Role of Early Left Atrial Functional Decline in Predicting Cardiotoxicity in HER2 Positive Breast Cancer Patients Treated With Trastuzumab.

Trastuzumab is widely used in HER2 breast cancer. However, it may cause left ventricular (LV) dysfunction. A decrease in LV global longitudinal strain (GLS) has been previously demonstrated to be a good predictor of subsequent cancer therapy related dysfunction (CTRCD). Left atrial morphological remodeling during Trastuzumab therapy has also been shown. The aim of this study is exploring the relationship between early changes in left atrial function and the development of Trastuzumab-induced cardiotoxicity. Consecutive patients with diagnosis of HER2+non-metastatic breast cancer treated with Trastuzumab were prospectively enrolled. A clinical, conventional, and advanced echocardiographic assessment was performed at baseline and every three months, until a one-year follow-up was reached. One-hundred-sixteen patients completed the 12 months follow-up, 10 (9%) cases of CTRCD were observed, all after the sixth month. GLS and LVEF significantly decreased in the CTRCD group at 6 months of follow-up, with an earlier (3 months) significant worsening in left atrial morpho-functional parameters. Systolic blood pressure, early peak atrial longitudinal strain (PALS), peak atrial contraction (PACS) and left atrial volume (LAVI) changes resulted independent predictors of CTRCD at multivariable logistic regression analysis. Moreover, early changes in PALS and PACS resulted good predictors of CTRCD development (AUC 0.85; p = 0.008, p < 0.001 and 0.77; p = 0.008, respectively). This prospective study emphasizes that the decline in PALS and PACS among trastuzumab-treated patients could possibly increase the accuracy in identifying future CTRCD in non-metastatic HER2 breast cancer cases, adding predictive value to conventional echocardiographic assessment.

Synergistic Effects of Weight Loss and Catheter Ablation: Can microRNAs Serve as Predictive Biomarkers for the Prevention of Atrial Fibrillation Recurrence?

In atrial fibrillation (AF), multifactorial pathologic atrial alterations are manifested by structural and electrophysiological changes known as atrial remodeling. AF frequently develops in the context of underlying cardiac abnormalities. A critical mechanistic role played by atrial stretch is played by abnormal substrates in a number of conditions that predispose to AF, including obesity, heart failure, hypertension, and sleep apnea. The significant role of overweight and obesity in the development of AF is known; however, the differential effect of overweight, obesity, cardiovascular comorbidities, lifestyle, and other modifiable risk factors on the occurrence and recurrence of AF remains to be determined. Reverse remodeling of the atrial substrate and subsequent reduction in the AF burden by conversion into a typical sinus rhythm has been associated with weight loss through lifestyle changes or surgery. This makes it an essential pillar in the management of AF in obese patients. According to recently published research, microRNAs (miRs) may function as post-transcriptional regulators of genes involved in atrial remodeling, potentially contributing to the pathophysiology of AF. The focus of this review is on their modulation by both weight loss and catheter ablation interventions to counteract atrial remodeling in AF. Our analysis outlines the experimental and clinical evidence supporting the synergistic effects of weight loss and catheter ablation (CA) in reversing atrial electrical and structural remodeling in AF onset and in recurrent post-ablation AF by attenuating pro-thrombotic, pro-inflammatory, pro-fibrotic, arrhythmogenic, and male-sex-associated hypertrophic remodeling pathways. Furthermore, we discuss the promising role of miRs with prognostic potential as predictive biomarkers in guiding approaches to AF recurrence prevention.

Left atrial size modify the association between uric acid and atrial fibrillation in patients with coronary artery disease.

