Jian Sun

The roles of Contactin-2 (CNTN2) and ferroptosis in heart failure and cardiac remodeling remain incompletely understood. CNTN2 was significantly upregulated in hypertrophic cardiomyopathy patients and heart failure mice. In cardiomyocyte specific CNTN2 conditional knockout (CNTN2 cKO) mice, transverse aortic constriction (TAC) induced markedly exacerbated heart failure, cardiac remodeling and ferroptosis compared to control mice. Ferroptosis inhibition substantially attenuated heart failure in CNTN2 cKO mice subjected to TAC, indicating that enhanced ferroptosis contributes to the detrimental effects of CNTN2 deficiency. RNA sequencing identified NUPR1, a ferroptosis repressor, as a downstream molecule of CNTN2. Mechanistically, CNTN2 activated the Lyn/eIF2α/ATF4 pathway to regulate NUPR1. CNTN2 overexpression attenuated Angiotensin II-induced cardiomyocyte ferroptosis and pathological remodeling, whereas these protective effects were abolished by Lyn or NUPR1 inhibitors. We further revealed CNTN2 and Lyn interacted with each other, and that CNTN2 interacted with Lyn through its 1-328aa domain. In vivo NUPR1 overexpression via AAV9 significantly mitigated TAC-induced heart failure and cardiac remodeling in CNTN2 cKO mice. Our study demonstrates that CNTN2 protects against pressure overload induced heart failure and cardiac remodeling by regulating ferroptosis through the Lyn/eIF2α/ATF4/NUPR1 pathway, suggesting CNTN2 as a potential therapeutic target.

Background: Left atrial appendage (LAA) patency after catheter ablation and LAA closure (LAAC) is a key determinant of postprocedure stroke. The effect of LAA electrical isolation (LAAEI) on LAA patency after LAAC in patients with atrial fibrillation (AF) remains unknown. Our objective was to explore the effect of LAAEI on LAA patency after catheter ablation and LAAC in patients with AF. Methods: Patients with persistent AF who underwent combined catheter ablation and LAAC were enrolled. LAA patency was detected by cardiac computed tomographic angiography at 3 months after the procedure. Results: A total of 686 patients with persistent AF with 3‐month device surveillance by cardiac computed tomographic angiography were included initially. Propensity score matching analysis was conducted on the basis of clinical features, echocardiographic parameters and procedural characteristics, and 469 patients were matched, including 363 with non‐LAAEI and 106 with LAAEI. Patients in matched groups showed 53.7% complete closure (no patency). Of the 46.3% of cases with LAA patency, visible peridevice leak was seen in 72.8%, and 27.2% had patency without visible peridevice leak. Compared with the non‐LAAEI group, the LAAEI group had a lower rate of LAA patency (49.6% versus 34.9%; adjusted odds ratio, 0.69 [95% CI, 0.48–0.98]; P =0.040). LAAEI was protective against LAA patency with an odds ratio of 0.68, and the other predictor of contrast leak into the LAA was maximum diameter of LAA orifice (odds ratio, 1.04 [95% CI, 1.00–1.08]; P =0.046). Conclusions: LAAEI is an effective strategy for reducing LAA patency in patients with persistent AF undergoing combined catheter ablation and LAAC. Registration: URL: clinicaltrials.gov ; Unique Identifier: NCT03788941.

During an episode of atrial fibrillation, the effective contractile function of the left atrium (LA) is lost, increasing the risk of thrombus formation. Notably, blood, as a typical non-Newtonian fluid, exhibits pronounced shear-thinning behavior, a phenomenon that is particularly evident in the low shear rate flow environment within the left atrial appendage (LAA). However, the predictions of existing non-Newtonian blood models show considerable differences in the low shear rate range, which brings challenges to the accurate simulation of thrombus formation risk in patient-specific LAA. This study constructs a personalized blood model based on clinical data from different patients. Using the same LA geometry, the simulation results of the personalized model were compared with those of two general non-Newtonian models, the Carreau–Yasuda model and the Cross model. The differences in thrombus risk prediction were evaluated through non-Newtonian rheological properties, from the aspects of blood stasis and endothelial damage. The results indicate that general non-Newtonian blood models have significant limitations in the precise assessment of thrombotic risk in the LAA. Meanwhile, for the same LA model, as blood viscosity increases, both the risks of blood stasis and endothelial damage increase, resulting in a higher thrombotic risk. These findings demonstrate that patient-specific non-Newtonian blood properties are critically important in hemodynamic simulations and hold significant implications for advancing precision medicine.

