| With the development of study on human sleep medicine, we found that sleepapnea syndrome (SAS) is not only a risk factor of coronary heart disease,hypertension, hyperlipidemia, acute myocardial infarction, arrhythmia, heart failure,dilated cardiomyopathy, type2diabetes, stroke, anxiety, depression, obesity, memorydecline, but also the common cause of clinical death. SAS means that the recurrentapnea or low ventilation occurs during sleep, apnea index upper than or equal5timesper hour, and associated with snoring, daytime sleepiness and other clinicalmanifestations. Obstructive sleep apnea syndrome (OSAHS) is the most clinicalfeature of SAS.In recent years, the treatment of moderate and severe OSAHS at home andabroad has reached a consensus. Continuous positive airway pressure (CPAP) is thefirst recommend treatment choice, for the CPAP can effectively improve sleep quality,reduce the endothelial damage and inflammatory cytokine production, reduce thedamage of complications to body.There by, achieve the goal of disease progressioncontroll. But clinical treatment on patients with mild OSAHS is still lack of effectivemethods, because of slight symptoms and poor compliance to treatment methods byCPAP, lose weight, changing posture, which leads to the occult progress of disease,threatening the live of patients at any time.Therefore drug therapy is one of the mainproblems to be solved urgently. Statins lowers low density lipoprotein (LDL) receptors through inhibitingcompounding3-hydroxy-3-mqethyl glutaric of acyl coenzyme A reductase, and playsthe role of reducing cholesterol synthesis in hepatocytes.Studies has shown that statins can also play a variety of physiological functions.Such as improve endothelial function, reduce inflammation, slow hardening ofthe arteries, by inhibiting the synthesis of isoamyl which is necessary forextraceccular matrix proteins.Evidence-based medicine indicates that, compared withother statins, rosuvastation have a stronger adventage of lipid-lowering capacity,arterial plaques stabilizing.Up to now, there is no any literature reporting thatrosuvastation could relieve cardiovascular complication by improving the OSAHScondition.Our study intends to investigate the relationship between rosuvastatin andOSAHS,coronary heart disease by observing the differences between the levels ofapnea index (AHI), endothelin-1(ET-1), C-reactive protein (CRP), amino terminalpro-brain natriuretic peptide (NT-proBNP)and intima-media thickness (IMT) inpatients with various degree of OSAHS and the extent of coronary stenosis,the effectsof different doses rosuvastatin (5mg/d,10mg/d,20mg/d) on AHI, ET-1, CRP,NT-proBNP, IMT in coronary heart disease patients with mild OSAHS, androsuvastatin (40mg/kg/d) whether or not have a protective effect on OSAHS-rat-model with chronic in termittent hypoxia (CIH), provide an important scientific basisfor drug choices for patients with OSAHS.Part Ⅰ The relationship between AHI, ET-1, CRP, NT-proBNP,IMT and degree of coronary artery stenosis in patients with OSAHS,and the research on rosuvastatin interventingObjectiveTo investigate the relationship between the levels of AHI, ET-1, CRP, NT-proBNP and IMT in patients with various degree of OSAHS and Gensini score,andthe influence of rosuvastatin intervening. MethodOne thousand two hundred and fifty-eight patients with symptom of chest and ahistory of snoring were collected from first affiliated hospital of Zhengzhouuniversity, Henan province people’s hospital and Zhoukou central hospital (Oct.2011-Sep.2012).493patients were diagnosis OSAHS with coronary heart disease bypolysomnography and coronary angiography. of which298cases were male,195cases were female, average age is64.7±4.35years. According to the criteria for thediagnosis of OSAHS and disease severity (mild5≤AHI＜15, moderate15≤AHI＜30, severe AHI≥30).Patients were divided into three groups: mild OSAHS group(mild OSAHS combined with coronary heart disease), moderate OSAHS group(moderate OSAHS combined with coronary heart disease),and severe OSAHS group(severe OSAHS combined with coronary heart disease).60cases of normal peoplefrom physical examination center were choosed as control group.1. Clinical feature of four groups were ananlyzed according to