动物造模,心力衰竭动物模型 z-bio 2021-10-14 765

　　Introduction: Heart failure is one of the leading causes of death and disease in the world. It can be defined as abnormalities in the structure and function of the heart, which may lead to ventricular filling or impaired drainage. Heart failure can be divided into two types: reduced ejection fraction (HFREF) and heart failure with normal ejection fraction (HFPEF). HFREF systolic dysfunction is characterized by the contraction of the heart muscle and the inability to drain enough blood. HFPEF diastolic heart failure, systolic function is normal or near normal (thereby maintaining ejection fraction). In addition, HFpEF does not show cardiac dilatation, but has higher filling pressure and lung congestion, dyspnea and intolerance. For these reasons, exercise testing plays an important role in diagnosing patients. Myocardial remodeling HFpEF is characterized by abnormal left ventricular (LV) dilation. This may be caused by increased stiffness, abnormal ventricular artery function, increased vascular stiffness, vascular endothelial dysfunction, heart rate, relaxation and/or impaired cardiovascular reserve. The most important mechanism of diastolic dysfunction is ventricular muscle relaxation and/or changes in the passive nature of the ventricular wall. However, it is not necessarily related to interstitial fibrosis with concentric remodeling/hypertrophy of the left ventricle and atrial enlargement. These patients are usually older, mainly female, and exhibit many comorbidities such as diabetes, hypertension, obesity, and renal failure. HFpEF is a multifactorial disease. The heterogeneity of patients not only affects the heart, but also affects the entire cardiovascular system. The lack of suitable animal models hinders effective treatment strategies for HFPEF. There are few animal models, and it is difficult to replicate the clinical features of HFpEF animal models. Most of them are cardiac overload models, which can be further developed into concentric hypertrophy and left ventricular diastolic dysfunction, but rarely show the hemodynamic characteristics of human HFpEF. There is little evidence that the preclinical evaluation of potential new therapeutic targets is reliable. This article provides an overview of currently available animal models, adoption studies (including rodent and large animal models), and the advantages and disadvantages of these models. HFpEF animal model: The main limitation of the animal model is the study of mechanism and pathophysiology. Most heart failure models are mainly HFrEF. Animal models of diastolic dysfunction have also become more extensive, and are very similar to the pathophysiological mechanisms of the disease. Currently available animal models try to reproduce the main factors that cause diastolic dysfunction and HfpEF: aging, diabetes, and hypertension. HFpEF rodent model: Aortic stenosis and systemic hypertension: Hypertension is an important risk factor for certain heart diseases and the main cause of HfpEF. Therefore, it is not surprising that many studies on the HfpEF model have increased left ventricular afterload and afferent hypertrophy (ie, coarctation of the aorta or systemic arterial hypertension). Dahl/SS rats were selected from SD rats showing hypertension and reproduced. Dahl/SS rats have the most representative animal models of sodium hypersensitivity and HfpEF. At 12-19 weeks after eating a high-salt diet from 7 weeks of age, Dahl/SS rats developed renal failure, hypertension (175 mmHg), left ventricular hypertrophy, and HfpEF. At week 12, Dahl/SS rats developed diastolic dysfunction, including increased cavity stiffness (left end diastolic pressure-volume transition (EDPVR) end diastolic volume reduction). Within 16-20 weeks, the Dar/SS heart enlarges, and end-diastolic and EDPVR become age-matched controls. At the same time, the pump function curve tends to be controlled, the ejection fraction decreases, and gradually changes to HfpEF. The main pump function is normal or enhanced at certain times, but left ventricular end diastolic pressure (LVEDP) and lung wet weight increase, indicating the development of heart failure. The rat model induced by deoxycorticosterone acetate (DOCA) salt represents a drug-induced hypertension model. One week after unilateral nephrectomy, at 7 weeks of age, intraperitoneal or subcutaneous injection can induce DOCA. Within 4-5 weeks of chronic corticosterone treatment, it can cause hypertension, renal hypertrophy, glomerular sclerosis, cardiac hypertrophy and perivascular fibrosis. Suitable for rats and mice. Isotonic saline is the only drinking solution that can accelerate and aggravate the progression of hypertension. DOCA salt hypertensive rats develop myocarditis, oxidative stress, fibrosis and diastolic dysfunction. A related model was then established, including exposure to aortic stenosis for 2 weeks before using DOCA, normal left ventricular systolic pressure, partial shortening, hypertrophy, fibrosis, and diastolic dysfunction (high LVEDP and EDPVR), and showing the lungs. The weight gain is consistent. Use HfpEF. Long-term stimulation of hypertrophic promoters such as angiotensin II and isoproterenol are used as models for systolic and diastolic dysfunction and left ventricular hypertrophy. Rats fed with Hypertensive Peptide II exhibited hypertension, left ventricular hypertrophy, fibrosis and natriuretic peptide expression. By increasing the time of left ventricular volume relaxation/deterioration (IVRT), etc., diastolic dysfunction is caused by myocardial function index, no left ventricular size, mass change, or change in excretion score. Similarly, the use of isoproterenol showed myocardial hypertrophy, myocardial fibrosis and reduced ventricular diastole. Blockers of the renin-angiotensin-aldosterone system or β-adrenergic receptors did not show significant HFpEF. Coarctation of the aorta is an effective surgical method for the treatment of chronic hypertension and rodent hypertrophy. Coarctation of the aorta can cause concentric left ventricular hypertrophy in the early stage, which may lead to obvious ventricular compensatory function and abnormal diastolic filling. These abnormalities were further amplified at 12 and 18 weeks. The main limitation of using aortic coarctation or hypertension model constriction is that even if blood pressure is controlled, most patients with HFpEF still have symptoms of heart failure. Diabetes: About one-third of HFpEF patients have type 2 diabetes, and cardiovascular disease is the main cause of morbidity and death in diabetic patients. Interestingly, diastolic dysfunction is an early cardiac symptom of diabetes. This is because young diabetic patients mainly exhibit diastolic abnormalities, while HFREF rarely occurs in middle-aged obese diabetic patients. Insulin resistance, type 2 diabetes and hyperinsulinemia are a series of various muscles, including stimulating hypertrophy, increasing oxidative stress and inflammation/fibrosis, and inducing adverse changes in cardiomyocyte function and extracellular matrix, which have certain effects. . Many type 2 diabetes models summarize the characteristics of HFPEF patients, such as ob/ob mice lacking leptin and db/db mice lacking leptin receptors. Changes in leptin balance include narcolepsy, hyperglycemia, and hyperglycemia. Glycemia. blood sugar. Insulinemia and diabetes complications. In db/db mice, the left ventricular mass and wall thickness increase at 9 weeks of age, which can lead to cardiac hypertrophy. This is related to the decrease in the end-diastolic volume of the left ventricle. The progression of diabetic cardiomyopathy is accompanied by an increase in reactive oxygen species and interstitial fibrosis. Five-month-old mice exhibited hemodynamic changes, such as increased LVEDP and EDPVR, and decreased dp/dtmin to extend diastole. At this age, transthoracic echocardiography confirmed a decrease in systolic function and an increase in IVRT. A lower E/A clearly indicates diastolic heart failure. Application of angiotensin II to db/db mice for 4 weeks can induce the expression of myocardial hypertrophy and fibrosis markers, but does not affect the heart structure or cause HFpEF. Obese mice are animal models of obesity and diabetes, indicating that lipid accumulation in the heart can cause diastolic dysfunction. Ob/ob mice experience cardiac hypertrophy and triglyceride accumulation, as well as left ventricular diastolic dysfunction. This animal model gradually evolved into diabetic cardiomyopathy, with impaired contractility and relaxation.

