The Cardiac Protective Effect Of Chronic Intermittent Hypobaric Hypoxia On The Metabolic Syndrome Rats

The metabolic syndrome (MetS) is a common metabolic disorders anddisplays as hyperglycosemia, hyperlipemia, hypertension and higher insulin.More and more evidences show that insunlin resistance and central obesity playa cental role in the genesis and development of MetS. In recent years, theincidence of MetS and the related cardiaovascular diseases as well as type2diabetes diseases is increasing. There is a closed relationship between MetS andcoronary artery disease. MetS aggravates cardiac ischemia, diminishes thetolerance of myocardium to ischemia or hypoxia, decreases the survival rate ofpatients after cardiac surgery, and induces arrhythmia.Chronic intermittent hypobaric hypoxia (CIHH) has many benefits on thebody function including improving glucose and lipid metabolism, loweringdown serum cholesterol and artery blood pressure, enhancing myocardialantioxidant, and protecting heart against the ischemia/reperfusion (I/R) injuryand I/R-induced arrhythmia. However, the effect of CIHH on myocardialischemia/reperfusion injury and arrhythmia in MetS has not been elucidated.The purpose of the present study was to investigate the CIHHcardioprotective effect and the underlying mechanism in the metabolicsyndrome rats by applications of electrophysiological, biochemistrical andradioimmunoassaical technologies. The study was divided into two parts:(1) toexplore the protective effect of CIHH against cardiac ischemia/reperfusioninjury in the metabolic syndrome rats and the underlying mechanism throughusing coronary artery ligation method and Langendorff isolated heart perfusiontechnique.(2) to explore anti-arrhythmic effect of CIHH and the electrophysio-logic mechanism in the metabolic syndrome rats by using coronary arteryligation method and electrophysiological technique. â…  The cardioprotective effect of chronic intermitent hypobaric hypoxiaagainst the ischmia/reperfusion injury in fructose-induced metabolicsyndrome ratsObjective: The metabolic syndrome increases risk of coronary heartdisease and aggravates myocardial ischemia. CIHH significantly enhancesmyocardial antioxidation and promotes the recovery of cardiac function fromischemia/reperfusion. The purpose of this part study was to investigatecardioprotective effects of CIHH in the fructose-induced metabolic syndromerats.Methods: Male Sprague–Dawley rats were randomly divided into fourgroups: Fructose-fed group (Fruc-fed), CIHH group, CIHH plus fructosefeeding group (CIHH-F) and control group. The rats in Fruc-fed group were fedwith10%fructose in drinking water. The rats in CIHH group were put into ahypobaric chamber to get hypobaric hypoxia treatment simulating5000maltitude (PB=404mmHg, PO₂=84mmHg) for42days,6hours per day. Therats in CIHH-F group received both10%frucotse drinking and CIHH treatment.The rats in control group were given natural water and kept in a normoxicenvironment for a corresponding period. In anesthsia rats, the heart experienced30min ischemia followed by120min reperfusion induced by coronary arteryligation and left ventricular systolic function was observed. In isolated rat heart,Langendorff technique was used to observe the effect of CIHH on leftventricular function before and after30min ischemia/60min reperfusion,respectively. Also superoxide dismutase (SOD) activity and malondialdehyde(MDA) content in myocardium were determined by biochemical methods.Results:1. The body weight of Fruc-fed rats was significantly increased comparedwith control, CIHH and CIHH-F rats (P<0.05). However, no difference of bodyweight was observed among control, CIHH and CIHH-F rats (P>0.05).2. The ratio of whole ventricle weight to body weight (HW/BW) and theratio of left ventricle weight to whole heart weight (LVW/HW) in Fruc-fed ratswere increased significantly compared with control, CIHH and CIHH-F rats (P<0.01). However, no differences of HW/BW and LVW/HW were observedamong control, CIHH and CIHH-F rats (P>0.05).3. In Fruc-fed rats, blood serum glucose (GLU), total cholesterol(TG),triglyceride (TC), fasting insulin (Ins) and insulin c (C-p) petide weresignificant higher than those in other three groups rats (P<0.05). Excepting thatthe total cholesterol was significiantly lower in CIHH rats than that in controlrats (P<0.05), there were no differences of other biomarkers among CIHH,CIHH-F and control rats (P>0.05).4. In basic condition, Systolic artery pressure (SAP) and diastolic arterypressure (DAP) in Fruc-fed rats was significant higher than those in control,CIHH and CIHH-F rats (P<0.05). However, there was no differences of SAPand DAP among control, CIHH and CIHH-F rats (P>0.05). After ocoronaryarterial ligation, SAP and DAP declined, but the decline of SAP and DAP inCIHH-F rats was