fibrillation Research Articles

Premature senescence of cardiac fibroblasts and atrial fibrosis in patients with atrial fibrillation.

Premature senescence is associated with atrial fibrosis and has an antifibrotic effect in mice. However, the role of senescence in atrial fibrillation (AF) remains unclear. Here, we investigated the association of premature senescence with fibrosis and also determined the role of senescence in the recurrence of AF after surgery ablation. Western blot, Sirius red staining, SA-β-gal staining and immunohistochemistry were performed to detect the degree of atrial fibrosis ,the expression of TGF-β and collagens, and also the senescence markers in 72 tissue specimens of left atrial appendage in this study. Then the patients undergoing successful surgical ablation were followed up for 12 months. The expression of collagens and TGF-β was paralleled by a high level of atrial fibrosis and were increased in AF group, especially in the persistent AF group. Western blotting of P16 and SA-β-gal staining showed an increased premature senescence in the sinus rhythm, paroxysmal AF and persistent AF groups. In addition, positive area of senescence markers, SA-β-gal and P16, was correlated positively with fibrotic lesions. We also found a lower ratio of P16/TGF-β in patients with recurrence of AF than in patients without recurrent AF. In conclusion, premature senescence is associated with atrial fibrosis in AF, and may have an antifibrotic role in AF.

Autonomic nervous system modulation and clinical outcome after pulmonary vein isolation using the second-generation cryoballoon.

The intrinsic cardiac autonomic nervous system (ANS) plays a significant role in atrial fibrillation (AF) mechanisms. This study evaluated the incidence and impact of intraprocedural vagal reactions and ANS modulation by pulmonary vein isolation (PVI) using second-generation cryoballoons on outcomes. One hundred three paroxysmal AF patients underwent PVI with one 28-mm second-generation balloon. The median follow-up was 15.0 (12.0-18.0) months. ANS modulation was defined as a >20% cycle length decrease on 3-minute resting electrocardiograms at 1, 3, 6, and 12 months postindex procedure relative to baseline if sinus rhythm was maintained. Marked sinus arrests/bradycardia and atrioventricular block (intraprocedural vagal reaction) occurred in 14 and 2 patients, and all sinus arrest/bradycardia occurred in 44 patients with left superior pulmonary veins (PVs) targeted before right PVs. ANS modulation was identified in 66 of 95 (69.5%) patients, and it persisted 12-month postprocedure in 36 (37.9%) patients. Additional β-blocker administration was required in 9 patients for sinus tachycardia. ANS modulation was similarly observed in patients with and without intraprocedural vagal reactions (P = 0.443). Forty-eight (46.6%) patients experienced early recurrences, and the single procedure success at 12 months was 72.7%. Neither intraprocedural vagal reactions nor ANS modulation predicted AF freedom within or after the blanking period. Thirty-three patients underwent second procedures, and reconnections were detected in 39 of 130 (30.0%) PVs among 23 (69.7%) patients. The incidence of reconnections was similar in patients with and without ANS modulation. Increased heart rate persisted in 37.9% of patients even at 12-month post-second-generation cryoballoon PVI. Neither intraprocedural vagal reactions nor increased heart rate predicted a single procedure clinical outcome.

The protective role of small heat shock proteins in cardiac diseases: key role in atrial fibrillation

Atrial fibrillation (AF) is the most common tachyarrhythmia which is associated with increased morbidity and mortality. AF usually progresses from a self-terminating paroxysmal to persistent disease. It has been recognized that AF progression is driven by structural remodeling of cardiomyocytes, which results in electrical and contractile dysfunction of the atria. We recently showed that structural remodeling is rooted in derailment of proteostasis, i.e., homeostasis of protein production, function, and degradation. Since heat shock proteins (HSPs) play an important role in maintaining a healthy proteostasis, the role of HSPs was investigated in AF. It was found that especially small heat shock protein (HSPB) levels get exhausted in atrial tissue of patients with persistent AF and that genetic or pharmacological induction of HSPB protects against cardiomyocyte remodeling in experimental models for AF. In this review, we provide an overview of HSPBs as a potential therapeutic target for normalizing proteostasis and suppressing the substrates for AF progression in experimental and clinical AF and discuss HSP activators as a promising therapy to prevent AF onset and progression.

