Effects Of Transesophageal Sympathetic Surgery On Left Ventricular Remodeling After Acute Myocardial Infarction

Chapter 1 Creating Post Myocardial Infarction Ventricular Remodeling model in Chinese Mini-swine with Closed-chest Coronary Artery Occlusion-Reperfusion Technique by BalloonBackground:Sustainable and reproducible large animal models that closely replicate the clinical sequelae of cardiovascular diseases are important for the translation of basic science research into bedside medicine. The coronary artery anatomy, size, structure and distribution are comparable between swine and human vasculature, so that swine are well accepted by the scientific community for cardiovascular research. Compared with the original porcine models of myocardial infarction(MI) created with open-chest coronary artery ligation, closed-chest approach using clinical cardiac catheterization techniques maybe a better mothod with less anethesia period and morbidity. Besides, after occlusion, the myocardium will be fully reperfused to mimic the clinical MI disease model with relevant interventions in humans. Reperfusion of the heart after coronary artery occlusion minimizes additional myocardial cell death and decreases swine mortality. Furthermore, interventional approach minimizes additional sympathetic activation aroused by open-chest procedure and avoids cardiac sympathectomy by coronary artery ligation.Objective:To test and verify the protocol for using porcine models of MI created with a closed chest coronary artery occlusion-reperfusion technique, and observe the left ventricular remodeling post MI.Methods:Anterior MI was induced in 12 Chinese mini-swine by transient balloon occlusion of left anterior descending coronary artery for 1.5 hours. Serial hemodynamics and echocardiography were monitored at baseline,1.5 h after reperfusion and 8 weeks after MI to investigate the structural and functional change of heart. Postmortem morphometric analysis of the heart sections and histological examination were performed on hearts from all experiments.Results:After exclusion of 4 animals who died during induction of MI,8 survived to 8 weeks. Ischemia caused by occlusion significantly decreased mean arterial pressure (131.3 ± 28.54 vs.101.6±16.09, p=0.028), left ventricular systolic pressure(155.0 ± 35.6 vs.129.63 ±21.70, p=0.043), cardiac output (3.02±1.30 vs.2.14±0.85 L/min.m2, p=0.014), left ventricular eject fraction(73.65±8.55 vs.62.28±10.69, p=0.019) and shortening fraction (38.39±4.63 vs.32.88±5.46, p=0.045).8 weeks later, MI swine experienced an increase in left ventricular end-diastolic area(9.24 ±2.58 vs.12.66±3.06, p=0.025), and a decrease in ventricular tip wall thickness (1.25±0.20 vs.0.87±0.23, p=0.024), left ventricular eject fraction (73.65±8.55 vs.52.35±13.95, p=0.002) and shortening fraction (38.39±4.63 vs.32.90±8.82, p=0.037). Plasma BNP was significantly increased(119.48±66.17 vs.266.73±168.89, p=0.038). Post-mortem analysis showed left ventricular dilation and infarct scar thinning, the infracted myocardium replaced by myofibroblasts and collagen.Conclution:Closed-chest coronary artery occlusion-reperfusion technique by balloon successfully created a post myocardial infarction ventricular remodeling model in Chinese Mini-swine, which may be comfirmed by hemodynamics, echocardiography parameters, postmortem morphometric analysis and histological examination.Chapter 2 Effect of Catheter-based Renal Sympathetic Denervation on Left Ventricular Remodeling after Acute Myocardial Infarction in Chinese Mini-swineBackground:Activation of the sympathetic nerve system(SNS) is the main mechanism in post-MI myocardial remodeling which may result in heart failure. Renal sympathetic denervation is a novel, catheter-based technique that targets at the denervation of the renal sympathetic nervous system. A catheter connected to a radiofrequency generator is introduced percutaneously to the lumen of the main renal artery via femoral access and used to disrupt efferent sympathetic and sensory afferent fibres of the renal nerves located in the adventitia of these arteries, which may help to reduce renal and systemic SNS activity.Objective:To assess whether catheter-based renal sympathetic denervation(RDN) could prevent left ventricular(LV)remodeling early after myocardial infarction.Methods:Anterior MI was induced in Chinese mini-swine by transient balloon occlusion of left anterior descending coronary artery. After reperfusion for 2 hours, the swine were randomly assigned to receive bilateral catheter-based RDN (the RDN group) or sham-denervation (the sham group) and were studied up to 8 weeks. All