Background The circadian variation pattern of sudden cardiac arrest (SCA) occurred in Chinese community including both community healthcare centres and primary hospitals remains unknown. This study analysed the circadian variation of SCA in the Chinese community. Methods Data between 2018 and 2022 from the remote ECG diagnosis system of Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine were analysed to examine the circadian rhythm of SCA, stratified by initial shockable (ventricular tachycardia or ventricular fibrillation) versus non-shockable (asystole or pulseless electrical activity) rhythm. Results Among 10 210 cases of SCA, major cases (8736, 85.6%) were non-shockable and 1474 (14.4%) cases were shockable. The circadian rhythm of SCA was as follows: peak time was from 08:00 to 11:59 (30.1%), while deep valley was from 00:00 to 03:59 (7.5%). The proportions of events by non-shockable and shockable events were similar and both reached their peak from 08:00 to 11:59, with a percentage of 29.0% and 36.4%, respectively. Multivariable analysis showed that the relative risk of shockable compared with non-shockable arrests was lower between 00:00 and 03:59 (adjusted OR (aOR): 0.72, 95% CI: 0.54 to 0.97, p=0.028) and 04:00 to 07:59 (aOR: 0.60, 95% CI: 0.46 to 0.79, pConclusions In Chinese community, there is a distinct circadian rhythm of SCA, regardless of initial rhythms. Our findings may be helpful in decision-making, in that more attention and manpower should be placed on the morning hours of first-aid and resuscitation management in Chinese community.

BACKGROUND: The prognostic impact of left atrial appendage (LAA) patency, including those with and without visible peri-device leak (PDL), post–LAA closure in patients with atrial fibrillation, remains elusive. METHODS: Patients with atrial fibrillation implanted with the WATCHMAN 2.5 device were prospectively enrolled. The device surveillance by cardiac computed tomography angiography was performed at 3 months post-procedure. Adverse events, including stroke/transient ischemic attack (TIA), major bleeding, cardiovascular death, all-cause death, and the combined major adverse events (MAEs), were compared between patients with complete closure and LAA patency. RESULTS: Among 519 patients with cardiac computed tomography angiography surveillance at 3 months post–LAA closure, 271 (52.2%) showed complete closure, and LAA patency was detected in 248 (47.8%) patients, including 196 (37.8%) with visible PDL and 52 (10.0%) without visible PDL. During a median of 1193 (787–1543) days follow-up, the presence of LAA patency was associated with increased risks of stroke/TIA (adjusted hazard ratio for baseline differences, 3.22 [95% CI, 1.17–8.83]; P =0.023) and MAEs (adjusted hazard ratio, 1.12 [95% CI, 1.06–1.17]; P =0.003). Specifically, LAA patency with visible PDL was associated with increased risks of stroke/TIA (hazard ratio, 3.66 [95% CI, 1.29–10.42]; P =0.015) and MAEs (hazard ratio, 3.71 [95% CI, 1.71–8.07]; P =0.001), although LAA patency without visible PDL showed higher risks of MAEs (hazard ratio, 3.59 [95% CI, 1.28–10.09]; P =0.015). Incidences of stroke/TIA (2.8% versus 3.0% versus 6.7% versus 22.2%; P =0.010), cardiovascular death (0.9% versus 0% versus 1.7% versus 11.1%; P =0.005), and MAEs (4.6% versus 9.0% versus 11.7% versus 22.2%; P =0.017) increased with larger PDL (0, >0 to ≤3, >3 to ≤5, or >5 mm). Older age and discontinuing antiplatelet therapy at 6 months were independent predictors of stroke/TIA and MAEs in patients with LAA patency. CONCLUSIONS: LAA patency detected by cardiac computed tomography angiography at 3 months post–LAA closure is associated with unfavorable prognosis in patients with atrial fibrillation implanted with WATCHMAN 2.5 device. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03788941.