Prognostic value of elevated high-sensitivity cardiac troponin T in patients admitted to an emergency department with atrial fibrillation.

Elevated levels of high-sensitivity cardiac troponin T (hsTnT) indicate underlying heart disease and are known to predict adverse outcomes in various patient populations. Their role in atrial fibrillation (AF) is still under debate. This retrospective study included 2898 consecutive patients presenting with AF to the emergency department of the Department of Cardiology, Heidelberg University Hospital. Multivariable Cox regression was used to assess associations between hsTnT and mortality. Elevated hsTnT levels were associated with increased risk of all-cause mortality in all patients with AF, as well as in each subtype of AF. After adjustment for multiple risk factors, both detectable hsTnT below the 99th percentile (5-14 ng/L, adjusted hazard ratio (HR): 4.86 [95% CI: 1.77-13.34], P = 0.002) and elevated hsTnT (>14 ng/L, adjusted HR: 13.42 [95% CI: 4.95-36.40], P < 0.001) were associated with a higher risk of mortality in patients with AF, compared to undetectable hsTnT (<5 ng/L). Elevated hsTnT was also associated with higher mortality after exclusion of patients with myocardial infarction, as well as in the subgroup of patients with AF as main admission diagnosis. The inclusion of hsTnT significantly improved the performance of the multivariable model for mortality prediction. Elevated hsTnT levels are associated with higher mortality in patients with AF, and provide added prognostic information independent of major cardiovascular risk factors and clinical characteristics. Measurement of hsTnT should be considered for risk assessment in patients presenting to an emergency department with AF. http://www.clinicaltrials.gov; Unique identifier: NCT02542189.

Cardiac hyaluronan may be associated with the persistence of atrial fibrillation.

Hyaluronan (HA), a primary component of the extracellular matrix, is associated with several cardiovascular diseases. However, its precise cardiac origin and role in atrial fibrillation (AF) remain unclear. We investigated chamber-specific HA levels in patients with paroxysmal AF (PAF) or persistent AF (PSAF). The levels of HA, a diacron-reactive oxygen metabolite (dROM) as a marker for oxidative stress, at different cardiac sites, and peripheral brain natriuretic peptide (BNP) levels were measured in patients with PAF (n = 50) or PSAF (n = 35). HA levels in the coronary sinus (CS-HA) were significantly higher than those other sites, in both PAF and PSAF patients, and CS-HA levels were significantly higher in PSAF patients than in PAF patients [37.1 (interquartile range, 31.2-48.3) vs. 30.6 (23.7-40.2) pg/mL, P < 0.01]. CS-HA levels were correlated with CS-dROM levels and peripheral BNP levels in PSAF patients (r = 0.417, P = 0.03 and r = 0.579, P < 0.001, respectively), but not in PAF patients (r = -0.115, P = 0.421 and r = 0.048, P = 0.740, respectively). CS-HA levels were elevated in both PAF and PSAF patients and were correlated with cardiac oxidative stress and BNP levels in PSAF patients. Cardiac HA may be associated with the persistence of AF.

Recurrent Post-Ablation Paroxysmal Atrial Fibrillation Shares Substrates With Persistent Atrial Fibrillation : An 11-Center Study.

The role of atrial fibrillation (AF) substrates is unclear in patients with paroxysmal AF (PAF) that recurs after pulmonary vein isolation (PVI). We hypothesized that patients with recurrent post-ablation (redo) PAF despite PVI have electrical substrates marked by rotors and focal sources, and structural substrates that resemble persistent AF more than patients with (de novo) PAF at first ablation. In 175 patients at 11 centers, we compared AF substrates in both atria using 64 pole-basket catheters and phase mapping, and indices of anatomical remodeling between patients with de novo or redo PAF and first ablation for persistent AF. Sources were seen in all patients. More patients with de novo PAF (78.0%) had sources near PVs than patients with redo PAF (47.4%, p=0.005) or persistent AF (46.9%, p=0.001). The total number of sources per patient (p=0.444), and number of non-PV sources (p=0.701) were similar between groups, indicating that redo PAF patients had residual non-PV sources after elimination of PV sources by prior PVI. Structurally, left atrial size did not separate de novo from redo PAF (49.5±9.5 vs. 49.0±7.1mm, p=0.956) but was larger in patients with persistent AF (55.2±8.4mm, p=0.001). Patients with paroxysmal AF despite prior PVI show electrical substrates that resemble persistent AF more closely than patients with paroxysmal AF at first ablation. Notably, these subgroups of paroxysmal AF are indistinguishable by structural indices. These data motivate studies of trigger versus substrate mechanisms for patients with recurrent paroxysmal AF after PVI.

