Characteristics, predictors and outcomes of new-onset QT prolongation in sepsis: a multicenter retrospective study.

BACKGROUND: Sepsis-induced myocardial injury is a serious complication of sepsis. QT prolongation is a proarrhythmic state which reflects myocardial injury in a group of heterogeneous disorders. However, the study on the clinical value of QT prolongation in sepsis is limited. METHODS: We aimed to investigate the clinical characteristics and predictors of new-onset QT prolongation in sepsis and its impact on the outcome in a multicenter retrospective cohort study. Electrocardiographic and clinical data were collected from patients with sepsis from the wards and intensive care units of four centers after exclusion of QT-influencing medications and electrolyte abnormalities. Clinical outcomes were compared between patients with and without QT prolongation (QTc > 450 ms). Multivariate analysis was performed to ascertain whether QT prolongation was an independent predictor for 30-day mortality. The factors predicting QT prolongation in sepsis were also analyzed. RESULTS: New-onset QT prolongation occurred in 235/1024 (22.9%) patients. The majority demonstrated similar pattern as type 1 long QT syndrome. Patients with QT prolongation had a higher 30-day in-hospital mortality (P < 0.001), which was also associated with increased tachyarrhythmias including paroxysmal atrial fibrillation or tachycardia (P < 0.001) and ventricular arrhythmia (P < 0.001) during hospitalization. QT prolongation independently predicted 30-day mortality (P = 0.044) after multivariate analysis. History of coronary artery disease (P = 0.001), septic shock (P = 0.008), acute respiratory (P < 0.001), heart (P = 0.021) and renal dysfunction (P = 0.013) were independent predictors of QT prolongation in sepsis. CONCLUSIONS: New-onset QT prolongation in sepsis was associated with increased mortality as well as atrial and ventricular arrhythmias, which was predicted by disease severity and organ dysfunction.

Acute epicardial pulmonary vein reconnection: Nondurable transmural lesion or late manifestation of conduction through intercaval bundle.

INTRODUCTION: Acute pulmonary vein reconnection (PVR) via epicardial fibers can be found during observation period after PV isolation, the characteristics and related factors have not been fully studied. We aimed to investigate the prevalence, locations, electrogram characteristics, and ablation parameters related to acute epicardial pulmonary vein reconnection (AEPVR). METHODS: Acute PVR was monitored during observation period after PV isolation. AEPVRs were mapped and distinguished from endocardial conduction gaps. The clinical, electrophysiological characteristics and lesion set parameters were compared between patients with and without PVR. They were also compared among AEPVR, gap-related reconnection, and epicardial PVR in repeat procedures. RESULTS: A total of 56.1% acute PVR were AEPVR, which required a longer waiting period (p < .001) than endocardial gap. The majority of AEPVR were connections from the posterior PV carina to the left atrial posterior wall, followed by late manifestation of intercaval bundle conduction from the right anterior carina to right atrium. AEPVR was similar to epicardial PVR in redo procedures in distribution and electrogram characteristics. Smaller atrium (p < .001), lower impedance drop (p = .039), and ablation index (p = .028) on the posterior wall were independently associated with presence of AEPVR, while lower interlesion distance (p = .043) was the only predictor for AEPVR in acute PVR. An integrated model containing multiple lesion set parameters had the highest predictive ability for AEPVR in receiver operating characteristics analysis. CONCLUSIONS: Epicardial reconduction accounted for the majority of acute PVR. AEPVR was associated with anatomic characteristics and multiple ablation-related parameters, which could be explained by nondurable transmural lesion or late manifestation of conduction through intercaval bundle.

AMPAkines have site-specific analgesic effects in the cortex.

