Role of S100ß in Patients with Unstable Angina Pectoris: Insights from Quantitative Flow Ratio.

BACKGROUND AND OBJECTIVE: Disturbed autonomic nervous system (ANS) may promote inflammatory, immune, and oxidative stress responses, which may increase the risk of acute coronary events. S100ß has been proposed as a biomarker of neuronal injury that would provide an insightful understanding of the crosstalk between the ANS, immune-inflammatory cells, and plaques that drive atherosclerosis. This study investigates the correlation between S100ß, and functional coronary stenosis as determined by quantitative flow ratio (QFR). METHODS: Patients with unstable angina pectoris (UAP) scheduled for coronary angiography and QFR were retrospectively enrolled. Serum S100ß levels were determined by enzyme-linked immunosorbent assay. The Gensini score was used to estimate the extent of atherosclerotic lesions and the cumulative sum of three-vessel QFR (3V-QFR) was calculated to estimate the total atherosclerotic burden. RESULTS: Two hundred thirty-three patients were included in this study. Receiver operator characteristic (ROC) curve indicated that S100ß>33.28 pg/mL predicted functional ischemia in patients with UAP. Multivariate logistic analyses showed that a higher level of S100ß was independently correlated with a functional ischemia-driven target vessel (QFR ≤0.8). This was also closely correlated with the severity of coronary lesions, as measured by the Gensini score (OR = 5.058, 95% CI: 2.912-8.793, p <0.001). According to 3V-QFR, S100ß is inversely associated with total atherosclerosis burden (B = -0.002, p <0.001). CONCLUSIONS: S100ß was elevated in the functional ischemia stages of UAP. It was independently associated with coronary lesion severity as assessed by Gensini score and total atherosclerosis burden as estimated by 3V-QFR in patients with UAP.

Mast cell stabilizer, an anti-allergic drug, reduces ventricular arrhythmia risk via modulation of neuroimmune interaction.

Mast cells (MCs) are important intermediates between the nervous and immune systems. The cardiac autonomic nervous system (CANS) crucially modulates cardiac electrophysiology and arrhythmogenesis, but whether and how MC-CANS neuroimmune interaction influences arrhythmia remain unclear. Our clinical data showed a close relationship between serum levels of MC markers and CANS activity, and then we use mast cell stabilizers (MCSs) to alter this MC-CANS communication. MCSs, which are well-known anti-allergic agents, could reduce the risk of ventricular arrhythmia (VA) after myocardial infarction (MI). RNA-sequencing (RNA-seq) analysis to investigate the underlying mechanism by which MCSs could affect the left stellate ganglion (LSG), a key therapeutic target for modulating CANS, showed that the IL-6 and γ-aminobutyric acid (GABA)-ergic system may be involved in this process. Our findings demonstrated that MCSs reduce VA risk along with revealing the potential underlying antiarrhythmic mechanisms.

Efficacy of a WeChat-Based Multimodal Digital Transformation Management Model in New-Onset Mild to Moderate Hypertension: Randomized Clinical Trial.