Background: Managing patients with atrial fibrillation (AF) and comorbid heart failure (HF) with reduced (HFrEF) or mildly reduced ejection fraction (HFmrEF) is of clinical importance but a great challenge. This study aimed to evaluate the clinical benefit of the combined radiofrequency catheter ablation (RFCA) and left atrial appendage closure (LAAC) procedure in AF patients complicated with systolic HF. Methods: AF patients with HFrEF or HFmrEF who underwent the combined RFCA and LAAC procedure were prospectively enrolled in the LAACablation registry. The procedural complications and long-term outcomes were evaluated. Another cohort of AF patients with systolic HF who did not undergo either RFCA or LAAC were used for prognosis comparison. Results: Among 802 AF patients who underwent the combined procedure, 65 patients were comorbid with systolic HF (25 with HFrEF and 40 with HFmrEF). The overall procedural complication rate was 9.2%, which was mainly attributed to acute decompensated HF (6.2%). Accompanied with markedly reduced AF burden (from median [25th, 75th percentile]: 100 [100, 100] to 0 [0, 1.2]%, p < 0.001), upward trajectories of cardiac function were observed in 51 (78.4%) patients, showing improvement in New York Heart Classification (p < 0.01), natriuretic peptide levels (from 1492 [809, 3259] to 413 [163, 880] pg/mL, p < 0.001) and left ventricular EF (from 42.6 ± 5.3 to 53.8 ± 8.2%, p < 0.001). During the 27-month follow-up period, death, thromboembolism, major bleeding, and HF rehospitalization were observed in three, one, one, and four patients, respectively. The observed event rates showed a significant reduction compared with the non-procedure AF-HF cohort (n = 138; for composite endpoint: hazard ratio: 2.509, 95% confidence interval: 1.415–4.449, p = 0.002) and with the respective rates predicted by risk scores. Conclusions: Combining RFCA and LAAC achieves acceptable safety and credible long-term efficacy in AF patients with systolic HF. Further randomized studies are warranted in a larger patient cohort.

Background: With population aging, the prevalence of both cancer and atrial fibrillation (AF) have increased. However, there is scarce epidemiological data concerning the comorbid state of cancer and AF in low- and middle-income countries, including China. Objective: We aimed to evaluate the site-, sex-, and age-specific profiles of cancer and AF comorbidities in Chinese populations. Methods: Data from the Shanghai Municipal Health Commission database between 2015 and 2020 were screened, covering all medical records of Shanghai residents with medical insurance. Site-specific cancer profiles were evaluated for the population with AF relative to the age- and sex-adjusted population of residents without AF. The sex distribution and peak age of cancer diagnosis were also assessed. Results: A total of 25,964,447 adult patients were screened. Among them, 22,185 patients presented cancers comorbid with AF (median 77, IQR 67-82 years of age; men: n=13,631, 61.44%), while 839,864 presented cancers without AF (median 67, IQR 57-72 years of age; men: n=419,020, 49.89%), thus yielding a higher cancer prevalence among residents with AF (8.27%) than among those without AF (6.05%; P<.001). In the population with AF, the most prevalent cancer type was lung cancer, followed by colorectal, male genital organ, stomach, breast, liver, bladder, thyroid, leukemia, and esophageal cancers. AF was associated with an average of nearly 1.4-fold (prevalence ratio [PR] 1.37, 95% CI 1.35-1.38) increased prevalence of cancer after adjusting for age and sex. For site-specific analyses, an increased prevalence of cancer in the population with AF was observed in 20 of 21 cancer sites. This increased prevalence was most prominent for nonsolid tumors, including multiple myeloma (PR 2.56, 95% CI 2.28-2.87), leukemia (PR 1.73, 95% CI 1.57-1.90), and non-Hodgkin lymphoma (PR 1.59, 95% CI 1.43-1.77); intrathoracic malignancies, including mediastinum (PR 2.34, 95% CI 1.89-2.90), lung (PR 1.64, 95% CI 1.59-1.69), and esophageal cancers (PR 1.41, 95% CI 1.28-1.56); bone and soft tissue neoplasms (PR 1.56, 95% CI 1.37-1.77); and kidney cancer (PR 1.53, 95% CI 1.36-1.72). Cancer prevalence in the population with AF relative to that in the population without AF was higher in men than in women in 14 of 18 cancer sites, and female predominance was only observed for thyroid cancer. The peak age of index cancer diagnosis was lower in the population with AF (age group: 70-74 years) than in that without AF (age group: 75-79 years), especially for specific cancer types, including thyroid, central nervous system, mediastinum, esophageal, bladder, and biliary cancers. Conclusions: Patients with AF are associated with increased prevalence, heightened male predominance, and younger peak age of cancer. Further studies are needed to determine whether early screening of specific cancers is cost-effective and beneficial for patients with AF.