gender, age, BMI,systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting blood glucose(FBG), total cholesterol (TC) and triglyceride (TG).2. AHI was calculated, according to serum levels of ET-1,CRP,NT-proBNP byenzyme linked immunosorbent assay(ELISA), IMT was measured by ultrasonic testinstrument, Gensini scores was calculated by the result of angiography.3. The correlation between AHI、ET-1、CRP、NT-proBNP、IMT and Gensiniscore were investigated by related Perason analysis.4. The differences of hypertension, type2diabetes and prevalence rate of strokeamong mild OSAHS group, moderate OSAHS group and severe OSAHS group werecompared.5. The correlation between hypertension, type2diabetes, stroke and OSAHSwere investigated by Logistic multi factors regression analysis.6. Sixty patients with mild OSAHS and coronary heart disease were randomlydivided into three groups: low dose group (rosuvastatin5mg/d), midum dose group(rosuvastatin10mg/d), the high dose group (rosuvastatin20mg/d). The differences of levels of AHI, ET-1, CRP, NT-proBNP and IMT among the3groups wereobserved after six months.Result1. There was no difference between the four groups in gender and age (P>0.05).The BMI, SBP, DBP, FBG, TC, TG of severe OSAHS group were significantlyhigher than the moderate OSAHS group, the mild OSAHS group and the controlgroup, the [BMI (kg/m2):28.72±1.70vs25.19±1.58vs23.74±1.49vs20.82±1.92,(P<0.05)];[SBP (mmHg):166.75±6.94vs159.69±4.71vs150.31±4.21vs122.29±8.71,(P<0.05)];[DBP (mmHg):125.63±3.90vs115.66±5.97vs92.83±9.16vs74.66±3.61,(P<0.05)];[FBG (mmoL/L):12.7±1.71vs8.47±1.00vs6.53±1.56vs5.42±1.45,(P<0.05)];[TC (mmoL/L):9.00±0.32vs6.62±0.77vs5.74±0.41vs4.10±0.48,(P<0.05)];[TG (mmoL/L):3.65±0.38vs2.73±0.14vs2.32±0.15vs1.40±0.23,(P<0.05)].2. The AHI, ET-1, CRP, NT-proBNP, IMT, Gensini score of severe OSAHSgroup were significantly higher than the moderate OSAHS group, the mild OSAHSgroup and the control group,[AHI (events/H):34.33±1.23vs23.63±2.93vs10.94±2.08vs3.00±1.51,(P<0.05)];[ET-1(pg/mL):55.55±1.33vs38.59±1.60vs24.89±1.51vs13.33±1.68,(P<0.05)];[CRP (mg/L):19.44±2.28vs15.93±2.50vs11.96±1.56vs7.57±1.52,(P<0.05)];[NT-proBNP (fmoL/mL):685.64±26.36vs567.99±21.03vs460.40±32.20vs133.40±20.15,(P<0.05)];[IMT (mm):1.75±0.14vs1.46±0.13vs1.23±0.15vs0.76±0.16,(P<0.05)];[Gensini score:42.74±2.36vs21.30±2.94vs13.40±1.39vs0,(P<0.05)].3. AHI and the Gensini score were significantly positively related (r=0.937, P<0.05);ET-1and the Gensini score were significantly positively related (r=0.945, P<0.05);CRP and the Gensini score were significantly positively related (r=0.827, P<0.05);NT-proBNP and Gensini score were significantly positively related (r=0.883,P<0.05);The IMT and the Gensini score were significantly positively related (r=0.936,P<0.05).4. The prevalence rate of hypertension, type2diabetes, stroke in severe OSAHSgroup was significantly higher than the moderate OSAHS group, the mild OSAHS group, hypertension prevalence rate (%):0.56vs0.34vs0.21,(P<0.05); Type2diabetes prevalence (%):0.32vs0.21vs0.16,(P<0.05); Stroke prevalence rate (%):0.38vs.0.26vs0.19,(P<0.05).5. Hypertension (OR2.5,95%confidence interval0.855-7.314, P<0.05), type2diabetes mellitus (OR1.15,95%confidence interval1.025-1.301, P<0.05), stroke(OR2.02,95%confidence interval1.017-5.759, P<0.05) are independent risk factorsfor the development of OSAHS.6. The dose rosuvastatin after the trial of ET-1, CRP significantly lower thanbefore the trial,[ET-1(pg/mL):18.24±2.28vs24.89±1.51,(P<0.05)];[CRP(mg/L):8.14±0.43vs11.96±1.56,(P<0.05)]; AHI, ET-1, CRP, NT-proBNP andIMT were significantly lower after the high dose of rosuvastatin experiment [AHI(events/H):6.10±1.21vs10.94±2.08,(P<0.05)],[ET-1(pg/mL):7.01±1.06vs24.89±1.51,(P<0.05)],[CRP (mg/L):6.08±0.15vs11.96±1.56,(P<0.05)],[theNT-proBNP (fmoL/mL):345.98±22.68vs460.40±32.20,(P<0.05)],[IMT (mm):0.89±0.17vs1.23±0.15,(P<0.05)].Conclusion1.With the aggravation of OSAHS, BMI, SBP, DBP, FBG, TC and TG levels,hypertension, type2diabetes, stroke prevalence, AHI, ET-1, CRP, NT-proBNP, IMT,Gensini score increased gradually.2. The correlation analysis results showed that AHI, ET-1, CRP, NT-proBNP andIMT were positively related with Gensini score, the higher AHI, ET-1, CRP andintima-media thickness with the