BACKGROUND: The advantages of multimodal digitally transformed mobile health management for patients diagnosed with mild to moderate hypertension are not yet established. OBJECTIVE: We aim to evaluate the therapeutic benefits of a novel WeChat-based multimodal digital transforming management model in mobile health blood pressure (BP) management. METHODS: This randomized controlled clinical trial included 175 individuals with new-onset mild to moderate hypertension who were admitted to our center between September and October 2022. The patients were randomly assigned to either the multimodal intervention group (n=88) or the usual care group (n=87). The primary composite outcome was home and office BP differences after 6 months. The major secondary outcomes were 6-month quality-of-life scores, including the self-rating anxiety scale, self-rating depression scale, and Pittsburgh Sleep Quality Index. RESULTS: The mean home BP decreased from 151.74 (SD 8.02)/94.22 (SD 9.32) to 126.19 (SD 8.45)/82.28 (SD 9.26) mm Hg in the multimodal intervention group and from 150.78 (SD 7.87)/91.53 (SD 9.78) to 133.48 (SD 10.86)/84.45 (SD 9.19) mm Hg in the usual care group, with a mean difference in systolic blood pressure and diastolic blood pressure of -8.25 mm Hg (95% CI -11.71 to -4.78 mm Hg; P<.001) and -4.85 mm Hg (95% CI -8.41 to -1.30 mm Hg; P=.008), respectively. The mean office BP decreased from 153.64 (SD 8.39)/93.56 (SD 8.45) to 127.81 (SD 8.04)/ 82.16 (SD 8.06) mm Hg in the multimodal intervention group and from 151.48 (SD 7.14)/(91.31 (SD 9.61) to 134.92 (SD 10.11)/85.09 (SD 8.26) mm Hg in the usual care group, with a mean difference in systolic blood pressure and diastolic blood pressure of -9.27 mm Hg (95% CI -12.62 to -5.91 mm Hg; P<.001) and -5.18 mm Hg (95% CI -8.47 to -1.89 mm Hg; P=.002), respectively. From baseline to 6 months, home BP control <140/90 mm Hg was achieved in 64 (72.7%) patients in the multimodal intervention group and 46 (52.9%) patients in the usual care group (P=.007). Meanwhile, home BP control <130/80 mm Hg was achieved in 32 (36.4%) patients in the multimodal intervention group and 16 (18.4%) patients in the usual care group (P=.008). After 6 months, there were significant differences in the quality-of-life total and graded scores, including self-rating anxiety scale scores (P=.04), self-rating depression scale scores (P=.03), and Pittsburgh Sleep Quality Index scores (P<.001), in the multimodal intervention group compared with the usual care group. CONCLUSIONS: The WeChat-based multimodal intervention model improved the BP control rates and lowered the BP levels more than the usual care approach. The multimodal digital transforming management model for hypertension represents an emerging medical practice that utilizes the individual's various risk factor profiles for primary care and personalized therapy decision-making in patients with hypertension. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2200063550; https://www.chictr.org.cn/showproj.html?proj=175816.

Effects of pulsed field ablation on autonomic nervous system in paroxysmal atrial fibrillation: A pilot study.

BACKGROUND: Vagal responses and phrenic activation are commonly observed during pulsed field ablation (PFA). However, whether the vagal responses and phrenic activations are nerve damage or a neurological stress response due to electrical stimulation is unclear. OBJECTIVE: The purpose of this study was to evaluate the effect of a PFA system for performing pulmonary vein isolation on the autonomic nervous system. METHODS: Patients with paroxysmal atrial fibrillation (AF) who underwent PFA between August 2021 and November 2021 were included. Nerve injury biomarkers and heart rate variability were obtained preablation and postablation. Patients were scheduled to undergo magnetic resonance imaging and diffusion-weighted imaging to evaluate cerebral microembolus formation postablation. RESULTS: Acute electrical isolation was achieved in 100% of pulmonary veins (n = 72) in the 18 patients. Mean total procedural time was 64.1 ± 18.2 minutes, and mean fluoroscopy time was 12.3 ± 3.5 minutes. Serum nerve injury biomarkers did not show any changes preablation and immediately postablation and 24 hours after ablation (all P >.05). Preablation and 30-day postablation heart rate variability did not differ (all P >.05). Postablation diffusion-weighted imaging revealed no acute cerebral microembolus events. Moreover, there were no other procedure-related complications. The 8-month Kaplan-Meier estimate of freedom from arrhythmia was 83% ± 9%. CONCLUSION: PFA does not induce nerve injury during pulmonary vein isolation for paroxysmal AF.

Prediction of major adverse cardiovascular events in patients with acute coronary syndrome: Development and validation of a non-invasive nomogram model based on autonomic nervous system assessment.