BACKGROUND AND AIMS: The potential influence of left atrial size on the relationship between uric acid and atrial fibrillation has not been fully investigated. This study aims to evaluate the interaction effect of left atrial size on the association between uric acid and atrial fibrillation in patients with coronary artery disease. METHODS AND RESULTS: This retrospective cohort study, conducted from January 2018 to October 2022, included 2004 patients undergoing Drug-Eluting Stent implantation for coronary artery disease. Utilizing logistic regression models with the product of left atrial enlargement (LAE) and uric acid, interaction effects were assessed. Among the participants, 383 had LAE, and 159 experienced atrial fibrillation. After adjusting for covariates, continuous uric acid levels were associated with an increased risk of atrial fibrillation in patients without LAE (OR:1.631, 95% CI: 1.284-2.072), but not in those with LAE (OR:1.069, 95% CI: 0.848-1.348). A significant interaction of uric acid levels was observed between groups with and without LAE (p = 0.046). Restricted cubic spline curves indicated a J-shaped relationship between uric acid and atrial fibrillation in the absence of LAE. However, the association between uric acid levels and atrial fibrillation in the LAE group remained unchanged with increasing uric acid levels. CONCLUSION: The study suggested that left atrial size modified the association between uric acid and atrial fibrillation in patients with coronary artery disease. Uric acid serves as a potential biomarker for atrial fibrillation risk, especially in individuals without LAE.

Gender Differences in Cardiac Organ Damage in Arterial Hypertension: Assessing the Role of Drug Nonadherence.

INTRODUCTION: Cardiac organ damage like left ventricular (LV) hypertrophy and left atrial (LA) enlargement is more prevalent in women than men with hypertension, but the mechanisms underlying this gender difference remain unclear. METHODS: We tested the association of drug nonadherence with the presence of LV hypertrophy and LA enlargement by echocardiography in 186 women and 337 men with uncontrolled hypertension defined as daytime systolic blood pressure (BP) ≥ 135mmHg despite the prescription of at least two antihypertensive drugs. Drug adherence was assessed by measurements of serum drug concentrations interpreted by an experienced pharmacologist. Aldosterone-renin-ratio (ARR) was measured on actual medication. RESULTS: Women had a higher prevalence of LV hypertrophy (46% vs. 33%) and LA enlargement (79% vs 65%, both p < 0.05) than men, while drug nonadherence (8% vs. 9%, p > 0.514) did not differ. Women were older and had lower serum renin concentration and higher ARR than men, while 24-h systolic BP (141 ± 9 mmHg vs. 142 ± 9 mmHg), and the prevalences of obesity (43% vs. 50%) did not differ (all p > 0.10). In multivariable analyses, female gender was independently associated with a two-fold increased risk of LV hypertrophy (OR 2.01[95% CI 1.30-3.10], p = 0.002) and LA enlargement (OR 1.90 [95% CI 1.17-3.10], p = 0.010), while no association with drug nonadherence was found. Higher ARR was independently associated with LV hypertrophy in men only (OR 2.12 [95% CI 1.12-4.00] p = 0.02). CONCLUSIONS: Among patients with uncontrolled hypertension, the higher prevalence of LV hypertrophy and LA enlargement in women was not explained by differences in drug nonadherence. REGISTRATION: URL:  https://www. CLINICALTRIALS: gov ; Unique identifier: NCT03209154.

Pathophysiology and clinical relevance of atrial myopathy.

Atrial myopathy is a condition that consists of electrical, structural, contractile, and autonomic remodeling of the atria and is the substrate for development of atrial fibrillation, the most common arrhythmia. Pathophysiologic mechanisms driving atrial myopathy are inflammation, oxidative stress, atrial stretch, and neurohormonal signals, e.g., angiotensin-II and aldosterone. These mechanisms initiate the structural and functional remodeling of the atrial myocardium. Novel therapeutic strategies are being developed that target the pathophysiologic mechanisms of atrial myopathy. In this review, we will discuss the pathophysiology of atrial myopathy, as well as diagnostic and therapeutic strategies.

Characterizing the influence of cardiorespiratory fitness on left atrial size and function in the general population.