significantly smaller than that in Fruc-fed rats (P<0.05).During reperfusion, SAP and DAP in CIHH-F rats recovered significantlybetter than that in Fruc-fed rats (P<0.05). There was no significant difference ofSAP between Fruc-fed and control rats, but DAP in Fruc-fed rats wassignificantly higher than that in control rats (P<0.05).5. In vivo and in vitro experiments showed that the left cardiac functiondecreased significiantly after ischemia/reperfusion in Fruc-fed compared withother group rats (P<0.05). And the recovery of left cardiac function fromischemia/reperfusion was much better in CIHH rats than that in other threegroup rats (P<0.05), and the recovery of left cardiac function in CIHH-F ratswas better than that in Fruc-fed (P<0.05).6. The myocardial SOD activity was the lowest and MDA content was thehighst in fructose-fed rats after ischemia/reperfusion compared with any othergroup rats (P<0.05). The activity of SOD and the content of MDA were higherand lower in CIHH rats than those in control, CIHH-F and Fruc-fed rats(P<0.05). There was no difference of SOD and MDA between CIHH andCIHH-F rats (P>0.05).Summary: This study demonstrates for the first time that CIHH confers effective cardioprotection against metabolic cardiac hypertrophy and ischemia/reperfusion injury in fructose-induced metabolic syndrome rats, which might berelated to enhancement of antioxydation, improvement of metabolic disorderand insulin resistance by CIHH.â…¡ The anti-arrhythmia effect of chronic intermittent hypobaric hypoxia infructose-induced metabolic syndrome ratsObjective: The purpose of this part of study was to investigateanti-arrhythmic effect of chronic intermittent hypobaric hypoxia and theunderlying electrophysiological mechanism through using coronary ligationmethod and intracelluar recording technique in the metabolic syndrome rats.Methods: Male Sprague–Dawley rats were randomly divided into fourgroups: Fructose-fed group (Fruc-fed), CIHH group, CIHH plus fructosefeeding group (CIHH-F) and control group. Each group was treated same as inthe first part study. The coronary artery was ligated to induce30min ischemia/120min reperfusion.The severity of the arrhythmia was evaluted by arrhythmiascore according to standard lead II ECG. For the isolated ventricular papillarymuscle,15min simulated ischemia and30min reperfusion was given and actionpotential (AP) was recorded before and during ischemia/reperfusion in themetabolic syndrome rats by intracellular electrophysiological recordingtechnique.Rasults:1. Coronary artery ligation resulted in varied degrees of cardiacarrhythmias for each group rats, such as premature, tachycardia and ventricularfibrillation. The arrhythmia score was significantly higher in control andFruc-fed rats than that in CIHH and CIHH-F rats (P<0.05). During2hoursreperfusion, Fruc-fed rats showed most serious arrhythmia than any other grouprats (P<0.05). The arrhythmia score in CIHH rats was significantly lower thanany other group rats (P<0.05). And the arrhythmia score in CIHH-F rats wassmaller than that in Fruc-fed rats (P<0.05).2. Under basic condition, there was no difference of APD₅₀and APD₉₀ ofaction potential found between Fruc-fed and control rats (P>0.05). However, APD₅₀and APD₉₀in CIHH rats were prolonged significiantly compared withcontrol rats (P<0.05). The APD₅₀and APD₉₀in CIHH-F rats were significiantlylonger than those in Fruc-fed rats (P<0.05) but not in CIHH rats (P>0.05).3. During15min simulated ischemia, the action potential parameters inFruc-fed and control group reduced significantly compared with the baseline(P<0.01). Compared with control rats, APD₅₀and APD₉₀in Fruc-fed rats weresignificantly decreased (P<0.05), but other parameters, such as RP, OS, APAand Vmaxwere not changed significantly (P>0.05). Compared with baseline,there was no change of action potential during ischemia in CIHH and CIHH-Frats (P>0.05). During ischemia, the APD₅₀ and APD₉₀in CIHH-F rats weresignificiantly longer than those in Fruc-fed rats (P<0.01) but not in CIHH rats(P>0.05).4. After120min reperfusion with normal Tyrode solution, except APD₂₀unchanged, other parameters such as the OS, APA Vmax APD₅₀and APD₉₀inFruc-fed rats were dicreased significantly compared with baseline (P<0.01).Compared with baseline, there was no change of action potential afterreperfusion in CIHH and CIHH-F rats (P>0.05). After reperfusion,APD₅₀andAPD₉₀in CIHH-F rats were significantly longer than those in Fruc-fed rats(P<0.01) but not in CIHH rats (P>0.05).Summary: This study demonstrates for the first time that CIHH conferseffective antiarrhythmic effect on ischemia/reperfusion-induced arrhythmia inthe metabolic syndrome rats, which might be ralated to the prolongation ofaction potential and the antagonized effect on ischemia-induced inhibition ofaction potential by CIHH.