A systematic review of biochar aging and the potential eco-environmental risk in heavy metal contaminated soil.

Biochar is widely accepted as a green and effective amendment for remediating heavy metals (HMs) contaminated soil, but its long-term efficiency and safety changes with biochar aging in fields. Currently, some reviews have qualitatively summarized biochar aging methods and mechanisms, aging-induced changes in biochar properties, and often ignored the potential eco-environmental risk during biochar aging process. Therefore, this review systematically summarizes the study methods of biochar aging, quantitatively compares the effects of different biochar aging process on its properties, and discusses the potential eco-environmental risk due to biochar aging in HMs contaminated soil. At present, various artificial aging methods (physical aging, chemical aging and biological aging) rather than natural field aging have been applied to study the changes of biochar's properties. Generally, biochar aging increases specific surface area (SSA), pore volume (PV), surface oxygen-containing functional group (OFGs) and O content, while decreases pH, ash, H, C and N content. Chemical aging method has a greater effect on the properties of biochar than other aging methods. In addition, biochar aging may lead to HMs remobilization and produce new types of pollutants, such as polycyclic aromatic hydrocarbons (PAHs), environmentally persistent free radicals (EPFRs) and colloidal/nano biochar particles, which consequently bring secondary eco-environmental risk. Finally, future research directions are suggested to establish a more accurate assessment method and model on biochar aging behavior and evaluate the environmental safety of aged biochar, in order to promote its wider application for remediating HMs contaminated soil.

Chinese Guidelines for the Diagnosis and Management of Atrial Fibrillation.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, significantly impacting patients' quality of life and increasing the risk of death, stroke, heart failure, and dementia. Over the past two decades, there have been significant breakthroughs in AF risk prediction and screening, stroke prevention, rhythm control, catheter ablation, and integrated management. During this period, the scale, quality, and experience of AF management in China have greatly improved, providing a solid foundation for the development of guidelines for the diagnosis and management of AF. To further promote standardized AF management, and apply new technologies and concepts to clinical practice in a timely and comprehensive manner, the Chinese Society of Cardiology of the Chinese Medical Association and the Heart Rhythm Committee of the Chinese Society of Biomedical Engineering have jointly developed the Chinese Guidelines for the Diagnosis and Management of Atrial Fibrillation. The guidelines have comprehensively elaborated on various aspects of AF management and proposed the CHA2DS2-VASc-60 stroke risk score based on the characteristics of AF in the Asian population. The guidelines have also reevaluated the clinical application of AF screening, emphasized the significance of early rhythm control, and highlighted the central role of catheter ablation in rhythm control.

Schwann cells acquire a repair phenotype after assembling into spheroids and show enhanced in vivo therapeutic potential for promoting peripheral nerve repair.

The prognosis for postinjury peripheral nerve regeneration remains suboptimal. Although transplantation of exogenous Schwann cells (SCs) has been considered a promising treatment to promote nerve repair, this strategy has been hampered in practice by the limited availability of SC sources and an insufficient postengraftment cell retention rate. In this study, to address these challenges, SCs were aggregated into spheroids before being delivered to an injured rat sciatic nerve. We found that the three-dimensional aggregation of SCs induced their acquisition of a repair phenotype, as indicated by enhanced levels of c-Jun expression/activation and decreased expression of myelin sheath protein. Furthermore, our in vitro results demonstrated the superior potential of the SC spheroid-derived secretome in promoting neurite outgrowth of dorsal root ganglion neurons, enhancing the proliferation and migration of endogenous SCs, and recruiting macrophages. Moreover, transplantation of SC spheroids into rats after sciatic nerve transection effectively increased the postinjury nerve structure restoration and motor functional recovery rates, demonstrating the therapeutic potential of SC spheroids. In summary, transplantation of preassembled SC spheroids may hold great potential for enhancing the cell delivery efficiency and the resultant therapeutic outcome, thereby improving SC-based transplantation approaches for promoting peripheral nerve regeneration.

The Transplantation of 3-Dimensional Spheroids of Adipose-Derived Stem Cells Promotes Achilles Tendon Healing in Rabbits by Enhancing the Proliferation of Tenocytes and Suppressing M1 Macrophages.