Background: Disruption of the autonomic nervous system (ANS) can lead to acute coronary syndrome (ACS). We developed a nomogram model using heart rate variability (HRV) and other data to predict major adverse cardiovascular events (MACEs) following emergency coronary angiography in patients with ACS. Methods: ACS patients admitted from January 2018 to June 2020 were examined. Holter monitors were used to collect HRV data for 24 h. Coronary angiograms, clinical data, and MACEs were recorded. A nomogram was developed using the results of Cox regression analysis. Results: There were 439 patients in a development cohort and 241 in a validation cohort, and the mean follow-up time was 22.80 months. The nomogram considered low-frequency/high-frequency ratio, age, diabetes, previous myocardial infarction, and current smoking. The area-under-the-curve (AUC) values for 1-year MACE-free survival were 0.790 (95% CI: 0.702-0.877) in the development cohort and 0.894 (95% CI: 0.820-0.967) in the external validation cohort. The AUCs for 2-year MACE-free survival were 0.802 (95% CI: 0.739-0.866) in the development cohort and 0.798 (95% CI: 0.693-0.902) in the external validation cohort. Development and validation were adequately calibrated and their predictions correlated with the observed outcome. Decision curve analysis (DCA) showed the model had good discriminative ability in predicting MACEs. Conclusion: Our validated nomogram was based on non-invasive ANS assessment and traditional risk factors, and indicated reliable prediction of MACEs in patients with ACS. This approach has potential for use as a method for non-invasive monitoring of health that enables provision of individualized treatment strategies.

Metabolism regulator adiponectin prevents cardiac remodeling and ventricular arrhythmias via sympathetic modulation in a myocardial infarction model.

The stellate ganglia play an important role in cardiac remodeling after myocardial infarction (MI). This study aimed to investigate whether adiponectin (APN), an adipokine mainly secreted by adipose tissue, could modulate the left stellate ganglion (LSG) and exert cardioprotective effects through the sympathetic nervous system (SNS) in a canine model of MI. APN microinjection and APN overexpression with recombinant adeno-associated virus vector in the LSG were performed in acute and chronic MI models, respectively. The results showed that acute APN microinjection decreased LSG function and neural activity, and suppressed ischemia-induced ventricular arrhythmia. Chronic MI led to a decrease in the effective refractory period and action potential duration at 90% and deterioration in echocardiography performance, all of which was blunted by APN overexpression. Moreover, APN gene transfer resulted in favorable heart rate variability alteration, and decreased cardiac SNS activity, serum noradrenaline and neuropeptide Y, which were augmented after MI. APN overexpression also decreased the expression of nerve growth factor and growth associated protein 43 in the LSG and peri-infarct myocardium, respectively. Furthermore, RNA sequencing of LSG indicated that 4-week MI up-regulated the mRNA levels of macrophage/microglia activation marker Iba1, chemokine ligands (CXCL10, CCL20), chemokine receptor CCR5 and pro-inflammatory cytokine IL6, and downregulated IL1RN and IL10 mRNA, which were reversed by APN overexpression. Our results reveal that APN inhibits cardiac sympathetic remodeling and mitigates cardiac remodeling after MI. APN-mediated gene therapy may provide a potential therapeutic strategy for the treatment of MI.

Enrichment of the Postdischarge GRACE Score With Deceleration Capacity Enhances the Prediction Accuracy of the Long-Term Prognosis After Acute Coronary Syndrome.

