HAT2CH2 score performance predicting neurologic events after cardiac implantable electronic device.

Objectives: The HAT2CH2 score has been evaluated for predicting new-onset atrial fibrillation in several clinical conditions, but never for adverse neurologic events. We aimed to evaluate the effectiveness of HAT2CH2 score in predicting neurologic events in patients with cardiac implantable electronic device (CIED), comparing with atrial high-rate episodes (AHRE). Methods: This case-control study enrolled 314 consecutive patients aged 18 years or older with CIED implantation between January 2015 and April 2021. Patient data were analyzed retrospectively. The primary endpoint was subsequent neurologic events (NE) after implantation. AHRE was defined as > 175 bpm (Medtronic®) lasting ≥ 30 seconds. Variables associated with independent risk of NE were identified using multivariate Cox regression analysis with time-dependent covariates. Results: Patients' median age was 73 years and 61.8% of them were male. During follow-up (median 32 months), 18 NE occurred (incidence rate 2.15/100 patient-years, 95% CI 1.32-4.30). Multiple Cox regression analysis showed that the HAT2CH2 score (HR 2.424, 95% CI 1.683 - 3.492, p < 0.001) was an independent predictor for NE. Optimal HAT2CH2 score cutoff value was 3 with highest Youden index (AUC, 0.923; 95% CI, 0.881-0.966; p < 0.001). Both AHRE ≥ 1 minute and HAT2CH2 score ≥ 3 had the highest AUC of the receiver-operating characteristic (0.898, 95% CI, 0.831-0.965, p < 0.001). Significant increase was observed in NE occurrence rates using the HAT2CH2 score (p < 0.001). Conclusion: The HAT2CH2 score and episodes of AHRE lasting ≥ 1 minute are independent risk factors for NE in patients with CIED.

The performance of five models compared with atrial high rate episodes predicts new atrial fibrillation after cardiac implantable electronic devices implantation.

AIMS: Several predicting models have been evaluated for new-onset atrial fibrillation (AF) in several clinical conditions, but never in patients with cardiac implantable electronic devices (CIED). We aimed to evaluate the five predicting models compared with atrial high rate episodes (AHRE) to predict new AF in patients with CIED. METHODS AND RESULTS: We retrospective enrolled 470 consecutive patients with CIED and without a history of AF. The five predicting models, including CHA2 DS2 -VASc score, C2 HEST score, mCHEST score, HAT2 CH2 score, and HAVOC score were used. The primary endpoint was new AF documented by 12-lead electrocardiography (ECG) or 30-s ECG strip. Multivariable Cox regression analysis was used to determine variables associated with independent factors of new AF. Patients' median age was 76 years and 58.7% were male. During follow-up (median 29 months), 34 new AF occurred (incidence rate 2.99/100 patient-years, 95% CI 1.67-6.20). Multivariable Cox regression analysis showed AHRE ≥6 min and 24 h, and HAT2 CH2 score were independent predictors for new AF. Optimal AHRE cutoff value was 9.3 min with highest Youden index (AUC, 0.806; 95% CI, 0.722-0.889; p < .001). The AF occurrence rate of AHRE ≥9.3 min was 7 times AHRE <9.3 min (p < .001). CONCLUSIONS: We compared 5 predicting models for new AF in patients with CIED and without a history of AF. AHRE ≥6 min and 24 h, and HAT2 CH2 score were independent predictors for AF.

Asclepius and Yellow Ribbon techniques: Efficacious alternative strategies for advancing a coronary sinus electrophysiology catheter.

BACKGROUND: Inserting an electrophysiological (EP) catheter into the coronary sinus (CS) via the femoral vein can be difficult and time-consuming in patients with variants of the CS orifice or lumen curve. Our experience with such patients inspired us to develop two new techniques: the Asclepius and Yellow Ribbon techniques. METHODS: Data from a 4-year period were retrieved from records of patients undergoing radiofrequency ablation for paroxysmal supraventricular tachycardia (PSVT) or Wolff-Parkinson-White (WPW) syndrome. Data were analyzed to determine the success and complication rates of conventional and alternative techniques for catheter placement. RESULTS: The success rate of the Asclepius technique was 96.7% (30/31) and that of the Yellow Ribbon technique was 100.0% (7/7). The overall success rate of these two techniques was 97.3% (37/38). CONCLUSIONS: With a high success rate, shorter procedure time, and no complications, the Asclepius and Yellow ribbon techniques may be safe, inexpensive, and effective alternative strategies for EP catheter placement in patients with difficult coronary sinus orifice access.

