Atrial Muscle Research Articles

Atrial fibrillation and atrial flutter in the practice of the emergency medical team in Poland

Background: Atrial Fibrillation (AF) is one of the most common heart arrhythmias globally. It is characterized by irregular, chaotic contractions of the atrial muscle, leading to an irregular and often rapid heart rhythm. The prevalence of this arrhythmia increases with age, which is associated with both the aging population and cardiovascular risk factors such as hypertension, coronary artery disease, and diabetes. Atrial Flutter (AFL) represents a less common variant of atrial fibrillation, occurring significantly less frequently - in relation to atrial fibrillation (AF), it is estimated to account for less than one-tenth of cases. The aim of the study was to analyze emergency medical services delivered to patients diagnosed with atrial fibrillation (AF) and atrial flutter (AFL) in the Voivodeship of Warmia and Mazury (Poland). The patients were classified according to the 10th Revision of the International Classification of Diseases (ICD-10 )[1]. Methods: The study was based on a retrospective data analysis. From a total population of 400,251 subjects (n= 400,251), 4715 patients were selected for the study. The majority of the patients were women (n=2941; 62.38%), whereas men accounted for 37.62% of the examined sample (n=1774). The analysis relied on a database administered by the Governor of the Voivodeship of Warmia and Mazury in Olsztyn [2]. The analyzed data included the area of intervention, the patient's age and sex, and the diagnoses made by physicians, paramedics, and emergency nurses. Three research hypotheses postulating the presence of relationships between the patient's sex and the diagnosis (1), the patient's age and the diagnosis (2), and a life-threatening emergency and the patient's age (3) were formulated. Results: The results of the study suggest that the patient's sex affects the medical diagnosis. In particular, women were more frequently diagnosed with chest pain, whereas the probability of the remaining diagnoses was similar in both sexes. The patient's age does not significantly influence the diagnosis. The patient's sex is not a significant predictor of a life-threatening emergency. Conclusion: The conducted study on the dataset from the Warmian-Masurian Voivodeship revealed significant correlations between demographic variables and the diagnosis of atrial fibrillation (AF) and atrial flutter (AFL) in patients. Analyzing this data may have significant implications for emergency medical systems, enabling the adaptation of intervention strategies to different patient categories.

Relationship between epicardial adipose tissue and ventricular fibrillation in Brugada syndrome by cardiac computed tomography analysis

Abstract Background Fibrofatty changes in the myocardium of the right ventricular (RV) to right ventricular outflow tract (RVOT) in patients with Brugada syndrome (BrS) may contribute to ventricular conduction delay and ultimately in the development of ventricular fibrillation (VF). In patients with atrial fibrillation (AF), inflammatory infiltration of epicardial adipose tissue (EAT) into the atrial muscle, along with reduced quantity and quality of EAT, has been demonstrated to be associated with the development of AF. We hypothesized that EAT in the RVOT from the RV in patients with BrS may lead to organic abnormalities in the ventricular muscle, resulting in VF. Purpose The purpose of this study was to evaluate the quantity and quality of EAT in patients with BrS using cardiac computed tomography (CT) and to determine the relationship with the occurrence of VF. Methods We retrospectively evaluated 61 of 82 patients with BrS regularly followed in our outpatient clinic from January 2000 to December 2023, who underwent cardiac CT scans. Patients were divided into two groups: those with VF events during follow-up (VF event group) and those without events (VF non-event group). Patient background, various parameters, volume of epicardial adipose tissue (EAT), and CT values from cardiac CT scans were compared between the two groups. EAT volume and CT values were measured for the entire heart and four specific regions: right ventricle (RV-EAT), right ventricular outflow tract (RVOT) to pulmonary artery bifurcation (RVOT-EAT), left ventricle (LV-EAT), and the left coronary artery main trunk circumference (LV summit-EAT) were measured for four specific sites. Results Median age at first diagnosis of BrS was 43 years, 98% were male patients, 41 patients (71%) had symptomatic BrS, and 18 patients (31%) had a family history. During a median follow-up of 72 months (30-136 months), 22 patients (38%) had VF events, including 2 arrhythmic sudden deaths. The median time from diagnosis to the first VF event was 14.3 months (4.3-24.5 months). The VF event group had more overall EAT volume (98.3 cm3 [range: 77.4 to 120.3 cm3] vs. 70.1 cm3 [range: 53.8 to 98.0 cm3], P=0.02) and significantly more RV-EAT volume (18.4 cm3 [range: 11.5 to 28.0 cm3] vs. 11.0 cm3 [range: 7.9 to 18.3 cm3], P=0.008). The CT value of RV-EAT was significantly lower in the VF event group (-83.1±6.1 vs -78.0±6.2, P=0.003), although the RV-EAT/LV-EAT density ratio was not different between the two groups (1.01±0.05 vs 0.99±0.07, P=0.14). On the other hand, the density ratio of RVOT-EAT/LV-EAT was significantly lower in the VF event group (0.95±0.08 vs. 1.00±0.08, P=0.03). Conclusions EAT analysis via CT in patients with BrS revealed that those experiencing VF events during follow-up tended to exhibit greater RV-EAT volume, lower CT values of RV-EAT, and higher CT values of RVOT-EAT density. These findings suggest EAT involvement in VF occurrence in patients with BrS.

