Jin-Tao Wu

CHADS2 and CHA2DS2-VASc Scores Predict the Risk of Ischemic Stroke Outcome in Patients with Interatrial Block without Atrial Fibrillation.

Aim: To evaluate the role of CHADS2 and CHA2DS2-VASc scores in predicting the risk of ischemic stroke or transient ischemic attack (TIA) outcomes in patients with interatrial block (IAB) without a history of atrial fibrillation (AF). Methods: A retrospective study was conducted, including 1,046 non-anticoagulated inpatients (612 males, 434 females; mean age: 63 ± 10 years) with IAB and without AF. IAB was defined as P-wave duration > 120 ms using a 12-lead electrocardiogram. CHADS2 and CHA2DS2-VASc scores were retrospectively calculated. The primary outcomes evaluated were ischemic stroke or TIA. Results: During the mean follow-up period of 4.9 ± 0.7 years, 55 (5.3%) patients had an ischemic stroke or TIA. Receiver operating characteristic (ROC) curve analysis showed that the CHADS2 score [area under the curve (AUC), 0.638; 95% confidence interval (CI), 0.562–0.715; P = 0.001] and the CHA2DS2-VASc score (AUC, 0.671; 95% CI, 0.599–0.744; P <0.001) were predictive of ischemic strokes or TIA. Cut-off point analysis showed that a CHADS2 score ≥ 3 (sensitivity = 0.455 and specificity = 0.747) and a CHA2DS2-VASc score ≥ 4 (sensitivity = 0.564 and specificity = 0.700) provided the highest predictive value for ischemic stroke or TIA. The multivariate Cox regression analysis showed that CHADS2 [hazard ratio (HR), 1.442; 95% CI, 1.171–1.774; P = 0.001] and CHA2DS2-VASc (HR, 1.420; 95% CI, 1.203–1.677; P <0.001) scores were independently associated with ischemic stroke or TIA following adjustment for smoking, left atrial diameter, antiplatelet agents, angiotensin inhibitors, and statins. Conclusions: CHADS2 and CHA2DS2-VASc scores may be predictors of risk of ischemic stroke or TIA in patients with IAB without AF.

Advanced interatrial block predicts clinical recurrence of atrial fibrillation after catheter ablation

BACKGROUND It has been demonstrated that advanced interatrial block (IAB) is associated with an increased risk of atrial fibrillation (AF); however, the impact of advanced IAB on recurrence of paroxysmal AF after catheter ablation is not clear. METHODS 204 consecutive patients with paroxysmal AF who underwent index circumferential pulmonary vein (PV) isolation were prospectively enrolled. In all patients, a resting electrocardiogram in sinus rhythm was evaluated for the presence of advanced IAB, defined as a P-wave duration >120ms and biphasic (±) morphology in the inferior leads. Advanced IAB was detected in 20.1% of patients. AF recurrence was defined as the occurrence of confirmed atrial tachyarrhythmia lasting more than 30s beyond 3 months after the catheter ablation in the absence of any antiarrhythmic treatment. RESULTS During the mean follow-up period of 13.9±6.2 months (range, 3-27 months), 62 patients (30.4%) developed recurrence of AF. The recurrence rate was higher in patients with advanced IAB than those without advanced IAB (46.3% vs. 26.4%, p=0.006). Cox regression analysis with adjustment for age, P-wave duration, CHADS2 score, and PV isolation identified advanced IAB (hazard ratio, 2.111; 95% confidence interval, 1.034-4.308; p=0.040) and left atrial diameter (hazard ratio, 1.051; 95% confidence interval, 1.004-1.100; p=0.034) as two independent predictors of recurrence of AF. CONCLUSIONS Patients with advanced IAB were at an increased risk of AF recurrence after catheter ablation.

Regulator of calcineurin 1-1L protects cardiomyocytes against hypoxia-induced apoptosis via mitophagy.