Increased left atrial (LA) size and reduced LA function have been associated with heart failure and atrial fibrillation (AF) in at-risk populations. However, atrial remodeling has also been associated with exercise training and the relationship between fitness, LA size, and function has not been defined across the fitness spectrum. In a cross-sectional study of 559 ostensibly healthy participants, comprising 304 males (mean age, 46 ± 20 yr) and 255 females (mean age, 47 ± 15 yr), we sought to define the relationship between cardiorespiratory fitness (CRF), LA size, and function. We also aimed to interrogate sex differences in atrial factors influencing CRF. Echocardiographic measures included biplane measures of LA volumes indexed to body surface area (LAVi) and atrial deformation using two-dimensional speckle tracking. CRF was measured as peak oxygen consumption (V̇o2peak) during cardiopulmonary exercise testing (CPET). Using multivariable regression, age, sex, weight, and LAVi (P < 0.001 for all) predicted V̇o2peak (P < 0.001, R2 = 0.66 for combined model). After accounting for these variables, heart rate reserve added strength to the model (P < 0.001, R2 = 0.74) but LA strain parameters did not predict V̇o2peak. These findings add important nuance to the perception that LA size is a marker of cardiac pathology. LA size should be considered in the context of fitness, and it is likely that the adverse prognostic associations of increased LA size may be confined to those with LA enlargement and low fitness.NEW & NOTEWORTHY Left atrial (LA) structure better predicts cardiorespiratory fitness (CRF) than LA function. LA function adds little statistical value to predictive models of peak oxygen uptake (V̇o2peak) in healthy individuals, suggesting limited discriminatory for CRF once LA size is factored. In the wider population of ostensibly healthy individuals, the association between increased LA volume and higher CRF provides an important counter to the association between atrial enlargement and heart failure symptoms in those with cardiac pathology.

Recurrence After Atrial Fibrillation Ablation and Investigational Biomarkers of Cardiac Remodeling.

BACKGROUND: Recurrence after atrial fibrillation (AF) ablation remains common. We evaluated the association between recurrence and levels of biomarkers of cardiac remodeling, and their ability to improve recurrence prediction when added to a clinical prediction model. METHODS AND RESULTS: Blood samples collected before de novo catheter ablation were analyzed. Levels of bone morphogenetic protein-10, angiopoietin-2, fibroblast growth factor-23, insulin-like growth factor-binding protein-7, myosin-binding protein C3, growth differentiation factor-15, interleukin-6, N-terminal pro-brain natriuretic peptide, and high-sensitivity troponin T were measured. Recurrence was defined as ≥30 seconds of an atrial arrhythmia 3 to 12 months postablation. Multivariable logistic regression was performed using biomarker levels along with clinical covariates: APPLE score (Age >65 years, Persistent AF, imPaired eGFR [<60 ml/min/1.73m2], LA diameter ≥43 mm, EF <50%; which includes age, left atrial diameter, left ventricular ejection fraction, persistent atrial fibrillation, and estimated glomerular filtration rate), preablation rhythm, sex, height, body mass index, presence of an implanted continuous monitor, year of ablation, and additional linear ablation. A total of 1873 participants were included. A multivariable logistic regression showed an association between recurrence and levels of angiopoietin-2 (odds ratio, 1.08 [95% CI, 1.02-1.15], P=0.007) and interleukin-6 (odds ratio, 1.02 [95% CI, 1.003-1.03]; P=0.02). The area under the receiver operating characteristic curve of a model that only contained clinical predictors was 0.711. The addition of any of the 9 studied biomarkers to the predictive model did not result in a statistically significant improvement in the area under the receiver operating characteristic curve. CONCLUSIONS: Higher angiopoietin-2 and interleukin-6 levels were associated with recurrence after atrial fibrillation ablation in multivariable modeling. However, the addition of biomarkers to a clinical prediction model did not significantly improve recurrence prediction.