Effects of SZV-2649, a new multiple ion channel inhibitor mexiletine analogue

The antiarrhythmic and cardiac electrophysiological effects of SZV-2649 that contains a 2,6-diiodophenoxy moiety but lacks the benzofuran ring system present in amiodarone, were studied in mammalian cell line, rat and dog cardiac preparations. SZV-2649 exerted antiarrhythmic effects against coronary artery occlusion/reperfusion induced ventricular arrhythmias in rats and in acetylcholine- and burst stimulation induced atrial fibrillation in dogs. SZV-2649 inhibited hERG and GIRK currents in HEK cells (IC50: 342 and 529 nM, respectively). In canine ventricular myocytes, SZV-2649 (10 µM) decreased the densities of IKr, and Ito outward and INaL and ICaL inward currents. The compound (2.5–10 µM) elicited Class IB type Vmax reducing and Class III type action potential duration prolonging effects in dog right ventricular muscle preparations. In canine atrial muscle, SZV-2629 (2.5–10 µM) moderately prolonged action potential duration and this effect was greatly augmented in preparations pretreated with 1 µM carbachol. In conclusion, SZV-2649, has antiarrhythmic effects based on its multiple ion channel blocking properties. Since its chemical structure substantially differs from that of amiodarone, it is expected that SZV-2649 would exhibit fewer adverse effects than the currently used most effective multichannel inhibitor drug amiodarone and may be a promising molecule for further development.

Similarities and differences in morphology, CD31 and CD68 expression of male vs. female sinoatrial node and its surrounding atrial muscle in ageing and obesity

Research purposeThe sinoatrial node (SN) is the main pacemaker site, and it is located in the junctional area of the superior vena cava within the right atrium (RA). The precise micro-anatomy of the SN in males and females in ageing and obesity remains unclear. Basic proceduresHuman SN/RA specimens were dissected from 25 post-mortem hearts (preserved in 4 % formaldehyde solution), under Polish local ethical rules. The SN/RA tissue blocks were embedded in paraffin. Masson's Trichrome staining and immunohistochemistry for CD31 (a marker of endothelial cells) and CD68 (a marker of macrophages) were performed. Images at different magnifications were taken and analysed. 12-lead ECGs from 24 patients under Polish local ethical rules were obtained. Heart rate and P wave morphologies from lead II, lead III and lead aVF were analysed. Statistical analysis was performed with the unpaired t-test. Principal resultsHeart weight to body weight ratio was significantly higher in aged obese males vs. their female counterparts. In the RA samples, there was an increase in connective tissue and decreased myocyte content from aged obese females compared to aged obese males. Aged non-obese males had significantly increased cellular hypertrophy than the aged non-obese females. Both the aged obese and aged non-obese females showed more CD3 but less CD68 expressing cells than males. In the SN samples, CD31 and CD68 expressing cells were higher in both aged non-obese and aged obese males than their female counterparts. Major conclusionsAgeing and/or obesity are more likely to impact these cardiac tissues through increased inflammation, increased immune response and hypertrophy.

Contractile Effects of Semaglutide in the Human Atrium.

Semaglutide is a glucagon-like peptide 1 receptor (GLP-1R) agonist. GLP-1R agonists are used to treat type 2 diabetes and obesity. It is currently unknown whether semaglutide can directly increase force of contraction (FOC) in the human heart. We tested the hypothesis that semaglutide might increase the FOC in the isolated human atrium. To this end, we conducted contraction experiments in isolated human right atrial muscle preparations (HAP). HAP were obtained during open-heart surgery. We detected a concentration- and time-dependent positive inotropic effect (PIE) of semaglutide in HAP. These PIEs were accompanied by increases in the rates of tension development and tension relaxation and a reduction in muscle relaxation time. The PIE of semaglutide in HAP was attenuated by H89, an inhibitor of the cyclic AMP-dependent protein kinase and by ryanodine, an inhibitor of sarcoplasmic Ca2+ release. Semaglutide up to 100 nM failed to exert a PIE in isolated electrically paced (1 Hz) wild-type mouse left atrial preparations studied for comparison. Our data suggest that semaglutide can increase the FOC in the atria of patients at therapeutic drug concentrations.

