Hypoxia, hypoxia-inducible factors and inflammatory bowel diseases.

Adequate oxygen supply is essential for maintaining the body's normal physiological function. In chronic inflammatory conditions such as inflammatory bowel disease (IBD), insufficient oxygen reaching the intestine triggers the regulatory system in response to environmental changes. However, the pathogenesis of IBD is still under investigation. Recent research has highlighted the significant role of hypoxia in IBD, particularly the involvement of hypoxia-inducible factors (HIF) and their regulatory mechanisms, making them promising therapeutic targets for IBD. This review will delve into the role of hypoxia, HIF, and the associated hypoxia-inflammatory microenvironment in the context of IBD. Potential interventions for addressing these challenging gastrointestinal inflammatory diseases will also be discussed within this framework.

Catheter ablation for patients on hemodialysis with symptomatic atrial fibrillation.

BACKGROUND: There are limited studies on the efficacy and safety of catheter ablation (CA) for patients with atrial fibrillation (AF) who receive intermittent hemodialysis (HD). This gap in the contemporary literature is notable as patients with AF receiving HD has higher incidence of AF and does not often tolerate medical management due to renal failure. METHODS: From Mar 2015 and Jan 2018, 25 consecutive patients on regular HD from two cardiac centers who underwent CA were retrospectively enrolled. Another 100 patients without HD or renal impairment, matched by age, sex, and AF type, were enrolled from these cardiac centers as the control group. All patients were followed up at month 3, 6, and every 6 months after the first CAs for 4 years, and 2.5 years after a second CA (if applicable), unless endpoints were reached. The primary endpoint was AF recurrence after CA, and the secondary endpoints included symptomatic AF and all-cause mortality during the follow-up period. RESULTS: AF patients receiving intermittent HD had a higher prevalence of hypertension (P=0.005), and heart failure (P=0.041). During the mean follow-up period of 37.6±17.4 months after the first CA, 14 out of the 25 HD patients (56.0%) remained free from AF recurrence, compared with 77 in the control patients (77.0%; P=0.021). Twenty (80.0%) patients in the HD group did not experience symptomatic AF. Second CAs were performed on 5 HD patients and 11 control patients, consequently 4 out of 5 (80.0%) HD patients and 7 out of 11 (63.6%) control patients had no AF recurrence (P=0.626) within 21.1±12.0 months after the second CA. Tamponade was the only procedural complication documented in both groups. All-cause mortality was higher in the HD group (log-rank P=0.004); however, the observed mortality was not related to AF recurrence. CONCLUSIONS: CA is a potential efficacious and safe treatment of AF for HD patients. The AF recurrence rate is higher after a single ablation compared with the general population, but multiple ablations seem to improve outcomes for HD patients.

Assessment of ventricular mechanical synchronization after left bundle branch pacing using 2-D speckle tracking echocardiography.

BACKGROUND: The left bundle branch pacing (LBBP) makes the ventricular depolarization closer to the physiological state and shortens QRS duration. The purpose of this study is to explore the ventricular systolic mechanical synchronization after LBBP in comparison with traditional right ventricular pacing (RVP) using two-dimensional strain echocardiography (2D-STE). METHODS: Thirty-two patients who received LBBP (n = 16) or RVP (n = 16) from October 2018 to October 2019 and met the inclusion criteria were included in this retrospective study. Electrocardiogram (ECG) characteristics, pacing parameters, pacing sites, and safety events were assessed before and after implantation. Acquisition and analysis of ventricular systolic synchronization were implemented using 2D-STE. RESULTS: In RVP group, ECG showed left bundle branch block patterns. At LBBP, QRS morphology was in the form of right bundle branch block, and QRS durations were significantly shorter than that of the RVP QRS (109.38 ± 12.89 vs 149.38 \± 19.40 ms, P < .001). Both the maximum time differences (TD) and SDs of the 18-segments systolic time to peak systolic strain were significantly shorter under LBBP than under RVP (TD, 66.62 ± 37.2 vs 148.62 ± 43.67 ms, P < .01; SD, 21.80 ± 12.13 vs 52.70 ± 17.72 ms, P < .01), indicating that LBBP could provide better left ventricular mechanical synchronization. Left and right ventricular pre-ejection period difference was significantly longer in RVP group than in LBBP group (10.23 ± 3.07 vs 39.94 ± 14.81 ms, P < .05), indicating left and right ventricular contraction synchronization in LBBP group being better than in RVP group. CONCLUSION: LBBP is able to provide a physiologic ventricular activation pattern, which results in ventricular mechanical contraction synchronization.

Recent approaches to His-Purkinje system pacing.