BACKGROUND: Tendons have limited regenerative potential, so healing of ruptured tendon tissue requires a prolonged period, and the prognosis is suboptimal. Although stem cell transplantation-based approaches show promise for accelerating tendon repair, the resultant therapeutic efficacy remains unsatisfactory. HYPOTHESIS: The transplantation of stem cells preassembled as 3-dimensional spheroids achieves a superior therapeutic outcome compared with the transplantation of single-cell suspensions. STUDY DESIGN: Controlled laboratory study. METHODS: Adipose-derived stem cells (ADSCs) were assembled as spheroids using a methylcellulose hydrogel system. The secretome of ADSC suspensions or spheroids was collected and utilized to treat tenocytes and macrophages to evaluate their therapeutic potential and investigate the mechanisms underlying their effects. RNA sequencing was performed to investigate the global difference in gene expression between ADSC suspensions and spheroids in an in vitro inflammatory microenvironment. For the in vivo experiment, rabbits that underwent Achilles tendon transection, followed by stump suturing, were randomly assigned to 1 of 3 groups: intratendinous injection of saline, rabbit ADSCs as conventional single-cell suspensions, or preassembled ADSC spheroids. The tendons were harvested for biomechanical testing and histological analysis at 4 weeks postoperatively. RESULTS: Our in vitro results demonstrated that the secretome of ADSCs assembled as spheroids exhibited enhanced modulatory activity in (1) tenocyte proliferation (P = .015) and migration (P = .001) by activating extracellular signal-regulated kinase (ERK) signaling and (2) the suppression of the secretion of interleukin-6 (P = .005) and interleukin-1α (P = .042) by M1 macrophages via the COX-2/PGE2/EP4 signaling axis. Gene expression profiling of cells exposed to an inflammatory milieu revealed significantly enriched terms that were associated with the immune response, cytokines, and tissue remodeling in preassembled ADSC spheroids. Ex vivo fluorescence imaging revealed that the engraftment efficiency of ADSCs in the form of spheroids was higher than that of ADSCs in single-cell suspensions (P = .003). Furthermore, the transplantation of ADSC spheroids showed superior therapeutic effects in promoting the healing of sutured stumps, as evidenced by improvements in the tensile strength (P = .019) and fiber alignment (P < .001) of the repaired tendons. CONCLUSION: The assembly of ADSCs as spheroids significantly advanced their potential to harness tenocytes and macrophages. As a proof of concept, this study clearly demonstrates the effectiveness of using ADSC spheroids to promote tendon regeneration. CLINICAL RELEVANCE: The present study lays a foundation for future clinical applications of stem cell spheroid-based therapy for the management of tendon injuries.

LCZ696 Ameliorates Oxidative Stress and Pressure Overload-Induced Pathological Cardiac Remodeling by Regulating the Sirt3/MnSOD Pathway.

AIMS: We aimed to investigate whether LCZ696 protects against pathological cardiac hypertrophy by regulating the Sirt3/MnSOD pathway. METHODS: In vivo, we established a transverse aortic constriction animal model to establish pressure overload-induced heart failure. Subsequently, the mice were given LCZ696 by oral gavage for 4 weeks. After that, the mice underwent transthoracic echocardiography before they were sacrificed. In vitro, we introduced phenylephrine to prime neonatal rat cardiomyocytes and small-interfering RNA to knock down Sirt3 expression. RESULTS: Pathological hypertrophic stimuli caused cardiac hypertrophy and fibrosis and reduced the expression levels of Sirt3 and MnSOD. LCZ696 alleviated the accumulation of oxidative reactive oxygen species (ROS) and cardiomyocyte apoptosis. Furthermore, Sirt3 deficiency abolished the protective effect of LCZ696 on cardiomyocyte hypertrophy, indicating that LCZ696 induced the upregulation of MnSOD and phosphorylation of AMPK through a Sirt3-dependent pathway. CONCLUSIONS: LCZ696 may mitigate myocardium oxidative stress and apoptosis in pressure overload-induced heart failure by regulating the Sirt3/MnSOD pathway.

Resting heart rate control and prognosis in coronary artery disease patients with hypertension previously treated with bisoprolol: a sub-group analysis of the BISO-CAD study.