Abstract We045: Development of SA Node Organoids: A Multicellular Approach to Biological Pacemaking

The rising prevalence of sinoatrial (SA) node dysfunction, attributed to the aging population, is emerging as a critical health issue. The SA node, a natural organoid within the heart, comprises the pacemaker cells embedded within a connective tissue matrix, insulated electrically from the surrounding atrial muscle cells. This isolated architecture, along with a heterogeneous cellular composition, is crucial for the SA node's robust pacemaking and electrical conduction. Developing methods to reconstruct this crucial heterogeneous structure could offer a long-term solution for individuals with SA node dysfunction. However, the use of current biological pacemakers, which typically involve a single cell type, has often led to unstable heart rhythms during one-month in vivo integration, challenging their long-term clinical application as biological pacemakers. To address existing SA node model limitations, we developed a SA node organoid that reproduces the human SA node's multicellular tissue structure. Initially, we developed a protocol for generating cardiac SA node organoids by employing a lentivirus to deliver dox-inducible genes for key pacemaker transcription factors, specifically TBX-18 or Shox-2. We mixed wild-type human-induced pluripotent stem cells (hiPSCs) with those modified to express TBX-18 or Shox-2. These cell mixtures were aggregated, embedded in a diluted Matrigel, and then exposed to a cardiac differentiation protocol, activating TBX-18 or Shox-2 at specific times (D1 or D7) via Dox administration. By D9, these organoids began to exhibit contraction, which lasted beyond 60 days, with notable upregulation of two transcription factors and pacemaker-specific genes following Dox treatment. Subsequently, we integrated the SA node organoid into 2D hiPSC-derived atrial muscle tissue constructs, maintaining geometric isolation within the cardiac tissue to enhance source-sink mismatch. This isolation allowed the SA node organoid to successfully trigger activity in adjacent dormant cardiomyocytes, preserving the rhythm for over 60 days. These findings could redefine the role of tissue architecture and cell diversity in the SA node's pacemaking function, potentially leading to a high-fidelity, tissue-level biological pacemaker as a new treatment strategy for SA node dysfunctions.

KCa3.1 Promotes the Migration of Macrophages From Epicardial Adipose Tissue to Induce Vulnerability to Atrial Fibrillation During Rapid Pacing

BackgroundThe relationship between local epicardial adipose tissue (EAT) macrophages and atrial fibrillation (AF) remains unclear. The purpose of this study was to investigate the role of KCa3.1 in the migration of macrophages from EAT to adjacent atrial tissue during rapid pacing. MethodsPart 1: Eighteen beagles were randomly divided into the sham group, pacing group, and pacing + clodronate liposome (CL) group. Part 2: Eighteen beagles were randomly divided into the sham group, pacing group, and pacing + TRAM-34 group. HL-1 cells and RAW264.7 cells were co-cultured to explore the specific migratory mechanism of macrophages. ResultsDepleting EAT macrophages significantly reduced macrophage infiltration in the adjacent atrium and the induction of AF in canines with rapid atrial pacing. TRAM-34 significantly inhibited the migration of macrophages from EAT to the adjacent atrium and electrical remodelling in canines with rapid atrial pacing. Compared with those of the control HL-1 cells, the secretion of CCL2 and the number of migrating macrophages in pacing HL-1 cells was significantly increased, which could be reversed by TRAM-34. Further in vitro experiments showed that KCa3.1 regulated CCL2 secretion through the p65/STAT3 signalling pathway. ConclusionsInhibiting myocardial KCa3.1 reduced the migration of EAT macrophages to adjacent atrial muscles caused by rapid atrial pacing, thereby decreasing vulnerability to AF. The mechanism by which KCa3.1 regulates CCL2 may be related to the p65/STAT3 signalling pathway.