Role of the MAPKs/TGF-β1/TRAF6 signaling pathway in postoperative atrial fibrillation

ObjectivesTo explore the relationship between the MAPKs/TGF-β1/TRAF6 signaling pathway and atrial fibrosis in patients with rheumatic heart disease (RHD) and its role in atrial fibrillation (AF) after cardiac surgery on the basis of our previous animal study of the MAPKs/TGF-β1/TRAF6 signaling pathway in atrial fibrosis.MethodsA total of 57 patients with RHD without a history of AF consented to left atrial biopsy. Histopathology quantified the percentage of fibrosis, and real-time PCR and western blot assessed the mRNA and protein expression of TGF-β1, TRAF6, and connective tissue growth factor (CTGF), respectively. Western blot was also used to measure the protein expression of phosphorylated MAPKs and TGF-β-activated kinase 1 (TAK1). Serum angiotensin II (Ang II) levels were assayed using enzyme-linked immunosorbent assay (ELISA).ResultsEighteen patients developed AF, whereas 39 remained in sinus rhythm (SR). The severity of atrial fibrosis was significantly higher in patients who developed AF versus those who remained in SR; the mRNA and protein expression of TGF-β1, TRAF6 and CTGF were significantly higher in patients with AF. The protein expression of phosphorylated MAPKs and TAK1 was significantly increased in patients who developed AF compared with the patients who remained in SR. Serum Ang II levels were significantly higher in patients who developed AF versus those who remained in SR.ConclusionThe MAPKs/TGF-β1/TRAF6 signaling pathway is involved in atrial fibrosis in patients with RHD, which results in the occurrence of AF after cardiac surgery.

Serum galectin-3 level as a marker of thrombogenicity in atrial fibrillation.

Left atrial appendage flow velocity (LAAFV) and presence of spontaneous echo contrast (SEC) have been reported to be predictors of thromboembolism in atrial fibrillation (AF) patients. Galectin-3 is a biomarker reflecting pro-inflammatory status, whose role in AF has recently drawn attention, particularly in persistent AF population. In this study we aimed to investigate the association between serum galectin-3 levels and echocardiographic predictors of thromboembolism in persistent AF patients. We included 65 persistent AF patients (55.50±10.67years, 46.15% male). Transesophageal echocardiography (TEE) was performed to assess LAAFV and presence of left atrial (LA)/LA appendage (LAA)-located SEC and thrombus prior to direct current cardioversion or catheter ablation for AF. Median galectin-3 level was 0.63ng/mL. Serum galectin-3 levels were significantly correlated with LAAFV (r=-.440, P<.001). Serum galectin-3 levels were associated with presence of SEC (P<.001), and LA thrombus (P=.008). Receiver operating characteristic analysis revealed that a serum galectin-3 greater or equal to the cut-off value of 0.69 predicted presence of SEC with a sensitivity and specificity of 91.00% and 79.00%, respectively (P<.001). In conclusion, in the setting of persistent AF, serum galectin-3 levels are associated with presence of SEC and LAAFV on TEE. Our findings suggest that serum galectin-3 level may have a place in thromboembolism risk stratification in persistent AF patients.

