Protective Effects Of HCN Inhibitor On Post-Resuscitation Myocardial Function In A Porcine Model Of Cardiac Arrest

BackgroundCardiac arrest?CA?,an acute illness,is dangerous and has got high clinical mortality rate.With the update guidelines of Cardiopulmonary Resuscitation?CPR?,the success rate of return to spontaneous circulatio?ROSC?in CA patients continues to increase,but still globally occupy a higher mortality rate.The cause of death is closely related to cardiac dysfunction and brain damage after CPR.Post-resuscitation myocardial dysfunction?PRMD?is one of the most important causes in the early phase within ROSC 24 to 72 hours.Therefore,it is always the focus and hotspot of researchers to explore new methods of the protection of myocardial tissue,to improve cardiac systolic and diastolic dysfunction after resuscitation,and improve the survival rate of patients after ROSC.In the treatment of cardiac arrest,epinephrine was recommended as the first drug by American Heart Association Cardiopulmonary Resuscitation and Cardiovascular First Aid Guideline.Its?-adrenergic actions such as positive inotropic and chronotropic effects increased heart rate?HR?,excessive myocardial oxygen consumption and decreased myocardial perfusion.This disequilibrium between oxygen supply and demand,in turn,aggravates PRMD and myocardial injury.Previous CA animal studies have shown that?-blockers could reduce the number of defibrillation,heart rate and the incidence of arrhythmia after resuscitation,myocardial oxygen consumption and improve PRMD and survival time.However,the routine use of?-blockers might cause or worsen hemodynamic instability,exacerbate heart failure,and cause bradyarrhythmias,which limited its wide application in cardiac arrest patient.And,only a few observational studies have found that beta blockers could improve the prognosis of patients with PRMD.Therefore,research on a drug for improving PRMD and improving patients survival rate have been gradually taken into consideration by clinicians.Ivabradine?IVA?was a new type of drug in reducing heart rate,the mechanism of which was selectively inhibited I_f current by delaying the diastolic depolarization slope of sinoatrial node cells through blocking the opening of hyperpolarization-activated cyclic nucleotide-gated channels in the sinoatrial node cells.And it will not influence myocardial contractility and reduce myocardial oxygen consumption without inducing arrhythmia.It is mainly used to improve the clinical symptoms and prognosis of patients with chronic stable angina pectoris,heart failure,AMI,arrhythmia?sinus tachycardia,atrial fibrillation?,especially for those who are banned or intolerant of?-blockers.In this study,We hypothesized that the rational use of IVA would effectively improve post-resuscitation myocardial and cerebral function and duration of survival in a porcine model of CA and resuscitation.And it might have scientific,innovative and potential application value for cardiopulmonary resuscitation?CPR?research in improving PRMD.ObjectiveTo investigate the effects of HCN inhibitor on post-resuscitation myocardial function in a porcine model of cardiac arrest.Methods?1?Ten healthy male pigs were used in the present study,ventricular fibrillation was induced and untreated for 8 minutes in anesthetized domestic swine while defibrillation was attempted after 8 minutes of cardiopulmonary resuscitation.Animals were randomized into two groups:Ivabradine and Placebo.?2?In the IVA group,an intravenous bolus dose of IVA 5 mg was given at the 15minutes of ROSC,and then IVA 0.5 mg/kg/h was continuously pumped for 8 hours;the Placebo group received the same amount of normal saline at the same time point after ROSC.?3?Continuous monitoring and recording of hemodynamic parameters,such as heart rate?HR?,mean arterial pressure?MAP?,and end-tidal CO₂?ETCO₂?at 1,2,4,and 8 h after ROSC.?4?Tissue Doppler?TD?Ultrasound was used to monitor left ventricular systolic and diastolic function at baseline 1,2,4,8,24 h after ROSC,including mitral E/A,E/e'?Mitral E/A ratio and E/e'velocity ratio?and left ventricular ejection fraction?LVEF?.?5?Serum venous blood was separated and serum was separated.Enzyme-linked immunosorbent assay?ELISA?was used to detect Cardiac troponin I?cTnI?and N-terminal pro-brain natriuretic peptide?NT-proBNP?levels in myocardial injury markers at 1,4,and 24 h after Baseline and ROSC.?6?The neurological deficit score?NDS?and survival outcome time of the animals were observed and evaluated at 24 h after ROSC.The experimental animals were then euthanized,myocardial tissue was taken for hematoxylin-eosin?HE?staining,and myocardial histopathological changes were observed under high power optical microscope.Results?1?There were no significant differences in basic physiological parameters such as body weight,HR,MAP,and ETCO₂,as well as the number of defibrillation,mitral E/A,E/e',and LVEF.?2?Ten pigs all recovered back successfully after 8 minutes ventricular fibrillation and 8minutes precordial compression.There was no significant difference when compared the recovery success rate between the two groups?P>0.05?.?3?Compared with the baseline,heart rate of the two group animals increased significantly after ROSC.While in the IVA group,HR decreased significantly from 1hour to 8 hours after ROSC,showing a significantly decreased heart rate compared with the placebo group?P<0.05?.?4?There were no significant difference in MAP,ETCO₂ and PH between the IVA group and the Placebo group at 1,2,4 and 8 hours after ROSC?P>0.05?.?5?Left ventricular diastolic and systolic function in the IVA group were significantly improved at 1,2,4,8,and 24 h after ROSC compared with the Placebo group.The mitral E/A,E/e',and LVEF were better than the Placebo group?P<0.05?.?6?Pearson analysis showed a negative correlation between mitral E/A and HR at 4 h after ROSC?r=-0.832,P=0.003?;E/e?was positively correlated with HR?r=0.905,P=0.000?;LVEF was negatively correlated with HR?r=-0.700,P=0.024?.?7?The serum levels of cTnI and NT-proBNP were dramatically elevated from 1 h to 4hrs and then descended at 24 hrs in the IVA and placebo groups.Both cTnI and NT-proBNP levels were significantly lower in the IVA group than those in the Placebo group?P<0.05?.?8?After ROSC,the animals in both two groups survived for 24 h,and the survival rate was 100%.The NDS of the experimental animals in the IVA group was lower than that in the Placebo group?P<0.05?.?9?Myocardial injury in the IVA group was less than that of the Placebo group at 24hours after ROSC,which was characterized by less interstitial edema,less necrotic cardiomyocytes,less cell swelling,regular myocardial fiber bundles,less contraction necrosis,and less inflammatory cell infiltration.Conclusions?1?The model was established by 8 minutes ventricular fibrillation and 8 minutes of cardiopulmonary resuscitation in anesthetized domestic swine proved to be stable.Tissue Doppler ultrasound could effectively assess changes in systolic and diastolic function after resuscitation?2?After resuscitation,there were myocardial dysfunction and damage in animals,mainly in the decrease of EF and E/A values and the increase of E/e'value and serum myocardial injury markers such as cTnI and NT-proBNP concentration.?3?IVA,HCN channel inhibitor,could slow down heart rate safely and effectively,and improve systolic and diastolic function such as EF and E/A and E/e'values,and reduce serum myocardial injury markers cTnI and NT-proBNP after resuscitation;and it has potential application prospects in clinical cardiopulmonary resuscitation research.