Different brain areas have distinct roles in the processing and regulation of pain and thus may form specific pharmacological targets. Prior research has shown that AMPAkines, a class of drugs that increase glutamate signaling, can enhance descending inhibition from the prefrontal cortex (PFC) and nucleus accumbens. On the other hand, activation of neurons in the anterior cingulate cortex (ACC) is known to produce the aversive component of pain. The impact of AMPAkines on ACC, however, is not known. We found that direct delivery of CX516, a well-known AMPAkine, into the ACC had no effect on the aversive response to pain in rats. Furthermore, AMPAkines did not modulate the nociceptive response of ACC neurons. In contrast, AMPAkine delivery into the prelimbic region of the prefrontal cortex (PL) reduced pain aversion. These results indicate that the analgesic effects of AMPAkines in the cortex are likely mediated by the PFC but not the ACC.

Anterior cingulate cortex regulates pain catastrophizing-like behaviors in rats.

Negative pain expectation including pain catastrophizing is a well-known clinical phenomenon whereby patients amplify the aversive value of a painful or oftentimes even a similar, non-painful stimulus. Mechanisms of pain catastrophizing, however, remain elusive. Here, we modeled pain catastrophizing behavior in rats, and found that rats subjected to repeated noxious pin pricks on one paw demonstrated an aversive response to similar but non-noxious mechanical stimuli delivered to the contralateral paw. Optogenetic inhibition of pyramidal neuron activity in the anterior cingulate cortex (ACC) during the application of repetitive noxious pin pricks eliminated this catastrophizing behavior. Time-lapse calcium (Ca2+) imaging in the ACC further revealed an increase in spontaneous neural activity after the delivery of noxious stimuli. Together these results suggest that the experience of repeated noxious stimuli may drive hyperactivity in the ACC, causing increased avoidance of subthreshold stimuli, and that reducing this hyperactivity may play a role in treating pain catastrophizing.

Efferocytosis-inspired nanodrug treats sepsis by alleviating inflammation and secondary immunosuppression.

Uncontrolled inflammation storm induced by sepsis may lead to severe organ dysfunction and secondary immunosuppression, which is one of the main reasons for high mortality and prolonged hospitalization of septic patients. However, there is a lack of effective treatments for it at present. Here, we report an efferocytosis-inspired nanodrug (BCN@M) to treat sepsis and secondary immunosuppression via regulating the macrophage function. Bioactive molecular curcumin was loaded with bovine serum albumin and then coated with the damaged erythrocyte membrane derived from septic mice. It was found that the septic erythrocytes promoted the efferocytosis signal and BCN@M uptake efficiency by macrophages. The well-constructed BCN@M nanodrug reduced the hyperinflammation in sepsis and restored the bacterial clearance ability of macrophage in the secondary immunosuppression state. This study highlights BCN@M as an efferocytosis-inspired nanodrug to alleviate hyperinflammation and secondary immunosuppression of sepsis.

Multiple targets related to mitochondrial function unveiled by metabolomics and proteomics profiles of hearts from atrial fibrillation patients.

Background: The prominent mitochondrial metabolic changes of the atrium reportedly have significant impact on electrical signals and structural remodeling which play important roles in the occurrence and development of atrial fibrillation (AF). However, the mechanism is not completely known. Objective: This study was aimed to explore the mitochondrial metabolism reprogrammed in AF patients by integrating metabolomics as well as proteomics of human atrium tissues. Methods and Results: Left atrial tissue samples were harvested from 10 non-valvular AF patients and 10 matched samples from healthy donors for transplantation. In metabolomics analysis, 113 metabolites were upregulated and 10 metabolites were downregulated in AF, where multiple pathways related to mitochondrial energy metabolism were enriched. Correlation analysis between the differentially expressed proteins and metabolites identified several hub proteins related to mitochondrial function including Glycerol-3-phosphate dehydrogenase 2 (GPD2), Synemin (SYNM), Plectin (PLEC), with MCC score of 27, 17, 16, respectively, which have the most interactions with the dysregulated metabolites and ranked at the top in network string interactions scored by MCC method. All 330 differentially expressed proteins including 225 upregulated and 105 downregulated molecules were revealed and analyzed, which identified the downregulation of GPD2 (p = 0.02 and FC = 0.77), PLEC (p < 0.001 and FC = 0.71) and SYNM (p = 0.04 and FC = 0.76) in AF patients. Gene Set Variation Analysis (GSEA) showed mitochondrial metabolism-associated pathways including oxidative phosphorylation (NES: -1.73) and ATP biosynthetic process (NES: -2.29), were dramatically diversified in human AF. In GSVA, the expression levels of GPD2, PLEC, and SYNM were demonstrated to be associated with multiple metabolic pathways related to mitochondrial function (e.g., lipid metabolism and AMP activated protein kinase signaling) and cardiac structural and electrical remodeling (e.g., contractile fiber, ion homeostasis), which were proven vital in the development and maintenance of AF. Conclusion: In all, this study provides new insights into understanding the mechanisms of AF progression, especially the reprogramming mitochondrial metabolism, and identifies several genes related to mitochondrial function as novel targets for AF, which may be involved in the occurrence and development of AF.