Comparison of Minimally Invasive Thrombectomy with Percutaneous Balloon Angioplasty for Organized Thrombi in Hemodialysis Access.

BACKGROUND: Thrombi are an important challenge when establishing hemodialysis access for hemodialysis. We developed a minimally invasive thrombectomy (MIT) salvage treatment to solve this problem when traditional percutaneous transluminal angioplasty (PTA) fails. OBJECTIVES: The study aimed to investigate the safety and patency rate following MIT as a rescue procedure for traditional PTA with organized thrombi obstructing hemodialysis access. METHODS: This was a prospective study of MIT as a rescue procedure for traditional PTA to remove organized thrombi and establish hemodialysis access. We included patients with (1) stenotic lesions, (2) vascular access thrombi, (3) high venous pressure, (4) vascular collapse and suction. Nephrologists evaluated hemodialysis access immediately post-thrombi removal and patency at 7, 30, 60, 120, and 180 days post-removal, in addition to complications. Kaplan-Meier survival analysis was performed to analyze the primary and secondary patency rates after clinical procedural success. RESULTS: From June 2014 to May 2015, 746 patients underwent PTA in our hospital, and 425 patients consented to participate in this study. Of these patients, we enrolled 46 who underwent simultaneous PTA and MIT. Immediate clinical success was achieved in 100% of the patients in the MIT group. No complications were observed in any of the 46 patients, including major bleeding, shock, or hospitalization. The primary and secondary patency rates did not differ between MIT and PTA alone (p = 0.93 and p = 0.28, respectively). CONCLUSIONS: MIT can be considered a safe rescue procedure for removing organized thrombi to establish vascular access for hemodialysis when initial and traditional PTA fails.

Proteomic analysis of kidney and protective effects of grape seed procyanidin B2 in db/db mice indicate MFG-E8 as a key molecule in the development of diabetic nephropathy.

Diabetic nephropathy, as a severe microvascular complication of diabetic mellitus, has become the leading cause of end-stage renal diseases. However, no effective therapeutic strategy has been developed to prevent renal damage progression to end stage renal disease. Hence, the present study evaluated the protective effects of grape seed procyanidin B2 (GSPB2) and explored its molecular targets underlying diabetic nephropathy by a comprehensive quantitative proteomic analysis in db/db mice. Here, we found that oral administration of GSPB2 significantly attenuated the renal dysfunction and pathological changes in db/db mice. Proteome analysis by isobaric tags for relative and absolute quantification (iTRAQ) identified 53 down-regulated and 60 up-regulated proteins after treatment with GSPB2 in db/db mice. Western blot analysis confirmed that milk fat globule EGF-8 (MFG-E8) was significantly up-regulated in diabetic kidney. MFG-E8 silencing by transfection of MFG-E8 shRNA improved renal histological lesions by inhibiting phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2), Akt and glycogen synthase kinase-3beta (GSK-3ß) in kidneys of db/db mice. In contrast, over-expression of MFG-E8 by injection of recombinant MFG-E8 resulted in the opposite effects. GSPB2 treatment significantly decreased protein levels of MFG-E8, phospho-ERK1/2, phospho-Akt, and phospho-GSK-3ß in the kidneys of db/db mice. These findings yield insights into the pathogenesis of diabetic nephropathy, revealing MFG-E8 as a new therapeutic target and indicating GSPB2 as a prospective therapy by down-regulation of MFG-E8, along with ERK1/2, Akt and GSK-3ß signaling pathway.

Optimal combination of right ventricular functional parameters using echocardiography in pulmonary arterial hypertension.