Early inhibition of the ATM/p53 pathway reduces the susceptibility to atrial fibrillation and atrial remodeling following acute myocardial infarction

Atrial fibrillation (AF) emerges as a critical complication following acute myocardial infarction (AMI) and is associated with a significant increased risk of heart failure, stroke and mortality. Ataxia telangiectasia mutated (ATM), a key player in DNA damage repair (DDR), has been implicated in multiple cardiovascular conditions, however, its involvement in the development of AF following AMI remains unexplored. This study seeks to clarify the contribution of the ATM/p53 pathway in the onset of AF post-AMI and to investigate the underlying mechanisms. The rat model of AMI was established by ligating left anterior descending coronary artery in the presence or absence of Ku55933 (an ATM kinase inhibitor, 5 mg/kg/d) treatment. Rats receiving Ku55933 were further divided into the early administration group (administered on days 1, 2, 4, and 7 post-AMI) and the late administration group (administered on days 8, 9, 11 and 14 post-AMI). RNA-sequencing was performed 14 days post-operation. In vitro, H2O2-challenged HL-1 atrial muscle cells were utilized to evaluate the potential effects of different ATM inhibition schemes, including earlier, middle, and late periods of intervention. Fourteen days post-AMI injury, the animals exhibited significantly increased AF inducibility, exacerbated atrial electrical/structural remodeling, reduced ventricular function and exacerbated atrial DNA damage, as evidenced by enhanced ATM/p53 signaling as well as γH2AX level. These effects were partially consistent with the enrichment results of bioinformatics analysis. Notably, the deleterious effects were ameliorated by early, but not late, administration of Ku55933. Mechanistically, inhibition of ATM signaling successfully suppressed atrial NLRP3 inflammasome-mediated pyroptotic pathway. Additionally, the results were validated in the in vitro experiments demonstrating that early inhibition of Ku55933 not only attenuated cellular ATM/p53 signaling, but also mitigated inflammatory response by reducing NLRP3 activation. Collectively, hyperactivation of ATM/p53 contributed to the pathogenesis of AF following AMI. Early intervention with ATM inhibitors substantially mitigated AF susceptibility and atrial electrical/structural remodeling, highlighting a novel therapeutic avenue against cardiac arrhythmia following AMI.

Morphology of human sinoatrial node and its surrounding right atrial muscle in the global obesity pandemic-does fat matter?

The sinus node (SN) is the main pacemaker site of the heart, located in the upper right atrium at the junction of the superior vena cava and right atrium. The precise morphology of the SN in the human heart remains relatively unclear especially the SN microscopical anatomy in the hearts of aged and obese individuals. In this study, the histology of the SN with surrounding right atrial (RA) muscle was analyzed from young non-obese, aged non-obese, aged obese and young obese individuals. The impacts of aging and obesity on fibrosis, apoptosis and cellular hypertrophy were investigated in the SN and RA. Moreover, the impact of obesity on P wave morphology in ECG was also analyzed to determine the speed and conduction of the impulse generated by the SN. Human SN/RA specimens were dissected from 23 post-mortem hearts (preserved in 4% formaldehyde solution), under Polish local ethical rules. The SN/RA tissue blocks were embedded in paraffin and histologically stained with Masson's Trichrome. High and low-magnification images were taken, and analysis was done for appropriate statistical tests on Prism (GraphPad, USA). 12-lead ECGs from 14 patients under Polish local ethical rules were obtained. The P wave morphologies from lead II, lead III and lead aVF were analyzed. Compared to the surrounding RA, the SN in all four groups has significantly more connective tissue (P ≤ 0.05) (young non-obese individuals, aged non-obese individuals, aged obese individuals and young obese individuals) and significantly smaller nodal cells (P ≤ 0.05) (young non-obese individuals, aged non-obese individuals, aged obese individuals, young obese individuals). In aging, overall, there was a significant increase in fibrosis, apoptosis, and cellular hypertrophy in the SN (P ≤ 0.05) and RA (P ≤ 0.05). Obesity did not further exacerbate fibrosis but caused a further increase in cellular hypertrophy (SN P ≤ 0.05, RA P ≤ 0.05), especially in young obese individuals. However, there was more infiltrating fat within the SN and RA bundles in obesity. Compared to the young non-obese individuals, the young obese individuals showed decreased P wave amplitude and P wave slope in aVF lead. Aging and obesity are two risk factors for extensive fibrosis and cellular hypertrophy in SN and RA. Obesity exacerbates the morphological alterations, especially hypertrophy of nodal and atrial myocytes. These morphological alterations might lead to functional alterations and eventually cause cardiovascular diseases, such as SN dysfunction, atrial fibrillation, bradycardia, and heart failure.

