Effect Of Hyperkalemia Preconditioning On Myocardium And Brain Ischemia Reperfusion Injury And Its Mechanism

Background and ObjectiveEarly studies at the cellular and organ levels have proven that hyperkalemia could alleviate the ischemia/reperfusion injury?IRI?of myocardium.But the effect of hyperkalemia on brain IRI has been seldom reported.In the clinical practice,patients suffer from cardiac arrest?CA?and the cardiopulmonary resuscitation?CPR?substantially build an overall IRI model.However,it is still unknown whether hyperkalemia could also alleviate the overall IRI,especially the IRI on heart and brain during CA/CPR.Our study mainly aim to explore the possible mechanism,which lead to the restoration of spontaneous circulation?ROSC?after the patients'prolong CA/CPR cause by hyperkalemia.Then using the CA/CPR model and the transient middle cerebral artery occlusion?tMCAO?model to explore the effect of hyperkalemia on heart and brain IRI overall,and the possible mechanism.This study is of great value to improve the success rate of CPR and alleviate brain damage after CPR.Method1.Reporting two cases,which were about the patients suffered from CA complicated by hyperkalemia and experienced prolong CPR,but without obvious nervous system damage after ROSC.From the views of clinical and experimental research,analyzing the possible mechanism of the two cases.2.Explore the effect of hyperkalemia preconditioning on CA/CPR and the myocardial compliance in rats.A total of 90 male Sprague Dawley?SD?rats were randomly divide into two groups:hyperkalemia preconditioning group and control group?45 rats/each group?.By previously intravenous administration potassium chloride?KCl??80 ug/g?or equal volume of normal saline?NS?respectively,the rat's CA/CPR model was built by electrical induction.After experiencing 6min,9min or 12min of CA,each group was further divide into three subgroups?15 rats/each subgroup?.The rate of ROSC,the time of CPR were measured in each subgroup.When rats were failed to ROSC,record the diastolic blood pressure before stopping CPR.Then the autopsy were made immediately to evaluated the rat's cardiac hardness score.The incidence of stone heart in each group was also measured.Additionally,the criterion of inducing CA:electrocardiogram monitoring showed ventricular fibrillation or pulse-less electrical activity,no pulsating wave and average arterial pressure<10mmHg.CA duration:the time from inducing CA to starting CPR.The criterion of ROSC:monitor shows the ventricular rhythm?including sinus,atrial or junctional rhythm?and associates with average arterial pressure>50mmHg more than 5min.Time of CPR:from starting CPR to ROSC.Failed to ROSC:CPR>10min but without ROSC.The criterion of stone heart:assess the cardiac hardness score base on the feeling by finger touch of the heart,each grade gets 1point,higher score represent harder.The cardiac hardness score?3 points defined as stone heart.3.Explore the effect of hyperkalemia preconditioning on IRI of rat's focal IRI and calcium overload.By previously intravenous administration?KCl 80ug/g and 40 ug/g?or equal volume of NS respectively,the rat's tMCAO model was built.After experiencing 90min ischemia and 24h reperfusion,the modified neurological severity score,the infarct volume of reperfusion brain,the concentration of K⁺,Ca²⁺and calmodulin?CaM?the activity of Ca²⁺-ATPase and the expression of Ca²⁺/calmodulin-dependent protein kinase II?CaMK II?and Na⁺/Ca²⁺exchange?NCX?1 in brain tissue between hyperkalemia groups and control group were also measured.Results1.The two patients were both had the precipitating factors and concomitant disease of hyperkalemia.Both were suffered from unconsciousness and CA,and experienced prolong CPR.But after ROSC patients were without any nervous system damage.The prognosis of the CPR in the two patients was better than other CA/CPR patients.The possible mechanism might be associated with inhibiting calcium overload of heart and brain caused by hyperkalemia.2.CA/CPR modelThe rate of ROSC was decreased as the extension of CA duration in each group.In hyperkalemia preconditioning group,the rate of ROSC?CA6min:100%vs 53.3%,P<0.05;CA9min:60%vs 13.3%,P<0.05;CA12min:33.3%vs0,P<0.05?was increased and the time of CPR?CA6min:1.17±0.41 vs6.39±1.74,P<0.05;CA9min:3.33±0.83 vs 7.85±0.92,P<0.05?was less compared with the control group.Among those rats which failed to ROSC,the cardiac hardness score in the hyperkalemia preconditioning group were less than those in the control group?CA9min:1.7±0.6 vs 4.2±0.7,P<0.05;CA12min:1.7±0.7 vs 4.7±0.5,P<0.05?.The incidence of stone heart in the hyperkalemia preconditioning group were less than those in the control group?CA9min:0 vs 100%,P<0.05;CA12min:20.0%vs 100%,P<0.05?.Rats in hyperkalemia preconditioning group were with higher diastolic blood pressure before stopping CPR?CA9min:36.4±5.3 vs-1.2±3.8,P<0.05;CA12min:26.2±5.2 vs-1.1±3.3,P<0.05?.While the rats in control group couldn't showed that phenomenon and the diastolic blood pressure even showed negative value.3.tMCAO modelAfter 24h reperfusion,the two hyperkalemia preconditioning groups were with less brain injury?mNSS score:HK80 vs NS:15.17±2.03 vs 12.67±1.49,P<0.05;HK40 vs NS:14.83±1.07 vs 12.67±1.49,P<0.05.TTC%:HK80 vs NS:8.72±1.62 vs 20.71±3.04,P<0.05;HK40 vs NS:13.29±2.07 vs 20.71±3.04,P<0.05?compared with NS group.Additionally,the two hyperkalemia preconditioning groups were with higher brain K⁺concentration?HK80 vs NS:1.2112±0.0155 vs 0.9789±0.0368,P<0.05;HK40 vs NS:1.0461±0.0410 vs0.9789±0.0368,P<0.05?,lower brain concentration of Ca²⁺?HK80 vs NS:0.0971±0.001 vs 0.1406±0.001,P<0.05;HK40 vs NS:0.1121±0.001 vs0.1406±0.001,P<0.05?and CaM?HK80 vs NS:59.5432±4.6084 vs72.3386±3.5612,P<0.05;HK40 vs NS:62.5883±4.5471 vs 72.3386±3.5612,P<0.05?,less expression of NCX1?HK80 vs NS:0.348±0.043 vs 0.463±0.072,P<0.05;HK40 vs NS:0.423±0.066 vs 0.463±0.072,P<0.05?,and the activity of Ca-ATPase?HK80 vs NS:4.3129±0.2454 vs 3.4213±0.2941,P<0.05;HK40 vs NS:3.9456±0.2681 vs 3.4213±0.2941,P<0.05?was elevated compared with NS group.Furthermore,rats in HK80 group showed a better trend of prognosis between the two hyperkalemia preconditioning groups.ConclusionHyperkalemia preconditioning could improve the rat's myocardium and brain tolerance to IRI.By inhibiting the calcium overload,hyperkalemia preconditioning could improve the CA/CPR rat's myocardial compliance,reduce the incidence of heart stone and increase successful rate of CPR.Furthermore,it could also alleviate the focal brain IRI in rats.To a certain extent,the results of our study could explain why the two hyperkalemia patients had better prognosis.And our study might provide a new thought to improve the prognosis of CPR and alleviate brain damage after CPR.