AIMS: Novel echocardiographic parameters of right ventricular (RV) function, including speckle-tracking-derived, three-dimensional, and RV-pulmonary artery coupling parameters, have emerged for the evaluation of pulmonary arterial hypertension (PAH). The relative role of these parameters in the risk stratification of PAH patients is unclear. We compared the performance of multiple RV parameters and sought to establish an optimal model for identifying the risk profile of patients with PAH. METHODS AND RESULTS: Comprehensive risk assessments were performed for 70 patients with PAH. The risk profile of every patient was determined based on the guideline recommendations. Conventional parameters, including fractional area change (FAC) and tricuspid annular plane systolic excursion (TAPSE), novel speckle-tracking-derived RV longitudinal strain (RVLS), and three-dimensional RV ejection fraction (3D-RVEF), were used to evaluate RV function. Pressure-strain loops were measured for the assessment of RV myocardial work, including RV global wasted work (RVGWW). RV-pulmonary artery coupling was assessed by indexing RV parameters to the estimated pulmonary artery systolic pressure (PASP). The median age was 34 (30-43) years, and 62 (88.6%) patients were female. Forty-five patients were classified into the low-risk group, while 25 patients were classified into the intermediate-high-risk group. Most RV parameters could be used to determine the risk profile and exhibited significantly improved diagnostic performance after indexing to PASP (including FAC/PASP, TAPSE/PASP, and 3D-RVEF/PASP). RVLS/PASP showed the best performance, with an area under the curve of 0.895. In multivariate analysis (Model 1), only RVGWW (>90.5 mmHg%), RVLS (> -16.7%), and TAPSE (<17.5 mm) remained significant (all P < 0.05). Model 1 outperformed every single RV parameter, with a significantly larger area under the curve (all P < 0.05). With PASP indexing in Model 2, RVLS/PASP > -0.275 [odds ratio (OR) 20.63, 95% confidence interval (CI) 4.62-92.11, P < 0.001] and RVGWW > 90.5 mmHg% (OR 6.17, 95% CI 1.37-27.76, P = 0.018) independently identified a higher risk profile. The addition of RVGWW to two models determined incremental value in identification (continuous net reclassification improvement 1.058, 95% CI 0.639-1.477, P < 0.001). CONCLUSIONS: The combination models for RV function outperformed any single parameter in identifying the risk profile of patients with PAH. Comprehensive assessment of RV-pulmonary artery coupling using multiparametric methods is clinically meaningful in patients with PAH.

Congenital heart disease: types, pathophysiology, diagnosis, and treatment options.

Congenital heart disease (CHD) is a structural abnormality of the heart and/or great vessels and patients with CHD are at an increased risks of various morbidities throughout their lives and reduced long-term survival. Eventually, CHD may result in various complications including heart failure, arrhythmias, stroke, pneumonia, and sudden death. Unfortunately, the exact etiology and pathophysiology of some CHD remain unclear. Although the quality of life and prognosis of patients with CHD have significantly improved following technological advancement, the influence of CHD is lifelong, especially in patients with complicated CHD. Thus, the management of CHD remains a challenge due to its high prevalence. Finally, there are some disagreements on CHD among international guidelines. In this review, we provide an update of the pathophysiology, diagnosis, and treatment in most common type of CHD, including patent foramen ovale, atrial septal defect, ventricular septal defect, atrioventricular septal defect, patent ductus arteriosus, coarctation of the aorta, transposition of the great arteries, congenitally corrected transposition of the great arteries, coronary anomalies, left and right ventricular outflow tract obstruction, tetralogy of Fallot and Ebstein anomaly. In particular, we focus on what is known and what is unknown in these areas, aiming to improve the current understanding of various types of CHD.

Laparoscopic Double Hepatic Artery Banding/Ligation for Patients With Hepatic Hereditary Haemorrhagic Telangiectasia (HHHT).

Introduction: Hepatic hereditary haemorrhagic telangiectasia (HHHT) is a rare autosomal dominant genetic disease. Some patients may develop cardiac failure, portal hypertension, and biliary ischaemia. To date, there is no standard surgical treatment for HHHT. The present authors propose a move from open to laparoscopic surgery; however, laparoscopic surgery has not been reported previously as a surgical treatment for HHHT. Report: Two women were admitted with histories of exertional dyspnoea and upper abdominal pain, respectively. Combined with recurrent epistaxis and their positive family history, a diagnosis of clinical HHHT was made based on Curacao criteria after comprehensive evaluation of imaging features. Next generation sequencing (NGS) results also confirmed typical gene mutations responsible for HHT. Both patients underwent laparoscopic double hepatic artery banding and or ligation successfully and were discharged four to six days after operation without severe complications. The symptoms of cardiac insufficiency including exertional dyspnoea and shortness of breath of the first patient improved six months after the operation. The second patient, with epigastric pain, remained pain free without medication three months after the operation. Discussion: Laparoscopic surgery for HHHT is technically challenging. Clinical data and follow up information showed that laparoscopic double hepatic artery banding and or ligation was a technically feasible surgical approach for HHHT patients with simple hepatic artery dilation.

