Inhibition of intermittent calcium-activated potassium channel (SK4) attenuates Ang II-induced hypertrophy of human-induced stem cell-derived cardiomyocytes via targeting Ras-Raf-MEK1/2-ERK1/2 and CN-NFAT signaling pathways.

Cardiac hypertrophy caused by angiotensin II (Ang II) is essential for the pathological process of heart failure. The intermediate calcium-activated potassium channel (SK4) has been shown to be involved in the process of the inflammatory response, cell proliferation, and apoptosis. However, the role of SK4 in cardiac hypertrophy has not been elucidated. Cardiac hypertrophy in human-induced pluripotent stem cells-derived cardiomyocytes (HiPSC-CMs) was induced by Ang II. Cells were transfected with SK4 adenovirus or treated with SK4 inhibitor (TRAM-34). TUNEL staining was used to assess the levels of apoptosis. Real-time polymerase chain reaction and Western blot analysis were used to measure messenger RNA (mRNA) and protein levels, respectively. The present results showed that SK4 expression was upregulated in HiPSC-CMs stimulated by Ang II. The downregulation of SK4 by a specific inhibitor TRAM-34 markedly ameliorated cardiac hypertrophy (reflected by the mRNA levels of atrial natriuretic peptide, brain natriuretic peptide, and ß-myosin heavy chain) and apoptosis (reflected by the level of Caspase 3, Bax, and Bcl-2) induced by Ang II treatment. The action of SK4 in cardiac hypertrophy was mediated by Ras-Raf-mitogen-activated protein kinases 1/2 (MEK1/2)-extracellular-regulated protein kinases 1/2 (ERK1/2) and calcineurin (CN)-nuclear factors of activated T cells (NFAT) activation. Our studies demonstrated that inhibition of SK4 significantly alleviated cardiac hypertrophy induced by Ang II in hiPSC-CMs by targeting Ras-Raf-MEK1/2-ERK1/2 signaling and CN-NFAT signaling pathway. Our studies suggest that SK4 may serve as a potential therapeutic target that could delay hypertrophy.

Blockade of SK4 channels suppresses atrial fibrillation by attenuating atrial fibrosis in canines with prolonged atrial pacing.

Background: We previously found that intermediate conductance Ca2+-activated K+ channel (SK4) might be an important target in atrial fibrillation (AF). Objective: To investigate the role of SK4 in AF maintenance. Methods: Twenty beagles were randomly assigned to the sham group (n=6), pacing group (n=7), and pacing+TRAM-34 group (n=7). Rapid atrial pacing continued for 7 days in the pacing and TRAM-34 groups. During the pacing, the TRAM-34 group received TRAM-34 intravenous injection (10 mg/Kg) 3 times per day. Atrial fibroblasts isolated from canines were treated with angiotensin II or adenovirus carrying the SK4 gene (Ad-SK4) to overexpress SK4 channels. Results: TRAM-34 treatment significantly suppressed the increased intra-atrial conducting time (CT) and AF duration in canines after rapid atrial pacing (P<0.05). Compared with the sham group, the expression of SK4 in atria was higher in the pacing group, which was associated with an increased number of myofibroblasts and levels of extracellular matrix in atrium (all P<0.05), and this effect was reversed by TRAM-34 treatment (all P<0.05). In atrial fibroblasts, the increased expression of SK4 induced by angiotensin II stimulation or Ad-SK4 transfection contributed to higher levels of P38, ERK1/2 and their downstream factors c-Jun and c-Fos, leading to the increased expression of α-SMA (all P<0.05), and all these increases were markedly reduced by TRAM-34 treatment. Conclusion: SK4 blockade suppressed AF by attenuating cardiac fibroblast activity and atrial fibrosis, which was realized through not only a decrease in fibrogenic factors but also inhibition of fibrotic signaling pathways.

Comparison of HPMC Inhalation-Grade Capsules and Their Effect on Aerosol Performance Using Budesonide and Rifampicin DPI Formulations.