　　Obesity: The global increase in the incidence of obesity heralds a continuous increase in the burden of cardiovascular disease. This is especially true for HFpEF, because the prevalence of obesity is 41-46% and is associated with an increased risk of hypertension. Dyslipidemia and diabetes are independent risk factors for its development. Many available obesity models are derived from selective mating between rats, including one of the two most important mutations in the leptin receptor. Zucker rats were originally genetic models of obesity and hypertension. Obese Zucker rats showed a left ventricular mass, early diastolic dysfunction and long-term IVRT. In contrast, in the case of mild hypertension and severe diastolic dysfunction, obese diabetic Zucker (ZDF) rats did not increase left ventricular mass. Cardiovascular metabolic syndrome: Dahl/SS obese rats were obtained by mating Dahl/SS rats with Zucker rats as a new metabolic syndrome model. At 15 weeks of age, female Dahl/SS/obese rats developed left ventricular diastolic dysfunction, severe left ventricular hypertrophy, fibrosis, and increased oxidative stress and inflammation of the heart. The recently discovered HFpEF model is obese ZSF1 rats. ZSF1 rats are a mixture of non-hypertensive lean female Zucker diabetic obese rats and naturally occurring hypertensive heart failure male rats (SHHF/MCC). The two rats have a common genetic background. 20-week-old ZSF1 obese rats have a powerful metabolic syndrome model because they exhibit hypertension, obesity, type 2 diabetes, insulin resistance, hyperinsulinemia, hypertriglyceridemia, hypercholesterolemia, and heart work Exhaustion. This cardiovascular metabolic risk model will produce diastolic dysfunction, such as long-term τ, upward displacement of EDPVR and increased arterial elasticity. In animal models, an important human characteristic diagnosis-exercise intolerance, appeared for the first time. At the same time, left ventricular hypertrophy and left atrium dilatation, and no signs of renal failure after 20 weeks. In male obese ZSF1 rats, the increase in myocardial stiffness is mainly due to changes in muscle filaments without obvious interstitial fibrosis.

