Poincaré plot can help predict the curative effect of metoprolol for pediatric postural orthostatic tachycardia syndrome.

Purpose: To study whether a Poincaré plot can help predict the curative effect of metoprolol for postural orthostatic tachycardia syndrome (POTS) in children. Methods: Pediatric patients with POTS who were administered metoprolol were retrospectively included. The collected data included general data (sex, age, height, weight, and body mass index), the manifestations and treatment (baseline orthostatic intolerance symptom score and course of metoprolol treatment), vital signs (supine heart rate [HR], supine blood pressure, and increased HR during the standing test), HR variability indexes (standard deviation of normal-to-normal intervals [SDNN]; standard deviation of the averages of normal-to-normal intervals [SDANN]; mean standard deviation of the NN intervals for each 5-min segment [SDNNI]; root mean square of the successive differences [rMSSD]; percentage of adjacent NN intervals that differ by >50 ms [pNN50]; triangular index; ultra-low [ULF], very low [VLF], low [LF], and high frequency [HF]; total power [TP]; and LF/HF ratio), and graphical parameters of the Poincaré plot (longitudinal axis [L], transverse axis [T], and L/T). Receiver operator characteristic curves were used to calculate the predictive function of the indexes with significant differences between patients who responded and those who did not. The index combination with the highest predictive value was obtained through series-parallel analysis. Results: Overall, 40 responders and 23 non-responders were included. The L and T in the Poincaré plots and rMSSD, pNN50, HF, and TP of the HR variability data were significantly lower in participants who responded to metoprolol than in participants who did not (p < 0.001). The L/T of participants who responded to metoprolol was greater than that of non-responders (p < 0.001). Moreover, we noted a strong correlation between every two indexes among L, T, rMSSD, pNN50, HF, TP, and L/T (p < 0.05). T < 573.9 ms combined with L/T > 2.9 had the best performance for predicting the effectiveness of metoprolol, with a sensitivity of 85.0%, specificity of 82.6%, and accuracy of 84.1%. Conclusion: In the Poincaré plot, a T < 573.9 ms combined with an L/T > 2.9 helps predict good outcomes of using metoprolol to treat pediatric POTS.

Hypoxia inducible factor-1α is an important regulator of macrophage biology.

Hypoxia-inducible factor-1 (HIF-1), a heterodimeric transcription factor composed of the α and ß subunits, regulates cellular adaptive responses to hypoxia. Macrophages, which are derived from monocytes, function as antigen-presenting cells that activate various immune responses. HIF-1α regulates the immune response, viability, migration, phenotypic plasticity, and metabolism of macrophages. Specifically, macrophage-derived HIF-1α can prevent excessive pro-inflammatory responses by attenuating the transcriptional activity of nuclear factor-kappa B in vivo and in vitro. HIF-1α modulates macrophage migration by inducing the release of various chemokines and providing necessary energy. HIF-1α promotes macrophage M1 polarization by targeting glucose metabolism. Additionally, HIF-1α induces the upregulation of glycolysis-related enzymes and intermediates of the tricarboxylic acid cycle and pentose phosphate pathway. HIF-1α promotes macrophage apoptosis, necroptosis and reduces autophagy. The current review highlights the mechanisms associated with the regulation of HIF-1α stabilization in macrophages as well as the role of HIF-1α in modulating the physiological functions of macrophages.

ITPKC polymorphism (rs7251246 T > C), coronary artery aneurysms, and thrombosis in patients with Kawasaki disease in a Southern Han Chinese population.