BACKGROUND: Resting heart rate (RHR) is considered as a strong predictor of total mortality and hospitalization due to heart failure in hypertension patients. Bisoprolol fumarate, a second-generation beta-adrenoreceptor blockers (ß-blocker) is commonly prescribed drug to manage hypertension. The present study was to retrospectively evaluate changes in the average RHR and its association with cardiovascular outcomes in bisoprolol-treated coronary artery disease (CAD) patients from the CAD treated with bisoprolol (BISO-CAD) study who had comorbid hypertension. METHODS: We performed ad-hoc analysis for hypertension sub-group of the BISO-CAD study (n = 866), which was a phase IV, multination, multi-center, single-arm, observational study carried out from October 2011 to July 2015 across China, South Korea, and Vietnam. Multivariate regression analysis was used to identify factors associated with incidence of composite cardiac clinical outcome (CCCO), the results were presented as adjusted odds ratio (OR) along with 95% confidence interval (CI) and adjusted P value. RESULTS: A total of 681 patients (mean age: 64.77 ± 10.33 years) with hypertension from BISO-CAD study were included in the analysis. Bisoprolol improved CCCOs in CAD patients with comorbid hypertension, with RHR <65 and <70 beats/min compared with RHR ≥65 and ≥75 beats/min, respectively, in the efficacy analysis (EA) set. In addition, it lowered RHR in both intent-to-treat (ITT) and EA groups after 6, 12, and 18 months of treatment. Further, RHR 70 to 74 beats/min resulted in significantly higher risk of CCCOs EA set of patients (adjusted OR: 4.34; 95% CI: 1.19-15.89; P = 0.03). Also, events of hospitalization due to acute coronary syndrome were higher when RHR 69 to 74 beats/min compared to RHR <69 beats/min in ITT patients. CONCLUSION: Bisoprolol can effectively reduce RHR in Asian CAD patients with comorbid hypertension and hence, improve CCCO without affecting their blood pressure.

A Practical Method for Ablation Catheter Reintroduction into the Left Atrium via Prior Transseptal Puncture, without Radiation.

BACKGROUND: We evaluated the feasibility and safety of reintroducing an ablation catheter (ABL) into the left atrium (LA) through a previously punctured interatrial septum under guidance of the show-catheter image-track function of the CARTO 3 3-dimensional (3D) electroanatomic mapping system. METHODS: One hundred consecutive paroxysmal or persistent drug-refractory atrial fibrillation (AF) patients (men: 55; mean age, 64.7 ± 12.1 years) who had undergone 2 fluoroscopy-guided transseptal punctures and anatomical LA reconstruction under CARTO 3-guidance, and required ABL reinsertion into the LA during mapping or ablation, were included. They were randomized 1:1 to the show-catheter (reintroduction under the CARTO 3 show-catheter image-track function) or fluoroscopy group (reintroduction under conventional fluoroscopy). RESULTS: Although the reconstructed 3D anatomy map was displaced in 21/100 patients (21.0%), the ABL was successfully reintroduced in all patients. In the show-catheter and fluoroscopy groups, model displacement incidence (18% versus 24%), tachyarrhythmias (46.0% versus 52.0%), complications (2% versus 4%), and number of ABLs reintroduced into the LA (3.3 ± 0.8 versus 3.1 ± 0.9) were similar (all P > .05). The show-catheter group displayed shorter ABL reintroduction time (9.5 ± 5.5 s versus 156.4 ± 35.5 s, P < .01), ABL reintroduction X-ray exposure time (0 s versus 39.3 ± 13.8 s, P < .01), and total X-ray exposure time (4.1 ± 1.4 min versus 4.7 ± 0.8, P < .05). CONCLUSION: During AF ablation, the catheter can be safely reintroduced into the LA, without additional fluoroscopy, under guidance of the CARTO 3 show-catheter image track function.

Comparison of transthoracic echocardiography with computed tomography in evaluation of pulmonary veins.