Extant clinical research has underscored that patients suffering from atrial fibrillation (AF) bear an elevated risk for stroke, predominantly driven by the formation of thrombus in the left atrial appendage (LAA). As such, accurately identifying those at an increased risk of thrombosis becomes paramount to facilitate timely and effective treatment. This study was designed to shed light on the mechanisms underlying thrombus formation in the LAA by employing three-dimensional (3D) left atrium (LA) models of AF patients, which were constructed based on Computed Tomography (CT) imaging. The distinct benefits of Computational Fluid Dynamics (CFD) were leveraged to simulate the blood flow field within the LA, using three distinct blood flow models, both under AF and sinus rhythm (SR) conditions. The potential risk of thrombus formation was evaluated by analyzing the Relative Residence Time (RRT) and Endothelial Cell Activation Potential (ECAP) values. The results gleaned from this study affirm that all three blood flow models align with extant clinical guidelines, thereby enabling an effective prediction of thrombosis risk. However, noteworthy differences emerged when comparing the intricacies of the flow field and thrombosis risk across the three models. The single-phase non-Newtonian blood flow model resulted in comparatively lower residence times for blood within the LA and lower values for the Oscillatory Shear Index (OSI), RRT, and ECAP within the LAA. These findings suggest a reduced thrombosis risk. Conversely, the two-phase non-Newtonian blood flow model exhibited a higher residence time for blood and elevated RRT value within the LAA, suggesting an increased risk for thrombosis.

Atrial fibrillation (AF) is a common and life-threatening disease. For the patients with AF, more than 90% of the thrombi are formed in the left atrial appendage (LAA), thrombus dislodgement can cause vascular embolism, making them is becoming a high-risk group for stroke. Therefore, identifying the patients with high risk of thrombosis is crucial for advanced stroke warning. To better investigate the mechanism behind thrombus formation in the LAA, this study reconstructed the 3-D Left Atrium (LA) models of six AF volunteer patients by corresponding Computed Tomography (CT) images. Combine the advantages of Computational Fluid Dynamics (CFD), the blood flow field in LA both in AF and sinus heart rate states were studied. The risk of thrombus was evaluated based on the blood viscosity, shear rate thrombus prediction model and Time Average Wall Shear Stress (TAWSS), Oscillatory Shear Index (OSI), and Relative Residence Time (RRT) values. The results showed that the left atrium had lower blood flow velocity and TAWSS values at the LAA in both AF and sinus rhythm, thus the LAA is the most thrombogenic region in the LA. Besides, the RRT value of LAA was generally higher in AF than in sinus rhythm. Therefore, AF carries a higher risk of thrombosis.