Effect of electroacupuncture on myocardial electrical remodeling in rats with acute myocardial infarction. / ç”µé’ˆå¯¹æ€¥æ€§å¿ƒè‚Œæ¢—æ­»å¤§é¼ å¿ƒè‚Œç”µé‡æž„çš„å½±å“åŠå ¶æœºåˆ¶ç ”ç©¶.

OBJECTIVES: To investigate the mechanism of electroacupuncture (EA) at "Neiguan" (PC6) in impro-ving myocardial electrical remodeling in rats with acute myocardial infarction (AMI) by enhancing transient outward potassium current. METHODS: A total of 30 male SD rats were randomly divided into control, model and EA groups, with 10 rats in each group. The AMI model was established by subcutaneous injection with isoprenaline (ISO, 85 mg/kg). EA was applied to left PC6 for 20 min, once daily for 5 days. Electrocardiogram (ECG) was recorded after treatment. TTC staining was used to observe myocardial necrosis. HE staining was used to observe the pathological morphology of myocardial tissue and measure the cross-sectional area of myocardium. Potassium ion-related genes in myocardial tissue were detected by RNA sequencing. The mRNA and protein expressions of Kchip2 and Kv4.2 in myocardial tissue were detected by real-time fluorescence quantitative PCR and Western blot, respectively. RESULTS: Compared with the control group, cardiomyocyte cross-sectional area in the model group was significantly increased (P<0.01), the ST segment was significantly elevated (P<0.01), and QT, QTc, QTd and QTcd were all significantly increased (P<0.05, P<0.01). After EA treatment, cardiomyocyte cross-sectional area was significantly decreased (P<0.01), the ST segment was significantly reduced (P<0.01), and the QT, QTc, QTcd and QTd were significantly decreased (P<0.01, P<0.05). RNA sequencing results showed that a total of 20 potassium ion-related genes co-expressed by the 3 groups were identified. Among them, Kchip2 expression was up-regulated most notablely in the EA group. Compared with the control group, the mRNA and protein expressions of Kchip2 and Kv4.2 in the myocardial tissue of the model group were significantly decreased (P<0.01, P<0.05), while those were increased in the EA group (P<0.01, P<0.05). CONCLUSIONS: EA may improve myocardial electrical remodeling in rats with myocardial infarction, which may be related to its functions in up-regulating the expressions of Kchip2 and Kv4.2.

Administration of USP7 inhibitor p22077 alleviates Angiotensin II (Ang II)-induced atrial fibrillation in Mice.

Atrial fibrillation (AF), the most common cardiac arrhythmia, is an important contributor to mortality and morbidity. Ubquitin-specific protease 7 (USP7), one of the most abundant ubiquitin-specific proteases (USP), participated in many cellular events, such as cell proliferation, apoptosis, and tumourigenesis. However, its role in AF remains unknown. Here, the mice were treated with Ang II infusion to induce the AF model. Echocardiography was used to measure the atrial diameter. Electrical stimulation was programmed to measure the induction and duration of AF. The changes in atrial remodeling were measured using routine histologic analysis. Here, a significant increase in USP7 expression was observed in Ang II-stimulated atrial cardiomyocytes and atrial tissues, as well as in atrial tissues from patients with AF. The administration of p22077, the inhibitor of USP7, attenuated Ang II-induced inducibility and duration of AF, atrial dilatation, connexin dysfunction, atrial fibrosis, atrial inflammation, and atrial oxidase stress, and then inhibited the progression of AF. Mechanistically, the administration of p22077 alleviated Ang II-induced activation of TGF-ß/Smad2, NF-κB/NLRP3, NADPH oxidases (NOX2 and NOX4) signals, the up-regulation of CX43, ox-CaMKII, CaMKII, Kir2.1, and down-regulation of SERCA2a. Together, this study, for the first time, suggests that USP7 is a critical driver of AF and revealing USP7 may present a new target for atrial fibrillation therapeutic strategies.

