[Effect of electroacupuncture on pyroptosis of synovial tissues in rats with knee osteoarthritis].

OBJECTIVE: To observe the effect of electroacupuncture (EA) on pyroptosis-related proteins in synovium of knee joint in rats with knee osteoarthritis(KOA), in order to explore its mechanism underlying improvement of KOA. METHODS: Forty male SD rats were randomly divided into control， model, EA and medication groups, with 10 rats in each group. The KOA model was established by injecting 0.2 mL 4% papain solution into the right intra-articular cavity, followed by repeating the injection again on day 4 and 7 after the first injection. After successful modeling, rats of the EA group received EA stimulation of "Neixiyan" (EX-LE4) and "Dubi"(ST35) on the right limb for 15 min, once every day, 6 days per week, for a total of 4 weeks, and those of the medication group received gavage of celecoxib 24 mg/kg, once every day, 6 days per week, for a total of 4 weeks. The severity of dysfunction of the right knee was assessed by using Lequesne's score. Serum interleukin(IL)-1ß and IL-18 contents were detected by ELISA. Histopathological changes of the synovium tissue of the right knee joint were observed to give score (synovial pathological score) after H.E. staining. The expression position and intensity of Nod-like receptor pyrin domain 3 (NLRP3) in syno-vial tissue were observed by immunohistochemistry. The expression levels of NLRP3, apoptosis-associated speck-like protein containing card (ASC), Caspase-1, Gasdermin D(GSDMD), IL-1ß and IL-18 mRNAs and proteins (including GSDMD-N) in the synovial tissue of the right knee joint were detected by real-time fluorescence quantitative PCR and Western blot, separately. RESULTS: Compared with the control group, the model group had a significant increase in the Lequesne's score, synovial pathological score, serum IL-1ß and IL-18 contents, and the expression levels of NLRP3, ASC, Caspase-1, GSDMD, IL-1ß, IL-18 mRNAs and proteins and GSDMD-N protein (P<0.01). Whereas relevant to the model group, both the EA and medication groups had marked lower levels of Lequesne's score and synovial pathological score, serum IL-1ß and IL-18 contents, and expression levels of NLRP3, ASC, Caspase-1, IL-1ß, IL-18 mRNAs and proteins, GSDMD mRNA and GSDMD-N protein (P<0.01, P<0.05). Comparison between two intervention groups showed that the contents of serum IL-1ß and IL-18, and the expression levels of IL-1ß mRNA and protein were significantly higher in the EA group than in the medication group (P<0.05, P<0.01). No significant differences were found between the EA and medication groups in the Lequesne's score, synovial pathological score, NLRP3, ASC, Caspase-1 and IL-18 mRNAs and proteins, as well as GSDMD mRNA (P>0.05). CONCLUSION: EA can alleviate the inflammatory response of synovial tissues of knee joints in KOA rats, which may be related to its function in down-regulating the expression levels of synovial NLRP3, ASC, Caspase-1, IL-1ß and IL-18 mRNAs and proteins, and GSDMD mRNA and GSDMD-N proteins, reducing the occurrence of pyroptosis.

[Using changes of left cardiac functional parameters and CPET evaluated the clinical effectiveness of individualized precise exercise overall program management of chronic disease I --Analysis between groups].