Despite the fact that capsules play an important role in many dry powder inhalation (DPI) systems, few studies have been conducted to investigate the capsules' interactions with respirable powders. The effect of four commercially available hydroxypropyl methylcellulose (HPMC)inhalation-grade capsule types on the aerosol performance of two model DPI formulations (lactose carrier and a carrier-free formulation) at two different pressure drops was investigated in this study. There were no statistically significant differences in performance between capsules by using the carrier-based formulation. However, there were some differences between the capsules used for the carrier-free rifampicin formulation. At 2-kPa pressure drop conditions, Embocaps® VG capsules had a higher mean emitted fraction (EF) (89.86%) and a lower mean mass median aerodynamic diameter (MMAD) (4.19 µm) than Vcaps® (Capsugel) (85.54%, 5.10 µm) and Quali-V® I (Qualicaps) (85.01%, 5.09 µm), but no significant performance differences between Embocaps® and ACGcaps™ HI. Moreover, Embocaps® VG capsules exhibited a higher mean respirable fraction (RF)/fine particle fraction (FPF) with a 3-µm-sized cutoff (RF/FPF< 3 µm) (33.05%/35.36%) against Quali-V® I (28.16%/31.75%) (P < 0.05), and a higher RF/FPF with a 5-µm-sized cutoff (RF/FPF< 5 µm) (49.15%/52.57%) versus ACGcaps™ HI (38.88%/41.99%) (P < 0.01) at 4-kPa pressure drop condition. Aerosol performance variability, pierced-flap detachment, as well as capsule hardness and stiffness, may all influence capsule type selection in a carrier-based formulation. The capsule type influenced EF, RF, FPF, and MMAD in the carrier-free formulation.

Left Stellate Ganglion Ablation Inhibits Ventricular Arrhythmias through Macrophage Regulation in Canines with Acute Ischemic Stroke.

AIMS: To investigate the potential mechanism of ventricular arrhythmias (VAs) after acute ischemic stroke and explore the effects of left stellate gangling (LSG) ablation on VAs induced by stroke in canines. Materials and Methods: Twenty canines were randomly divided into the sham-operated group (n=6), AS group (n=7) and SGA group (n=7). Cerebral ischemic model was established in the AS group and the SGA group by right acute middle cerebral artery occlusion (MCAO). LSG ablation was performed in the SGA group as soon as MCAO. After 3 days, atrial electrophysiology and neural activity were measured in vivo. The levels of norepinephrine (NE) in plasma and ventricle were detected by ELISA. The levels of monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-α (TNF-α) and NF-κB p65 in ventricle were detected by western blotting. The pro-inflammatory polarization of macrophages in ventricle was detected by immunofluorescence. Results: Higher ventricular tachycardia (VT) inducibility and lower ventricular fibrillation threshold (VFT) were observed in the AS group compared with those in the sham-operated group, associated with higher LSG activity and NE levels, increased number of M1 macrophages and secretion of inflammatory cytokines in ventricle (all P<0.001). Compared with the AS group, the SGA group had lower VT inducibility and higher VFT, combined with lower NE levels, and reduced number of M1 macrophages and secretion of inflammatory cytokines in ventricle (all P<0.001). Conclusion: LSG ablation could reduce VAs vulnerability after acute stroke by preventing the macrophages polarization and activation induced by sympathetic hyperactivity.

The Role of α7nAChR-Mediated Cholinergic Anti-Inflammatory Pathway in Vagal Nerve Regulated Atrial Fibrillation.

The aim was to investigate the role of the α7nAChR-mediated cholinergic anti-inflammatory pathway in vagal nerve regulated atrial fibrillation (AF).18 beagles (standard dogs for testing) were used in this study, and the effective refractory period (ERP) of atrium and pulmonary veins and AF inducibility were measured hourly during rapid atrial pacing at 800 beats/minute for 6 hours in all beagles. After cessation of 3 hours of RAP, the low-level vagal nerve stimulation (LL-VNS) group (n = 6) was given LL-VNS and injection of salinne (0.5 mL/GP) into four GPs, the methyllycaconitine (MLA, the antagonist of α7nAChR) group (n = 6) was given LL-VNS and injection of MLA into four GPs, and the Control group (n = 6) was given saline into four GPs and the right cervical vagal nerve was exposed without stimulation. Then, the levels of the tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), acetylcholine (ACh), STAT3, and NF-κB proteins were measured. During the first 3 hours of RAP, the ERPs gradually decreased while the dispersion of ERPs (dERPs) and AF inducibility gradually increased in all three groups. During the last 3 hours of 6 hours' RAP in this study, the ERPs in the LL-VNS group were higher, while the dERPs and AF inducibility were significantly lower when compared with the Control and MLA groups at the same time points. The levels of ACh in the serum and atrium in the LL-VNS and MLA groups were higher than in the Control group, and the levels of TNF-α and IL-6 were higher in the Control and MLA groups than in the LL-VNS group. The concentrations of STAT3 in RA and LA tissues were higher in the LL-VNS group while those of NF-κB were lower.In conclusion, the cholinergic anti-inflammatory pathway mediated by α7nACh plays an important role in low-level vagal nerve-regulated AF.