Interleukin-33/ST2 axis involvement in atrial remodeling and arrhythmogenesis.

Interleukin (IL)-33, a cytokine involved in immune responses, can activate its receptor, suppression of tumorigenicity 2 (ST2), is elevated during atrial fibrillation (AF). However, the role of IL-33/ST2 signaling in atrial arrhythmia is unclear. This study explored the pathological effects of the IL-33/ST2 axis on atrial remodeling and arrhythmogenesis. Patch clamping, confocal microscopy, and Western blotting were used to analyze the electrical characteristics of and protein activity in atrial myocytes (HL-1) treated with recombinant IL-33 protein and/or ST2-neutralizing antibodies for 48 hrs. Telemetric electrocardiographic recordings, Masson's trichrome staining, and immunohistochemistry staining of the atrium were performed in mice receiving tail vein injections with nonspecific immunoglobulin (control), IL-33, and IL-33 combined with anti-ST2 antibody for 2 weeks. IL-33-treated HL-1 cells had a reduced action potential duration, lower L-type Ca2+ current, greater sarcoplasmic reticulum (SR) Ca2+ content, increased Na+/Ca2+ exchanger (NCX) current, elevation of K+ currents, and increased intracellular calcium transient. IL-33-treated HL-1 myocytes had greater activation of the calcium-calmodulin-dependent protein kinase II (CaMKII)/ryanodine receptor 2 (RyR2) axis and nuclear factor kappa B (NF-κB) / NLR family pyrin domain containing 3 (NLRP3) signaling than did control cells. IL-33 treated cells also had greater expression of Nav1.5, Kv1.5, NCX, and NLRP3 than did control cells. Pretreatment with neutralizing anti-ST2 antibody attenuated IL-33-mediated activation of CaMKII/RyR2 and NF-κB/NLRP3 signaling. IL-33-injected mice had more atrial ectopic beats and increased AF episodes, greater atrial fibrosis, and elevation of NF-κB/NLRP3 signaling than did controls or mice treated with IL-33 combined with anti-ST2 antibody. Thus, IL-33 recombinant protein treatment promotes atrial remodeling through ST2 signaling. Blocking the IL-33/ST2 axis might be an innovative therapeutic approach for patients with atrial arrhythmia and elevated serum IL-33.

The role of cellular senescence in profibrillatory atrial remodelling associated with cardiac pathology.

AIMS: Cellular senescence is a stress-related or aging response believed to contribute to many cardiac conditions; however, its role in atrial fibrillation (AF) is unknown. Age is the single most important determinant of the risk of AF. The present study was designed to (i) evaluate AF susceptibility and senescence marker expression in rat models of aging and myocardial infarction (MI), (ii) study the effect of reducing senescent-cell burden with senolytic therapy on the atrial substrate in MI rats, and (iii) assess senescence markers in human atrial tissue as a function of age and the presence of AF. METHODS AND RESULTS: AF susceptibility was studied with programmed electrical stimulation. Gene and protein expression was evaluated by immunoblot or immunofluorescence (protein) and digital polymerase chain reaction (PCR) or reverse transcriptase quantitative PCR (messenger RNA). A previously validated senolytic combination, dasatinib and quercetin, (D+Q; or corresponding vehicle) was administered from the time of sham or MI surgery through 28 days later. Experiments were performed blinded to treatment assignment. Burst pacing-induced AF was seen in 100% of aged (18-month old) rats, 87.5% of young MI rats, and 10% of young control (3-month old) rats (P ≤ 0.001 vs. each). Conduction velocity was slower in aged [both left atrium (LA) and right atrium (RA)] and young MI (LA) rats vs. young control rats (P ≤ 0.001 vs. each). Atrial fibrosis was greater in aged (LA and RA) and young MI (LA) vs. young control rats (P < 0.05 for each). Senolytic therapy reduced AF inducibility in MI rats (from 8/9 rats, 89% in MI vehicle, to 0/9 rats, 0% in MI D + Q, P < 0.001) and attenuated LA fibrosis. Double staining suggested that D + Q acts by clearing senescent myofibroblasts and endothelial cells. In human atria, senescence markers were upregulated in older (≥70 years) and long-standing AF patients vs. individuals ≤60 and sinus rhythm controls, respectively. CONCLUSION: Our results point to a potentially significant role of cellular senescence in AF pathophysiology. Modulating cell senescence might provide a basis for novel therapeutic approaches to AF.

