Study On TCM Syndrome Evaluation Of Mice Heart Failure Model With Aortic Bow Compression

Objective:To establish KM Mouse Model of Heart failure caused by elevated afterload induced by transverse aortic constriction (TAC), and to evaluate the evolution of the pathophysiology and Traditional Chinese Medicine (TCM) Syndromes of the established model, in order to provide disease and syndrome combination animal model for the study of efficacy of Traditional Chinese Medicine on chronic Heart Failure.Methods:1. KM mice were divided into two groups:Transverse Aortic Constriction (TAC) group (operated with TAC) and Sham-operation (SH) group.At 2 weeks,4 weeks,6 weeks,8 weeks,12 weeks and 16 weeks after surgery, the animals of the two groups were examined to evaluate pathological characteristics of the heart failure animal models comprehensively from aspects including pathogeny, pathological anatomy, pathophysiology and symptom. Echocardiography was performed to evaluate cardiac function. Histological examination was performed to evaluate the change in heart structures. Observation of anatomy was used to assess the change of the heart shape. Symptoms and signs were observed to be compared with the pathological characteristics of the disease.2. Macroscopic indications were collected to assess the overall state of bodily functions at different time point after surgery. Behavioral detections were used to assess independent exercise capacity. After the images of planta pedis and nose had been taken, the color indexes of the images were analyzed by Photoshop software, and the chromatic aberration was also computed at the same time. After comprehensive syndrome-attribute-associated information of animal models were obtained, objective evaluation of Syndrome attribute of the animal models were carried out according to TCM Deficiency syndrome reference standard revised by the National Integrative Medicine Deficiency Disease and Geriatrics Research Specialized Committee in May 1986, the Qi Deficiency and Blood Stasis syndrome diagnosis criteria in Guidelines for Clinical Research of TCM New Drugs,2002 edition and main points of diagnosis in Diagnostics in Chinese Medicine.Results:1. Compared with sham-operated animals at the same time point, there were some significant changes as follows in animals of the TAC group. Cardiac ultrasound showed that left ventricular mass (LVM) and left ventricular/weight index increased significantly (P<0.05). Left ventricular ejection fraction (LVEF) was continuously lower than the sham-operated animals with significant reduce after 6 weeks and 8 weeks (P<0.05) and extremely significant reduce after 12 weeks (P<0.01). Left ventricular fractional shortening (LVFS) was consistently lower than sham-operated animals with highly significant reduce after 4 weeks,8 weeks and 12 weeks (P<0.01). Degrees of ventricular wall thickening Varied. Left ventricular posterior wall; systolic (LVPWs), left ventricular anterior wall; systolic (LVAWs) and left ventricular anterior wall; diastolic (LVAWd) thickened significantly after 2 weeks (P<0.05). LVAWd also thickened significantly after 4 weeks (P<0.05); And extremely significant LVAWd, LVPWs, and left ventricular posterior wall; diastolic (LVPWd) thickening after 8 weeks and LVPWd thickening after 2 weeks and 16 weeks existed (P<0.01).The internal diameter and the volume of the ventricular first decreased and then increased. Left ventricular internal diameter; diastolic (LVIDd) and left ventricular end-diastolic volume (LVEDV) reduced significantly after 2 weeks (P <0.05). LVIDd, left ventricular internal diameter; systolic (LVIDs), LVEDV and LVESV were higher than SH after 4-12 weeks, with significant increase of LVIDs and LVESV after 6 weeks and 16 weeks(P<0.05), significant increase of LVEDV after 8 weeks(P<0.05), extremely significant increase of LVIDd and LVEDV after 12 weeks and 16 weeks (P<0.01), and extremely significant increase of LVIDs and LVESV after 8 weeks and 12 weeks (P<0.01). Heart tissue morphology showed increased vascular lumen, vessel wall thickening, and connective tissue proliferating in the outer wall after 2 weeks. After 4-8 weeks, lesions were worse than before with myocardial hypertrophy, myocardial fibers widening and fibroblast increase outside of myocardial fibers. After 12 to 16 weeks, lesions aggravated with widened myocardial fiber gap and proliferation of fibrous connective tissue between the muscle bundles. Manifestations of pulmonary congestion were visually observed at each time point. Animals of TAC group were observed with locomotor activity decrease after 4 weeks, swollen soles after 12 weeks, and respiratory distress followed by sudden death after 12 weeks.2. Compared with sham-operated animals, TAC group animals also showed difference in the following aspects. Color anomalies of the lungs of TAC group were visually observed after 2 weeks. Decreased activity, locomotor activity and sensitivity, less resistance to being caught and shorter independent travel distance were also observed after 4 weeks (P<0.05). After 8 weeks, the color of the noses, lips, soles turned dark purple and Chromatic aberration (â–³E00>5) matched the visual changes. At this time point, visual inspection also showed lung congestion indications of different extents as well as abnormally increased heart, and congestion of different degrees at the auricular appendix. After 12 weeks and 16 weeks, the state continued as it was at Week 8 and aggravated with appearance of edema.Conclusion:1. Transverse aortic constriction successfully induced elevated afterload of KM mice and caused Myocardial Hypertrophy/Heart failure in mice. After 2 weeks, concentric cardiac hypertrophy appeared in the TAC mice. After 4 weeks, heart function tended to decrease. After 6 weeks, the trend of eccentric cardiac hypertrophy appeared, and heart function decreased. After 8 weeks, eccentric cardiac hypertrophy occurred, and cardiac function decreased significantly; The period from 2 to 8 weeks after surgery belonged to pre-clinical stage of heart failure. 12 weeks after surgery belonged to clinical stage of heart failure, during which cardiac function was poorer and distinct clinical signs and symptoms appeared.16 weeks after surgery belonged to refractory stage of heart failure.2. Chronic heart failure mouse model induced by TAC exhibited different syndromes characteristics at different time point. Specifically, Qi Deficiency syndrome appeared and persisted after 4 weeks, and Blood Stasis syndrome appeared and persisted after 8 weeks. Water Retention syndrome appeared after 12 weeks. After 4 weeks, Qi Deficiency syndrome coexisted. From Week 8 to Week 12 after surgery, Qi Deficiency syndrome and Blood Stasis syndrome coexisted. After 12 weeks, Qi Deficiency syndrome,Blood Stasis syndrome and Water Retention syndrome coexisted.