A Comparison of Intranasal Dexmedetomidine and Dexmedetomidine-Ketamine Combination Sedation for Transthoracic Echocardiography in Pediatric Patients With Congenital Heart Disease: A Randomized Controlled Trial.

OBJECTIVES: To compare the effects of intranasal dexmedetomidine (DEX) and DEX-ketamine (KET) on hemodynamics and sedation quality in children with congenital heart disease. DESIGN: A randomized controlled, double-blind, prospective trial. SETTING: A tertiary care teaching hospital. PARTICIPANTS: The study comprised 60 children undergoing transthoracic echocardiography (TTE). INTERVENTIONS: Patients were randomly allocated into the DEX group (group D [n = 30]) or the DEX-KET group (group D-K [n = 30]). Group D received 2 µg/kg of intranasal DEX; group D-K received 2 µg/kg of DEX and 1 mg/kg of KET intranasally. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the change in hemodynamics, measured using mean arterial pressure (MAP) and heart rate (HR). Secondary outcomes were onset time, wake-up time, and discharge time. No differences were found in mean arterial pressure or heart rate. The onset time was significantly shorter in group D-K than in group D (9.6 ± 2.9 minutes v 14.3 ± 3.4 minutes; p = 0.031). The wake-up time was longer in group D-K than in group D (52 ± 14.7 minutes v 39.6 ± 12.1 minutes; p = 0.017). The discharge time was longer in group D-K than in group D (61.33 ± 11.59 minutes v 48.17 ± 8.86 minutes; p < 0.001). No differences in hemodynamics were found between the 2 groups. Intranasal DEX was found to be as effective for TTE sedation as intranasal DEX-KET, with longer onset time and shorter recovery and discharge times. CONCLUSION: No differences in hemodynamics were found between the 2 groups. Intranasal DEX was found to be as effective for TTE sedation as is intranasal DEX-KET, with longer onset time and shorter recovery and discharge times.

LncRNA PVT1 regulates atrial fibrosis via miR-128-3p-SP1-TGF-ß1-Smad axis in atrial fibrillation.

BACKGROUND: Long non-coding RNAs (lncRNA) plasmacytoma variant translocation 1 (PVT1) has been shown to be associated with liver fibrosis. Nevertheless, the role of PVT1 in atrial fibrosis remains undefined. This study aims to elucidate the pathophysiological role of lncRNA PVT1 in the regulation of atrial fibrosis and to explore the underlying mechanism. METHODS: Expression of PVT1, miR-128-sp, and Sp1 were examined in human atrial muscle tissues and angiotensin-II (Ang-II)-induced human atrial fibroblasts. Furthermore, the role of PVT1 in regulating atrial fibrosis in Ang-II-treated human atrial fibroblasts and Ang-II-induced atrial fibrosis in mice was investigated. Moreover, the interaction among PVT1, miR-128-3p, and Sp1 were examined using bioinformatics, expression correlation analysis, gain- or loss-of-function assays, RIP assays, and luciferase reporter assays. The involvement of transforming growth factor beta 1 (TGF-ß1)/Smad pathway in this process was also explored. RESULTS: PVT1 was increased in atrial muscle tissues from AF patients and positively with collagen I and collagen III. In vitro assay revealed that PVT1 overexpression facilitated the Ang-II-induced atrial fibroblasts proliferation, collagen production, and TGF-ß1/Smad signaling activation, whereas PVT1 knockdown caused the opposite effect. In vivo assay further confirmed that PVT1 knockdown attenuated the Ang-II-induced mouse atrial fibrosis. Mechanically, PVT1 acted as a sponge for miR-128-3p to facilitate Sp1 expression, thereby activating the TGF-ß1/Smad signaling pathway. CONCLUSION: LncRNA PVT1 promotes atrial fibrosis via miR-128-3p-SP1-TGF-ß1-Smad axis in atrial fibrillation.

Effect of acupuncture at Neiguan point combined with amiodarone therapy on early recurrence after pulmonary vein electrical isolation in patients with persistent atrial fibrillation.