Objectives: Kawasaki disease (KD) is a commonly acquired pediatric systemic vasculitis disease resulting in coronary artery aneurysm (CAA). The relationship between the ITPKC polymorphism (rs7251246) and the severity and susceptibility to KD in the Han Chinese population in Southern China remains unclear. Methods: We enrolled 262 children as controls and 221 children with KD (46 [20.8%] with intravenous immunoglobulin resistance and 82 [37.1%] with CAA). The relationship between the ITPKC rs7251246 polymorphism, KD susceptibility, and CAA formation was investigated. Results: While the ITPKC rs7251246 T>C polymorphism was not significantly associated with KD susceptibility, it was significantly related to the CAA risk in children with KD [CC/CT vs. TT: adjusted odds ratio [OR] 2.089, 95% confidence interval [CI] 1.085-4.020]. Male children with the rs7251246 CT/TT genotype had a significantly lower risk of thrombosis [CT/TT vs. CC: adjusted OR 0.251, 95% CI 0.068-0.923]. Children with KD, especially those with CAA, had significantly downregulated ITPKC mRNA compared to healthy children. ITPKC mRNA levels were lower in children with CAA who developed thrombosis (P=0.039). In children with KD, the CC genotype showed lower mRNA levels of ITPKC (P=0.035). Conclusion: The ITPKC rs7251246 T>C polymorphism may be a risk factor for CAA and thrombosis in children with KD in the Han Chinese population, likely due to differences in mature mRNA levels caused by interference of RNA splicing. Dual antiplatelet therapy for thrombosis is recommended for male children with the rs7251246 CC genotype.

Risk Factors for Coronary Artery Aneurysm in a Chinese Pediatric Population with Kawasaki Disease at Low Risk of Intravenous Immunoglobulin Resistance: A Retrospective Cohort Study.

INTRODUCTION: Multiple scoring systems for predicting intravenous immunoglobulin (IVIG) resistance have been developed. Although low-scoring patients with Kawasaki disease (KD) have a favorable prognosis, many develop coronary artery aneurysms (CAAs). Herein, we determined the risk factors for CAA development among patients with KD with low risk of IVIG resistance. METHODS: We compared 14 scoring systems for predicting IVIG resistance among patients with KD hospitalized from 2003 to 2022. Patients were risk stratified using an optimal scoring system. Association between baseline characteristics and CAA development was assessed within the low-risk group. RESULTS: Overall, 664 pediatric patients with KD were included; 108 (16.3%) had IVIG resistance, and the Liping scoring system had the highest area under the curve (0.714). According to this system, 444 (66.9%) patients with KD were classified as having low risk of developing IVIG resistance (<5 points). CAA development was significantly associated with male sex (odds ratio [OR], 1.946; 95% CI: 1.015-3.730), age <6 months at fever onset (OR, 3.142; 95% CI: 1.028-9.608), and a baseline maximum Z score of ≥2.72 (OR, 3.451; 95% CI: 2.582-4.612). CAA incidence increased with the number of risk factors, and comparisons with a Kobayashi score of <5 points among patients with KD revealed similar results. CONCLUSIONS: Predicting the response to IVIG might help further reduce CAA development in patients with KD.

Prognostic nutritional index value in the prognosis of Kawasaki disease with coronary artery lesions.