Abstract: Mitochondrial dysfunction induced by myocardial ischemia is the primary cause of cardiac cell death. Specific removal of damaged mitochondria through mitophagy may be beneficial for cardiomyocyte protection against ischemia. Regulator of calcineurin 1-1L (Rcan1-1L) has been implicated in mitophagy induction in neurons. However, whether or not Rcan1-1L can evoke mitophagy in cardiomyocytes during hypoxia remains unknown. This study aims to investigate the effect of Rcan1-1L overexpression on cardiomyocytes during hypoxia and the possible underlying mechanism. The results of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that Rcan1-1L overexpression inhibited cell growth under normoxic conditions, whereas Rcan1-1L overexpression significantly reversed the growth inhibition induced by hypoxia. The results of terminal deoxynucleotidyl transferase biotin-dUTP nick end-labeling assay showed that cell apoptosis induced by hypoxia was markedly reduced by Rcan1-1L overexpression. In addition, Rcan1-1L overexpression inhibited the expression of the proapoptotic protein Bcl-2–associated death promoter and increased that of the antiapoptotic protein Bcl-2. Rcan1-1L overexpression opened the mitochondrial permeability transition pore and decreased mitochondrial mass. Meanwhile, the release of reactive oxygen species from mitochondria was suppressed by Rcan1-1L. Autophagy flow activation represented by mammalian target of rapamycin inhibition and microtubule-associated protein light chain 3 (LC3) upregulation was also demonstrated. Compared with endoplasmic reticulum and Golgi apparatus protein markers, the mitochondrial protein marker translocase of outer mitochondrial membranes 20 (TOM20) was downregulated by Rcan1-1L overexpression. Moreover, Rcan1-1L increased mitophagy receptor Parkin translocation into mitochondria from cytosol. Additionally, the effect of Rcan1-1L on cell growth, cell apoptosis and mitochondria mass was blocked by Parkin expression silencing. Overall, these data suggest that Rcan1-1L protects cardiomyocytes from hypoxia-induced apoptosis by inducing mitophagy partly through Parkin. This study provided novel insights into the prevention and treatment of ischemic heart disease.

Icariin Inhibits Foam Cell Formation by Down‐Regulating the Expression of CD36 and Up‐Regulating the Expression of SR‐BI

Icariin is an important pharmacologically active flavonol diglycoside that can inhibit inflammation in lipopolysaccharide (LPS)‐stimulated macrophages. However, little is known about the molecular mechanisms underlying the inhibitory effect of Icariin in the formation of foam cells. In this study, macrophages were cultured with LPS and oxidized low‐density lipoprotein (oxLDL) in the presence or absence of Icariin. RT‐PCR and western blot were used to detect the levels of mRNA and protein expression of CD36, scavenger receptor class B type I (SR‐BI) and the phosphorylation of p38MAPK. It was demonstrated that 4 µM or 20 µM Icariin treatment significantly inhibited the cholesterol ester (CE)/total cholesterol (TC) and oxLDL‐mediated foam cell formation (P < 0.05). The binding of oxLDL to LPS‐activated macrophages was also significantly hindered by Icariin (P < 0.05). Furthermore, Icariin down‐regulated the expression of CD36 in LPS‐activated macrophages in a dose‐dependent manner and CD36 over‐expression restored the inhibitory effect of Icariin on foam cell formation. The phosphorylation of p38MAPK was reduced by Icariin, indicating that Icariin reduced the expression of CD36 through the p38MAPK pathway. In addition, Icariin up‐regulated SR‐BI protein expression in a dose‐dependent manner, and SR‐BI gene silencing restored the inhibitory effect of Icariin on foam cell formation. These data demonstrate that Icariin inhibited foam cell formation by down‐regulating the expression of CD36 and up‐regulating the expression of SR‐BI. Therefore, our findings provide a new explanation as to why Icariin could inhibit atherosclerosis. J. Cell. Biochem. 9999:1–9, 2015.

Usefulness of a Combination of Interatrial Block and a High CHADS2 Score to Predict New Onset Atrial Fibrillation

Interatrial block (IAB) is associated with an increased risk of atrial fibrillation (AF). The aim of this retrospective study was to investigate the association of a combination of IAB and the CHADS2 score, an AF-related risk score for ischemic stroke, with new onset AF in patients in sinus rhythm. A total of 1,571 patients (803 males, 768 females; mean age: 58 ± 16 years) were included in this study. IAB was defined as a P-wave duration > 120 ms in the 12-lead electrocardiogram, and a high CHADS2 score as ≥ 2 points. During the mean follow-up period of 4.8 ± 0.7 years, new onset AF occurred in 122 patients (16.1 per 1,000 patient-years). The incidence of new onset AF was 4.0 per 1,000 patient-years in patients with no IAB and a low CHADS2 score, and 44.0 per 1,000 patient-years in patients with IAB and a high CHADS2 score. In multivariate Cox regression analysis, the hazard ratio for IAB and a high CHADS2 score compared with no IAB and a low CHADS2 score was 12.18 (95% confidence interval: 6.22-23.87, P < 0.001), after adjustment for age, sex, coronary artery disease, valvular heart disease, smoking, medications, and echocardiographic parameters. In conclusion, IAB and a high CHADS2 score independently and synergistically predict new onset AF in patients in sinus rhythm, indicating an approximately 12-fold higher risk in patients with both IAB and a high CHADS2 score. Patients meeting these criteria should have more aggressive early intervention to prevent AF.