OBJECTIVE: Early atrial fibrillation (AF) recurrences are common and have been shown to predict AF recurrences late after AF ablation during follow-up. Neiguan point acupuncture has been recognized to be therapeutic in treating AF in clinical practice. METHODS AND RESULTS: Eighty-five patients were enrolled in succession due to persistent AF. All patients were randomized divided into control group and acupuncture group. In the control group (n = 45), amiodarone was orally taken from the first day after pulmonary vein isolation (PVI). In the acupuncture group (n = 40), patients were treated with Neiguan point acupuncture for 7 days and amiodarone was prescribed as same as the control group after PVI. The levels of inflammatory factors were analyzed before operation, 1 week after the operation and 3 months later. After 3 months, the acupuncture group had a lower rate of early recurrences than the control group (5/40 [12.5%] vs 15/45 [33.3%], P = 0.039). The inflammatory factors level in the two groups were significantly increased after ablation. However, compared with the control group, the levels of TNF-α, IL-6, CRP, TGF-ß1, MMP2 in the acupuncture group significantly lower (P < 0.05). In a multivariate analysis, acupuncture was an independent factor associated with a lower rate of early recurrences during the blanking period (odds ratio, 0.17; 95% confidence interval, 0.05-0.63; P = 0.008). CONCLUSION: Neiguan point acupuncture combined with amiodarone is superior to amiodarone alone in reducing early recurrences of patients with persistent AF after PVI. The efficacy of Neiguan acupuncture therapy on the early recurrence is associated with the decreased inflammation factors.

Newly Detected Atrial Fibrillation after Acute Stroke: A Narrative Review of Causes and Implications.

Cardiac arrhythmias occur frequently in patients with acute stroke, with atrial fibrillation (AF) being the most common. Newly detected AF may lead to increased risk of ischemic stroke, which in turn generates stroke recurrence and adverse outcomes. Currently, most studies are focusing on the role of AF in ischemic stroke and attributing cryptogenic ischemic stroke to previously undetected AF. However, in these studies, subjects used to have neither symptoms of palpitation nor evidence of AF. A better understanding of this association will contribute to the management and therapy for patients after clinical decisions regarding stroke patients. Currently, the definition of newly detected AF has not come to an agreement, and the pathophysiology remains incompletely understood, possibly involving complex alterations in both the autonomic network and humoral regulation. Therefore, this review aims to introduce the definition and epidemiology of newly detected AF after stroke with updated information and elucidate the potential pathophysi-ology, such as autonomic imbalance, catecholamine surge, poststroke systematic inflammation, and microvesicles and microRNAs.

Median nerve stimulation prevents atrial electrical remodelling and inflammation in a canine model with rapid atrial pacing.

Aims: Studies have shown that stellate ganglion nerve activity has association with atrial electrical remodelling and atrial fibrillation (AF) inducibility, while median nerve stimulation (MNS) decreases cardiac sympathetic drive. In this study, we tested the hypothesis that MNS suppresses atrial electrical remodelling and AF vulnerability. Methods and results: The atrial effective refractory period (AERP) and AF inducibility at baseline and after 3 h of rapid atrial pacing were determined in dogs undergoing MNS (n = 7), MNS+ application of methyllycaconitine (n = 7) or sham procedure (n = 6). Then, the levels of tumour necrosis factor-alpha (TNF-a), interleukin-6 (IL-6), and acetylcholine (Ach) in the plasma and atrial tissues were measured. The control dogs (n = 4) were assigned to measure atrial inflammation cytokines. Short-term rapid atrial pacing induced shortening of the AERP, an increase in AERP dispersion, and an increase AF vulnerability in the sham dogs, which were all suppressed by MNS. Levels of TNF-a and IL-6 were higher, and Ach levels were lower in the left and the right atrium in the sham dogs than in the MNS dogs. Methyllycaconitine blunted the effects of MNS on the AERP, AERP dispersion, the AF vulnerability, and TNF-a and IL-6 levels in the atrium, but had no impact on the levels of Ach. Conclusions: The effects of MNS on atrial electrical remodelling and AF inducibility might be associated with the cholinergic anti-inflammatory pathway.

Effects of extrinsic cardiac nerve stimulation on atrial fibrillation inducibility: The regulatory role of the spinal cord.