Background: Cardiac autonomic nerve imbalance has been well documented to provide a critical foundation for the development of acute coronary syndrome (ACS) but is not included in the postdischarge GRACE score. We investigated whether capturing cardiac autonomic nervous system (ANS)-related modulations by 24-h deceleration capacity (DC) could improve the capability of existing prognostic models, including the postdischarge Global Registry of Acute Coronary Events (GRACE) score, to predict prognosis after ACS. Method: Patients with ACS were assessed with 24-h Holter monitoring in our department from June 2017 through June 2019. The GRACE score was calculated for postdischarge 6-month mortality. The patients were followed longitudinally for the incidence of major adverse cardiac events (MACEs), set as a composite of non-fatal myocardial infarction and death. To evaluate the improvement in its discriminative and reclassification capabilities, the GRACE score with DC model was compared with a model using the GRACE score only, using area under the receiver-operator characteristic curve (AUC), Akaike's information criteria, the likelihood ratio test, category-free integrated discrimination index (IDI) and continuous net reclassification improvement (NRI). Results: Overall, 323 patients were enrolled consecutively. After the follow-up period (mean, 43.78 months), 41 patients were found to have developed MACEs, which were more frequent among patients with DC <2.5 ms. DC adjusted for the GRACE score independently predicted the occurrence of MACEs with an adjusted hazard ratio (HR) of 0.885 and 95% CI of 0.831-0.943 (p < 0.001). Moreover, adding DC to the GRACE score only model increased the discriminatory ability for MACEs, as indicated by the likelihood ratio test (χ2 = 9.277, 1 df; p < 0.001). The model including the GRACE score combined with DC yielded a lower corrected Akaike's information criterion compared to that with the GRACE score alone. Incorporation of the DC into the existing model that uses the GRACE score enriched the net reclassification indices (NRIe>0 7.3%, NRIne>0 12.8%, NRI>0 0.200; p = 0.003). Entering the DC into the GRACE score model enhanced discrimination (IDI of 1.04%, p < 0.001). Conclusion: DC serves as an independent and effective predictor of long-term adverse outcomes after ACS. Integration of DC and the postdischarge GRACE score significantly enhanced the discriminatory capability and precision in the prediction of poor long-term follow-up prognosis.

Novel Insight Into Long-Term Risk of Major Adverse Cardiovascular and Cerebrovascular Events Following Lower Extremity Arteriosclerosis Obliterans.

Background: Patients with lower extremity arteriosclerosis obliterans (LEASO) are more likely to appear to be associated with adverse cardiovascular outcomes. Currently, few studies have reported the sex-specific characteristics and risk of major cardiovascular and cerebrovascular adverse events (MACCEs) in LEASO. Our study was conducted to determine the characteristics and contributions of LEASO to MACCEs in males and females. Methods: We conducted a single-center retrospective study of consecutively enrolled patients with first-diagnosed LEASO at Renmin Hospital of Wuhan University from November 2017 to November 2019. The ratio of patients between the LEASO and control groups was 1 to 1 and based on age, sex, comorbid diabetes mellitus and hypertension, current smoking and medications. The occurrence of MACCEs was used as the primary endpoint of this observational study. Results: A LEASO group (n = 430) and control group (n = 430) were enrolled in this study. A total of 183 patients experienced MACCEs during an average of 38.83 ± 14.28 months of follow-up. Multivariate Cox regression analysis indicated that LEASO was an independent predictor of the occurrence of MACCEs in all patients (HR: 2.448, 95% CI: 1.730-3.464, P < 0.001). Subgroup analysis by sex subgroup was conducted for sex, and LEASO was also an independent predictor of the occurrence of MACCEs in both male cases (HR: 2.919, 95% CI: 1.776-4.797, P < 0.001) and female cases (HR: 1.788, 95% CI: 1.110-2.880, P = 0.017). Moreover, Kaplan-Meier analysis indicated no significant difference in event-free survival between patients of different sexes with LEASO (χ2 = 0.742, P = 0.389). Conclusion: LEASO tended to a useful risk stratified indicator for MACCEs in both male and female patients in our study. Notably, attention should be given to patients with LEASO who should undergo comprehensive cardiovascular evaluation and intervention, even if there is a lack of traditional cardiovascular risk factors.

Deceleration Capacity Improves Prognostic Accuracy of Relative Increase and Final Coronary Physiology in Patients With Non-ST-Elevation Acute Coronary Syndrome.