OBJECTIVE: Physiologic cardiac pacing is a novel technique which has been largely popularized in recent decades. His bundle pacing (HBP) has been long considered the most physiologic pacing method; however, with the widespread implementation of this method, its disadvantages have become apparent. In this context, left bundle branch pacing (LBBP)-directly engaged in the His-Purkinje system-has been foreseen as the best pacing method to mimic physiologic activation patterns. This review aimed to summarize recent approaches to physiologic cardiac pacing. DATA SOURCES: This review included fully peer reviewed publications up to July 2018, found in the PubMed database using the keywords "His bundle branch pacing," "right ventricular pacing," and "physiologic pacing." STUDY SELECTION: All selected articles were in English, with no restriction on study design. RESULTS: The HBP has been studied worldwide, and is currently considered the most physiologic pacing method. However, it has disadvantages, such as high pacing threshold, unsatisfactory sensing and long procedure times, among others. Although LBBP is theoretically superior to HBP, the clinical relevance of this difference remains under debate, as few large randomized clinical trials with LBBP have been published. CONCLUSIONS: Although HBP indeed appears to be the most physiologic pacing method, it has certain shortcomings, such as high pacing threshold, difficult implantation due to specific anatomic features, and others. Further studies are required to clarify the clinical significance of LBBP.

Targeting HMGB1 ameliorates cardiac fibrosis through restoring TLR2-mediated autophagy suppression in myocardial fibroblasts.

BACKGROUND: Extracellular high-mobility group box 1 (HMGB1) has been identified as playing a critical role in the pathogenesis of tissue fibrosis. However, the underlying mechanism of its involvement in cardiac fibrosis is still not well-defined. Here, we aim to investigate whether toll-like receptor 2 (TLR2) contributes to the extracellular HMGB1-mediated development and progression of cardiac fibrosis. METHODS: A mouse model of cardiac fibrosis was induced by subcutaneous injection of isoproterenol (ISO). Glycyrrhizic acid (GA), an inhibitor of HMGB1 derived from natural products, was simultaneously administered by intraperitoneal injection. Echocardiography, H&E and Sirius red staining were used to evaluate cardiac function and fibrosis. The myocardial expression of autophagy-associated proteins was examined using immunoblotting. Cardiac fibroblasts were treated with different concentrations of HMGB1 to examine the expression levels of α-SMA, collagen I and autophagy markers. Interactions of HMGB1/TLR2 and α-SMA/p62 were examined by immunoprecipitation and immunofluorescence. RESULTS: ISO-treated mice showed characteristic cardiac fibrosis, increased expression and co-localization of HMGB1 and TLR2, as well as impaired autophagic signals in myocardial tissues, which could be prevented by silencing TLR2. Exogenous administration of HMGB1 blocked the autophagic flux in fibroblasts, which caused extensive accumulation of collagen I and α-SMA. In addition, cardiac fibrosis was alleviated by GA treatment through abrogating the interaction between HMGB1 and TLR2. CONCLUSIONS: Our study suggests that the interaction between TLR2 and HMGB1 contributes to the pathogenesis of cardiac fibrosis via suppressing fibroblast autophagy, and that inhibiting HMGB1 with GA provides therapeutic benefits for the treatment of fibroproliferative heart diseases.

A case report of Brugada-like ST-segment elevation probably due to coronary vasospasm.

RATIONALE: Vasospastic angina is caused by sudden occlusive vasoconstriction of a segment of an epicardial artery, with transient ST-segment elevation on electrocardiography. Brugada Syndrome is an inherited arrhythmogenic cardiac disorder with a diagnostic electrocardiography characterized by coved-type ST-segment elevation in right precordial leads (V1-V3). Those two diseases usually have no correlation. In this report, we discuss an interesting case of a patient who was diagnosed as vasospastic angina according to his coronary angiography, but his electrocardiography showed a Brugada-like ST-segment elevation. PATIENT CONCERNS: Our patient had a 9-month history of temporary but progressive substernal burning sensation with acid bilges of shoulders and arms, as well as profuse sweating at night. DIAGNOSES: Although he had no abnormal laboratory test result, no dysfunctional recorded echocardiogram or documented arrhythmia after being admitted to the hospital, his electrocardiography showed a Brugada-like ST-segment elevation. The coronary angiography result confirmed a diagnosis of vasospastic angina. INTERVENTIONS: The patient was prescribed diltiazem, aspirin, isosorbide mononitrate and rosuvastatin and was strongly advised to quit cigarettes and alcohol. OUTCOMES: Follow-up at half a year turned out well. LESSONS: This case links Brugada syndrome to coronary vasospasm. They may share similar mechanisms. Provocation test and gene test needs to be ran to distinguish both. Long-term follow-up is essential for it may bring a warning sign for life threatening ventricular arrhythmias.

Increased Local Sympathetic Nerve Activity During Pathogenesis of Ventricular Arrhythmias Originating from the Right Ventricular Outflow Tract.