Rcan1-1L overexpression induces mitochondrial autophagy and improves cell survival in angiotensin II-exposed cardiomyocytes.

Mitochondrial autophagy is an important adaptive stress response and can be modulated by various key molecules. A previous study found that the regulator of calcineurin 1-1L (Rcan1-1L) may regulate mitochondrial autophagy and cause mitochondria degradation in neurocytes. However, the effect of Rcan1-1L on cardiomyocytes has not been determined. In the present study, we aimed to investigate the role of Rcan1-1L in angiotensin II (Ang II)-exposed human cardiomyocytes. Above all, Human adult cardiac myocytes (HACMs) were exposed to 200nmol/L Ang II for 4 days. Enhanced H2O2 production, cytochrome C release and mitochondrial permeability were observed in these cells, which were blocked by valsartan. Consistently, Ang II exposure significantly reduced cardiomyocyte viability. However, transfection of Rcan1-1L vector promoted cell viability and ameliorated the apoptosis caused by Ang II. Rcan1-1L clearly promoted mitochondrial autophagy in HACMs, with elevated autophagy protein (ATG) 5 and light chain 3 (LC3) expression. Transient mitochondrial biogenesis and reduced cytochrome C release was also induced by Rcan1-1L. Additionally, Rcan1-1L significantly inhibited calcineurin/nuclear factor of activated T cells (NFAT) signaling. We thus conclude that Rcan1-1L may play a protective role in Ang II-treated cardiomyocytes through the induction of mitochondrial autophagy, and may be an alternative method of cardiac protection.

MicroRNA‐217 suppresses homocysteine‐induced proliferation and migration of vascular smooth muscle cells via N‐methyl‐D‐aspartic acid receptor inhibition

Hyperhomocysteine has become a critical risk for atherosclerosis and can stimulate proliferation and migration of vascular smooth muscle cells (VSMCs). N‐methyl‐D‐aspartic acid receptor (NMDAR) is a receptor of homocysteine and mediates the effects of homocysteine on VSMCs. Bioinformatics analysis has shown NMDAR is a potential target of microRNA‐217 (miR‐217), which exerts multiple functions in cancer tumorigenesis and carotid plaque progression. In this study, we sought to investigate the role of miR‐217 in VSMCs phenotype transition under homocysteine exposure and elucidate its effect on atherosclerotic plaque formation. After treating with several doses of homocysteine (0–8 × 10−4 mol/L) for 24 hours, the expression of miR‐217 in HA‐VSMCs and rat aortic VSMCs was not altered. Intriguingly, the expression of NMDAR mRNA and protein was reduced by homocysteine in a dose‐dependent manner. Transfection of miR‐217 mimic significantly inhibited the proliferation and migration of VSMCs with homocysteine treatment, while transfection of miR‐217 inhibitor promoted VSMCs migration. Moreover, miR‐217 mimic down‐regulated while miR‐217 inhibitor up‐regulated NMDAR protein expression but not NMDAR mRNA expression. Through luciferase reporter assay, we showed that miR‐217 could directly bind to the 3′‐UTR of NMDAR. MiR‐217 mimic transfection also released the inhibition of cAMP‐response element‐binding protein (CREB)‐PGC‐1α signalling induced by homocysteine. Additionally, restoration of PGC‐1α expression via AdPGC‐1α infection markedly suppressed VSMCs proliferation through the degradation of NADPH oxidase (NOX1) and reduction of reactive oxygen species (ROS). Collectively, our study identified the role of miR‐217 in regulating VSMCs proliferation and migration, which might serve as a target for atherosclerosis therapy.