OBJECTIVE: To investigate the effect of the mutual regulation of the extrinsic cardiac nerves on atrial electrophysiology and atrial fibrillation (AF) vulnerability. METHODS AND RESULTS: Fourteen dogs were randomly divided into two groups: spinal cord stimulation (SCS) group (n = 7) and spinal cord block (SCB) group (n = 7). SCS was performed with 90% of the threshold voltage stimulating the T1 -T2 spinal level, while SCB was performed by injecting 2% lidocaine into the epidural space at the T2-3 level. The effective refractory period (ERP), ERP dispersion, and AF inducibility were measured during atrial pacing combined with different extrinsic cardiac nerve stimulation. ERPs were decreased in the atrium and pulmonary veins and ERP dispersion was increased from baseline during left cervical vagus nerve stimulation (VNS) or left stellate ganglion stimulation (SGS) in the two groups. When combined with SCS, VNS resulted in diminished ERPs at all recording sites, longer ERP dispersion and more episodes of AF than were observed during VNS, whereas ERPs were greater and correspondingly fewer episodes of AF occurred during SCS combined with SGS than SGS. In the SCB group, ERPs were shortened, ERP dispersion was lengthened, and episodes of AF were increased during SGS after SCB. SCS enhanced the activity of the left vagus nerve but attenuated the left stellate ganglion and superior left ganglionated plexus. CONCLUSION: SCS modulates extrinsic and intrinsic cardiac nerve activity among the vagus nerve, stellate ganglion, and ganglionated plexus. SCS facilitates the effect of VNS and attenuates the effect of SGS on atrial electrophysiology.

Effect of renal sympathetic denervation on the progression of paroxysmal atrial fibrillation in canines with long-term intermittent atrial pacing.

AIMS: The aim of the present study was to explore the effect of renal sympathetic denervation (RSD) on the progression of paroxysmal atrial fibrillation (AF) in canines with long-term intermittent atrial pacing. METHODS AND RESULTS: Nineteen beagles were randomly divided into sham-operated group (six dogs), control group (six dogs), and RSD group (seven dogs). Sham-operated group were implanted with pacemakers without pacing; control group were implanted with pacemakers with long-term intermittent atrial pacing; and RSD group underwent catheter-based RSD bilaterally and were simultaneously implanted with pacemakers. Atrial pacing was maintained for 8 h a day and a total of 12 weeks in the control group and RSD group. Echocardiography showed that the left atrial structure and function were significantly improved in the RSD group compared with the control group (P < 0.05). Compared with the control group, the RSD group had fewer incidences of AF and a shorter duration of AF (P < 0.05) after long-term intermittent atrial pacing. In addition to increased atrial effective refractory period (AERP) and AF cycle length, AERP dispersion and P-wave duration and dispersion were significantly decreased in the RSD group compared with the control group (P < 0.05). Atrial morphological evaluation suggested that fibrosis and ultrastructural changes induced by long-term intermittent atrial pacing were markedly suppressed in the RSD dogs compared with controls (P < 0.05). Immunohistochemistry results showed that connexin 43 distribution in RSD mid-myocardial was significantly fewer heterogeneous than that in control mid-myocardial (P < 0.05). CONCLUSION: Renal denervation inhibits the progression of paroxysmal AF, which might be related to the suppression of atrial electrophysiology and structural heterogeneity.

[Renal sympathetic denervation suppresses ventricular substrate remodeling in a canine high-rate pacing model].

OBJECTIVE: To explore the role of renal sympathetic denervation (RSD) on ventricular substrate remodeling in dogs with pacing-induced heart failure (HF). METHODS: A total of 19 dogs were randomized into 3 groups of sham-operated control (n = 7), right ventricular pacing induction of HF (n = 6) and RSD (n = 6). After 8-week pacing induction of HF. Hemodynamic variables were monitored at baseline and after HF. Masson's trichrome staining, enzyme-linked immunosorbent assay (ELISA) and Western blot were used to measure ventricular interstitial fibrosis, brain natriuretic peptide (BNP), angiotensin II (Ang II), aldosterone and transforming growth factor-beta (TGF-ß). RESULTS: All dogs in HF and HF+RSD groups showed increased left and right ventricular diastolic dimensions [left ventricle: (27.0 ± 2.4) vs (37.0 ± 2.8) mm, P < 0.01 and (30.0 ± 2.5) vs (36.0 ± 2.8) mm, P < 0.05; right ventricle: (11.0 ± 1.5) vs (14.0 ± 1.7) mm, P = 0.03 and (12.0 ± 1.1) vs (14.0 ± 1.2) mm, P < 0.05]. Compared with HF + RSD dogs, HF dogs had higher left ventricular end-diastolic pressure (LVEDP) [(25.0 ± 3.7) vs (3.3 ± 1.6) mmHg, P < 0.01] and more fibrous tissue (left ventricle:24.1% ± 4.8% vs 8.5% ± 1.9%, P < 0.01; right ventricle:17.2% ± 5.2% vs 11.8% ± 3.9%, P < 0.01). The levels of BNP, Ang II, aldosterone and TGF-ß in ventricular tissue increased in HF dogs compared to sham-operated and HF+RSD dogs. CONCLUSION: RSD could suppress ventricular substrate remodeling induced by long-term rapid ventricular pacing.