Objective: To explore and study the clinical usefulness of continuous dynamic recording of left cardiac function changes forevaluation the improvement in patients with chronic disease after 3 months of intensive control of individualized precision exercise overall manage program. Methods: From 2018 to 2021, 21 patients with chronic cardiovascular and cerebrovascular metabolic diseases mainly controlled by our team were selected to complete the cardiopulmonary exercise test (CPET) and Non-invasive synchronous cardiac function detector (N-ISCFD), electrocardiogram, radial pulse wave, jugular pulse wave and cardiogram data were continuously recorded for 50s.According to the titration results under CPET and continuous functional parameters monitoring, a holistic plan with individualized moderate exercise intensity as the core was developed for 3 months of intensive management, and then N-ISCFD data collection was repeatedafter signing the informed consent. All N-ISCFD data were analyzed in the 50s according to the optimal report mode of Fuwai Hospital and 52 cardiac functional indexes were calculated. The data before and after the enhanced control were compared and the paired T-test was used to statistically analyze the changes of groups. Results: Twenty-one patients with chronic diseases (16 male and 5 female) were (54.05±12.77,29~75) years, BMI (25.53±4.04,16.62~31.7) kg/m2.Comparison with baseline,the whole group analysis: ①The body weight, BMI, systolic blood pressure and diastolic blood pressure of patients were significantly decreased(P＜0.01).②CPET Peak VO2 was (64.93±24.22, 26.96~103.48) %Pred before enhanced control, and (85.22±30.31, 43.95~140.48) %Pred after enhanced control, and increased (35.09±27.87, 0.12~129.35) % after enhanced control compared with before enhanced control. The AT, Peak VO2/HR, Peak Work Rate, OUEP, FVC, FEV1, FEV3/FVC% and MVV were significantly increased (P＜0.01) and the Lowest VE/VCO2 and VE/VCO2 Slope were significantly decreased(P＜0.01).③Core indicators of left heart function:Ejection fraction was significantly increased from (0.60±0.12,0.40~0.88) to(0.66±0.09, 0.53~0.87)(P＜ 0.01), by (12.39±14.90,-12.32~41.11)%. The total peripheral resistance was significantly decreased from (1579.52±425.45,779.46~2409.61) G/(cm4·s),to(1340.44±261.49,756.05~1827.01) G/(cm4·s)(P＜0.01), by (12.00±17.27,37.79~28.61) %.The left stroke index, cardiac total power, ejective pressure and left ventricular end diastolic volumewere significantly improved (P＜0.05).The change analysis of each indicator for each patient is shown in the individualized analysis section of this study. Conclusion: Use CPET and continuous functional monitoring we can safely and effectively develop the overall program of individualized exercise in patients with chronic diseases. Long-term intensive management and control can safely and effectively significantly improve the cardiovascular function of patients. Continuous dynamic recording of changes in left and right cardiac functional parameters can be a simple way to supplement CPET to evaluate cardiovascular function.

[Cardiopulmonary exercise testing (CPET)to evaluate the efficacy after intensive control of personalized precise exercise training for cardiovascular and cerebrovascular chronic diseases].

Objective: To study the symptom-restricted extreme cardiopulmonary exercise testing (CPET) to evaluate the improvement of the overall function of patients with long-term chronic diseases after intensive control of personalized precise exercise training for 3 months. Methods: We selected 20 patients with chronic cardiovascular and cerebrovascular metabolic diseases who were intensively controlled by our team from 2014 to 2016. After signing the informed consent form, based on the results of CPET and continuous functional tests, we formulated the overall management plan with individualized moderate exercise intensity as the core. After 3 months, CPET was performed. The changes of CPET indicators before and after intensive control in each patient were analyzed individually. Then the difference value and percentage difference value were calculated. Results: In this study, 20 patients (18 males and 2 females) with chronic cardiovascular and cerebrovascular metabolic diseases, aged (55.75±10.80, 26~73) years, height (172.20±8.63, 153~190) cm, weight (76.35±15.63, 53~105) kg, all patients were not any dangerous events during the period of CPET and intensive control.①After intensive control, the static pulmonary function index, resting systolic blood pressure, rate blood pressure product and fasting blood glucose were significantly improved (P<0.05).②Before intensive control, the peak oxygen uptake is (55.60±15.69, 34.37~77.45) % pred and anaerobic threshold is (60.11±12.26, 43.29~80.63)% pred; after intensive control, the peak oxygen uptake is (71.85±21.04, 42.40~102.00) % pred and anaerobic threshold (74.95±17.03, 51.90~99.47) %pred. Compared with before the intensive control, the peak oxygen uptake and anaerobic threshold of all patients after intensive control were significantly increased by (29.09±7.38,17.78~41.80) % and(25.16±18.38, 1.77~81.86)%(all P<0.01). Other core indexes were also improved significantly, including peak oxygen uptake,peak heart rate, peak work rate, oxygen uptake efficiency plateau, lowest value of carbon dioxide ventilatory efficiency, slope of ventilatory equivalent for carbon dioxide, ramp exercise duration(all P<0.01).③In terms of individualized analysis, after intensive control, the above 8 CPET core indexes were all improved in 15 cases, and 7 indexes in 5 cases were improved; the peak oxygen uptakeof all cases increased by more than 15%, 16 cases > 20%, 13 cases > 25%, 10 cases > 30%. Conclusion: CPET can safely, objectively and quantitatively evaluate the overall functional status and therapeutic effects, and guide the formulation of individualized precise exercise intensity. The overall plan of individualized precision exercise for three months can safely and effectively reverse the overall functional status of patients with long-term cardio-cerebrovascular metabolism diseases.