INFLUENCE OF BETA-BLOCKERS ON MORTALITY IN CHRONIC HEART FAILURE PATIENTS WITH ATRIAL FIBRILLATION: FINDINGS FROM THE GULF-SAFE

Background: Beta-blockers are known to decrease long-term mortality in patients with heart failure (HF). However, their role in atrial fibrillation (AF) patients with HF is controversial. We hypothesized that beta-blockade therapy in patients presenting to the emergency room (ER) due to AF, and have

Regulation of cardiac CACNB2 by microRNA-499: Potential role in atrial fibrillation

The L-type calcium channel (LTCC) is one of the major ion channels that are known to be associated with the electrical remodeling of atrial fibrillation (AF). In AF, there is significant downregulation of the LTCC, but the underlying mechanism for such downregulation is not clear. We have previously reported that microRNA-499 (miR-499) is significantly upregulated in patients with permanent AF and that KCNN3, the gene that encodes the small-conductance calcium-activated potassium channel 3 (SK3), is a target of miR-499. We found that CACNB2, an important subunit of the LTCC, is also a target of miR-499. We hypothesize that miR-499 plays an important role in AF electrical remodeling by regulating the expression of CACNB2 and the LTCC. In atrial tissue from patients with permanent AF, CACNB2 was significantly downregulated by 67% (n=4, p<0.05) compared to those from patients with no history of AF. Transfection of miR-499 mimic into HL-1 cells, a mouse hyperplastic atrial cardiac myocyte cell-line, resulted in the downregulation of CACNB2 protein expression, while that of miR-499 inhibitor upregulated CACNB2 protein expression. Binding of miR-499 to the 3′ untranslated region of CACNB2 was confirmed by luciferase reporter assay and by the increased presence of CACNB2 mRNA in Argonaute pulled-down microRNA-induced silencing complexes after transfection with the miR-499 mimic. In addition, downregulation of CACNB2 resulted in the downregulation of protein levels of the pore-forming α-subunit (CACNA1C). In conclusion, upregulation of atrial miR-499 induces the downregulation of CACNB2 expression and may contribute to the electrical remodeling in AF.

Update about atrial fibrillation genetics.

Atrial fibrillation is an important cause of morbidity in the aging population. The mechanisms responsible for the triggering and maintenance of the chaotic atrial rhythm are still poorly understood. In this review, we will focus on the genetic aspects of atrial fibrillation, to understand causality, with special emphasis on recent studies published in the field. Diseases such as hypertension, valvular heart disease, and heart failure may induce atrial fibrillation, which increases the risk of stroke and sudden cardiac death. Clinical studies published in these last two decades have provided evidence that genetics play a key role in atrial fibrillation. Thus, a family history of the disease has been identified in up to 30% of clinically diagnosed patients. In those genotyped families, most carry rare genetic variants in genes associated with ionic channels, calcium handling protein, or predisposing to fibrosis, conduction system disease, and inflammatory processes. Currently, atrial fibrillation is the most common sustained arrhythmia in clinical practice. The pathophysiological mechanisms of atrial fibrillation are complex. A better understanding of the molecular basis will help improve both current risk stratification and clinical management.

JAK-STAT signalling and the atrial fibrillation promoting fibrotic substrate.

Left-atrial (LA) fibrosis is an important feature of many atrial fibrillation (AF) substrates. The JAK-STAT system contributes to cardiac remodelling, but its role in AF is unknown. Here we investigated JAK-STAT changes in an AF-model and their potential contributions to LA-fibrosis. LA-remodelling was studied in dogs with heart failure (HF) induced by ventricular tachypacing (VTP, 240 bpm), and in mice with left-ventricular (LV) dysfunction due to myocardial infarction (MI). The selective STAT-3 inhibitor S3I-201 was administered to fibroblasts in vitro or mice in vivo (10 mg/kg/d, osmotic mini-pump). HF-dogs developed LA-selective fibrosis and AF-susceptibility at 1-week VTP. The mRNA-expression of platelet-derived growth factor (PDGF, a JAK-STAT activator) isoforms A, C and D, as well as JAK2, increased in LA fibroblasts from 1-week VTP. HF upregulated protein-expression of PDGF-receptor-β and phosphorylated (activated) signal transducer and activator of transcription 3 (STAT3) in LA. PDGF-AB stimulation of LA fibroblasts increased PDGFR-α, STAT3 and phosphorylated-STAT3 expression, as well as collagen-1 and fibronectin-1 protein secretion (by 1.6- to 20-fold), with smaller changes in LV fibroblasts. Phosphorylated-STAT3 and collagen upregulation were suppressed by the JAK2 inhibitor AG-490, PDGF receptor inhibitor AG1296 and STAT3-inhibitor SI3-201. In vivo S3I-201 treatment of MI-mice attenuated LA-fibrosis, LA-dilation and P-wave duration changes versus vehicle-control. HF activates the LA JAK-STAT system and enhances PDGF-signalling. JAK-STAT inhibition reduces the profibrotic effects of PDGF stimulation on canine fibroblasts in vitro while attenuating in vivo LA-fibrosis and remodelling in post-MI mice, suggesting that the JAK/STAT pathway contributes to LA-fibrogenesis and might be a potential target for LA-fibrosis prevention.