BACKGROUND: Transesophageal echocardiography may be used to assess pulmonary veins for atrial fibrillation ablation. No study focused on the role of transthoracic echocardiography (TTE) in evaluating the diameter and anatomy of pulmonary veins. METHODS: Among 142 atrial fibrillation patients (57.7% men; mean age, 60.5) hospitalised for catheter ablation, we assessed pulmonary veins and compared the measurements by TTE with cardiac computed tomography (CT) before ablation. Among 17 patients who had follow-up examinations, the second measurements were also studied. RESULTS: TTE identified and determined the diameters of 140 (98.6%) right and 140 (98.6%) left superior PVs, and 136 (95.7%) right and 135 (95.1%) left inferior PVs. A separate middle PV ostia was identified in 14 out of the 22 patients (63.6%) for the right side and in 2 out of 4 (50.0%) for the left side. The PV diameters before ablation assessed by CT vs. TTE were 17.96 vs. 18.07 mm for right superior, 15.92 vs. 15.51 mm for right inferior, 18.54 vs. 18.42 mm for left superior, and 15.56 vs. 15.45 mm for left inferior vein. The paired differences between the assessments of CT and TTE were not significant (P ≥ 0.31) except for the right inferior vein with a CT-minus-TTE difference of 0.41 mm (P = 0.018). The follow-up PV diameters by both CT (P ≥ 0.069) and TTE (P ≥ 0.093) were not different from baseline measurements in the 17 patients who had follow-up measurements. CONCLUSIONS: With a better understanding of PV anatomy in TTE imaging, assessing PV diameters by non-invasive TTE is feasible. However, the clear identification of anatomic variation might still be challenging.

The Role of Angle in the Evaluation of Ablation Accuracy in Pulmonary Vein Isolation Navigated by Image Integration.

BACKGROUND: The conventional index for ablation accuracy is to compare the distance between mapping points with and without treatment by using image integration. We attempted to quantitatively evaluate the role of angle as an index in the ablation accuracy in patients with atrial fibrillation (AF). METHODS: A total of 48 patients with AF were included in the present study. Virtual fluoroscopy planes were predicted by pulmonary vein (PV) angiography, and the standard image planes were defined on the basis of the computed tomography images. Ablations were performed, guided by image integration; and the ablation planes were defined by the actual ablation rings. The predicted angle (distance) was defined as the angle (distance) between the fluoroscopy (predicted) plane and image (standard) plane, whereas the actual angle (distance) was defined as the angle (distance) between the ablation (actual) planes and the image (standard) planes. RESULTS: We found that all actual angles were significantly smaller than the predicted angles (P <.05), but only the actual distances in the left PV, right inferior PV, right superior PV, and right PV were significantly smaller; the distances in the left inferior PV and left superior PV were not significantly different (P >.05). CONCLUSION: Our finding indicates that both the angle and the distance can be significantly reduced by navigation with image integration, but that the angle exhibited better sensitivity than the conventional index of distance. We suggest that the angle should be considered as a new index for ablation accuracy.

Common variants predict recurrence after nonfamilial atrial fibrillation ablation in Chinese Han population.

BACKGROUND: Genome-wide association studies (GWAS) have identified several loci associated with atrial fibrillation (AF) and have been reportedly associated with response to catheter ablation for AF in patients of European ancestry; however, associations between susceptibility loci and clinical recurrence of AF after catheter ablation have not been examined in Chinese Han populations. To the personalization of catheter ablation for AF, we examined whether these single nucleotide polymorphisms (SNPs) can predict clinical outcomes after catheter ablation for AF in Chinese Han population. METHODS AND RESULTS: The association between 8 SNPs and AF was studied in 1418 AF patients and 1424 controls by the unconditional logistic regression analysis. The survival analyses were used to compare AT/AF recurrence differences among 438 AF patients, which were classified by the genotype of rs2200733. rs2200733 and rs6590357 were significantly associated with AF in Chinese Han population. In addition, rs2200733 was associated with clinical recurrence of AF after catheter ablation. In Kaplan-Meier survival analysis, the recurrence-free rates for AF with TT and with TC+CC were 35.5% and 61.9%, respectively (P=0.0009). In multivariate Cox regression analysis, rs2200733 was strong independent risk factor for recurrence. CONCLUSION: rs2200733 risk allele at the 4q25 predicted impaired clinical response to catheter ablation for AF in Chinese Han population. Our findings suggested rs2200733 polymorphism may be used as a clinical tool for selection of patients for AF catheter ablation.

The prevalence, incidence, management and risks of atrial fibrillation in an elderly Chinese population: a prospective study.