Atrial high-rate episodes intensify R2CHA2DS2-VASc score for prognostic stratification in pacemaker patients.

Patients with device detected atrial high-rate episodes (AHRE) have an increased risk of MACE. The R2CHA2DS2-VASc, CHADS2, R2CHADS2 and CHA2DS2-VASc score have been investigated for predicting major adverse cardiovascular events (MACE) in different groups of patients. We aimed to evaluate the R2CHA2DS2-VASc score in combination with AHRE ≥ 6 min for predicting MACE in patients with dual-chamber PPM but no prior atrial fibrillation (AF). We retrospectively enrolled 376 consecutive patients undergoing dual-chamber PPM implantation and no prior AF. The primary endpoint was subsequent MACE. For all patients in the cohort, CHADS2, R2CHADS2, CHA2DS2-VASc, R2CHA2DS2-VASc scores and AHRE ≥ or < 6 min were determined. AHRE was recorded as a heart rate > 175 bpm (Medtronic) or > 200 bpm (Biotronik) lasting ≥ 30 s. Multivariate Cox regression analysis with time-dependent covariates was used to determine the independent predictors of MACE. ROC-AUC analysis was performed for CHADS2, R2CHADS2, CHA2DS2-VASc, and R2CHA2DS2-VASc scores and then adding AHRE ≥ 6 min to the four scores. The median age was 77 years, and 107 patients (28.5%) developed AHRE ≥ 6 min. After a median follow-up of 32 months, 46 (12.2%) MACE occurred. Multivariate Cox regression analysis showed that R2CHA2DS2-VASc score (HR, 1.485; 95% CI, 1.212-1.818; p < 0.001) and AHRE ≥ 6 min (HR, 2.125; 95% CI, 1.162-3.887; p = 0.014) were independent predictors for MACE. The optimal R2CHA2DS2-VASc score cutoff value was 4.5 (set at ≥ 5), with the highest Youden index (AUC, 0.770; 95% CI, 0.709-0.831; p < 0.001). ROC-AUC analysis of the four risk scores separately combined with AHRE ≥ 6 min all showed better discriminatory power than the four scores alone (All Z-statistic p < 0.05). In patients with PPM who develop AHRE ≥ 6 min, it is crucial to perform risk assessment with either four scores to further stratify risk for MACE.

The HAT2CH2 score predicts neurologic events in patients with cardiac implantable electronic devices without atrial fibrillation.

BACKGROUND: The HAT2CH2 score has been evaluated for predicting new-onset atrial fibrillation (AF) in several clinical conditions but never for adverse neurologic events. We aimed to evaluate the HAT2CH2 score for predicting neurologic events in patients with cardiac implantable electronic devices (CIED). METHODS AND RESULTS: We retrospectively reviewed 470 consecutive patients who had CIED without a history of AF. The primary endpoint was a neurologic event, i.e. ischemic stroke or transient ischemic attack. Multivariate Cox regression analysis with time-dependent covariates was used to determine variables associated with independent factors of neurologic events. Patients' median age was 76 years, and 58.7% were male. During follow-up (median 29 months), 21 neurologic events occurred (incidence rate 1.85/100 patient-years, 95% CI 1.03-3.83). Multivariable Cox regression analysis revealed that the HAT2CH2 score (HR 3.397, 95% CI 2.357-4.895, p < 0.001) was an independent predictor for neurologic events. Optimal HAT2CH2 score cut-off value was 3, with highest Youden index (AUC, 0.923; 95% CI, 0.886-0.959; p < 0.001). The rate of neurologic events increased significantly with increasing HAT2CH2 score (p < 0.001). CONCLUSIONS: The HAT2CH2 score can predict the occurrence of neurologic events in patients with CIED with no history of AF. Further study of the utility of the HAT2CH2 score for the assessment of neurologic event risk and the selection of anti-thrombotic therapy in patients with CIED without prior AF is warranted.

Selexipag-based triple combination therapy improves prognosis in Chinese pulmonary arterial hypertension patients.