heavier degree of coronary artery stenosis. Thehigher NT-proBNP level, the worse cardiac function. Which indicate that cardiacfunction can be improved by reducing the degree of coronary artery stenosis.3. Logistic multifactor regression analysis showed that hypertension, type2diabetes, stroke were the independent risk factors for the development of OSAHS.4. We found that high doses of rosuvastatin (20mg/d) can significantly reducethe AHI, ET-1, CRP, NT-proBNP and IMT in coronary heart disease patients withmild OSAHS, reduce cardiovascular damage and improve the prognosis. Thoseresults have important value for clinical application. PartⅡ Effect of Rosuvastatin to CIH in inducing cardiovasculardamage in ratsObjectiveTo discuss the mechanism of rosuvastatin effect on AHI, ET-1, CRP,NT-proBNP in the rats with chronic intermittent hypoxia.MethodSixty male SD rats were randomly divided into three groups: control group(normal feed and air controlled), CIH1group (normal feed and intermittent hypoxia),CIH2group (medical feed and intermittent hypoxia), and the experiment last for10weeks.1. OSAHS-rat-model was evaluated whether conforms to human OSAHS,accord ing to the sleep quality and arterial blood gas.2. The serum levels of ET-1, CRP, NT-proBNP in the rats after the first, third,sixth and tenth week were tested by ELISA.3. Investigate the relationship between the ET-1, CRP, NT-proBNP and AHI,using the Pearson related analysis.Results1. After10weeks,we found that the pause time of sleep and AHI in CIH1groupwas significantly higher than that of CIH2group and the control group, and theMSa02, LSa02of CIH1group were Statisticsly lower than CIH2group and the controlgroup [pause time of sleep (s):46.13±5.24vs14.16±1.59vs3.25±0.18,(P<0.05)];[AHI (events/H):38.36±5.79vs13.67±1.13vs1.55±0.17,(P<0.05)];[MSa02(%):68.58±4.34vs84.30±5.03vs94.36±5.70,(P<0.05)];[LSa02(%):52.37±5.46vs74.24±4.79vs89.79±2.74,(P<0.05)].2. The levels of ET-1in control group had no significant change in the experimental process, but the levels of ET-1in CIH1group began to rise graduallyafter the first week, and the levels of ET-1in CIH2group began to rise gradually afterthe sixth week. After10weeks, the levels of ET-1in CIH1group was obviouslyhigher than that of CIH2group and control group,[ET-1(pg/mL):28.82±3.37vs20.16±3.64vs12.36±2.57,(P<0.05)].3. The levels of CRP in control group had no significant change during theexperimental process, but the levels of CRP in CIH1group began to rise graduallyafter the first week, and the levels of CRP in CIH2group began to rise gradually afterthe sixth week. After10weeks, the levels of CRP of CIH1group was significantlyhigher than that of CIH2group and control group,[CRP (mg/L):12.16±1.85vs6.59±0.68vs1.14±0.45,(P<0.05)].4. The levels of NT-proBNP in control group had no significant change duringthe experimental process, but the levels of NT-proBNP in CIH1group began to risegradually after the third week, and the levels of NT-proBNP in CIH2group began torise gradually after the sixth week. After10weeks, the levels of NT-proBNP in CIH1group was significantly higher than that of CIH2group and control group,[theNT-proBNP (fmoL/mL):768.12±77.84vs475.12±42.24vs124.83±23.08,(P<0.05)].5. We found that ET-1were significantly positively related with AHI (r=0.267,P<0.05);CRP were significantly positively related with AHI (r=0.348, P<0.05);NT-proBNP were significantly positively related with AHI (r=0.417, P<0.05).Conclusion1. In a certain period of time, the rat model with severe OSAHS can besuccessfully established through change the sleep quality and blood oxygen bycontrolling the feeding chamber oxygen concentration changes, the rat model withmild OSAHS can be successfully established by rosuvastatin medical feedintervention.This intervention results on mild OSAHS shows that rosuvastatin canincrease MSa02, LSa02, reduce AHI, then alleviate the degree of OSAHS.2. CIH can improve the levels of ET-1, CRP, NT-proBNP in rats serum,rosuvastatin can significantly reduce levels of ET-1, CRP, NT-proBNP in serum. 3. With the increasing of AHI levels in rats serum, the ET-1, CRP, NT-proBNPalso subsequently increase, which can alleviate the cardiovascular organ damage ofOSAHS by reducing AHI. |
PDF Full Text Request