[Effect of different work rate increasing rate on the overall function evaluation of cardiopulmonary exercise testing I-peak parameters and changes in respiratory exchange rate].

Objective: To observe the effect of healthy volunteers different work rate increasing rate cardiopulmonary exercise test (CPET) on the peak exercise core indicators and the changes of respiratory exchange rate (RER) during exercise, to explore the effect of different work rate increasing rate on CPET peak exercise related indicators. Methods: Twelve healthy volunteers were randomly assigned to a moderate (30 W/min), a relatively low (10 W/min) and relatively high (60 W/min) three different work rate increasing rate CPET on different working days in a week. The main peak exercise core indicators of CPET data: VO2, VCO2, work rate (WR), breathe frequency(Bf), tidal volume (VT), ventilation (VE), heart rate (HR), blood pressure (BP), Oxygen pulse(O2P), exercise time and RER for each period of CPET were analyzed using standard methods. The ANOVA test and paired two-two comparison was performed on the difference of each index in the three groups of different work rate increasing rate. Results: Compared with the moderate work rate group, the peak work rate of the lower and higher work rate groups were relatively lower and higher, respectively ((162.04±41.59) W/min vs (132.92±34.55) W/min vs (197.42±46.14) W/min, P<0.01); exercise time was significantly prolonged and shortened ((5.69 ± 1.33) min vs (13.49 ± 3.43) min vs (3.56 ± 0.76) min, P<0.01); peak RER (1.27 ± 0.07 vs 1.18 ± 0.06 vs 1.33 ± 0.08, P<0.01~P<0.05) and the recovery RER maximum (1.72±0.16 vs 1.61±0.11 vs 1.81±0.14, P<0.01~P<0.05) were significantly decreased and increased. Conclusion: Different work rate increasing rate of CPET significantly change the Peak Work Rate, exercise time, Peak RER, and maximum RER during recovery. The CPET operator should choose an individualized work rate increasing rate that is appropriate for the subject, and also does not use a fixed RER value as a basis for ensuring safety, the subject's extreme exercise, and early termination of exercise.

[Effect of different work rate increasing rate on the overall function evaluation of cardiopulmonary exercise testing II- sub-peak parameters].