Association Between CHADS 2 Score and the Development of Interatrial Block

Interatrial block (IAB) is associated with a multitude of medical conditions. The aim of this retrospective study was to investigate whether CHADS2 (congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, prior stroke) score is positively associated with the development of IAB. A total of 1072 patients (men, 555; women, 517; mean age, 61 ± 14 years) were included in the study. P-wave duration was measured manually using a caliper. IAB was defined as a P-wave duration of ≥ 120 ms on a 12-lead electrocardiogram. CHADS2 scores were calculated retrospectively. Among the 1072 patients, the prevalence of IAB was 36.1% (387/1072). In multivariate analysis, increased CHADS2 score (odds ratio [OR], 1.810; 95% confidence interval [CI], 1.577-2.077; P < 0.001), coronary artery disease (OR, 1.536; 95% CI, 1.065-2.216; P = 0.022), and increased left atrial diameter (OR, 1.039; 95% CI, 1.008-1.071; P = 0.013) were independently associated with IAB. The percentages of patients with IAB among those with a CHADS2 score of 0, 1, 2, 3, 4, 5, and 6 were 20.6%, 33.0%, 45.0%, 55.9%, 61.9%, 77.8%, and 100%, respectively (P < 0.001). There was a greater percentage of patients with a CHADS2 score of ≥ 2 with IAB compared with a CHADS2 score of < 2 (26.5% vsrsus 52.0%; P < 0.001). In receiver operating curve (ROC) analysis, CHADS2 score (area under the curve, 0.670; 95% CI, 0.636-0.704; P < 0.001) was predictive of IAB. In conclusion, CHADS2 score was significantly associated with the development of IAB in this study population.

Usefulness of a Low Resting Heart Rate to Predict Recurrence of Atrial Fibrillation After Catheter Ablation in People ≥65 Years of Age

A low resting heart rate (RHR) is associated with an increased risk of atrial fibrillation (AF), and this is common in older people. Whether a low RHR in older people can predict recurrence of AF after catheter ablation is unclear. A total of 329 consecutive patients ≥65 years of age with paroxysmal AF who underwent index circumferential pulmonary vein isolation were prospectively enrolled. A 10-second standard resting 12-lead electrocardiogram in sinus rhythm was recorded to measure the RR interval, P-wave duration, and PR interval. The RHR was calculated based on the mean RR interval. During a mean follow-up period of 17.0 ± 8.3 months (range, 3 to 32 months), 96 (29.2%) patients developed recurrence of AF. The AF recurrence rate was 46.2%, 32.3%, and 25.4% in patients with an RHR <50, 50 to 59, and ≥60 beats/min, respectively (log-rank test, p = 0.009). Cox regression analysis with adjustment for P-wave duration and the CHADS2 score showed that an RHR <50 beats/min (hazard ratio [HR] 1.92, 95% confidence interval [CI] 1.12 to 3.28, p = 0.017), advanced interatrial block (HR 1.82, 95% CI 1.09 to 3.04, p = 0.022), and left atrial diameter (HR 1.05, 95% CI 1.00 to 1.09, p = 0.029) were independent predictors of recurrence of AF after catheter ablation. In conclusion, in people ≥65 years of age, an RHR <50 beats/min is an independent predictor of AF recurrence in patients who have undergone catheter ablation for paroxysmal AF.

Paeoniflorin blocks the proliferation of vascular smooth muscle cells induced by platelet‑derived growth factor‑BB through ROS mediated ERK1/2 and p38 signaling pathways

The proliferation of vascular smooth muscle cells (VSMCs) contributes to the development of vascular remodeling. In the present study, the effect of paeoniflorin (PAE) on the platelet derived growth factor-BB (PDGF-BB)-induced proliferation of primary cultured rat VSMCs and its molecular mechanism was investigated. The toxicity was determined by the try pan blue exclusion test. Cell proliferation was determined using a CCK-8 assay, DNA synthesis was assessed by measuring the incorporation of BrdU. Cell cycle progression was determined using PI staining and fluorescence-activated cell sorting. The level of intracellular reactive oxygen species (ROS) generation was assessed using dichlorodihydro fluorescein diacetate. mRNA expression was determined by reverse transcription quantitative polymerase chain reaction. Changes of p38, JNK, ERK1/2 signaling pathways were determined by western blot analysis. Cell migration was detected by scratch assay. PAE was demonstrated to significantly inhibit VSMC proliferation induced by PDGF-BB in a dose-and time-dependent manner without cell cytotoxicity. Thus, PAE blocked progression through the G0/G1 to Sphase of the cell cycle. Furthermore, inhibition of the cell cycle was associated with the inhibition of them RNA expression of cyclin D1, cyclin E, cyclin dependent kinase (CDK) 4 and CDK2 as well as with increased cyclin dependent kinase inhibitor 1A mRNA expression in PDGF-BB-stimulated VSMCs. Further studies showed that the beneficial effect of PAE on blocking VSMCs proliferation was related to the suppression of the ROS-mediated extra cellular signal-regulated kinase (ERK)1/2 and p38 signaling pathways, although PAE had no significant effect on the c-Jun N-terminal kinase signalling pathway. These results demonstrated that PAE suppressed PDGF-BB-induced VSMC proliferation through the ROS-mediated ERK1/2 and p38 signaling pathways, suggesting that it may be a feasible therapy for vascular remodelling diseases.