Why is early-onset atrial fibrillation uncommon in patients with Duchenne muscular dystrophy? Insights from the mdx mouse.

AIMS: A reduction in both dystrophin and neuronal nitric oxide synthase (NOS1) secondary to microRNA-31 (miR-31) up-regulation contributes to the atrial electrical remodelling that underpins human and experimental atrial fibrillation (AF). In contrast, patients with Duchenne muscular dystrophy (DMD), who lack dystrophin and NOS1 and, at least in the skeletal muscle, have raised miR-31 expression, do not have increase susceptibility to AF in the absence of left ventricular (LV) dysfunction. Here, we investigated whether dystrophin deficiency is also associated with atrial up-regulation of miR-31, loss of NOS1 protein, and increased AF susceptibility in young mdx mice. METHODS AND RESULTS: Echocardiography showed normal cardiac structure and function in 12-13 weeks mdx mice, with no indication by assay of hydroxyproline that atrial fibrosis had developed. The absence of dystrophin in mdx mice was accompanied by an overall reduction in syntrophin and a lower NOS1 protein content in the skeletal muscle and in the left atrial and ventricular myocardium, with the latter occurring alongside reduced Nos1 transcript levels (exons 1-2 by quantitative polymerase chain reaction) and an increase in NOS1 polyubiquitination [assessed using tandem polyubiquitination pulldowns; P < 0.05 vs. wild type (WT)]. Neither the up-regulation of miR-31 nor the substantial reduction in NOS activity observed in the skeletal muscle was present in the atrial tissue of mdx mice. At difference with the skeletal muscle, the mdx atrial myocardium showed a reduction in the constitutive NOS inhibitor, caveolin-1, coupled with an increase in NOS3 serine1177 phosphorylation, in the absence of differences in the protein content of other NOS isoforms or in the relative expression NOS1 splice variants. In line with these findings, transoesophageal atrial burst pacing revealed no difference in AF susceptibility between mdx mice and their WT littermates. CONCLUSION: Dystrophin depletion is not associated with atrial miR-31 up-regulation, reduced NOS activity, or increased AF susceptibility in the mdx mouse. Compared with the skeletal muscle, the milder atrial biochemical phenotype may explain why patients with DMD do not exhibit a higher prevalence of atrial arrhythmias despite a reduction in NOS1 content.

Clinical Characteristics and Rhythm Outcomes in Patients With Atrial Myopathy After Successful Catheter Ablation of Atrial Fibrillation.