Objective: To observe the effect of healthy volunteers different work rate increasing rate cardiopulmonary exercise testing (CPET) on the sub-peak parameters . Methods: Twelve healthy volunteers were randomly assigned to a moderate (30 W/min), a relatively low (10 W/min) and relatively high (60 W/min) three different work rate increasing rate CPET on different working days in a week. The core indicators related to CPET sub-peak exercise of 12 volunteers were compared according to standard Methods: anaerobic threshold (AT), oxygen uptake per unit power (ΔVO2/ΔWR), oxygen uptake eficiency plateau,（OUEP), the lowest average of 90 s of carbon dioxide ventilation equivalent (Lowest VE/ VCO2), the slope of carbon dioxide ventilation equivalent (VE/ VCO2 Slope) and intercept and anaerobic threshold oxygen uptake ventilation efficiency value (VO2/ VE@AT) and the anaerobic threshold carbon dioxide ventilation equivalent value (VE/ VCO2@AT). Paired t test was performed on the difference of each parameter in the three groups of different work rate increasing rate. Results: Compared with the relatively low and relatively high work rate increasing rate group, the moderate work rate increasing rate group uptake eficiency plateau, (42.22±4.76 vs 39.54±3.30 vs 39.29±4.29) and the lowest average of 90 s of carbon dioxide ventilation equivalent (24.13±2.88 vs 25.60±2.08 vs 26.06±3.05) was significantly better, and the difference was statistically significant (P<0.05); Compared with the moderate work rate increasing rate group, the oxygen uptake per unit work rate of the relatively low and relatively high work rate increasing rate group increased and decreased significantly ((8.45±0.66 vs 10.04±0.58 vs 7.16±0.60) ml/(min·kg)), difference of which was statistically significant (P<0.05); the anaerobic threshold did not change significantly ((0.87±0.19 vs 0.87±0.19 vs 0.89±0.19) L/min), the difference was not statistically significant (P>0.05). Conclusion: Relatively low and relatively high power increase rate can significantly change the CPET sub-peak sports related indicators such as the effectiveness of oxygen uptake ventilation, the effectiveness of carbon dioxide exhaust ventilation, and the oxygen uptake per unit work rate. Compared with the moderate work rate increasing rate CPET, the lower and higher work rate increasing rate significantly reduces the effectiveness of oxygen uptake ventilation and the effectiveness of carbon dioxide exhaust ventilation in healthy individuals. The standardized operation of CPET requires the selection of a work rate increasing rate suitable for the subject, so that the CPET sub-peak related indicators can best reflect the true functional state of the subject.

[A preliminary report on the variation of respiratory heart rate during sleep in normal subjects and patients with chronic diseases without sleep apnea].

Objective: The new theory of holistic integrative physiology and medicine, which describes the integrative regulation of respiratory, circulatory and metabolic systems in human body, generates the hypothesis of that breath is the origin of variability of circulatory parameters. We investigated the origin of heart rate variability by analyzing relationship between the breath and heart rate variability (HRV) during sleep. Methods: This retrospective study analyzed 8 normal subjects (NS) and 10 patients of chronic diseases without sleep apnea (CDs-no-SA). After signed the informed consent form, they performed cardiopulmonary exercise testing (CPET) in Fuwai Hospital and monitored polysomnography (PSG) and electrocardiogram (ECG) during sleep since 2014. We dominantly analyzed the correlation between the respiratory cycle during sleep and the heart rate variability cycle of the ECG R-R interval. The HRV cycle included the HR increase from the lowest to the highest and decrease from the highest to the lowest point. The number of HRV (HRV-n), average HRV time and other parameters were calculated. The breath cycle included complete inhalation and subsequent exhalation. The number of breath (B-n), average breath time and other breath parameters were analyzed and calculated. We analyzed each person's relationship between breath and HRV; and the similarities and differences between the NS and CDs-no-SA groups. Independent sample t test was used for statistical analysis, with P<0.05. Results: CPET core parameter such as Peak VO2 (83.8±8.9)% in NS were significantly higher than that (70.1±14.9)% in patients of chronic diseases without sleep apnea (P<0.05), but there was no difference between their AHI (1.7±1.3) in NS and AHI (2.9±1.2) in CDs-no-SA (P>0.05). The B-n and the HRV-n (6581.63±1411.90 vs 6638.38±1459.46), the average B time and the average HRV time (4.19±0.57)s vs (4.16±0.62)s in NS were similar without significant difference (P>0.05). The comparison of the numbers in CDs-no-SA were the number (7354.50±1443.50 vs 7291.20±1399.31) and the average times ((4.20±0.69)s vs (4.23±0.68)s) of B and HRV were similar without significant difference (P>0.05). The ratios of B-n/HRV-n in NS and CDs-no-SA were (0.993±0.027 vs 1.008±0.024) and both were close to 1 and similar without significant difference (P>0.05). The average magnitude of HRV in NS ((5.74±3.21) bpm) was significantly higher than that in CDs-no-SA ((2.88±1.44) bpm) (P<0.05). Conclusion: Regardless of the functional status of NS and CDs-no-SA, there is a similar consistency between B and HRV. The origin of initiating factors of HRV is the respiration.