BACKGROUND: There is limited information on prevalent and incident atrial fibrillation in Chinese. We aimed to investigate the prevalence, incidence, management and risks of atrial fibrillation in an elderly Chinese population. METHODS: In a population--based prospective study in elderly (≥ 60 years) Chinese, we performed cardiovascular health examinations including a 12-lead electrocardiogram at baseline in 3,922 participants and biennially during follow-up in 2,017 participants. We collected information on vital status during the whole follow-up period. RESULTS: The baseline prevalence of atrial fibrillation was 2.0 % (n = 34) in 1718 men and 1.6 % (n = 36) in 2204 women. During a median 3.8 years of follow-up, the incidence rate of atrial fibrillation (n = 34) was 4.9 per 1000 person-years (95 % confidence interval [CI], 3.4-6.9). In univariate analysis, both the prevalence and incidence of atrial fibrillation were higher with age advancing (P < 0.0001) and in the presence of coronary heart disease (P ≤ 0.02). Of the 104 prevalent and incident cases of atrial fibrillation, only 1 (1.0 %) received anticoagulant therapy (warfarin). These patients with atrial fibrillation, compared with those with sinus rhythm, had significantly higher risks of all-cause (n = 261, hazard ratio [HR] 1.87, 95 % CI, 1.09-3.20, P = 0.02), cardiovascular (n = 136, HR 3.78, 95 % CI 2.17-6.58, P < 0.0001) and stroke mortality (n = 44, HR 6.31, 95 % CI 2.81-14.19, P = 0.0003). CONCLUSIONS: Atrial fibrillation was relatively frequent in elderly Chinese, poorly managed and associated with higher risks of mortality.

Polymorphisms of renin-angiotensin-aldosterone system gene in chinese han patients with nonfamilial atrial fibrillation.

BACKGROUND: Atrial fibrillation(AF) is the most common arrhythmia in the adult population. The activated renin-angiotensin-aldosterone system (RAS) has been reported to play an important role in the pathogenesis of atrial fibrillation. The aim of this study was to investigate the association between nonfamilial AF and polymorphisms in RAS gene. METHODS: A total of 931 patients with nonfamilial AF, 663 non-AF heart disease patients and 727 healthy subjects were selected. 10 tagSNPs (tSNPs) (ACE gene rs8066114, AGT gene rs7539020, rs3789678, rs2478544, rs11568023, rs2478523, rs4762, rs699 and CYP11B2 rs3802230, rs3097) were chosen and genotyped in our study. Single-locus analysis and haplotype analysis were used in this study. RESULTS: In single-locus analysis, we found rs11568023 and rs3789678 in AGT gene were associated with nonfamilial AF in Chinese Han population. AF risk was associated with rs3789678 between the AF group and control groups. Under dominant model, the significant AF risk was observed in rs3789678 between the AF group and non AF heart control group; And the protective effect was found in rs11568023, compared with the non-AF heart disease control group. In multilocus haplotype analysis, the association between frequencies of the haplotypes and AF risk was showed in AGT gene (rs7539020-rs3789678), compared 'TT' haplotype with the common 'TC' haplotype, adjusted for age, gender, LVEF, LVEDD, LAD and frequency of hypertension and diabetes. The diplotype with 'TC', carrying rs3789678-C-allele, was associated with reduced risk of AF between the AF group and the healthy control group. The diplotype with 'TT' haplotype in the same block, carrying rs3789678-T-allele, was associated with increased risk of AF. CONCLUSIONS: Via a large-scale case-control study, we found that rs3789678 site was potential susceptible locus of AF whereas rs11568023 was protective factor.

Comparison of circumferential pulmonary vein anatomy mapping guided by 3D mapping versus a mesh mapping catheter.

OBJECTIVE: Catheter-based pulmonary vein isolation (PVI) is an established therapy for paroxysmal atrial fibrillation. The high-density mesh mapper (HDMM) guides circumferential PV-atrium isolation without the 3D electroanatomic mapping. This study aims to compare circumferential pulmonary vein (CPV) anatomy mapping between guiding by a 3D mapping system and the HDMM. METHODS: Forty-four consecutive patients with paroxysmal atrial fibrillation were scheduled for a first procedure for PVI. A CPV ostial anatomy map guided by HDMM was set up in the CARTO system while the operator was blinded to the CARTO screen. Then CARTO-guided ipsilateral PV maps were obtained and PVI was performed. This established another set of CPV ostial anatomy maps. The differences between the two mapping images were compared and analyzed. RESULTS: All 176 PVs in 44 patients could be mapped by both HDMM and CARTO. About 44.9% of the PV ostial anatomies were generally similar between the two different map images. The average point-to-point straight distance between the HDMM-guided map and the CARTO-guided map was 6.2 ± 1.4 mm. The area of the circumferential right PV (CRPV) in the HDMM map was larger than that in the CARTO map (P = 0.013). After a mean follow-up of 18.3 ± 4.3 months (6-24 months), 72.7% of patients (32/44) were free of atrial arrhythmia without anti-arrhythmic drugs (AADs). CONCLUSION: Compared to the CARTO-guided CPV anatomy image, a highly similar figure could be achieved by mapping guided by the HDMM. (Clinical trial.gov number, ChiCTR-TNRC-11001390.).