Subclinical cardiac involvement present as electrocardiographic abnormalities in various neuromuscular diseases.

Background: Cardiac involvement is commonly present in various neuromuscular diseases which may develop life-threatening consequences. The early manifestation is often asymptomatic which however has been insufficiently studied. Objectives: We aim to characterize electrocardiographic (ECG) changes in neuromuscular diseases without cardiac symptoms. Methods: Adults having genetically and/or pathologically confirmed type 1 myotonic dystrophy (DM1), Becker muscular dystrophy (BMD), limb girdle muscular dystrophies (LGMDs) and mitochondrial diseases (MtDs) but without history of heart diseases and cardiovascular symptoms were enrolled. The 12-lead ECG characteristics and other test results at diagnosis were retrieved and analyzed. Results: 196 patients with neuromuscular diseases (44 DM1, 25 BMD, 82 LGMDs, 45 MtDs) were consecutively enrolled. ECG abnormalities were identified in 107 (54.6%) patients with a prevalence of 59.1% in DM1, 76.0% in BMD, 40.2% in LGMDs and 64.4% in MtDs. Conduction block was more commonly present in DM1 than the other groups (P < 0.01), which had a longest PR interval and QRS duration of 186.1 ± 38.3 ms and 104.2 [90.0-108.0]ms, respectively. QT prolongation was most frequently seen in DM1 (P < 0.001). Left ventricular hypertrophy features were found in BMD, LGMDs and MtDs (P < 0.05) without intergroup difference, while a significantly higher right ventricular amplitude is observed in BMD than in other groups (P < 0.001). Conclusions: Subclinical cardiac involvement is commonly present as ECG abnormalities in multiple adult neuromuscular diseases before associated symptoms occur and show diversity in different groups.

Temporal pain processing in the primary somatosensory cortex and anterior cingulate cortex.

Pain is known to have sensory and affective components. The sensory pain component is encoded by neurons in the primary somatosensory cortex (S1), whereas the emotional or affective pain experience is in large part processed by neural activities in the anterior cingulate cortex (ACC). The timing of how a mechanical or thermal noxious stimulus triggers activation of peripheral pain fibers is well-known. However, the temporal processing of nociceptive inputs in the cortex remains little studied. Here, we took two approaches to examine how nociceptive inputs are processed by the S1 and ACC. We simultaneously recorded local field potentials in both regions, during the application of a brain-computer interface (BCI). First, we compared event related potentials in the S1 and ACC. Next, we used an algorithmic pain decoder enabled by machine-learning to detect the onset of pain which was used during the implementation of the BCI to automatically treat pain. We found that whereas mechanical pain triggered neural activity changes first in the S1, the S1 and ACC processed thermal pain with a reasonably similar time course. These results indicate that the temporal processing of nociceptive information in different regions of the cortex is likely important for the overall pain experience.

High-performance TM-pass polarizer based on anti-symmetric Bragg gratings.