Aim: Selexipag is an oral selective prostacyclin receptor agonist approved for treatment of patients with pulmonary arterial hypertension (PAH). In the present study, we aim to assess the safety and efficacy of selexipag in triple combination therapy with endothelial receptor antagonists (ERAs) and PDE5is for Chinese PAH patients. Methods and results: A single center retrospective study was performed on group 1 PAH patients (n = 68) initiating triple combination therapy with selexipag from 1 February 2020 to 31 August 2021 in Qilu Hospital of Shandong University (Shandong, China). Adolescents, children, and PAH patients with unrepaired congenital heart disease were excluded. The French pulmonary hypertension network (FPHN) non-invasive risk assessment, echocardiogram parameters, and clinical data, including tolerability, safety, and death/hospitalization events associated with PAH, were collected. Of the 68 patients, 31 (45.6%) patients had tolerable side effects while only a single patient discontinued selexipag due to severe diarrhea. In the analysis of the efficacy set of 62 patients, the median selexipag treatment time from selexipag initiation to last risk assessment was 27 (21, 33) weeks. Compared to baseline parameters, the percentage of WHO FC III/IV decreased from 77.4% (48) to 24.2% (15) (p = 0.000), median 6-min walk distance (6MWD) increased 82 m [from 398 (318, 450) to 480 (420, 506) m; p = 0.000], and NT-proBNP levels decreased from 1,216 (329, 2,159) to 455 (134, 1,678) pg/mL (p = 0.007). Patients who improved to three low-risk criteria increased from 9.7 to 38.7%. Right ventricular diameter (RV) diameter also decreased and was accompanied by an improved tricuspid annular plane systolic excursion (TAPSE). Patients transitioning from subcutaneous treprostinil to selexipag continued to show improvements in WHO FC, 6MWD (404 ± 94 vs. 383 ± 127 m) and NT-proBNP levels (2,319 ± 2,448 vs. 2,987 ± 3,770 pg/mL). Finally, the 1-year event free survival rate was 96.7% for patients initiating the triple combination therapy within 3 years of PAH diagnosis. Conclusion: Triple combination therapy with selexipag was safe and effective in Chinese PAH patients, which was confirmed by acceptable tolerability, and improved exercise capacity, right heart function, risk assessment, and prognosis.

let-7 microRNAs induce tamoxifen sensitivity by downregulation of estrogen receptor α signaling in breast cancer.

MicroRNAs (miRNAs) play an important regulatory role in breast tumorigenesis. Previously, we found that let-7 miRNAs were downregulated significantly in formalin-fixed paraffin-embedded (FFPE) breast cancer tissues. In this study, we further found that endogenous levels of let-7b and let-7i miRNAs are inversely correlated with levels of estrogen receptor (ER)-a36, a new variant of ER-α66, in the FFPE tissue set. Bioinformatic analysis suggested that ER-α36 may be another target of let-7 miRNAs. To test this hypothesis, cotransfection of let-7 mimics or inhibitors together with full-length or a fragment of ER-α36 3'UTR luciferase construct was performed, and we found that let-7b and let-7i mimics suppressed the activity of reporter gene significantly, which was enhanced remarkably by let-7b and let-7i inhibitors. Both mRNA and protein expression of ER-α36 were inhibited by let-7 mimics and enhanced by let-7 inhibitors. Furthermore, ER-α36 mediated nongenomic MAPK and Akt pathways were weakened by let-7b and let-7i mimics in triple negative breast cancer cell line MDA-MB-231. The reverse correlation between let-7 miRNAs and ER-α36 also exists in Tamoxifen (Tam)-resistant MCF7 cell line. Transfection of let-7 mimics to Tam-resistant MCF7 cells downregulated ER-α36 expression and enhanced the sensitivity of MCF7 cells to Tam in estrogen-free medium, which could be restored by overexpression of ER-α36 constructs without 3'UTR. Our results suggested a novel regulatory mechanism of let-7 miRNAs on ER-α36 mediated nongenomic estrogen signal pathways and Tam resistance.

Atrial high­rate episodes and risk of major adverse cardiovascular events in patients with dual chamber permanent pacemakers: a retrospective study.