BACKGROUND The contribution of local sympathetic nerves to ventricular arrhythmia (VA) originating from the right ventricular outflow tract (RVOT) has not been elucidated. This study used a canine model to investigate the anatomical changes of the RVOT associated with VA, and the distribution of local sympathetic nerves. MATERIAL AND METHODS The RVOT-VA canine model (6 dogs) was induced with a circular catheter and high-frequency stimulation (100 Hz) in the middle of the pulmonary artery trunk. Six dogs who were not given stimulation served as the control group. The serum levels of neurotransmitters, the extent of myocardial extension, and the sympathetic nerve density of the RVOT were also analyzed. RESULTS Ventricular arrhythmias, including premature ventricular contractions, were induced in the experimental group after high-frequency stimulation. Dogs from the RVOT-VA group showed enhanced myocardial extension and sympathetic nerve density in the septal wall as compared with those of the free wall of the RVOT. In the RVOT-VA dogs, serum norepinephrine and neuropeptide Y and the sympathetic nerve density were significantly higher compared with the control group. CONCLUSIONS Stimulation of the pulmonary artery could activate local sympathetic nerves and enhance myocardial extension, which may be the foundation of RVOT-VA. The RVOT voltage transitional zone positively correlated with myocardial extension, which may serve as an important target for the radiofrequency catheter ablation of RVOT-VA clinically.

Voltage combined with pace mapping is simple and effective for ablation of noninducible premature ventricular contractions originating from the right ventricular outflow tract.

BACKGROUND: Premature ventricular contractions (PVCs) from the right ventricular outflow tract (RVOT) can resist conventional mapping strategies. Studies regarding optimal mapping and ablation methods for patients with noninducible RVOT-PVCs are limited. We retrospectively evaluated the efficacy and safety of a novel mapping strategy for these cases: voltage mapping combined with pace mapping. HYPOTHESIS: METHODS: We retrospectively included symptomatic patients (n = 148; 76 males; age, 44.5 ± 1.4 years) with drug-refractory PVCs originating from the RVOT, who underwent radiofrequency catheter ablation (RFCA), and stratified them as Group 1 and Group 2. Group 1 patients had noninducible RVOT-PVCs, determined after programmed stimulation, burst pacing, and isoproterenol infusion (n = 21; 12 males; age, 39.5 ± 10.8 years). Group 2 patients had inducible PVCs. Group 1 patients were subjected to voltage mapping combined with pace mapping; Group 2 underwent conventional mapping. In all patients prior to RFCA, detailed 3-dimensional electroanatomic voltage maps of the RVOT were obtained during sinus rhythm using the CARTO system. RESULTS: Patients from both groups had similar success and complication rates associated with the RFCA. In Group 2, 89% (113/127) experienced the earliest and the successful ablation points in the voltage transitional zone. During the follow-up (36 ± 8 months), patients from both groups suffered similar rates of PVC relapse (2/21 and 7/127, respectively; P = 0.826). CONCLUSIONS: Voltage mapping combined with pace mapping is effective and safe for patients with noninducible RVOT-PVCs determined by conventional methods.

Rho-Kinase inhibitor fasudil suppresses high glucose-induced H9c2 cell apoptosis through activation of autophagy.

INTRODUCTION: Cardiac cell apoptosis plays a crucial role in the progression of diabetic cardiomyopathy. Recent studies have shown that fasudil, a Rho-kinase (ROCK) inhibitor, inhibits cardiac cell apoptosis; however, the underlying mechanism remains unclear. AIM: This study aimed to investigate whether fasudil protects H9c2 cells from high glucose-induced apoptosis via activation of autophagy. METHODS: Rat cardiomyocyte H9c2 cells were treated with high glucose and used as a diabetic cardiomyopathy model. Cell survival rate, apoptosis, and subcellular morphology were examined using the MTT assay, flow cytometry, and electron microscopy, respectively. ROCK1 and ROCK2 mRNA levels were determined using quantitative real-time PCR. Bcl-2 and Bax, myosin phosphatase target subunit-1 (MYPT-1), phosphorylated (p)-MYPT1, LC3-II/LC3-I, Beclin-1, soluble and insoluble P62 protein levels were determined by Western blot analysis. RESULTS: Fasudil reversed the high glucose-induced inhibition of cell proliferation and suppressed high glucose-induced early apoptosis. Fasudil also reversed the high glucose-suppressed Bcl-2 levels and decreased the high glucose-induced Bax levels. Further, Fasudil suppressed ROCK levels, expression, promoted autophagy via increasing the LC3-II/LC3-I ratio, Beclin-1 expression, and the number of autophagosomes in H9c2 cells treated with high glucose. These effects of fasudil were abrogated by 3-methyladenine (3-MA), an autophagy inhibitor. CONCLUSION: Fasudil inhibited high glucose-induced apoptosis in rat H9c2 cells through activating autophagy.