Atrial fibrillation in essential hypertension: an issue of concern.

Many clinical studies indicate that atrial fibrillation is closely related to hypertension. Atrial fibrillation is not only associated with the level of blood pressure (BP) but also with the circadian rhythms of BP. However, the underlying mechanisms of atrial fibrillation in essential hypertension patients remain largely unknown. Hypertension may facilitate the onset and persistence of atrial fibrillation by stretch-induced changes in the repolarization of atrial myocytes (triggers of atrial fibrillation) and atrial remodeling (structural and electrical remodeling). Importantly, the effects of hypertension on atrial fibrillation are progressive. These progressive anatomic, functional, electrophysiological and structural changes occur at different times. This characterization of the time course of atrial changes presents an intervention window before remodeling progresses to changes that are difficult to reverse. Given that the medium to long-term efficacy of antiarrhythmic drugs has proved poor, it is essential to seek new therapies to prevent the onset of atrial fibrillation and to effectively control recurrences of atrial fibrillation. The study of nonantiarrhythmic drugs that act on the atrial remodeling that constitutes the substrate of the arrhythmia is a new and very interesting field of research. Treatment with angiotensin-converting enzyme inhibitors angiotension-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) seems more promising. However, from recent trials, only hypertension with structural heart disease, left ventricular dysfunction and left ventricular hypertrophy benefit from ACEIs and ARBs. This article reviews many aspects of atrial fibrillatio in essential hypertension patients to provide the foundation of atrial fibrillatio treatment.

Efficacy and tolerability of a single-pill combination of telmisartan/hydrochlorothiazide 80/25 mg in Chinese and Korean patients with moderate to severe hypertension: a subgroup analysis of a randomized, double-blind, active-controlled trial.

BACKGROUND: Hypertension is an important issue in Asia, responsible for up to 66% of cardiovascular disease cases. This randomized controlled trial subgroup analysis compared telmisartan 80 mg (T80)/hydrochlorothiazide 25 mg (H25) singlepill combination with T80 monotherapy, specifically in Chinese and Korean patients. METHODS: Patients with grade 2/3 hypertension were randomized to receive telmisartan 40 mg (T40)/hydrochlorothiazide 12.5 mg (H12.5) combination or T40 monotherapy for one week, before uptitrating the dose to T80/H25 or T80, respectively, for the remaining 6 weeks. The primary endpoint was systolic blood pressure (SBP) mean change from baseline. Secondary endpoints included mean diastolic blood pressure (DBP) change from baseline, and blood pressure (BP) goal achievement. Adverse events were recorded. RESULTS: Of a total 888 patients who were treated, efficacy analyses for Chinese and Korean patients included 127 patients treated with T80/H25 and 54 patients treated with T80. At week 7, mean SBP reductions from baseline were -37.5 mmHg (1 mmHg = 0.133 kPa) and -26.9 mmHg in the T80/H25 and T80 groups (adjusted mean difference, -10.6 mmHg; 95% confidence interval (CI), -15.6 to -5.7). Mean DBP reductions were -19.0 and -14.1 mmHg in the T80/H25 and T80 groups (adjusted mean difference, -4.9 mmHg; 95% CI, -8.0 to -1.8). In total, 56.7% of patients receiving T80/H25 achieved BP goal (<140/90 mmHg) compared with 35.2% receiving T80. SBP goal attainment (<140 mmHg) and DBP goal attainment (<90 mmHg) were also higher in the T80/H25 group compared with the T80 group (SBP: 69.3% vs. 48.1%; DBP: 62.2% vs. 46.3%). A small number of treatment-related adverse events were observed in both T80/H25 (nine patients, 6.9%) and T80 monotherapy (two patients, 3.6%) groups. CONCLUSIONS: In Chinese and Korean patients with moderate-to-severe hypertension, treatment with T80/H25 provided large reductions in mean SBP and DBP, and high BP goal attainment rates. This once-daily combination is effective and well tolerated in this patient group.

Advanced glycation end products promote human aortic smooth muscle cell calcification in vitro via activating NF-κB and down-regulating IGF1R expression.