Association of AGTR1 and ACE2 gene polymorphisms with structural atrial fibrillation in a Chinese Han population.

The renin-angiotensin system (RAS) is thought to play an important role in atrial fibrillation (AF). The RAS contains the ACE/AngII/AGTR1 axis and the ACE2/Ang(1-7)/MAS axis, which restrict each other via mutual antagonism and regulate myocardial hypertrophy, fibrosis and remodelling. The aim of our study was to investigate the association between single nucleotide polymorphisms (SNPs) in angiotensin-II type-1 receptor (AGTR1) and angiotensin-converting enzyme 2 (ACE2) and structural AF in a Chinese Han population. The SNPs (rs1492100, rs1492099, rs1492097, rs3772616) in AGTR1 and the SNP rs6632677 in ACE2 were compared in 300 structural AF patients (67.61±12.56 years) and 300 controls (66.08±12.47 years). The genotype frequencies of SNP rs1492099 in AGTR1 in the structural AF cohort vs controls were as follows: GG, 72.7 vs 83.0%; AG 26.0 vs 16.3%; AA 1.3 vs 0.7% (P=0.009). The frequency of the minor allele of SNP rs1492099 in AGTR1 was 14.2% in the structural AF group compared with 8.8% in the controls (t=0.004; odds ratio [OR], 1.727; 95% confidence interval [CI]: 1.154-2.487). In addition, the genotype frequencies of SNP rs6632677 in ACE2 in the structural AF male patients vs male controls were as follows: GG, 70.5 vs 83.1%; CG 26.3 vs 15.6%; and CC 3.2 vs 1.3% (P=0.029). The frequency of the minor allele of SNP rs6632677 in ACE2 was 16.3% in structural AF male patients compared with 9.1% in male controls (P=0.008; OR, 1.954; 95%CI: 1.196-3.192). Furthermore, we found an interaction between the SNP rs6632677 in ACE2 and the SNPs (rs1492100/rs1492099/rs3772616) in AGTR1 in structural AF patients by the multifactor dimensionality reduction (MDR) method. The results indicate that polymorphism rs1492099 in the AGTR1 gene is associated with structural AF in a Chinese Han population. It was hypothesized that the ACE2 gene, which maps to the X chromosome, may be correlated with the risk of structural AF in a Chinese Han male population. Furthermore, we found an interaction between ACE2 and AGTR1 in structural AF patients in a Chinese Han population.

Is endothelin gene polymorphism associated with postoperative atrial fibrillation in patients undergoing coronary artery bypass grafting?

Background:The mechanism of development of atrial fibrillation (AF) in patients undergoing coronary artery bypass grafting (CABG) has not been clearly defined, and the involvement of multiple factors such as advanced age, withdrawal of β-blockers, inadequate atrial protection, and electrolyte imbalance, particularly hypomagnesemia has been documented by several authors. Despite all the available pharmacologic prophylaxis, incidence of AF still remains high in this group of patients. This unexplained cause could be genetic inheritance of endothelin-1 (ET-1) gene which is thought to have a pro-arrhythmogenic effect.Aim:This study aims to investigate the relationship between plasma ET-1 concentrations, ET-1 gene polymorphisms in loci -1370 T/G, -134 (3A/4A) Ins/del, Lys198Asn (G/T), and occurrence of AF in patients undergoing CABG.Methodology:Ninety-eight nonrelated, nondiabetic patients over a period of 4 years undergoing routine CABG were selected for the present study. All patients were genotyped for three single nucleotide polymorphisms (SNPs) in loci -1370 T/G, -134 (3A/4A) Ins/del, and Lys198Asn (G/T) in the ET-1 gene by gene sequencing. The plasma ET-1 concentrations were measured using an ET immunoassay.Results:Plasma ET-1 concentrations were higher in AF+ group (P = 0.001) as compared to AF− group. The allele frequencies between AF+ and AF− group were significantly different only with respect to the Lys198Asn (G/T) SNP of the ET-1 gene.Conclusion:The study described the possible correlation of polymorphism of ET gene in CABG population from India. The ET-1 gene might play a disease-modifying role in atrial fibrillation.