Unusual cardiac aneurysms: a surgical pathology experience

Among the cardiac outpouchings, left ventricular aneurysms or pseudo-aneurysms that develop secondary to myocardial infarctions are the most common. On the other hand, atrial appendageal and valvular aneurysms are uncommon occurrences. The appendageal aneurysms develop possibly due to congenital dysplasia of atrial pectinate muscles, while valvular aneurysms result from infective endocarditis, mechanical injury or degenerative changes. Despite their unusual locations, they are prone to life-threatening complications. We present our experience of unusual cardiac aneurysms in surgical cardiovascular material.

High-Salt Diet Inhibits the Expression of Bmal1 and Promotes Atrial Fibrosis and Vulnerability to Atrial Fibrillation in Dahl Salt-Sensitive Rats.

Hypertension is a risk factor for atrial fibrillation (AF), and brain and muscle arnt-like protein 1 (Bmal1) regulate circadian blood pressure and is implicated in several fibrotic disorders. Our hypothesis that Bmal1 inhibits atrial fibrosis and susceptibility to AF in salt-sensitive hypertension (SSHT) and our study provides a new target for the pathogenesis of AF induced by hypertension. The study involved 7-week-old male Dahl salt-sensitive that were fed either a high-salt diet (8% NaCl; DSH group) or a normal diet (0.3% NaCl; DSN group). An experimental model was used to measure systolic blood pressure (SBP), left atrial ejection fraction (LAEF), left atrial end-volume index (LAEVI), left atrial index (LAFI), AF inducibility, AF duration, and atrial fibrosis pathological examination and the expression of Baml1 and fibrosis-related proteins (TNF-α and α-SMA) in left atrial tissue. DSH increased TNF-α and α-SMA expression in atrial tissue, level of SBP and LAESVI, atrial fibrosis, AF induction rate, and AF duration, and decreased Bmal1 expression in atrial tissue, the circadian rhythm of hypertension, and level of LAEF and LAFI. Our results also showed that the degree of atrial fibrosis was negatively correlated with Bmal1 expression, but positively correlated with the expression of TNF-α and α-SMA. We demonstrated that a high-salt diet leads to circadian changes in hypertension due to a reduction of Bmal1 expression, which plays a crucial role in atrial fibrosis and increased susceptibility to AF in SSHT rats.

Resveratrol mediates mitochondrial function through the sirtuin 3 pathway to improve abnormal metabolic remodeling in atrial fibrillation.

This study investigated the impact of resveratrol on abnormal metabolic remodeling in atrial fibrillation (AF) and explored potential molecular mechanisms. An AF cell model was established by high-frequency electrical stimulation of HL-1 atrial muscle cells. Resveratrol concentrations were optimized using CCK-8 and flow cytometry. AF-induced increases in ROS and mitochondrial calcium, along with decreased adenosine triphosphate (ATP) and mitochondrial membrane potential, were observed. Resveratrol mitigated these changes and maintained normal mitochondrial morphology. Moreover, resveratrol acted through the SIRT3-dependent pathway, as evidenced by its ability to suppress AF-induced acetylation of key metabolic enzymes. SIRT3 overexpression controls acetylation modifications, suggesting its regulatory role. In conclusion, resveratrol's SIRT3-dependent pathway intervenes in AF-induced mitochondrial dysfunction, presenting a potential therapeutic avenue for AF-related metabolic disorders. This study sheds light on the role of resveratrol in mitigating AF-induced mitochondrial remodeling and highlights its potential as a novel treatment for AF.

Initial Characterization of a Transgenic Mouse with Overexpression of the Human H1-Histamine Receptor on the Heart.

There is a debate on whether H1-histamine receptors can alter contractility in the mammalian heart. We studied here a new transgenic mouse model where we increased genetically the cardiac level of the H1-histamine receptor. We wanted to know if histamine could augment or decrease contractile parameters in mice with cardiac-specific overexpression of human H1-histamine receptors (H1-TG) and compared these findings with those in littermate wild-type mice (WT). In H1-TG mice, we studied the presence of H1-histamine receptors by autoradiography of the atrium and ventricle using [3H]mepyramine. The messenger RNA for human H1-histamine receptors was present in the heart from H1-TG and absent from WT. Using in situ hybridization, we noted mRNA for the human H1-histamine receptor in cardiac cells from H1-TG. We noted that histamine (1 nM-10 µM) in paced (1 Hz) left atrial preparations from H1-TG, exerted at each concentration of histamine initially reduced force of contraction and then raised contractile force. Likewise, in spontaneously beating left atrial preparations from H1-TG, we noted that histamine led to a transient reduction in the spontaneous beating rate followed by an augmentation in the beating rate. The negative inotropic and chronotropic and the positive inotropic effects on histamine in isolated atrial muscle strips from H1-TG were attenuated by the H1-histamine receptor antagonist mepyramine. Histamine failed to exert an increased force or reduce the heartbeat in atrial preparations from WT. We concluded that stimulation of H1-histamine-receptors can decrease and then augment contractile force in the mammalian heart and stimulation of H1-histamine receptors exerts a negative chronotropic effect. SIGNIFICANCE STATEMENT: We made novel transgenic mice with cardiomyocyte-specific high expressional levels of the human H1-histamine receptor to contribute to the clarification of the controversy on whether H1-histamine receptors increase or decrease contractility and beating rate in the mammalian heart. From our data, we conclude that stimulation of H1-histamine receptors first decrease and then raise contractile force in the mammalian heart but exert solely negative chronotropic effects.