BACKGROUND: Although successful atrial fibrillation (AF) ablation can maintain sinus rhythm and reduce the left atrial (LA) dimension, blunted LA reverse remodeling can be observed in patients with atrial myopathy. We explored the potential mechanisms and long-term outcomes in patients with blunted LA reverse remodeling after successful AF catheter ablation. METHODS AND RESULTS: We included 1685 patients who underwent baseline and 1-year follow-up echocardiograms, had a baseline LA dimension ≥40 mm, and did not have a recurrence of AF within a year. The patients were divided into tertile groups according to the delta value of the change in LA dimension on the preprocedure and 1-year postprocedure echocardiography. After propensity score matching for age, sex, AF type, and LA dimension, 1272 patients were finally included in the analyses (424 in each group; the least/blunted, moderate, and the most reverse remodeling group). The patients in the T1 group (blunted LA reverse remodeling) were independently associated with higher left ventricular mass index (odds ratio [OR], 1.014 [95% CI, 1.005-1.022], P=0.001), change in ΔH2FPEF score (heavy, hypertensive, atrial fibrillation, pulmonary hypertension, elder, filling pressure) score (OR, 1.445 [95% CI, 1.121-1.861], P=0.004), ventricular epicardial adipose tissue volume (OR, 1.010 [95% CI, 1.003-1.017], P=0.003), thinner LA wall thickness (OR, 0.461 [95% CI, 0.271-0.785], P=0.004), lower LA voltage (OR, 0.670 [95% CI, 0.499-0.899], P=0.008), and showed higher long-term AF recurrence (log-rank P<0.001) than other groups. CONCLUSIONS: Blunted LA reverse remodeling after AF catheter ablation, which is suggestive of atrial myopathy, was independently associated with a larger ventricular epicardial adipose tissue volume and worsening of H2FPEF score. Blunted LA reverse remodeling after AF catheter ablation was also an independent predictor for higher recurrences of AF post-1-year AF catheter ablation.

From Atrial Fibrillation Management to Atrial Myopathy Assessment: The Evolving Concept of Left Atrium Disease in Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most prevalent genetically inherited cardiovascular disorder in adults and a significant cause of heart failure and sudden cardiac death. Historically, atrial fibrillation (AF) has been considered as a critical aspect in HCM patients as it is considered to be a marker of disease progression, escalates the frequency of heart failure hospitalisations, increases the risk of thromboembolic events, and worsens quality of life and outcome. Increasing evidence suggests that AF is the result of a subtle long-standing process that starts early in the history of HCM. The process of left atrial dilation accompanied by morphologic and functional remodelling is the quintessential prerequisite for the onset of AF. This review aims to describe the current understanding of AF pathophysiology in HCM, emphasising the role of left atrial myopathy in its development. In addition, we discuss risk factors and management strategies specific to AF in the context of HCM, providing insights into the complexities and challenges of treating this specific patient population.

Right Atrial Remodeling and Outcome in Patients with Secondary Tricuspid Regurgitation.

BACKGROUND: In patients with secondary tricuspid regurgitation (STR), right atrial remodeling (RAR) is a proven marker of disease progression. However, the prognostic value of RAR, assessed by indexed right atrial volume (RAVi) and reservoir strain (RAS), remains to be clarified. Accordingly, the aim of our study is to investigate the association with outcome of RAR in patients with STR. METHODS: We enrolled 397 patients (44% men, 72.7 ± 13 years old) with mild to severe STR. Complete two-dimensional and speckle-tracking echocardiography analysis of right atrial and right ventricular (RV) size and function were obtained in all patients. The primary end point was the composite of death from any cause and heart failure hospitalization. RESULTS: After a median follow-up of 15 months (interquartile range, 6-23), the end point was reached by 158 patients (39%). Patients with RAS <13% and RAVi >48 mL/m2 had significantly lower survival rates compared to patients with RAS ≥13% and RAVi ≤48 mL/m2 (log-rank P < .001). On multivariable analysis, RAS <13% (hazard ratio, 2.11; 95% CI, 1.43-3.11; P < .001) and RAVi > 48 mL/m2 (hazard ratio, 1.49; 95% CI, 1.01-2.18; P = .04) remained associated with the combined end point, even after adjusting for RV free-wall longitudinal strain, significant chronic kidney disease, and New York Heart Association class. Secondary tricuspid regurgitation excess mortality increased exponentially with values of 18.2% and 51.3 mL/m2 for RAS and RAVi, respectively. In nested models, the addition of RAS and RAVi provided incremental prognostic value over clinical, conventional echocardiographic parameters of RV size and function and RV free-wall longitudinal strain. CONCLUSIONS: In patients with STR, RAR was independently associated with mortality and heart failure hospitalization. Assessment of RAR could improve risk stratification of patients with STR, potentially identifying those who may benefit from optimization of medical therapy and a closer follow-up.