[Screening biomarkers for hypertensive heart disease: Analysis based on data from 7 medical institutions].

Objective: To screen the influencing factors of hypertensive heart disease (HHD), establish the predictive model of HHD, and provide early warning for the occurrence of HHD. Methods: Select the patients diagnosed as hypertensive heart disease or hypertensionfrom January 1, 2016 to December 31, 2019, in the medical data science academy of a medical school. Influencing factors were screened through single factor and multi-factor analysis, and R software was used to construct the logistics model, random forest (RF) model and extreme gradient boosting (XGBoost) model. Results: Univariate analysis screened 60 difference indicators, and multifactor analysis screened 18 difference indicators (P<0.05). The area under the curve (AUC) of Logistics model, RF model and XGBoost model are 0.979, 0.983 and 0.990, respectively. Conclusion: The results of the three HHD prediction models established in this paper are stable, and the XGBoost prediction model has a good diagnostic effect on the occurrence of HHD.

[Preliminary analysis of the influence of breathing on heart rate variability in chronically ill patients with sleep apnea].

Objective: Based on the hypothesis that respiration causes variability of circulatory indicators proposed by the holistic integrated physiology and medicine theory, the correlation between respiration and heart rate variability during sleep in chronically ill patients with abnormal sleep breathing is analyzed. Methods: Eleven chronically ill patients with abnormal sleep breathing and apnea-hypopnea index (AHI) ≥15 times/hr are recruited. After signing the informed consent, they completed the standardized symptomatic restrictive extreme exercise cardiopulmonary exercise testing (CPET) and sleep breathing monitoring Calculate and analyze the rules of respiratory nasal airflow and ECG RR interval heart rate variability during the oscillatory breathing (OB) phase and the normal steady breathing phase of the patient during sleep, and use the independent sample t test to compare with normal people and no sleep breathing abnormalities in the same period in this laboratory. Of patients with chronic diseases are more similar and different. Results: The peak oxygen uptake and anaerobic threshold (AT) of CPET in chronic patients with abnormal sleep apnea were (70.8±13.6)% Pred and (71.2±6.1)% Pred; 5 cases of CPET had exercise induced oscillatory breathing (EIOB), 6 An example is unstable breathing, which indicates that the overall functional status is lower than normal. In this group of patients with chronic diseases, AHI (28.8±10.0) beats/h, the ratio of the total time of abnormal sleep breathing to the total time of sleep (0.38±0.25); the length of the OB cycle (51.1±14.4)s. The ratio (Bn/HRV-B-n) of the number of breathing cycles in the normal and steady breathing period to the number of heart rate variability cycles in this group of patients with chronic diseases is 1.00±0.04, and the CV (SD of HRV-B-M/x) is (0.33 ±0.11), blood oxygen saturation (SpO2) did not decrease significantly, the average amplitude of heart rate variability (HRV-B-M) of each respiratory cycle rhythm was (2.64±1.59) bpm, although it was lower than normal people (P<0.05) , But it was similar to chronic patients without sleep apnea (P>0.05). In this group of patients with chronic diseases, the ratio of the number of respiratory cycles to the number of heart rate variability cycles (OB-Bn/OB-HRV-B-n) during OB is (1.22±0.18), and the average amplitude of heart rate variability for each respiratory cycle rhythm in OB (OB -HRV-B-M) is (3.56±1.57)bpm and its variability (OB-CV = SD of OB-HRV-B-M/x) is (0.59±0.28), the average amplitude of heart rate variability in each OB cycle rhythm (OB-HRV-OB-M) is (13.75±4.25)bpm, SpO2 decreases significantly during hypoventilation during OB, and the average decrease in SpO2 during OB (OB-SpO2-OB-M) is (4.79±1.39)%. The OB-Bn/OB-HRV-B-n ratio, OB-HRV-OB-M and OB-SpO2-OB-M in the OB period are all significantly higher than the corresponding indicators in the normal stable breathing period Large (P<0.01). Although OB-HRV-B-M has no statistically significant difference compared with HRV-B-M in normal stable breathing period (P>0.05), its variability OB-CV is significantly increased (P<0.01). Conclusion: The heart rate variability of chronic patients with abnormal sleep breathing in the OB phase is greater than that of the normal stable breathing period. When the breathing pattern changes, the heart rate variability also changes significantly. The number of breathing cycles in the stable breathing period is equal to the number of heart rate variability cycles.The ratio is the same as that of normal people and chronically ill patients without sleep apnea, confirming that heart rate variability is respiratory origin; and the reduction of heart rate variability relative to the respiratory cycle during OB is directly caused by hypopnea or apnea at this time, and heart rate variability is also breathing source.