Background: Both coronary physiology and deceleration capacity (DC) showed prognostic efficacy for patients with acute coronary syndrome (ACS). This retrospective cohort study was performed to evaluate the prognostic implication of DC combined with the relative increase and final coronary physiology as detected by quantitative flow ratio (QFR) for patients with non-ST-elevation ACS (NSTE-ACS) who underwent complete and successful percutaneous coronary intervention (PCI). Methods: Patients with NSTE-ACS who underwent PCI with pre- and post-procedural QFR in our department between January 2018 and November 2019 were included. The 24-hour deceleration capacity (DC 24h) was obtained via Holter monitoring. The incidence of major adverse cardiac and cerebrovascular events (MACCEs) during follow up was defined as the primary outcome. The optimal cutoffs of the relative increase, final QFR, and DC 24h for prediction of MACCEs were determined via receiver operating characteristic (ROC) analysis and the predictive efficacies were evaluated with multivariate Cox regression analysis. Results: Overall, 240 patients were included. During a mean follow up of 21.3 months, 31 patients had MACCEs. Results of multivariate Cox regression analyses showed that a higher post-PCI QFR [adjusted hazard ratio (HR): 0.318; 95% confidence interval (CI): 0.129-0.780], a higher relative QFR increase (HR: 0.161; 95% CI: 0.066-0.391], and a higher DC (HR: 0.306; 95% CI: 0.134-0.701) were all independent predictors of lower risk of MACCEs. Subsequently, incorporating low DC (≤2.42) into the risk predicting model with clinical variables, the predictive efficacies of low relative QRS increase (≤23%) and low post-PCI QFR (≤0.88) for MACCEs were both significantly improved. Conclusions: The DC combined with relative increase and final coronary physiology may improve the predictive efficacy of existing models based on clinical variables for MACCEs in NSTE-ACS patients who underwent complete and successful PCI.

Novel Insights Into the Interaction Between the Autonomic Nervous System and Inflammation on Coronary Physiology: A Quantitative Flow Ratio Study.

Background: Heart rate variability (HRV) was proposed as a noninvasive biomarker to stratify the risk of cardiovascular disease. However, it remains to be determined if HRV can be used as a surrogate for coronary artery physiology as analyzed by quantitative flow ratio (QFR) in patients with new-onset unstable angina pectoris (UAP). Methods: A total of 129 consecutive patients with new-onset UAP who underwent 24-h long-range 12-channel electrocardiography from June 2020 to December 2020 were included in this study. HRV, coronary angiography, and QFR information was retrieved from patient medical records, the severity of coronary lesions was evaluated using the Gensini score (GS), and total atherosclerotic burden was assessed using the three-vessel contrast QFR (3V-cQFR) calculated as the sum of cQFR in three vessels. Results: Multivariate logistic analysis showed that low-frequency power (LF) and high-sensitivity C-reactive protein (hs-CRP) were directly correlated with functional ischemia of target vessel, which were inversely correlated with total atherosclerotic burden as assessed by 3V-cQFR. Moreover, incorporation of the increase in LF into the existing model that uses clinical risk factors, GS, and hs-CRP significantly increased the discriminatory ability for evaluating coronary artery physiology of target vessel. Conclusions: LF and hs-CRP are independently associated with functional ischemia in patients with new-onset UAP. The relative increase of LF and hs-CRP could add value to the use of classical cardiovascular risk factors to predict the functional severity of coronary artery stenosis. Our results suggest a potential association between the autonomic nervous system, inflammation, and coronary artery physiology.

Impact of dissolved oxygen and loading rate on NH3 oxidation and N2 production mechanisms in activated sludge treatment of sewage.