Objectives: The prognostic nutritional index (PNI) is a purported predictor of intravenous immunoglobulin (IVIG) resistance and coronary artery aneurysm (CAA) development in patients with Kawasaki disease (KD). However, limited data exist on CAA regression. This study aimed to confirm whether the PNI is a predictor for CAA persistency in patients with KD. Methods: This retrospective study grouped 341 patients with KD based on the coronary artery status and time of aneurysm persistence. The clinical and laboratory parameters were compared, and multivariate logistic regression analysis was performed to identify the independent risk factors for persistent CAA. The receiver operating characteristic (ROC) curve was further used to assess the predictive values of the PNI in persistent CAA. Results: Among the study patients, 80 (23.5%) presented with CAA, including CAA persisting for 2 years in 17 patients (5.0%). Patients with CAA were more frequently treated with corticosteroids (p < 0.016). No statistically significant differences were found in the nutritional status and PNI among patients with or without coronary artery lesions, regardless of injury severity. Patients in the persistent CAA group presented with higher rates of overnutrition and showed lower PNI values and a higher incidence of thrombosis than those in the normal group (p < 0.05). The PNI and the maximum Z-score at 1 month of onset were significantly associated with CAA persisting for 2 years and may be used as predictors of persistent CAA. The area under the ROC curve was 0.708 (95% confidence interval, 0.569-0.847), and a 40.2 PNI cutoff yielded a sensitivity and specificity of 41 and 92%, respectively, for predicting CAA persisting for 2 years. Kaplan-Meier survival analysis revealed that the estimated median time of aneurysm persistence was significantly higher in patients with PNI values of ≤40 than in those with PNI values of >40 (hazard ratio, 2.958; 95% confidence interval, 1.601-5.464; p = 0.007). After sampling-time stratification, the PNI differed significantly between patients with and without persistent CAA when sampled on the second (p = 0.040), third (p = 0.028), and fourth days (p = 0.041) following disease onset. Conclusion: A lower PNI value is an independent risk factor for CAA persisting for 2 years in patients with KD, besides the maximum Z-score at 1 month after onset. Furthermore, the PNI obtained within 4 days from fever onset may possess greater predictive power for patients with persistent CAA.

Poincaré Plot Is Useful for Distinguishing Vasovagal Syncope From Postural Tachycardia Syndrome in Children.

Objectives: To explore the role of the Poincaré plot derived from a 24-hour Holter recording in distinguishing vasovagal syncope (VVS) from postural tachycardia syndrome (POTS) in pediatric patients. Materials and Methods: Pediatric patients with VVS or POTS, hospitalized in Peking University First Hospital between January 2012 and December 2018, were included in a derivation study. The transverse axis (T), longitudinal axis (L), T/L ratio, product T × L, distance between the origin and the proximal end of the longitudinal axis (pro-D), and distance between the origin and distal end of the longitudinal axis (dis-D) of the Poincaré plot were compared between the VVS and POTS groups, and the differential diagnostic performance of the above-mentioned graphic parameters was evaluated using receiver operating characteristic curve analysis. A validation study was conducted in pediatric patients hospitalized between January 2019 and December 2020. Results: In school-aged children, the T, L, T/L, T × L, and dis-D values of patients with VVS were greater than those of patients with POTS; in adolescents, the T, T/L, T × L, and pro-D values of patients with VVS were greater than those of patients with POTS. Using a T/L cut-off value of 0.3 to distinguish between the two diseases, the sensitivity and specificity were 91.0 and 90.5%, respectively, for the total participants; 91.6 and 88.9%, respectively, for the school-aged children; and 82.1 and 95.7%, respectively, for the adolescents. In the validation study, a T/L cut-off value of 0.3 yielded an accuracy, sensitivity, and specificity of 81.8, 87.2, and 77.6%, respectively, in the total participants; 76.5, 82.6, and 71.4%, respectively, in the school-aged children; and 89.2, 93.8, and 85.7%, respectively, in the adolescents, in distinguishing VVS from POTS validated by clinical diagnosis. Conclusions: The graphic parameters of the Poincaré plot are significantly different between VVS and POTS in pediatric patients, and the T/L of the Poincaré plot may be a useful measure to help differentiate VVS from POTS in children and adolescents.

Poincaré Plot Can Be a Useful Tool to Select Potential Responders to Metoprolol Therapy in Children with Vasovagal Syncope.