Sequential changes of endoplasmic reticulum stress and apoptosis in myocardial fibrosis of diabetes mellitus-induced rats.

The endoplasmic reticulum (ER) is an organelle in which proteins form their appropriate structures. However, several of these proteins become unfolded or misfolded when exposed to stimuli, including hyperglycemia, oxidative stress, ischemia, disturbance of calcium homeostasis and overexpression of abnormal proteins, which activates ER stress and the unfolded protein response (UPR). To date, investigations have demonstrated that ER stress is important in diabetic myocardial fibrosis by inducing cardiac cell apoptosis. Therefore, in the present study, the polymerase chain reaction, western blotting analysis and tissue staining were performed to identify the changes in UPR signaling proteins and apoptotic proteins in diabetic rats at different time points, and to determine whether the myocardial fibrosis is associated with ER-stress-mediated apoptosis using a diabetes mellitus (DM) rat model. It was found that the upregulation of ER stress markers and apoptotic molecules developed over time. It was also demonstrated that anti­apoptotic markers and proapoptotic markers were activated early following model establishment, and then decreased in months 4 and 5. The changes in myocardial fibrosis were found to accelerate in a time-dependent manner with apoptosis in the DM rats.

Sequential changes in autophagy in diabetic cardiac fibrosis.

Autophagy is considered to be associated with cardiac fibrosis. However, whether autophagy accelerates or ameliorates fibrosis remains to be elucidated. In the present study, 36 rats were divided into two groups: Control rats and diabetic rats. The diabetic rats were established by feeding the animals a high fat diet combined with streptozotocin. From the two groups, six rats were sacrificed after 1, 6 and 7 months. Cardiac systolic functions were measured. The collagen volume fraction was calculated using Masson's trichome staining and the mRNA expression levels of type­I and type­III collagen were measured using reverse transcription­quantitative polymerase chain reaction (RT­qPCR) to assess the levels of cardiac fibrosis. The protein contents of microtubule­associated protein 1 light chain 3 (LC3) and sequestosome 1 (P62) were evaluated using western blotting, and the mRNA expression of Beclin 1 was measured using RT­qPCR, in order to assess autophagy. The results revealed that, in the diabetic rats, cardiac fibrosis developed and cardiac systolic function was reduced. In the hearts of the diabetic rats, the mRNA expression levels of collagen type I and III, and Beclin1 were upregulated; the ratio of the protein level of LC3­II/LC3­I was increased and the content of P62 was decreased. All the changes were aggravated as time increased. The changes in autophagy were correlated with those of cardiac fibrosis, suggesting that autophagy may have a synergistic role in diabetic cardiac fibrosis.

The effect of the Ras homolog gene family (Rho), member A/Rho associated coiled-coil forming protein kinase pathway in atrial fibrosis of type 2 diabetes in rats.

Diabetes mellitus promotes atrial structural remodeling, thereby producing atrial arrhythmogenicity. Atrial arrhythmia can substantially increase the risk of premature death. The aim of this study was to investigate the role of Ras homolog gene family, member A (RhoA)/Rho associated coiled-coil forming protein kinase (ROCK) in atrial fibrosis in diabetic hearts, and the effects of fasudil hydrochloride hydrate on atrial fibrosis. An eight-week-old male Sprague-Dawley rat model of type 2 diabetes was established using a high-fat diet combined with streptozotocin [30 mg/kg, once, intraperitoneal (i.p.)]. Animals were randomly divided into three groups: Control rats, untreated diabetic rats that received vehicle, and treated diabetic rats that received Rho kinase inhibitor fasudil hydrochloride hydrate (10 mg/kg/day, i.p., for 14 weeks). The morphological features of atrial fibrosis were observed using Masson staining. The mRNA expression levels of RhoA, ROCK1, ROCK2, type-I and type-III procollagen were assessed with quantitative polymerase chain reaction. The protein levels of RhoA, ROCK1 and ROCK2 were evaluated using western blot analysis. The atria of untreated diabetic rats showed evident atrial fibrosis as compared to the control rats; the mRNA expression levels of RhoA, ROCK1, ROCK2, type-I and type-III procollagen were upregulated; and the protein levels of RhoA, ROCK1 and ROCK2 were increased. The treatment with fasudil hydrochloride hydrate significantly reduced atrial fibrosis, mRNA levels of RhoA, ROCK1, ROCK2, type-I and type-III procollagen, and the protein levels of RhoA, ROCK1 and ROCK2. The results suggested that RhoA/ROCK was involved in atrial fibrosis, and that fasudil hydrochloride hydrate ameliorates atrial fibrosis through the RhoA/ROCK pathway in rats with type 2 diabetes.