of the RDN procedures were performed by experienced operators, strictly adhering to recommendations provided by the catheter manufacturer. Serial hemodynamics and echocardiography were monitored at baseline,1.5 h after reperfusion,30min after RDN/sham-denervation and 8 weeks after MI to investigate the structural and functional change of heart. Postmortem morphometric analysis of the heart sections and histological examination were performed on hearts and renal arteries from all experiments.Results:Overall,24 Chinese mini-swine were included in 2 sets of experiments. After exclusion of 7 animals who died during induction of MI,17 survived to 8 weeks,1 animal experienced renal artery stenosis, which lead to unilateral nephrarctia, and was also excluded. There were no other complications related to RDN in our experiment.There were 8 swine in each group.Ischemia caused by occlusion significantly increased heart rate, and decreased mean arterial pressure, left ventricular systolic pressur, cardiac output, left ventricular eject fraction and shortening fraction. There were no differences between the RDN and sham group in the hemodynamics or echocardiography parameters at baseline or after reperfusion.8 weeks later, both the sham and RDN swine experienced an obvious LV remodeling, with increases in LV diastolic area by 37.1%(p=0.025) and 66.6%(p=0.085), LV systolic area by 109.8%(p=0.047) and 89.9%(p<0.001), as well as decreases in fractional shortening by 14.3%(p=0.037) and 9.8%(p=0.036), infarct wall thickness by 26.1%(p=0.030) and 30.0%(p=0.024), and LVEF by 28.9%(p=0.002) and 15.9%(p=0.017) in the RDN group and sham group, respectively. Compared with baseline, the plasma BNP significantly rose in both the RDN group (141.53±97.44 vs.282.21±152.17, p=0.049) and the sham group (119.48±66.17 vs.266.73±168.89, p=0.038) after 8 weeks. Meanwhile, no significant differences were observed in remodeling parameters after 8 weeks between the RDN and sham groups. Renal arteries showed transmural media damage and proteoglycan replacement of smooth muscle cell loss in the absence of media thinning(Movat stain). Nerve injuries after radiofrequency ablation were in various phases (hematoxylin and eosin-stained).Conclusions:This study found no specific therapeutic effects of RDN on post-MI LV remodeling. It is probably because cardiac remodeling is a complex progress involving different mechanisms. RDN will not affect systemic hemodynamics during the acute phase of myocardial infarction in large animal model. The histological result suggested gradual damage and recovery of the renal arterial wall and surrounding nerves.Chapter 3 Effect of Catheter-based Renal Sympathetic Denervation on Activity of Sympathetic Nerver System and Renin-Angiotensin-Aldosterone System after Acute Myocardial Infarction in Chinese Mini-swineBackground:The chronic overactivity of the sympathetic nervous system(SNS) with associated up-regulation of the renin-angiotensin-aldosterone system(RAAS) plays a major role in cardiac remodeling after a myocardial infarction(MI).Objective:To evaluate the effect of RND on activity of the systemic, renal and cardiac sympathetic nerve and RAAS after an acute myocardial infarction in Chinese Mini-swine.Methods:The activity of the systemic, renal and cardiac sympathetic nerve would be determined by measuring peripheral vein plasma, venae renales plasma and tissue NE, E at basline, derectly after RDN and after 8 weeks. In parallel, RAS activation would be determined by measuring plasma renin activity and concentration of angiotensin-Ⅱ and angiotensin.Results:There were no differences between the RDN and sham group in the peripheral vein plasma and venae renales plasma concentration of noradrenaline(NE), epinephrine(E), angiotensin Ⅱ(AII), aldosterone (Ald) and renin activity(RA) at baseline. After 8 weeks, concentration of peripheral vein plasma Ald differed in the RDN and sham groups (0.08±0.03 vs.0.19±0.5, p=0.001). Venae renales PRA(2.05±1.73vs.0.19± 0.21,p=0.037)、E(0.07±0.01 vs.0.05±0.01,p=0.048) significantly decreased compared with baseline in the RDN group. Both Venae renales PRA and All rose post MI and fell to baseline post RDN. Furthermore, there were no differences between the RDN and sham group in PRA、AII、Adl of the cardiac tissue, nor in NE、E、PRA、AII、Adl in renal tissue.Conclusions:Venae renales plasma biochemical indicators are more sensitive compared with the peripheral vein in co-related with RDN process. Besides, more easily performed clinical measurements are needed to confirm the procedural success, i.e. that RDN indeed leads to sufficient disruption of renal nerves.