Atrial fibrillation: Therapeutic potential of atrial K+ channel blockers.

Despite the epidemiological scale of atrial fibrillation, current treatment strategies are of limited efficacy and safety. Ideally, novel drugs should specifically correct the pathophysiological mechanisms responsible for atrial fibrillation with no other cardiac or extracardiac actions. Atrial-selective drugs are directed toward cellular targets with sufficiently different characteristics in atria and ventricles to modify only atrial function. Several potassium (K+) channels with either predominant expression in atria or distinct electrophysiological properties in atria and ventricles can serve as atrial-selective drug targets. These channels include the ultra-rapidly activating, delayed outward-rectifying Kv1.5 channel conducting IKur, the acetylcholine-activated inward-rectifying Kir3.1/Kir3.4 channel conducting IK,ACh, the Ca2+-activated K+ channels of small conductance (SK) conducting ISK, and the two pore domain K+ (K2P) channels TWIK-1, TASK-1 and TASK-3 that are responsible for voltage-independent background currents ITWIK-1, ITASK-1, and ITASK-3. Here, we briefly review the characteristics of these K+ channels and their roles in atrial fibrillation. The antiarrhythmic potential of drugs targeting the described channels is discussed as well as their putative value in treatment of atrial fibrillation.

Relation of Resting Heart Rate to Incident Atrial Fibrillation (from the Henry Ford Hospital Exercise Testing Project)

Autonomic nervous system (ANS) dysfunction plays a role in atrial fibrillation (AF) initiation. Cardiorespiratory fitness modulates ANS function and is inversely associated with resting heart rate (RHR) and risk of AF. Thus, we sought to study the association between RHR, as a surrogate for ANS function, and incident AF independent of exercise capacity (EC). We analyzed 51,436 subjects without previous AF who underwent a clinically indicated exercise stress test. Incident AF was ascertained through claims files. RHR was measured before stress testing, and EC was estimated by peak metabolic equivalents of task. We studied the association between RHR categories (<70, 70 to 85 [reference], and >85 beats/min) and incident AF using Cox models adjusted for risk factors and for EC. We tested for interaction between RHR and age, gender, smoking, and EC. Mean (SD) age was 53 (13) years, 53% were men, and 28% were black. Participants with RHR <70 beats/min were older, more likely to be men, have higher EC, and more likely to smoke but less likely to have diabetes and hypertension. Over a median of 5.5years, RHR <70 beats/min was associated with 14% increased risk of AF (95 CI 6% to 25%) in fully adjusted models, whereas RHR >85 beats/min was not associated with AF risk after adjusting for EC. Results for RHR analyzed continuously and by quartile were similar. No interaction was seen. In conclusion, subjects with low RHR at all levels of EC are at increased risk of AF and may benefit from heart rhythm surveillance, particularly in the presence of other AF risk factors.

Oxidized Low-density Lipoprotein (ox-LDL) Cholesterol Induces the Expression of miRNA-223 and L-type Calcium Channel Protein in Atrial Fibrillation.

Atrial fibrillation (AF) is the most common sustained arrhythmia causing high morbidity and mortality. While changing of the cellular calcium homeostasis plays a critical role in AF, the L-type calcium channel α1c protein has suggested as an important regulator of reentrant spiral dynamics and is a major component of AF-related electrical remodeling. Our computational modeling predicted that miRNA-223 may regulate the CACNA1C gene which encodes the cardiac L-type calcium channel α1c subunit. We found that oxidized low-density lipoprotein (ox-LDL) cholesterol significantly up-regulates both the expression of miRNA-223 and L-type calcium channel protein. In contrast, knockdown of miRNA-223 reduced L-type calcium channel protein expression, while genetic knockdown of endogenous miRNA-223 dampened AF vulnerability. Transfection of miRNA-223 by adenovirus-mediated expression enhanced L-type calcium currents and promoted AF in mice while co-injection of a CACNA1C-specific miR-mimic counteracted the effect. Taken together, ox-LDL, as a known factor in AF-associated remodeling, positively regulates miRNA-223 transcription and L-type calcium channel protein expression. Our results implicate a new molecular mechanism for AF in which miRNA-223 can be used as an biomarker of AF rheumatic heart disease.

