| The tricuspid regurgitation(TR) is one of the most common clinical valvular diseases, which is usually induced by left cardiac valve diseases, pulmonary arterial hypertension. It is early accept that TR would disappear after the treatment of left heart valve diseases, however, later research demonstrated that TR wouldn’t lessen or disappear after the operation of left heart valve diseases, and some of them would be more serious gradually, which influenced survival rate and quality of life. The prognosis of patients with severe TR who underwent operation of left heart valve diseases is poor, which has become a troublesome problem of valve surgery. The operation of TR indication, method, time and long-term outcome remain uncertain. Generally, patients with severe TR should undergo tricuspid valve repair or replacement before the occurrence of irreversible right heart failure. There is still no objective standard of how to distinguish between reversible and irreversible right heart impairment. At present, the patients’ right heart function with TR are evaluated mainly according to the clinical symptoms and the echocardiography.With the progress of science and technology, various imaging methods can be used to display the right ventricular function. Currently, the most commonly used imaging technology to evaluate right ventricular structure and function are echocardiography and cardiac magnetic resonance (CMR). CMR is considered to be the gold standard for assessment of the right ventricular function. Alternatives such as multilayer CT scan and radionuclide imaging are valuable in some special patients. Although the data of using M and2D ultrasound to evaluate the right ventricular function, which is affected by the complex shape and position of right ventricle, has good correlation compared with cardiac magnetic resonance, the data is lack of accuracy and repeatability. The echocardiography guideline suggest at least one of the echocardiography parameters instead of volume parameters should be applied to realize the quantitative rather than qualitative assessment of right heart function:1) the right ventricular myocardial performance index, Tei index;2) fractional area change, FAC;3) tissue Doppler velocity peak;4) tricuspid annular plane systolic excursion, TAPSE. However there is no any single parameter can be applied to evaluate right heart function in different conditions, and its effect on the prognosis of the disease and treatment remains uncertain.At present, the cellular and molecular mechanism researches of the right heart remodeling focus mainly on right ventricular remodeling induced by the pulmonary arterial hypertension(PAH). Nerve endocrine signals, oxidative stress, inflammation, ischemia, cell death, etc. would affect or accelerate progress in right heart remodeling and failure, but the specific mechanism is still not clear. Moreover, most of the data source of research on the mechanism of right heart remodeling is come from the mature studies of left ventricular remodeling. However the myocardial cells in early development, cell signaling and calcium regulation are also different between the left and right ventricle, suggesting that the mechanism of left and right ventricle remodeling may be fundamentally different.Myocardial remodeling is a key pathological change from compensatory to decompensatory of cardiac function, myocardial fibrosis (MF), the common pathological change of various heart diseases, and is one of the main expressions of myocardial remodeling. MF showed the fibroblast cells, especially muscle fibroblast cells, synthetize extracellular matrix (ECM) protein excessively under the stimulation such as myocardial damage, oxidative stress, inflammation, mechanical stretch. Muscle fibroblast cells play an important role in the process of fibrosis by producing a variety of growth factors, cytokines, chemokines, ECM protein and various zymogen,. The change of matrix metalloproteinases (MMPS) plays a key role in ventricular remodeling process, and become a research focus at present. The sympathetic nervous system and the renin angiotensin aldosterone system also play a very important role in myocardial remodeling. As to severe PAH patients, in order to overcome the pulmonary hypertension, right ventricle become hypertrophy adaptively to increase the contractility. The myocardial systolic function will gradually decline. In order to compensate the ejection volume, the right ventricle will store more blood, and the pre load will increase, resulting in dilatation of the right ventricle. The ventricular wall tension and myocardial oxygen consumption increase, then right ventricular perfusion will decrease, which further damaging the right ventricular contraction and relaxation function, forming a vicious spiral. However, TR is mainly due to the occurrence of tricuspid annular dilatation and right ventricular enlargement. Firstly, tricuspid ring will expand by increasing right ventricular pressure or volume load (first stage). At this stage, the TR happens or not depends on the tricuspid annular dilatation and tricuspid leaflets coaptation. With the progression of the disease and the enlargement of right ventricle, the tricuspid annular is becoming larger and larger, and the leaflets coaptation is poorer and poorer, causing severe TR (second stage). Finally, the continuous centrifugal enlargement of the right ventricle (right ventricle remodeling) not only causes the expansion of tricuspid annular, also bounds the tricuspid chordae