　　Aging: The prevalence of HFpEF in female patients increases with age. Spontaneously aging mice (SAMP8) tend to provide a good model of aging-related cardiac function. At 6 months of age, the animal model showed a significant reduction in the E/A ratio and fibrosis. There was no difference in systolic function or mean arterial pressure in SAMP8 mice. FVB/N mice represent a strong inbred line. Male mice showed diastolic dysfunction within 12 months, but this phenomenon was not observed in female mice. HFpEF large animal model: Compared with large mammals, especially the human heart, rodents have inherent limitations due to their size, heart structure and function. Therefore, the experimental model of human heart failure is also summarized in large animal models, which is particularly helpful for elucidating some important pathophysiology of diastolic dysfunction and HFpE.

　　Aortic valve stenosis: Studies have shown that, especially during exercise, there is vascular endothelial dysfunction, which promotes cell apoptosis in abnormal energy metabolism, myocardial perfusion failure during exercise and excessive oxygen consumption during exercise. Myocardial perfusion reserve is impaired. Over time, it may cause diastolic failure in this model. Cardiac dysfunction usually fluctuates, and the levels of cardiomyocytes are still abnormal, but they are not always obvious in the body. In their study, the increase in left ventricular fibrosis was due to collagen stability rather than increased expression, and collagen content was related to myocardial stiffness. Animal models of obesity, metabolic syndrome and diabetes: There are few large animal models of obesity and metabolic syndrome (for example, combined with a high-fat diet or experimental diabetes) that induce HFpEF. However, in type 2 diabetic rhesus monkeys, although the degree of diastolic dysfunction varies, LV histology was performed in only one diseased animal. In addition, some large animal models with the characteristics of metabolic syndrome show changes in the function and structure of coronary arteries. Porcine models of obesity and metabolic syndrome show coronary microvascular dilatation, which is associated with decreased coronary blood flow, myocardial ischemia, and coronary artery drug-resistant microvascular remodeling. In the pre-atherosclerotic type 2 pig model of diabetes, small coronary arteries show reduced bioavailability of nitric oxide and reduced endothelin-1 response. Unfortunately, there is no cardiac function research yet, and further research is needed to evaluate the impact of these coronary vascular abnormalities on cardiac function.

　　Animal model of aging: With age, the cardiovascular system will harden, thereby increasing the incidence of patients. Therefore, old dogs are used to study the effect of age on function. Aging does not significantly affect the structure and function of the left ventricle. However, although myocardial fibrosis is similar to the control level, aging and renal encapsulation can lead to impaired diastolic function. It has been suggested that high blood pressure is the cause of ageing. It was observed that the left ventricular dilatation of elderly dogs was less than that of puppies, and the left ventricular end-diastolic volume decreased with the increase of LVEDP. Ejection fraction and left ventricular mass are not affected. This model reflects many aspects of HFpEF and may be useful for future research.

　　Conclusion: Researchers need to determine the risk factors or risk factor combinations that lead to multifactorial diseases. Therefore, choosing the right model is very important. This will help you better understand and discover new knowledge about your disease.