AIM: To investigate the effects of advanced glycation end products (AGEs) on calcification in human aortic smooth muscle cells (HASMCs) in vitro and the underlying mechanisms. METHODS: AGEs were artificially prepared. Calcification of HASMCs was induced by adding inorganic phosphate (Pi, 2 mmol/L) in the media, and observed with Alizarin red staining. The calcium content in the supernatant was measured using QuantiChrome Calcium Assay Kit. Expression of the related mRNAs and proteins was analyzed using real-time PCR and Western blot, respectively. Chromatin immunoprecipitation (ChIP) assay was used to detect the binding of NF-κB to the putative IGF1R promoter. RESULTS: AGEs (100 µg/mL) significantly enhanced Pi-induced calcification and the levels of osteocalcin and Cbfα1 in HASMCs. Furthermore, the treatment decreased the expression of insulin-like growth factor 1 receptor (IGF1R). Over-expression of IGF1R in HASMCs suppressed the AGEs-induced increase in calcium deposition. When IGF1R expression was knocked down in HASMCs, AGEs did not enhance the calcium deposition. Meanwhile, AGEs time-dependently decreased the amounts of IκBα and Flag-tagged p65 in the cytoplasmic extracts, and increased the amount of nuclear p65 in HASMCs. In the presence of NF-κB inhibitor PDTC (50 µmol/L), the AGEs-induced increase in calcium deposition was blocked. Over-expression of p65 significantly enhanced Pi-induced mineralization, but suppressed IGF1R mRNA level. Knockdown of p65 suppressed the AGEs-induced increase in calcium deposition, and rescued the IGF1R expression. The ChIP analysis revealed that NF-κB bound the putative IGF1R promoter at position -230 to -219 bp. The inhibition of IGF1R by NF-κB was abolished when IGF1R reporter plasmid contained mutated binding sequence for NF-κB or an NF-κB reporter vector. CONCLUSION: The results demonstrate that AGEs promote calcification of human aortic smooth muscle cells in vitro via activation of NF-κB and down-regulation of IGF1R expression.

Lysophosphatidic acid increases the electrophysiological instability of adult rabbit ventricular myocardium by augmenting L-type calcium current.

Lysophosphatidic acid (LPA) has diverse actions on the cardiovascular system and is widely reported to modulate multiple ion currents in some cell types. However, little is known about its electrophysiological effects on cardiac myocytes. This study investigated whether LPA has electrophysiological effects on isolated rabbit myocardial preparations. The results indicate that LPA prolongs action potential duration at 90% repolarization (APD(90)) in a concentration- and frequency-dependent manner in isolated rabbit ventricular myocytes. The application of extracellular LPA significantly increases the coefficient of APD(90) variability. LPA increased L-type calcium current (I(Ca,L)) density without altering its activation or deactivation properties. In contrast, LPA has no effect on two other ventricular repolarizing currents, the transient outward potassium current (I(to)) and the delayed rectifier potassium current (I(K)). In arterially perfused rabbit left ventricular wedge preparations, the monophasic action potential duration, QT interval, and Tpeak-end are prolonged by LPA. LPA treatment also significantly increases the incidence of ventricular tachycardia induced by S(1)S(2) stimulation. Notably, the effects of LPA on action potentials and I(Ca,L) are PTX-sensitive, suggesting LPA action requires a G(i)-type G protein. In conclusion, LPA prolongs APD and increases electrophysiological instability in isolated rabbit myocardial preparations by increasing I(Ca,L) in a G(i) protein-dependent manner.

Effects of propofol on ischemia-induced ventricular arrhythmias and mitochondrial ATP-sensitive potassium channels.