A novel tsRNA-5008a promotes ferroptosis in cardiomyocytes that causes atrial structural remodeling predisposed to atrial fibrillation.

Atrial fibrillation (AF) is an extremely common clinical arrhythmia disease, but whether its mechanism is associated with ferroptosis remains unclear. The tRNA-derived small RNAs (tsRNAs) are involved in a variety of cardiovascular diseases, however, their role and mechanism in atrial remodeling in AF have not been studied. We aimed to explore whether tsRNAs mediate ferroptosis in AF progression. The AF models were constructed to detect ferroptosis-related indicators, and Ferrostatin-1 (Fer-1) was introduced to clarify the relationship between ferroptosis and AF. Atrial myocardial tissue was used for small RNA sequencing to screen potential tsRNAs. tsRNA functioned on ferroptosis and AF was explored. Atrial fibrosis and changes in the cellular structures and arrangement were observed in AF mice model, and these alterations were accompanied by ferroptosis occurrence, exhibited by the accumulation of Fe2+ and MDA levels and the decrease of expression of FTH1, GPX4, and SLC7A11. Blocking above ferroptosis activation with Fer-1 resulted in a significant improvement for AF. A total of 7 tsRNAs were upregulated (including tsRNA-5008a) and 2 tsRNAs were downregulated in atrial myocardial tissue in the AF group compared with the sham group. We constructed a tsRNA-mRNA regulated network, which showed tsRNA-5008a targeted 16 ferroptosis-related genes. Knockdown of tsRNA-5008a significantly suppressed ferroptosis through targeting SLC7A11 and diminished myocardial fibrosis both in vitro and in vivo. On the contrary, tsRNA-5008a mimics promoted ferroptosis in cardiomyocytes. Collectively, tsRNA-5008a involved in AF through ferroptosis. Our study provides novel insights into the role of tsRNA-5008a mediated ferroptosis in AF progression.

Exerkine ß-aminoisobutyric acid protects against atrial structural remodeling and atrial fibrillation in obesity via activating AMPK signaling and improving insulin sensitivity.

Moderate exercise decreases the risk for atrial fibrillation (AF), an effect which is probably mediated via exercise-stimulated release of exerkines. ß-Aminoisobutyric acid (BAIBA), a novel exerkine, has been reported to provide protective benefits against many cardiovascular diseases, yet its role in AF remains elusive. Herein, using a mouse model of obesity-related AF through high-fat diet (HFD) feeding, we found that 12-week drinking administration of BAIBA (170 mg/kg/day) decreased AF susceptibility in obese mice. Atrial remodeling assessment showed that BAIBA attenuated obesity-induced atrial hypertrophy and interstitial fibrosis, thereby ablating the substrate for AF. Of note, to our knowledge, this is the first report of the direct association of BAIBA and hypertrophy. BAIBA has been reported to be a key regulator of glucose and lipid metabolism, and we found that BAIBA alleviated insulin resistance in obese mice. Transcriptional analysis of metabolism-related genes showed that BAIBA increased the transcription of fatty acids metabolism-related genes in the atria of lean mice but not in that of obese mice. Mechanistic investigation showed that BAIBA stimulated AMP-activated protein kinase (AMPK) signaling in the atria of obese mice and palmitic acid (PA)-treated neonatal rat cardiomyocytes (NRCM), whereas inhibition of AMPK via Compound C attenuated BAIBA-conferred cardioprotection against hypertrophy and insulin resistance in PA-treated NRCM. Collectively, BAIBA attenuates AF susceptibility in obese mice via activated AMPK signaling and resultant improvement of insulin sensitivity, thereby providing perspectives on the potential therapeutic role of BAIBA in AF treatment.