tendineae attached on the papillary muscle of right ventricular free wall, be more severity TR (third stage). In patients with severe TR, the right atrium and ventricle will further dilate, forming a vicious spiral. The systolic and diastolic dysfunction of right heart, decreased cardiac output, and increasing TR, eventually lead to decompensated right heart failure. These pathologic changes is very similar to functional mitral regurgitation of dilated cardiomyopathy, so functional TR may be regarded as special dilated cardiomyopathy involving the right ventricle.The study of molecular and cellular mechanism of TR helps identify new strategies for the diagnosis, prevention and treatment of TR caused by right heart remodeling and dysfunction. Because the human myocardial tissues are difficult to obtain, the majority studying on right heart remodeling are the establishment of right heart dysfunction or failure animal model. Since the right ventricle is more sensitive to pressure overload, the successful establishment of right ventricular remodeling animal model induced by pressure overload taking less time, so most scholars established right heart remodeling model through pulmonary artery hypertension. But this model does not reflect the pathophysiological process of TR causing by right heart volume overload. Although considering to be the volume overload animal model through the method of folding, resection, or intervention of pulmonary valves to cause pulmonary regurgitation, the tricuspid valve and right atrium was normal in the early period, which is not consistent with the pathophysiological process of TR. Therefore, it is necessary to establish an animal model of TR. However, the animal model of TR caused by volume overload was reported less, because of a certain degree of difficulty in technology and taking long time to establish the animal model.Transcriptome analysis of the gene function and structure, the molecular mechanism of specific biological processes and diseases has been widely used in the field of basic research, clinical diagnosis and drug research and development. Now there is no literature research on molecular and genetic analysis of volume overload induced right heart remodeling, so the mechanism of TR induced right heart remodeling is still not clear. Our study aims to establish an beagle dog model of severe TR, and then undergo the physiological and molecular biological research after the long-term dynamic observation, especially system analysis of the heart tissue and blood genes by transcriptome sequencing technology(RNA-seq technology). We are trying to find biomarkers of the right heart dilatation or failure caused by TR to guide the right heart function assessment, the timing of operation, to predict prognosis and to seek the prevention and target treatment of TR caused by right heart remodeling.,Objective:To establish a new animal model of right heart remodeling caused by tricuspid regurgitation.Methods:The beagle dogs were taken as experimental objects (n=14).Firstly, the superior and inferior vena cava were blocked briefly, secondly the right atrium was open, at last the tricuspid valves of beagle dogs were cut off under direct vision on the beating heart. The dogs were divided into operation group and sham operation group at random.Through the echocardiography data of pre-operation, post-operation3,6,12months respectively and autopsy results after sacrifice of two animals whom had been raised for14months to estimate right ventricular remodeling happens or not.Results:8beagle dogs were cut off the anterior tricuspid valve, and3dogs were cut off the anterior and posterior tricuspid valves with100%successful rate and100%survival rate. According to the ratio of TR area and right atrial area(TR/RA),the beagle dogs were divided into severe TR group(40%<TR/RA<70%) with8dogs and very severe TR group(TR/RA>70%) with3dogs and sham operation group with3dogs. The longest one has raised above540days, and no natural death occurred so far. The weight of operation group increased, and the echocardiography showed right atrium and ventricle enlargement and right heart dysfunction. The autopsy of one of operation group dogs found liver cirrhosis and ascites. The pathologic examination revealed right atrial fibrosis, whose degree was more severe than the right ventricle, right atrium and ventricle myocardial edema, disorganized, liver cell edema, suggesting the occurrence of right heart remodeling and failure. The gene analysis show very severe TR will cause right atrial distinct molecular remodeling, and increased gene expression of type Ⅱ collagen, decreased ribosomal protein synthesis and increased production and metabolism of lipid.All of the results indicated the occurrence of right heart remodeling and right heart failure. There is no significant difference in sham operation group before or after operation.Conclusion:By cutting off the tricuspid valves through lateral thoracotomy can established a new animal model of right heart remodeling caused by tricuspid regurgitation successfully, which is controllable, repeatable and high successful and survival rate. It is an ideal animal model for the study of right heart remodeling. Very severe TR may cause right atrial structural remodeling and molecular remodeling significantly, and its mechanism may be related to extracellular matrix collagen hyperplasia, decreased ribosomal protein synthesis, increased production of lipid metabolism related. |
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