Correlation of Atrial Natriuretic peptide (ANP) coding gene (NPPA) and Human Hypertension

Atrial natriuretic peptide (ANP) is a polypeptide hormone secreted by atrial muscle cells that has an endogenous antagonistic effect on the renin-angiotensin-aldosterone system (RAAS). It is believed to regulate salt and fluid balance and blood pressure. Blood samples (150) from males aged less than 20 to 55 years were collected from Al-Salam and Ibn-Sena Teaching Hospital in Mosul from 1/2/2022 to 1/9/2022. These samples, 5ml that include healthy and previously blood hypertension-diagnosed patients, were put into two tubes for hormonal and molecular study and divided into three classes: Control, which includes 50 samples from healthy individuals; hypertension without treatment patients 40 individuals and patients with treatment 60 individuals. Each class was divided into five groups according to their age. group (1) less than 20, group (2) 20-29, group (3) 30-39, group (4) 40-49 and group (5) 50-59 years. Serum ANP hormone concentration was measured, and the results revealed significant differences at between patients and healthy control groups. Hormone concentration had decreased in the 1,2 group while increased in groups 3,4,5 of treated and untreated patients compared with control groups with different group concentrations ranging from 28.86-23.16 pg/ml, indicating the effect of aging on hormone concentration. Also, the results revealed a different hormone concentration in untreated patient's groups that ranged between 12.97-28 pg./ml while the concentration of treated patient's groups ranged between 12.97-33.36 pg/ml, these differences in hormone concentration in all groups revealed the effect interference of aging and treatments that had a direct effect on the hormone concentration. Besides, the Amplicon copy numbers of the ANP coding gene (Nppa gene), considered an essential indicator of gene activities utilizing the real-time technique, showed a significant increase in patient groups, especially group (5) of both treated and untreated, compared with control. These results concluded that this hormone had an essential correlation with hypertension.

LncRNA LENGA sponges miR-378 to promote myocardial fibrosis in atrial fibrillation.

miR-378 is known to suppress myocardial fibrosis, while its upstream regulators have not been identified. lncRNA LENGA is a recently identified lncRNA in cancer biology. We observed the altered expression of LENGA in atrial fibrillation (AF) patients and predicted its interaction with miR-378. We then explored the interaction between LENGA and miR-378 in AF. Angiotensin-II (Ang-II)-induced human atrial cardiac fibroblasts and human atrial muscle tissues were collected and the expression of LENGA and miR-378 was determined by RT-qPCR. The interaction between LENGA and miR-378 was analyzed through bioinformatics analysis and confirmed by RNA pulldown assay. Cell proliferation and collagen production were analyzed through in vitro assay to analyze the role of LENGA and miR-378 in MF. AF patients showed increased expression of LENGA and deceased expression of miR-378 compared to the sinus rhythm group. LENGA and miR-378 interacted with each other, while they are not closely correlated with each other. Overexpression assay showed that LENGA and miR-378 overexpression failed to affect each other's expression. LENGA promoted collagen production and proliferation of Ang-II-induced atrial fibroblasts, while miR-378 played opposite roles. Moreover, LENGA suppressed the function of miR-378. Therefore, LENGA may sponge miR-378 to promote MF in AF.