Purpose: To explore the value of the longitudinal axis/transverse axis ratio (L/T) of Poincaré plot in selecting children with vasovagal syncope (VVS) who were suitable for metoprolol therapy. Patients and Methods: Children with VVS hospitalized in Peking University First Hospital between January 2012 and June 2019 and treated with metoprolol were retrospectively included as the training set, and children with VVS hospitalized between July 2019 and December 2020 were included as the validation set. The sex, age at admission, height, weight, body mass index, course of disease, syncope symptom score before metoprolol treatment, treatment duration, supine heart rate (HR), supine systolic pressure, supine diastolic pressure, peak HR during the head-up tilt test (HUTT), changes of HR during HUTT, hemodynamic response during HUTT, left ventricular ejection fraction, left ventricular fractional shortening and the L/T of Poincaré plot were compared between responders and nonresponders in the training set. Logistic regression analysis was conducted to explore predictors. Receiver operating characteristic curve was utilized to determine the value of the predictors for selecting potential responders. Finally, the value of the predictors was further verified. Results: In the training set including 105 children, the L/T in responders was distinctly higher than that in nonresponders (P < 0.001), and there was no apparent difference between the two groups in other indexes. The L/T was statistically related to the efficacy of metoprolol (P < 0.001). The L/T >2.7 yielded a sensitivity of 88.2% and a specificity of 82.8% for indicating responders to metoprolol. Taking L/T >2.7 to select potential responders in another 43 children with VVS in the validation set, the sensitivity was 96.6%, specificity 71.4%, and accuracy 88.4%. Conclusion: The L/T of Poincaré plot >2.7 can be a useful tool to select potential responders to metoprolol therapy in children with VVS.

Endogenous SO2-dependent Smad3 redox modification controls vascular remodeling.

Sulfur dioxide (SO2) has emerged as a physiological relevant signaling molecule that plays a prominent role in regulating vascular functions. However, molecular mechanisms whereby SO2 influences its upper-stream targets have been elusive. Here we show that SO2 may mediate conversion of hydrogen peroxide (H2O2) to a more potent oxidant, peroxymonosulfite, providing a pathway for activation of H2O2 to convert the thiol group of protein cysteine residues to a sulfenic acid group, aka cysteine sulfenylation. By using site-centric chemoproteomics, we quantified >1000 sulfenylation events in vascular smooth muscle cells in response to exogenous SO2. Notably, ~42% of these sulfenylated cysteines are dynamically regulated by SO2, among which is cysteine-64 of Smad3 (Mothers against decapentaplegic homolog 3), a key transcriptional modulator of transforming growth factor ß signaling. Sulfenylation of Smad3 at cysteine-64 inhibits its DNA binding activity, while mutation of this site attenuates the protective effects of SO2 on angiotensin II-induced vascular remodeling and hypertension. Taken together, our findings highlight the important role of SO2 in vascular pathophysiology through a redox-dependent mechanism.

Outcomes of Kawasaki disease with giant coronary aneurysms: a single-centre study in southwest China.

BACKGROUND: Giant coronary aneurysms are the most severe complications of Kawasaki disease. There are few reports of outcomes from China. Most previous studies were based only on absolute aneurysmal dimensions. The aim of the present study was to catalog the outcomes of Kawasaki disease with giant coronary aneurysms in southwest China based on absolute dimensions and the z-score adjusted for body surface area. METHODS AND RESULTS: All patients diagnosed with giant coronary aneurysms (z-score ≥ 10 or absolute dimension ≥ 8 mm) between December, 2002 and December, 2018 were included. We retrospectively analysed patient characteristics and clinical data from 38 patients with giant coronary aneurysms. Over a median follow-up period of 30.5 months (range from 1.7 months to 22.3 years), including patients in chronic phase who had been diagnosed prior to 2002, eight patients had myocardial infarction, including two deaths and one patient with coronary artery bypass grafting. The 1-, 2-, and 5-year event-free rates were 0.63, 0.63, and 0.53 for thrombosis, respectively, and 0.86, 0.81, and 0.81 for major adverse cardiac events, respectively. The 1-, 2-, and 5-year regression-free rates were 0.94, 0.85, and 0.67, respectively. A total of 73.7% of patients remained active. CONCLUSION: In the early stages of Kawasaki disease, patients with giant coronary aneurysms often experience major cardiovascular events; however, they are also likely to have normalisation of the coronary internal luminal diameter. With long-term anticoagulation, close cardiologic monitoring, and prompt thrombolytic therapy, most patients can achieve disease-free periods.