Microaerobic activated sludge (MAS) is a one-stage process operated at 0.5-1.0 mg l-1 dissolved oxygen (DO) aiming at simultaneous nitrification and denitrification. We used molecular techniques and a comprehensive nitrogen (N)-transformation activity test to investigate the dominant NH3 -oxidizing and N2 -producing mechanism as well as the dominant ammonia-oxidizing bacteria (AOB) species in sludge samples individually collected from an MAS system and a conventional anoxic/oxic (A/O) system; both systems were operated at a normal loading rate (i.e. 1.0 kg chemical oxygen demand (COD) m-3  day-1 and 0.1 kg NH4 + -N m-3  day-1 ) in our previous studies. The DO levels in both systems (aerobic: conventional A/O system; microaerobic: MAS system) did not affect the dominant NH3 -oxidizing mechanism or the dominant AOB species. This study further demonstrated the feasibility of a higher loading rate (i.e. 2.30 kg COD m-3  day-1 and 0.34 kg NH4 + -N m-3  day-1 ) with the MAS process during sewage treatment, which achieved a 40% reduction in aeration energy consumption than that obtained in the conventional A/O system. The increase in loading rates in the MAS system did not affect the dominant NH3 -oxidizing mechanism but did impact the dominant AOB species. Besides, N2 was predominantly produced by microaerobic denitrification in the MAS system at the two loading rates.

Achieving low-cost, highly selective nitrate removal with standard anion exchange resin by tuning recycled brine composition.

This study demonstrated the presence of a critical equivalent ratio of the competing anion (i.e., sulfate and bicarbonate) to chloride ion in recycled brine to achieve highly-selective nitrate removal from nitrate-rich groundwater in the standard-anion exchange resin (AER) (i.e., with trimethylamine functional groups) column process. With increasing bicarbonate (or sulfate):chloride equivalent ratio in brine used to circularly activate/regenerate the standard-AER column, considerable bicarbonate (sulfate) removal and dumping were observed. The critical bicarbonate (sulfate):chloride equivalent ratio of 2:5 (8:1) in brine effectively achieved zero net bicarbonate (sulfate) removal (<5%) from feedwater during long-term exhaustion-regeneration cyclic operation. The feed rate (6-18 BV/h) played a key role in determining the critical sulfate:chloride equivalent ratio in brine, while the feed sulfate concentration (145-345 mg/L) slightly changed the critical sulfate:chloride equivalent ratio. The use of optimized ternary brine (with a sulfate:chloride:bicarbonate equivalent ratio of 42:5:2) stably achieved long-term highly-selective nitrate removal from groundwater in the standard-AER column process with brine electrochemical treatment. The possible mechanism for nitrate selectivity included the modification of the sulfate: and bicarbonate:chloride equivalent ratios in the standard-AER column by the optimized brine in circular activation/regeneration mode; this changed the column elution and breakthrough curves, inhibited the competition of sulfate and bicarbonate for ion exchange sites during exhaustion according to the separation factor, and finally achieved selective nitrate removal from feedwater.

Autotrophic and heterotrophic nitrification-anoxic denitrification dominated the anoxic/oxic sewage treatment process during optimization for higher loading rate and energy savings.

This study clarified the dominant nitrogen (N)-transformation pathway and the key ammonia-oxidizing microbial species at three loading levels during optimization of the anoxic/oxic (A/O) process for sewage treatment. Comprehensive N-transformation activity analysis showed that ammonia oxidization was performed predominantly by aerobic chemolithotrophic and heterotrophic ammonia oxidization, whereas N2 production was performed primarily by anoxic denitrification in the anoxic unit. The abundances of ammonia-oxidizing bacteria (AOB), nitrite-oxidizing bacteria, and anaerobic AOB in activated sludge reflected their activities on the basis of high-throughput sequencing data. AOB amoA gene clone libraries revealed that the predominant AOB species in sludge samples shifted from Nitrosomonas europaea (61% at the normal loading level) to Nitrosomonas oligotropha (58% and 81% at the two higher loading levels). Following isolation and sequencing, the predominant culturable heterotrophic AOB in sludge shifted from Agrobacterium tumefaciens (42% at the normal loading level) to Acinetobacter johnsonii (52% at the highest loading level).