A novel role of human epicardial adipocyte-derived SPARCL1 in suppression of postoperative atrial fibrillation in patients undergoing cardiovascular surgery

Abstract Background Postoperative atrial fibrillation (POAF) occurs in 20-50% after cardiovascular surgery and is closely associated with the short and long-term morbidity/mortality. The epicardial adipose tissue (EAT) is in contact with the atrial muscle, and may have a potential predisposing factor to induce POAF within it. Purpose We tried to identify the specific gene expression profile of the human epicardial adipocyte associated with POAF. Methods We prospectively evaluated 126 patients without a history of AF (male 86 (68.3%); mean age 68.3 ± 11.7) who underwent scheduled open-heart cardiovascular surgery between May 2020 and November 2022. They were assigned to the POAF group and the Non-POAF group. POAF was defined as AF lasting more than 30 seconds documented by monitor or 12-lead electrocardiogram after the operation. Fresh human EAT samples were obtained from these patients during surgery, and preadipocytes were isolated from these samples. Isolated preadipocytes were terminally differentiated to mature adipocytes and RNAs were extracted. Genome-wide expression profiling of 6 vs. 6 matched samples of the POAF and Non-POAF groups was performed using Human Clariom S Assay-HT 16-Array Plate. The secreted protein levels in the adipocytes-cultured medium were also evaluated using enzyme-linked sorbent assay test to confirm the consistency of mRNA expression levels of adipocytes and its secreted protein levels. Results POAF was observed in 48 patients (38%). Patients in the POAF group were significantly older (p = 0.003) compared to the Non-POAF group. POAF occurred mainly within the first 3 postoperative days (median 2.5 days), and the median duration of POAF was 298 ± 581 minutes. The occurrence of POAF was significantly associated with longer postoperative hospitalization (p = 0.001) and intensive care unit stay (p = 0.04). Microarray analysis revealed that there were 132 down- or up-regulated cording genes (fold change >2.0 or `−2.0, p < 0.05) in epicardial adipocytes of the Non-POAF group compared to the POAF group. Of these genes, 11 genes cording secretable molecules were validated by qPCR, showing that only SPARCL1 had significantly higher expression in the Non-POAF group compared to the POAF group (p = 0.008). The mRNA expression levels of SPARCL1 significantly decreased when the preadipocyte were terminally differentiated to the mature adipocyte (p = 0.0009). SPARCL1 mRNA expression in adipocyte was significantly correlated with the concentration of SPARCL1 protein in the adipocyte-cultured medium (p < 0.0001, r = 0.7476). Conclusion The results of this study suggest that the expression of SPARCL1 in human epicardial adipocytes may play an important role in the suppression of POAF. Our findings suggested that SPARCL1 expression in human epicardial adipocytes may play an important role in the suppression of POAF. SPARCL1 secreted by epicardial adipocytes may be a potential therapeutic target for POAF prevention.Flowchart of patient selectionMicroarray analysis and qPCR varidation

DNA Methylation and Telomeres-Their Impact on the Occurrence of Atrial Fibrillation during Cardiac Aging.

Atrial fibrillation (AF) is the most common arrhythmia in humans. AF is characterized by irregular and increased atrial muscle activation. This high-frequency activation obliterates the synchronous work of the atria and ventricles, reducing myocardial performance, which can lead to severe heart failure or stroke. The risk of developing atrial fibrillation depends largely on the patient's history. Cardiovascular diseases are considered aging-related pathologies; therefore, deciphering the role of telomeres and DNA methylation (mDNA), two hallmarks of aging, is likely to contribute to a better understanding and prophylaxis of AF. In honor of Prof. Elizabeth Blackburn's 75th birthday, we dedicate this review to the discovery of telomeres and her contribution to research on aging.

An effective mathematical model of cardiac electrical activities for Bundle Branch Blocks

In this paper a mathematical model of cardiac induction system is developed. Sinoatrial node (SA), atrioventricular node (AV) and His Purkinje system (HP) are represented by modified Van der Pol-type oscillators (VDP) connected with time-delay coupling. Atrial and ventricular muscles are modeled using modified Aliev-Panfilov equations (AP), with stimulation current from the related pacemakers, to represent the P, QRS, Ta, and T waves. The main aim of this paper is to model bundle branch blocks (BBBs) for right (RBBB) and left (LBBB) branches. In fact, the right and left ventricles are directly affected by these blocks since the HP bundle is composed of right and left bundle branches that provide electrical signals, respectively, to the right and left ventricles. Four VDP oscillators are utilized, one for each of SA, AV, right HP, and left HP. The depolarization of the right and left ventricular muscles are represented by two systems of AP equations to produce right QRS and left QRS waves. The results of the simulation are compared with real normal and pathological electrocardiograms (ECGs) to show the effectiveness and the accuracy of the proposed model. The simulation proves that the model can reproduce the blocks in the HP bundle branches.