Patients with atrial high-rate episodes (AHRE) are at higher risk of major adverse cardiovascular events (MACE). The cutoff threshold for AHRE duration for MACE, with/without history of atrial fibrillation (AF) or myocardial infarction (MI), is unknown. A total of 481 consecutive patients with/without history of AF or MI receiving dual-chamber pacemaker implantation were included. The primary outcome was a composite endpoint of MACE after AHRE ≥ 5 min, ≥ 6 h, and ≥ 24 h. AHRE was defined as > 175 bpm (MEDTRONIC) or > 200 bpm (BIOTRONIK) lasting ≥ 5 min. Cox regression analysis with time-dependent covariates was conducted. Patients' mean age was 75.3 ± 10.7 years and 188 (39.1%) developed AHRE ≥ 5 min, 115 (23.9%) ≥ 6 h, and 83 (17.3%) ≥ 24 h. During follow-up (median 39.9 ± 29.8 months), 92 MACE occurred (IR 5.749%/year, 95% CI 3.88-5.85). AHRE ≥ 5 min (HR 5.252, 95% CI 2.575-10.715, P < 0.001) and ≥ 6 h (HR 2.548, 95% CI 1.284-5.058, P = 0.007) was independently associated with MACE, but not AHRE ≥ 24 h. Patients with history of MI (IR 17.80%/year) had higher MACE incidence than those without (IR 3.77%/year, p = 0.001). Significant differences were found between MACE patients with/without history of AF in AHRE ≥ 5 min but not AHRE ≥ 6 h or ≥ 24 h. Patients with dual-chamber pacemakers who develop AHRE have increased risk of MACE, particularly after history of AF or MI.

Duration of atrial high-rate episodes and CHA2DS2-VASc score to predict cardiovascular and cerebrovascular events in patients with dual chamber permanent pacemakers.

BACKGROUND: Patients with atrial high-rate episodes (AHRE) have a high risk of cardiovascular and cerebrovascular events (CCE); however, the optimal cut-off threshold for AHRE duration and the prediction power of AHRE with CHA2DS2-VASc score is unknown. METHODS: We enrolled 355 consecutive patients undergoing dual chamber pacemaker implantations. The primary endpoint was subsequent CCE after AHRE ≥ 30 seconds, 1 minute, 2 minutes, 5 minutes, 6 hours, and 24 hours. AHRE was defined as >175 bpm (Medtronic, Dublin, Ireland) or >200 bpm (Biotronik, Berlin, Germany) lasting ≥30 seconds. Multivariate Cox regression analysis with time-dependent covariates was used to determine the variables associated with higher risks of CCE. RESULTS: The average age of the patients was 75.6 ± 11.3 years, and 162 patients (45.6%) developed AHRE ≥ 30 seconds, 145 (40.8%) ≥1 minute, 125 (35.2%) ≥2 minutes, 107 (30.1%) ≥5 minutes, 55 (15.5%) ≥6 hours, and 37 (10.4%) ≥24 hours. During follow-up (mean 42.1 ± 31.2 months), 145 CCE occurred in 107 patients (incidence rate 11.64/100 patient-years, 95% CI 9.99-13.70). The optimal AHRE cut-off value was 1 minute (sensitivity, 57.9%; specificity, 66.0%; area-under-the-curve, 0.631; 95% CI, 0.563-0.698; p < 0.001). Multivariate Cox regression analysis demonstrated that all categories of AHRE duration were independently associated with CCE. The occurrence of CCE increased with AHRE ≥30 seconds and CHA2DS2-VASc score ≥2 (males) or ≥3 (females). CONCLUSION: Patients with dual chamber pacemakers who develop AHRE ≥ 30 seconds have an increased risk of CCE. The combination of AHRE duration ≥30 seconds and CHA2DS2-VASc score ≥2 (males) or ≥3 (females) is a useful risk-stratification predictor for subsequent CCE.

The optimal cutoff of atrial high-rate episodes for neurological events in patients with dual chamber permanent pacemakers.

BACKGROUND: Patients with atrial high-rate episode (AHRE) are at higher risk of neurological events. This study aimed to identify the optimal cutoff threshold for AHRE duration in patients with dual chamber permanent pacemakers (PPM) without prior atrial fibrillation. METHODS: We included 355 consecutive patients receiving dual chamber pacemaker implantation. Primary outcome was composite endpoint of subsequent neurological events after various AHRE durations. AHRE was defined as >175 bpm (MEDTRONIC) or > 200 bpm (BIOTRONIK) for longer than 30 s. Cox regression analysis with time-dependent covariates was conducted. RESULTS: The mean age of included patients was 75.6 ± 11.3 years. Among 355 included patients, some had multiple AHREs; 125 patients (35.2%) developed AHRE ≥2 min, 107 (30.1%) had ≥5 min, 55 (15.5%) had ≥6 h, and 37 (10.4%) had ≥24 h. The mean follow-up was 42.1 ± 31.2 months. During follow-up, 19 neurological events occurred. After adjustment for CHA2 DS2 -VASc score and device type, multivariate Cox regression analysis indicated AHRE ≥2 min (HR 13.605, 95% CI 3.010-61.498), and AHRE ≥5 min (HR 5.819, 95% CI 2.056-16.470) were significantly associated with neurological events. Hence, the optimal AHRE cutoff value was 2 min with the highest Youden index (sensitivity, 89.5%; specificity, 67.8%; AUC, 0.823, 95% CI, 0.763-0.884; p < 0.001). CONCLUSIONS: Patients with dual chamber PPM who develop AHRE have increased risk of neurological events. Comprehensive assessment of the risks and benefits of prescribing anticoagulants should be considered in PPM patients with AHRE ≥2 min.