[Beneficial effects of renal denervation on pulmonary vascular remodeling in experimental pulmonary artery hypertension].

OBJECTIVE: To explore the effects of renal sympathetic denervation (RSD) on pulmonary vascular remodeling in a model of pulmonary arterial hypertension (PAH). METHODS: According to the random number table, 24 beagles were randomized into control, PAH and PAH+RSD groups (n=8 each). The levels of neurohormone, echocardiogram and dynamics parameters were measured. Then 0.1 ml/kg dimethylformamide (control group) or 2 mg/kg dehydromonocrotaline (PAH and PAH+RSD groups) were injected. The PAH+RSD group underwent RSD after injection. At week 8 post-injection, the neurohormone levels, echocardiogram, dynamics parameters and pulmonary tissue morphology were observed. RESULTS: The values of right ventricular systolic pressure (RVSP) and pulmonary arterial systolic pressure (PASP) in PAH and PAH+RSD groups were both significantly higher than those in control group ((42.8±8.7), (30.8±6.8) vs (23.2±5.7) mmHg (1 mmHg=0.133 kPa) and (45.1±11.2), (32.6±7.9) vs (24.7±7.1) mmHg). Meanwhile, the values of RVSP and PASP in PAH group were higher than those in PAH+RSD group (all P<0.01). The levels of serum angiotensin II (Ang II) and endothelin-1 significantly increased after 8 weeks in PAH dogs ((228±41) vs (113±34) pg/ml and (135±15) vs (77±7) pg/ml, all P<0.01). And Ang II and endothelin-1 were higher in lung tissues of PAH group ((65±10) and (96±10) pg/ml) than in those of control group ((38±7) and (54±6) pg/ml) and PAH+RSD group ((46±8) and (67±9) pg/ml) (all P<0.01). Pulmonary tissues had marked collagen hyperplasia and lamellar corpuscles of type 2 alveolar cells were damaged more severely in PAH dogs than in PAH+RSD dogs. CONCLUSIONS: RSD suppresses pulmonary vascular remodeling and decreases pulmonary arterial pressure in experimental PAH. And the effect of RSD on PAH may contribute to decreased neurohormone levels.

Effects of renal sympathetic denervation on the atrial electrophysiology in dogs with pacing-induced heart failure.

BACKGROUND: Heart failure (HF) and atrial fibrillation (AF) are associated with sympathetic activation. Renal sympathetic denervation (RSD) can suppress AF vulnerability. The impact of RSD on atrial electrophysiology in experimental HF is unclear. METHODS: Twenty-two beagles were randomized into control, HF, and HF + RSD groups. Control dogs were implanted cardiac pacemakers without pacing. Dogs in the HF group underwent right ventricular pacing for 3 weeks at 240 beats/min to induce HF. The dogs in the HF + RSD group received RSD and underwent the same HF-inducing procedure. RESULTS: The P-wave dispersion was higher in HF dogs than in the control and HF + RSD dogs (19 ± 3.1 ms vs 13 ± 2.3 ms, 15 ± 2.9 ms, P = 0.04). Conduction time within the interatrium was significantly longer in the HF dogs than that in the control and HF + RSD dogs (39 ± 4 ms vs 31 ± 3 ms, 33 ± 4 ms; P = 0.03). Window of vulnerability (WOV) of AF was widened in the HF dogs than in the HF + RSD dogs (37 ± 5 ms vs 14 ± 3 ms; P < 0.01), while AF could not be induced (WOV = 0) in the control dogs during S1 S2 stimulation. The voltage in the threshold for AF inducibility was lower during ganglionated plexi stimulation in the HF dogs than in the control and HF + RSD dogs (1.8 ± 0.6 V vs 2.5 ± 0.6 V, 2.4 ± 0.4 V; P = 0.04). CONCLUSIONS: RSD could reverse the atrial electrical remodeling and decrease AF inducibility in dogs with pacing-induced HF.

Renal sympathetic denervation inhibits the development of left ventricular mechanical dyssynchrony during the progression of heart failure in dogs.