Increased α-Actinin-2 Expression in the Atrial Myocardium of Patients with Atrial Fibrillation Related to Rheumatic Heart Disease

Objectives: Atrial fibrosis, a marker of atrial structural remodeling, plays a critical role in atrial fibrillation (AF). α- Actinin-2 is associated with structural remodeling related to stretching. The transforming growth factor-β₁ (TGF-β1)/Smad pathway plays an important role in atrial fibrosis. We investigated the effects of the TGF-β1/Smad signaling pathway on α-actinin-2 in atrial fibrosis in patients with AF. Methods: Forty-one right atrial specimens obtained from patients with rheumatic heart disease (RHD) were divided into a chronic (c)AF group, i.e. RHD + cAF (n = 29), and a sinus rhythm group, i.e. RHD + sinus rhythm (n = 12). Patients with congenital heart disease (CHD) and sinus rhythm who underwent heart surgery served as controls (n = 10). Fibrosis was assessed by histological examination, and expression of α-actinin-2, TGF-β1 and Smad2/phosphorylated Smad2 (p-Smad2) was evaluated by immunohistochemistry, quantitative real-time PCR and Western blotting. In rat atrial fibroblasts treated with TGF-β1, the collagen content was measured using hydroxyproline detection, and α-actinin-2 and p-Smad2 were evaluated by semiquantitative reverse-transcription PCR and Western blotting. Results: The histology results revealed a significant increase in atrial fibrosis in AF patients. The collagen content, mRNA and protein expression levels of α-actinin-2 and the components of the TGF-β1/Smad signaling pathway were significantly gradually increased in the CHD + sinus rhythm, RHD + sinus rhythm and RHD + cAF groups (p < 0.05). The mRNA and protein levels of α-actinin-2 and TGF-β1 in RHD patients were positively correlated with the collagen volume fraction. A positive correlation between the expression of α-actinin-2 and TGF-β1 was also observed. In rat atrial fibroblasts treated with TGF-β1, the collagen content was greater than that in the control group (p < 0.05), and the expression levels of α- actinin-2 and p-Smad2 were also upregulated (p < 0.05). Conclusions: α-Actinin-2 expression was increased in the atrial tissues of patients with AF secondary to RHD. α-Actinin-2 was upregulated via the TGF-β1/Smad pathway in atrial fibroblasts, which suggests that it may be involved in TGF-β1/Smad pathway-induced atrial fibrosis in patients with AF.

Modulation of Cardiac Potassium Current by Neural Tone and Ischemia.

The cardiac action potential is generated by intricate flows of ions across myocyte cell membranes in a coordinated fashion to control myocardial contraction and the heart rhythm. Modulation of the flow of these ions in response to a variety of stimuli results in changes to the action potential. Abnormal or altered ion currents can result in cardiac arrhythmias. Abnormalities of autonomic regulation of potassium current play a role in the genesis of cardiac arrhythmias, and alterations in acetylcholine-activated potassium channels may play a key role in atrial fibrillation. Ischemia is another important modulator of cardiac cellular electrophysiology.

Atrial-Selective Potassium Channel Blockers.

Atrial fibrillation (AF) is associated with increased morbidity and mortality. Atrial-selective potassium (K(+)) channel blockers may represent a novel therapeutic target. The best validated atrial-specific ion currents are the acetylcholine-activated inward-rectifier K(+) current IK,ACh and ultrarapidly activating delayed-rectifier K(+) current IKur. Two-pore domain and small-conductance Ca(2+)-activated K(+) channels and Kv1.1 channels may also contribute to the atrial repolarization. We review the molecular and electrophysiologic characteristics of atrial-selective K(+) channels and their potential pathophysiologic role in AF. We summarize currently available K(+) channel blockers focusing on the most important compounds.