HATCH Score and Left Atrial Size Predict Atrial High-Rate Episodes in Patients With Cardiac Implantable Electronic Devices.

Background: Patients with sustained atrial high-rate episodes (AHRE) have a high risk of major adverse cardio/cerebrovascular events (MACCE). However, the prediction model and factors for the occurrence of AHRE are unknown. We aimed to identify independent factors and various risk models for predicting MACCE and AHRE. Methods: We retrospectively enrolled 314 consecutive patients who had cardiac implantable electronic devices (CIEDs). The primary endpoint was MACCE after AHRE ≥3, 6 min, and 6 h. Atrial high-rate episodes was defined as >175 bpm (Medtronic®) lasting ≥30 s. Multivariate Cox and logistic regression analysis with time-dependent covariates were used to determine variables associated with independent risk of MACCE and occurrence of AHRE ≥3 min, respectively. Results: One hundred twenty-five patients (39.8%) developed AHRE ≥3 min, 103 (32.8%) ≥6 min, and 55 (17.5%) ≥6 h. During follow-up (median 32 months), 77 MACCE occurred (incidence 9.20/100 patient years, 95% CI 5.66-18.39). The optimal AHRE cutoff value was 3 min for MACCE, with highest Youden index 1.350 (AUC, 0.716; 95% CI, 0.638-0.793; p < 0.001). Atrial high-rate episodes ≥3 min-6 h were independently associated with MACCE. HATCH score and left atrial diameter were independently associated with AHRE ≥3 min. The optimal cutoff for HATCH score was 3 and for left atrial diameter was 4 cm for AHRE ≥3 min. Conclusion: Patients with CIEDs who develop AHRE ≥3 min have an independently increased risk of MACCE. Comprehensive assessment using HATCH score and echocardiography of patients with CIEDs is warranted.

Atrial high-rate episodes predict major adverse cardio/cerebrovascular events in patients with cardiac implantable electrical devices.

Patients with atrial high-rate episodes (AHRE) have a high risk of neurologic events, although the causal role and optimal cutoff threshold of AHRE for major adverse cardio/cerebrovascular events (MACCE) are unknown. This study aimed to identify independent factors for AHRE and subsequent atrial fibrillation (AF) after documented AHRE. We enrolled 470 consecutive patients undergoing cardiac implantable electrical device (CIED) implantations. The primary endpoint was subsequent MACCE after AHRE ≥ 6 min, 6 h, and 24 h. AHRE was defined as > 175 beats per minute (bpm) (Medtronic®) or > 200 bpm (Biotronik®) lasting ≥ 30 s. Multivariate Cox regression analysis with time-dependent covariates was used to determine variables associated with independent risk of MACCE. The patients' median age was 76 year, and 126 patients (26.8%) developed AHRE ≥ 6 min, 63 (13.4%) ≥ 6 h, and 39 (8.3%) ≥ 24 h. During follow-up (median: 29 months), 142 MACCE occurred in 123 patients. Optimal AHRE cutoff value was 6 min, with highest Youden index for MACCE. AHRE ≥ 6 min ~ 24 h was independently associated with MACCE and predicted subsequent AF. Male gender, lower body mass index, or BMI, and left atrial diameter were independently associated with AHRE ≥ 6 min ~ 24 h. Patients with CIEDs who develop AHRE ≥ 6 min have an independently increased risk of MACCE. Comprehensive assessment of patients with CIEDs is warranted.

HAT2CH2 Score Predicts Systemic Thromboembolic Events in Elderly After Cardiac Electronic Device Implantation.