BACKGROUND: The purpose of this study was to investigate whether transcatheter renal sympathetic denervation (RSD) interfere with the development of left ventricular (LV) mechanical dyssynchrony during the progression of heart failure (HF). METHODS: Nineteen beagles were randomly divided into sham-operated group (six dogs), control group (seven dogs), and RSD group (six dogs). Sham-operated group were implanted with pacemakers without pacing; Control group were implanted with pacemakers and underwent 3 weeks of rapid right ventricular pacing; and RSD group underwent catheter-based RSD bilaterally and were simultaneously implanted with pacemakers. Both LV strain and LV dyssynchrony were analyzed via 2D speckle-tracking strain echocardiography to evaluate LV function. Longitudinal dyssynchrony was determined as the standard deviation for time-to-peak speckle-tracking strain on apical 4- and 2-chamber views. Radial and circumferential dyssynchrony was determined as the standard deviation for time-to-peak speckle-tracking strain in mid- and base-LV short-axis views. Each myocardial function was also evaluated by averaging the peak systolic strains. LV systolic pressure (LVSP) and LV end-diastolic pressure (LVEDP) were measured. The LV interstitial fibrosis was determined by histological analysis. Plasma angiotensin II (Ang II), aldosterone and norepinephrine (NE) levels were also measured. RESULTS: After 3 weeks, all of the dogs in both the control and RSD groups showed greater LV end-diastolic volume compared with the sham-operated group; however, the dogs in the RSD group had a higher LV ejection fraction (LVEF) than the dogs in the control group (p<0.001). The LV systolic strains were higher in the RSD group than in the control group (p<0.001 for longitudinal, circumferential and radial strain, respectively). The levels of LV dyssynchrony were lower in the RSD group than in the control group (p<0.001 for longitudinal, circumferential and radial dyssynchrony, respectively). Compared with dogs with control alone, RSD dogs had lower LV end-diastolic pressures and less fibrous tissue. The levels of plasma Ang II, aldosterone and NE were lower in the RSD group than in the control group. CONCLUSIONS: RSD inhibites the development of left ventricular mechanical dyssynchrony during the progression of heart failure in dogs.

M2 macrophage­derived exosomes alleviate KCa3.1 channel expression in rapidly paced HL­1 myocytes via the NF­κB (p65)/STAT3 signaling pathway.

The present study was designed to explore the role of M2 macrophage­derived exosomes (M2­exos) on the KCa3.1 channel in a cellular atrial fibrillation (AF) model using rapidly paced HL­1 myocytes. M2 macrophages and M2­exos were isolated and identified. MicroRNA (miR)­146a­5p levels in M2 macrophages and M2­exos were quantified using reverse transcription­quantitative PCR (RT­qPCR). HL­1 myocytes were randomly divided into six groups: Control group, pacing group, pacing + coculture group (pacing HL­1 cells cocultured with M2­exos), pacing + mimic­miR­146a­5p group, pacing + NC­miR­146a­5p group and pacing + pyrrolidine dithiocarbamate (PDTC; a special blocker of the NF­κB signaling pathway) group. Transmission electron microscopy, nanoparticle tracking analysis, western blotting, RT­qPCR and immunohistochemistry were performed in the present study. A whole­cell clamp was also applied to record the current density of KCa3.1 and action potential duration (APD) in each group. The results revealed that miR­146a­5p was highly expressed in both M2 macrophages and M2­exos. Pacing HL­1 cells led to a shorter APD, an increased KCa3.1 current density and higher protein levels of KCa3.1, phosphorylated (p­)NF­κB p65, p­STAT3 and IL­1ß compared with the control group. M2­exos, miR­146a­5p­mimic and PDTC both reduced the protein expression of KCa3.1, p­NF­κB p65, p­STAT3 and IL­1ß and the current density of KCa3.1, resulting in a longer APD in the pacing HL­1 cells. In conclusion, M2­exos and their cargo, which comprised miR­146a­5p, decreased KCa3.1 expression and IL­1ß secretion in pacing HL­1 cells via the NF­κB/STAT3 signaling pathway, limiting the shorter APD caused by rapid pacing.

Variation and disparity in awareness of atrial fibrillation in China: A national cross-sectional study.