We present an all-silicon transverse-magnetic-pass (TM-pass) polarizer based on anti-symmetric Bragg gratings. We obtain wide operation bandwidth and high polarization extinction ratio (PER) by maximizing the coupling between the forward TE0 mode and the backward TE1 mode through the reduction of the bridge element width. In the meantime, low insertion loss (IL) is acquired with long tapered structures and the exclusion of the center grating part. Experimental results indicate IL below 0.74 dB and PER over 40 dB covering the wavelength ranges of 1275-1360 nm and 1500-1523 nm, while the average IL within these ranges is as low as 0.27 dB. Additionally, simulation results suggest that the performance can be further improved by introducing chirp in the period of Bragg gratings, thus achieving IL < 0.11 dB and PER > 60 dB over a wide range of 280 nm (1290-1570 nm).

Thrombus-specific/responsive biomimetic nanomedicine for spatiotemporal thrombolysis and alleviation of myocardial ischemia/reperfusion injury.

Acute myocardial infarction (AMI) is usually caused by coronary thrombosis. However, the short half-life, lack of targetability and inevitable ischemia/reperfusion injury secondary to revascularization, which characterizes tissue plasminogen activator (tPA) limit its thrombolytic efficacy for AMI. To address the targeted and site-specific delivery of tPA, the current study reports the construction of a thrombus-targeting and responsive biomimetic nanoparticle (PTPN) for spatiotemporal treatment of AMI. PTPN was constituted by the thrombus microenvironment- responsive phenylboronic acid (PBA) nanocarrier, antioxidant molecular protocatechualdehyde (PC) and tPA with thrombolytic effect, which were enclosed by the platelet membrane. The thrombus-targeting capability of the platelet membrane enabled the adhesion of PTPN to damaged endothelial cells. The nanoparticle disintegrated under slightly acid condition and re-opened the infarct-related artery during the period of ischemia. Sequentially, ROS induced by blood reperfusion was eliminated by PC released from particle disintegration, and the cardiomyocyte mitochondrial function was protected from reperfusion injury. Therefore, this thrombus-specific/responsive biomimetic nanomedicine provides a spatiotemporal paradigm for AMI treatment with promising clinical translation prospects.

Lipocalin-2 participates in sepsis-induced myocardial injury by mediating lipid accumulation and mitochondrial dysfunction.

Background: Sepsis-induced cardiomyopathy (SIC) is one major cause of death for sepsis but lacks timely diagnosis and specific treatment due to unclear mechanisms. Lipocalin-2 (LCN-2) is a key regulator of lipid metabolism which has been recently proved closely related to sepsis, however, the relationship between LCN-2 and septic myocardial injury remains unknown. We aim to explore the role of LCN-2 in the pathological progress of SIC based on clinical and laboratory evidence. Methods: Consecutive patients admitted to the intensive care unit (ICU) from August 2021 to April 2022 fulfilling the criteria of severe sepsis were included. The level of LCN-2 in plasma was assayed and analyzed with clinical characteristics. Biostatistical analysis was performed for further identification and pathway enrichment. Mouse model for SIC was thereafter established, in which plasma and tissue LCN-2 levels were tested. RNA sequencing was used for verification and to reveal the possible mechanism. Mitochondrial function and intracellular lipid levels were assayed to further assess the biological effects of targeting LCN-2 in cardiomyocytes with small interference RNAs (siRNAs). Results: The level of LCN-2 in plasma was markedly higher in patients with severe sepsis and was associated with higher cardiac biomarkers and lower LVEF. In the in vivo experiment, circulating LCN-2 from plasma was found to increase in SIC mice. A higher level of LCN-2 transcription in myocardial tissue was also found in SIC and showed a clear time relationship. RNA sequencing analysis showed the level of LCN-2 was associated with several gene-sets relevant to mitochondrial function and lipid metabolism-associated pathways. The suppression of LCN-2 protected mitochondrial morphology and limited the production of ROS, as well as restored the mitochondrial membrane potential damaged by LPS. Neutral lipid staining showed prominent lipid accumulation in LPS group, which was alleviated by the treatment of siLCN2. Conclusion: The level of LCN-2 is significantly increased in SIC at both circulating and tissue levels, which is correlated with the severity of myocardial injury indicators, and may work as an early and great predictor of SIC. LCN-2 probably participates in the process of septic myocardial injury through mediating lipid accumulation and affecting mitochondrial function.