Background: The HAT2CH2 score has been evaluated for predicting new onset atrial fibrillation, but never for adverse systemic thromboembolic events (STE) in elderly. We aimed to evaluate the HAT2CH2 score and comparing to atrial high rate episodes (AHRE) ≥24 h for predicting STE in older patients with cardiac implantable electronic devices (CIED) implantation. Methods: We retrospective enrolled 219 consecutive patients ≥ 65 years of age undergoing CIED implantation. The primary endpoint was subsequent STE. For all patients in the cohort, the CHA2DS2-VASc, C2HEST, mC2HEST, HAVOC, HAT2CH2 scores and AHRE ≥ 24 h were determined. AHRE was defined as > 175 bpm lasting ≥ 30 s. Multivariate Cox regression analysis with time-dependent covariates was used to determine variables associated with independent risk of STE. Results: The median patient age was 77 years, and 61.2% of the cohort was male. During follow-up (median, 35 months), 16 STE occurred (incidence rate, 2.51/100 patient-years; 95% CI, 1.65-5.48). Multiple Cox regression analysis showed that the HAT2CH2 score (HR, 3.405; 95% CI, 2.272-5.104; p < 0.001) was an independent predictor for STE. The optimal HAT2CH2 score cutoff value was 3, with the highest Youden index (AUC, 0.907; 95% CI, 0.853-0.962; p < 0.001). The STE rate increased with increasing HAT2CH2 score (p < 0.001). Conclusions: This study is the first to show the prognostic value of the HAT2CH2 score for STE occurrence in older patients with CIEDs.

Therapeutic efficacy of the novel selective RNA polymerase I inhibitor CX-5461 on pulmonary arterial hypertension and associated vascular remodelling.

BACKGROUND AND PURPOSE: CX-5461 is a novel selective RNA polymerase I (Pol I) inhibitor. Previously, we found that CX-5461 could inhibit pathological arterial remodelling caused by angioplasty and transplantation. In the present study, we explored the pharmacological effects of CX-5461 on experimental pulmonary arterial hypertension (PAH) and PAH-associated vascular remodelling. EXPERIMENTAL APPROACH: PAH was induced in Sprague-Dawley rats by monocrotaline or Sugen/hypoxia. KEY RESULTS: We demonstrated that CX-5461 was well tolerated for in vivo treatments. CX-5461 prevented the development of pulmonary arterial remodelling, perivascular inflammation, pulmonary hypertension, and improved survival. More importantly, CX-5461 partly reversed established pulmonary hypertension. In vitro, CX-5461 induced cell cycle arrest in human pulmonary arterial smooth muscle cells. The beneficial effects of CX-5461 in vivo and in vitro were associated with increased activation (phosphorylation) of p53. CONCLUSION AND IMPLICATIONS: Our results suggest that pharmacological inhibition of Pol I may be a novel therapeutic strategy to treat otherwise drug-resistant PAH.

The molecular mechanism of protective effects of grape seed proanthocyanidin extract on reperfusion arrhythmias in rats in vivo.

Reperfusion arrhythmias (RA) especially ventricular tachycardia (VT) and ventricular fibrillation (VF) remain the most important causes of sudden death following reperfusion. In isolated rat hearts grape seed proanthocyanidin extract (GSPE) had been proved to reduce the incidence of reperfusion-induced VF and VT. However the mechanism of this protection remained unclear. The aim of this study was to elucidate the potential mechanism of this protection of GSPE. The myocardial ischemia reperfusion (IR) model was induced by 30 min coronary occlusion and 120 min reperfusion in open chest anesthetized rats. The ultrastructure of ischemic cardiomyocytes was observed. An isobaric tag labeling for relative and absolute quantification (iTRAQ) proteomics was used to identify differentially expressed membrane proteins. Western blot was performed to verify the results of iTRAQ. The results demonstrated GSPE can significantly reduce the incidence of VT and VF induced by reperfusion in vivo. We identified 92 differentially expressed proteins. Western blot analysis confirmed GSPE increased the expression of Na(+)/K(+)-ATPase alpha1 subunit (p<0.01). We found the subunit distribution of Na(+)/K(+)-ATPase was changed after reperfusion. Na(+)/K(+)-ATPase alpha1 subunit was decreased in IR group (without GSPE-treated) compared to sham group while it was significantly increased in GSPE group. The decrease of free radical generation induced by GSPE may lead to the up-regulation of Na(+)/K(+)-ATPase alpha1 subunit. This change of subunit distribution may lead to the increase of activity of Na(+)/K(+)-ATPase which may result in the protection of GSPE against reperfusion arrhythmias. Our experiments provided new avenues for the treatment of reperfusion arrhythmias.