[Max test verify further clinical research for whether individualized symptom-limited cardiopulmonary exercise testing is the maximum extreme exercise].

Objective: To verify that the cardiopulmonary exercise testing (CPET) performed by clinical subjects is the maximum extreme exercise, we designed The Max test（Max）during clinical CPET. We used Max to verify the accuracy of the quantitative CPET evaluation result, and whether it is feasible and safe to use the specific value of a certain index as the standard for stopping CPET. Methods: Two hundred and sixteen cases from Fuwai Hospital were selected during June 2017 to January 2019,including 41 healthy person（control group） and 175with cardiovascular diseases（patient group）,The patients had a CPET peak RER ≤ 1.10, or the peak heart rate and peak blood pressure were basically non-responsive.The Max was first attempted in 60 subjects,and this study is further expanded . When the CPET ended, they had a 5-minute break, then the Max, during which, they cycled with a velocity of ≥ 60 r/min, at a constant intensity equivalent to to 130% of peak work,until exhausted.The difference and percentage difference between the peak heart rate and the peak oxygen uptake were calculated. ①If the percentage difference of heart rate and oxygen uptake are all less than -10%,then the Max is defined as failure,otherwise it is succesful. 2 If the percentage difference is between -10%~10%, then the Max is successful, which proved that the CPET is precise.③If the difference is ≥10%, the Max is successful, which proves that the CPET is non-extreme exercise. Results: Patient group's Peak VO2(L/min,ml/(min·kg)),anaerobic threshold (L/min,ml/(min·kg),%pred),Peak VO2/HR(ml/beat, % pred),Peak RER,Peak SBP,Peak WR,peak heart rate,OUEP （ratio,%pred） were lower than those of the control group(P<0.05)．The VE/ VCO2 Slope （ratio,%pred）and Lowest VE/ VCO2（ratio,%pred） were higher in the patient group than in the control group (P<0.05)．No adverse events occurred during the CPET and Max in all cases. Among the 216 cases,Max was successful in 198 cases(91.7%)．CPET was proved to be maximum extreme exercise for 182 cases,non-maximum extreme exercise for 16 cases,and failed in 18 cases(8.3%)．Conclusion: For CPET with a low peak RER and a maximum challenge,the Max can confirm the accuracy of the objective quantitative assessment of CPET. Max is safe and feasible,and that deserved further research and clinical application.