AIM: To investigate the potential of propofol in suppressing ventricular arrhythmias and to examine whether mitochondrial ATP-sensitive potassium channels are involved. METHODS: Male Sprague-Dawley rats were pretreated with intravenous infusion of propofol (Prop), a selective mitochondrial KATP channel inhibitor 5-hydroxydecanoate (5-HD), propofol plus 5-HD (Prop+5-HD), a potent mitochondrial K(ATP) channel opener diazoxide (DZ) or NS, respectively. The dosage of each drug was 10 mg/kg. The animals then underwent a 30 min-ligation of the left anterior descending artery. The severity of arrhythmias, the incidence of ventricular fibrillation (VF), and the time of the first run of ventricular arrhythmias were documented using an arrhythmia scoring system. Mitochondrial membrane potential (ΔΨm) was measured in freshly isolated rat cardiomyocytes with a fluorescence microscope. RESULTS: The arrhythmia scores in the Prop and DZ group were 2.6(0-5) and 2.4(0-5), respectively, which were significantly lower than that in the control group [4.9(2-8)]. VF was not observed in both Prop and DZ groups. The first run of ventricular arrhythmias was significantly postponed in the Prop group (10.5±2.2 vs 7.3±1.9 min). Bracketing of propofol with 5-HD eliminated the anti-arrhythmic effect of propofol. In isolated rat cardiomyocytes, propofol (50 µmol/L) significantly decreased ΔΨm, but when propofol was co-administered with 5-HD, the effect on ΔΨm was reversed. CONCLUSION: Propofol preconditioning suppresses ischemia-induced ventricular arrhythmias in the rat heart, which are proposed to be caused by opening of mitochondrial K(ATP) channels.

Lysophosphatidic acid as a potential trigger of atrial fibrillation.

Atrial fibrillation (AF) is the most common arrhythmia in clinical practice, but its pathogenesis is incompletely understood. Current evidences have highlighted the progression of atrial fibrosis and electrophysiological remodeling in AF development. Lysophosphatidic acid (LPA), the simplest phospholipid, is associated with fibrotic disease and promotes proliferation of a wide variety of fibroblast. It was demonstrated that LPA stimulation in many cell types such as human endothelial cells, human renal fibroblasts, and myoblasts, significantly upregulates connective tissue growth factor (CTGF) expression, which acts as a downstream signaling effector for transforming growth factor-ß1 (TGF-ß1) to drive fibrosis. We hypothesized that LPA could also evoke growth factor-like responses to atrial fibroblast, and subsequently induce atrial fibrosis to trigger AF. LPA is also verified to involve in numerous electrophysiological activities in non-myocardiocytes. So LPA is a possible cause of AF by initiating fibrosis response and altering electrophysiological properties in atrium. If the hypothesis is confirmed, LPA will act as a new target for AF treatment and administration of LPA receptor blockers may be applied in the prophylaxis of AF.

Pharmacoinvasive therapy for ST elevation myocardial infarction in China: a pilot study.

Most patients with acute ST-elevation myocardial infarction (STEMI) cannot receive timely primary percutaneous coronary intervention (PCI) because of lack of facilities or delays in patient transfer or catheterization team mobilization. In these patients, early routine post-thrombolysis PCI might be a reasonable, useful strategy. This study investigated feasibility and safety of early PCI after successful half-dose alteplase reperfusion in a Chinese population. Patients with STEMI received half-dose alteplase if expected time delay to PCI was ≥90 min. Patients who reached clinical criteria of successful thrombolysis reperfusion were recommended to undergo diagnostic angiography within 3-24 h after thrombolysis. Patients with residual stenosis ≥70% in the infarct-related artery underwent PCI, regardless of flow or patency status. Epicardial arterial flow was assessed using thrombolysis in myocardial infarction (TIMI) flow grade and TIMI frame count (CTFC). Myocardial perfusion was assessed using myocardial blush grade (MBG) and TIMI myocardial perfusion frame count (TMPFC). Forty-nine patients were enrolled and underwent diagnostic angiography 3-11.3 h (median 6.5 h) after thrombolysis. Forty-six patients underwent PCI. No procedure-related complications occurred, except two patients who had no reflow after PCI. Twenty-two (47.8%) patients had TIMI grade 3 flow before PCI and 33 (71.7%) after PCI. CTFC was significantly improved after PCI (48.5 ± 32.1 vs. 37.9 ± 25.6, P = 0.01). MBG and TMPFC exhibited a similar improving trend after PCI, and the best myocardial perfusion tended to be achieved 3-12 h after lysis. During the 30-day follow-up, there were two deaths. The composite end point of death, cardiogenic shock, heart failure, reinfarction, and recurrent ischemia occurred in four patients. TIMI minor bleeding occurred in four patients. No TIMI major bleeding and stroke occurred. Early routine PCI after half-dose alteplase thrombolysis in Chinese population appears feasible. A larger clinical trial should be designed to further elucidate its efficacy and safety. Early PCI after thrombolysis in STEMI: The EARLY-PCI pilot feasibility study, ChiCTR-TNC-11001363.