Facile preparation of a novel chitosan-derived porous graphitized carbon biomaterial for highly efficient capture of N-glycans.

The comprehensive characterization of N-glycans is of significant importance for the discovery of potential biomarkers and the diagnosis and therapy of diseases. Herein, we designed and fabricated a porous graphitized carbon biomaterial (CS-900-1C) using cheap and available chitosan as the carbon source via a facile pyrolysis process and a post-oxidation strategy for the effective capture of N-glycans. Thanks to its large surface area (2846 m2 g-1), high graphitization degree, suitable oxidation degree and unique porous structure, the CS-900-1C biomaterial exhibits an ultralow detection limit (1 ng µL-1), an excellent size-exclusion effect (OVA digest : BSA protein : OVA protein, 1 : 1000 : 1000, w/w/w) and satisfactory reusability (at least 8 cycles) in the capture of standard N-glycans. Moreover, CS-900-1C has successfully been applied in profiling the difference of N-glycans during diabetes progression (obesity, impaired glucose tolerance, diabetes patients and healthy control) where we discovered that the expression levels of five N-glycans show a gradually increasing trend as diabetes progresses. Remarkably, the five specific N-glycans could be considered as biomarkers to accurately diagnose the progression of diabetes. Our work not only developed a novel porous graphitized carbon biomaterial for the large-scale characterization of N-glycans but also provided new guidance for the precise therapy of diabetes.

Anatomy-based characteristics of far-field SVC electrograms in right superior pulmonary veins after isolation.

Background. Far-field electrograms from superior vena cava (SVC) can be present in right superior pulmonary vein (RSPV) after pulmonary vein (PV) isolation. Objectives. To analyze the characteristics of far-field SVC potentials in RSPV after PV isolation and the local anatomy difference between patients with and without the potentials. Methods. Patients undergoing PV isolation were retrospectively reviewed, contrast-enhanced computed tomography (CT) was performed before procedure for observing the anatomical relationship between RSPV and SVC. The prevalence and characteristics of far-field SVC electrograms were described and compared to far-field left atrial potentials at the nearest point along the linear ablation lesion. The anatomical proximity of RSPV and SVC on a 2-dimensional horizontal CT view was compared between patients with and without far-field SVC potentials. Results. Far-field SVC electrograms were observed in 35/92(38%) patients with an amplitude of 0.24 ± 0.11 mV and a major deflection slope of 0.051 ± 0.036 mV, both significantly higher than far-field left atrial electrograms (p < .001). In patients with far-field SVC electrograms, 83% had connected RSPV-SVC, defined as distance between RSPV and SVC endocardium less than 3 mm at the layer of RSPV ostium roof, while in patients without far-field SVC electrograms, 70% had disconnected RSPV-SVC. Conclusions. Far-field SVC electrograms appeared in RSPV had a prevalence higher than previously reported and a sharper major deflection compared to far-field left atrial electrograms. Connected RSPV-SVC on CT was associated with the presence of far-field SVC electrograms.

Polydopamine stabilizes silver nanoparticles as a SERS substrate for efficient detection of myocardial infarction.