BACKGROUND: The latest information regarding the awareness of atrial fibrillation (AF) remains limited in China. OBJECTIVES: The present study aimed to understand the variation and disparity in awareness of AF in China. METHODS: The cross-sectional study used data from the 2020 nationwide epidemiology survey on AF among adults aged 18 years or older in mainland China to assess the prevalence of AF awareness. The awareness of AF diagnostic methods and outcomes was also assessed using an interviewer-administered questionnaire. RESULTS: Of the 114,039 adults responding to the survey, 1463 (age-standardized prevalence, 55.3% (95% confidence interval [CI], 47.7-62.9%) and 10,202 (8.2%, 95%CI 5.4-10.9%) were aware of AF in participants with and without AF, respectively. Of these, 36.4% (95%CI 30.0-42.9%) and 6.3% (95%CI 3.6-9.1%) considered electrocardiogram as a method of diagnosing AF, and 30.0% (95% CI 3.2-8.2%) and 5.2% (95%CI 2.7-7.6%) considered stroke as an outcome of AF. The proportion of participants who being aware of AF varied significantly across sociodemographic and cardiovascular disease subgroups, and was almost consistently lower in rural areas than those in urban areas. Overall, lack of AF awareness was associated with rural areas, geographical region, lower education levels, and without history and had no risk factors of cardiovascular disease. CONCLUSIONS: Nearly half of adults with AF, and >90% non-AF population are unaware of AF in China, with significant variation and disparity. Focused public health initiatives are needed to improve awareness and knowledge of AF among high-risk populations.

The seasonal variation in hospitalizations due to chronic systolic heart failure correlates with blood sodium levels and cardiac function.

BACKGROUND: Although seasonal variation in hospitalizations due to chronic heart failure is recognized, the possible contributors to such variability are less well documented. METHODS: Records from all admissions to 12 hospitals in Hubei province, China, over a 10-year period with diagnostic codes for chronic systolic heart failure (CSHF) were reviewed. A total of 16,145 patients with CSHF were analyzed. RESULTS: There was a marked seasonal variation in the number of hospitalizations due to CSHF, with two peaks in the monthly rate of hospitalization due to CSHF occurring in December and August compared with the spring and autumn months. Monthly hospitalizations due to CSHF for patients with New York Heart Association class III and IV ranged from a peak of 40.4% and 23.3% above average in December and August, respectively, to 18.6% below average in November, while hospitalizations due to CSHF for patients with New York Heart Association class I and II exhibited no obvious seasonal variation. Blood sodium level (95% CI 2.132 to 2.144; P=0.036) was an independent risk factor for hospitalizations due to CSHF in August. CONCLUSION: The number of hospitalizations due to CSHF increased during the colder and warmer months in China. A low blood sodium level was associated with the peak in hospitalizations in August.

Wenxin Keli suppresses atrial substrate remodelling after epicardial ganglionic plexi ablation.

BACKGROUND: The chronic effects of ganglionic plexi (GP) ablation on atrial fibrillation (AF) inducibility have not been elucidated. OBJECTIVE: To investigate the effect of Wenxin Keli (WK) on the inducibility of AF and atrial substrate remodelling after epicardial GP ablation. METHODS: Twenty dogs were randomly divided into a sham-operated group, a GP ablation group and a WK-treated group. All animals underwent a left thoracotomy at the fourth intercostal space. AF inducibility was assessed by burst rapid pacing at the right atrium. Both the GP ablation group and the WK-treated group received four major GP ablations. In the WK-treated group, dogs were treated with oral WK once per day, and all animals were allowed to recover for eight weeks, after which AF inducibility and AF duration were measured again. RESULTS: After eight weeks of WK treatment, AF inducibility was lower than in the GP ablation group, and was similar to that of the sham-operated group. Compared with the sham-operated group, the levels of atrial natriuretic peptide (ANP), tumour necrosis factor-alpha (TNF-α) and interleukin (IL)-6 in right atrial tissues were increased in GP ablation group (143.6±33.7 pg/mg versus 206.2±41.4 pg/mg, P=0.02; 75.3±12.1 pg/mg versus 141.3±64 pg/mg, P=0.03; and 175.1±42.5 pg/mg versus 351.7±101 pg/mg, P<0.01, respectively). There were no significant differences in levels of ANP, TNF-α and IL-6 in atrial tissues between the sham-operated group and WK treated group. Expression of connexin 43 in atrial tissues was increased after eight weeks of GP ablation, while WK administration inhibited connexin 43 remodelling. CONCLUSIONS: Epicardial GP ablation can induce atrial substrate remodelling, including Cx43 upregulation and increased levels of ANP, TNF-α and IL-6. These changes may be suppressed by long-term oral WK administration.