A-019 Integrative Analysis of Arrythmogenic Right Ventricular Cardiomyopathy of Potencial Biomarkers Through Bioinformatic Analysis

Abstract Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a disease usually associated with heterozygous or compound mutations in cardiac desmosomes genes. Pathologically, it is a disease characterized by fibrofatty replacement primarily in the right ventricle of normal cardiac tissue and clinically by sudden cardiac death in healthy young people. Diagnosis is often difficult due to the nonspecific nature of the disease and the broad spectrum of phenotypic variations, being commonly diagnostic post mostem. Non-coding RNAs are biomarkers that regulate gene expression and participate in various pathophysiological processes, becoming an important research field in cardiomyopathology for their potential as non-invasive clinical biomarkers and therapeutic. In this study, we aim to identify miRNAs that may serve as potentially effective targets in diagnosis and treatment as well as the exploration of regulatory miRNAs-mRNAs networks is beneficial for comprehensively understanding the molecular mechanism of ARVC development. Methods This study screened RNAs expression profiling studies from the Gene Expression Omnibus (GEO) database. The keyword “arrhythmogenic right ventricular cardiomyopathy” was used to search for suitable datasets that followed the criteria of being a comparable case-control human study, it was selected the GSE29819 and GSE164490 GEO series. The microarray GSE29819 set was analyzed using GEO2R, an interactive web tool disponibility in GEODataset site, resulting in the differential expression genes (DEGs) of this series, while high throughput sequencing GSE164490 set was preprocessing by miARma-Seq v 1.7.5 and for identifying DEGs was used R software v4.2.2 in R Studio (version: 2022.12.0 + 353) and Deseq2 package. The 2 sets used P < 0.05 and |log FC| > 1.5 as the cutoff criteria. An online prediction database, DIANA-microT CDS v 5.0 was used to obtain interactions with high confidence levels between miRNAs and target mRNAs. STRING online database v9 was used to predict protein-protein interactions (PPI) and functional enrichment analysis was conducted using the web-based utility Enrichr to uncover the roles of these molecules. Results The integrated analysis of the 2 datasets from GEO sequencing data from ARVC, after a criterium analysis, identify 04 common DEGs: hsa-miR-30d-5p, hsa-miR-200a-3p, hsa-miR-34a-5p and hsa-miR-125a-5p between them. Also, by constructing a PPI network, it was identified 04 genes among the overlapping DEGs, including PIK3R2, RARRES1, SCN2B, and SLCO5A1 (scores ≥0.7). The functional enrichment analyses demonstrated that the DEGs were enriched in some GO biological processes such as regulation of atrial cardiac muscle cell membrane and voltage-gated sodium channel activity involved in cardiac muscle cell action potential. Conclusion Our results suggest that these new network gene associations possibly play a potential role in metabolic pathways related to the pathogenesis of ARVC and are good candidates for further functional validation assays to confirm these findings.

A novel ablation strategy for recurrent atrial fibrillation: Fractionated signal area in the atrial muscle ablation 1-year follow-up.

Treatment of recurrent atrial fibrillation (AF) is sometimes challenging due to non-pulmonary vein (PV) foci. Fractionated signal area in the atrial muscle (FAAM) is a valid predictor of the location of non-PV foci. FAAM ablation has the potential to decrease the recurrence rate of atrial tachyarrhythmia in patients with recurrent AF. We compared the clinical impact of FAAM ablation for recurrent AF, using 1 year follow up date. A total of 230 consecutive patients with symptomatic recurrent AF who underwent catheter ablation specifically targeting non-PV foci as FAAM-guided ablation (n = 113) and non-FAAM-guided ablation (n = 117) were retrospectively analyzed. FAAM was assigned a parameter (peaks slider, which indicates the number of components of fractionated signals), ranging from 1 to 15, indicating the location of the FAAM (1: largest, 15: smallest). FAAM-guided ablation was performed by ablating FAAM until none inducibility of non-PV foci. On the other hand, non-FAAM-guided ablation was performed via linear ablation, complex fractionated atrial electrogram ablation, superior vena cava isolation, and focal ablation according to the location of the non-PV foci. The RHYTHMIA system was used to perform all the procedures. The primary endpoints were AF recurrence, atrial flutter, and/or atrial tachycardia. After a 1-year follow up, freedom from atrial tachyarrhythmia was achieved in 90.3% and 75.2% of patients in the FAAM and non-FAAM groups, respectively (hazard ratio = 0.438 [95% confidence interval: 0.243-0.788], p = .005). FAAM ablation showed a promising decrease in the recurrence rate of atrial tachyarrhythmia in patients with recurrent AF during a 1-year follow-up.