Rapid and accurate detection of myocardial infarction (MI) can boost the patient's chance of survival. Surface enhanced Raman scattering (SERS) is an outstanding diagnostic technique because of its strong light stability, high resolution, and qualitative and quantitative analysis based on the characteristic fingerprint. However, its reliability, stability and specificity remain to be improved, especially in the quantitative analysis of serum samples. In this study, we developed in situ silver nanoparticles (Ag NPs) on the surface of polydopamine (PDA) as a SERS substrate and found that PDA could act as a reducing agent to support the nucleation and growth of Ag NPs and control the distance and aggregation of Ag NPs to stabilize the Raman signal. In a standard phosphate buffered saline (PBS) environment, PDA@Ag could reach a low detection limit of 0.01 ng mL-1 cardiac troponin I (cTn I) with a good linear relationship. At the same time, the PDA@Ag substrate also possessed excellent stability, specificity and biocompatibility for cTn I detection. In addition, we verified the application potentiality of PDA@Ag in real serum samples and found that the performance of SERS was almost the same as that in PBS. This excellent detection performance of PDA@Ag could be attributed to both the enhanced electromagnetic field and the increased Raman cross-section, dominated by the gap distance between Ag NPs, reaction force between the antigen and the antibody and excellent biocompatibility and reducibility of PDA. In conclusion, this work may provide a new perspective for the in situ synthesis and growth of a uniform SERS substrate on the carrier to achieve the stability and specificity of SERS-based biological detection of MI.

Split accessory pathway potentials in a patient with antidromic AVRT.

INTRODUCTION: Accessory pathway potential often indicates a highly effective ablation target in Wolff-Parkinson-White syndrome. METHODS: A 27-year-old female presenting with palpitation underwent an electrophysiology study, who had mild pre-excitation in surface ECG. RESULTS: An accessory pathway with weak anterograde conduction was found. During isoproterenol infusion, the delta wave became prominent, an antidromic AV reentrant tachycardia was then induced. When the pathway was mapped, widely split double pathway potentials were observed at the 12 o'clock site of the tricuspid annulus during mild pre-excitation, demonstrating an example of intra-pathway conduction delay. Ablation at the site caused accelerated pathway rhythm and eliminated the pathway, rendering the tachycardia noninducible. CONCLUSION: Split pathway potentials can reflect slow conduction in patients with preexcitation.

A stricter control of low-density lipoprotein is necessary for thrombosis reduction in "lower thrombosis risk" patients with atrial fibrillation: a multicenter retrospective cohort study.

Patients with atrial fibrillation (AF) are associated with increased thrombotic events. Our previous case-control study showed low-density lipoprotein cholesterol (LDL-C) was an independent predictor of ischemic stroke in AF patients. To investigate the risks of thrombosis in relation to LDL-C among AF patients at different stroke risks by long-time follow-up. Atrial fibrillation patients without history of thrombosis enrolled from five hospitals were classified into low-risk (LR) and high-risk (HR) group according to CHA2DS2VASc score and followed up with a median period of 26 months. Univariate and multivariate logistic regression analysis were performed in each group. The best cut-off value calculated by receiver operating characteristic (ROC) analysis was used to divide patients into low LDL-C (L-LDL) and high LDL-C (H-LDL) subgroups. Propensity score matching (PSM) and inverse probability of treatment weighted (IPTW) were utilized in both subgroups, after which Kaplan-Meier curves for thrombosis were performed. Univariate and multivariate analysis showed LDL-C was significantly related to thrombosis in LR, but less significantly in HR group. The best cut-off value was 2.155 mmol/L in LR and 2.795 mmol/L in HR group. Lower LDL-C was associated with decreased thrombosis in both groups by PSM and IPTW. Kaplan-Meier curves displayed that H-LDL subgroup was at higher thrombosis risk with significant difference at 24th month in LR patients. LDL-C independently predicts thrombosis with different cut-off values in AF patients at different risks. A stricter control of LDL-C level is necessary for thrombosis reduction in patients with lower score.

Fasciculoventricular accessory pathway unmasked by a pseudo gap phenomenon.

A 28 year old female with manifest preexcitation underwent electrophysiology study for intermittent palpitation. During progressively premature atrial extrastimuli, bypass tract was blocked before relative refractory period of AV node, making it unfeasible to observe the change of H-V interval and QRS morphology during decremental nodal conduction. However, dual AV node physiology, presented as a marked increase of A-H interval, occurred when a short-coupled extrastimulus was delivered, followed by a preexcited QRS with an H-V interval identical to that in sinus rhythm. This was an example of gap phenomenon involving accessory pathway and AV node. Diagnosis of fasciculoventricular bypass tract was made and ablation was therefore not performed.