心力衰竭动物模型 z-bo 2020-12-07 353

　　Introduction: Heart failure is one of the leading causes of death and disability worldwide. It can be defined as abnormalities in the structure and function of the heart, which can lead to ventricular filling or impaired ejection function. Heart failure can be divided into two types, namely reduced cardiac ejection fraction (HFREF) and heart failure with normal ejection fraction (HFPEF). HFREF systolic dysfunction is characterized by the inability of the heart muscle to contract and drain enough blood. HFPEF diastolic dysfunction, normal or near-normal systolic function (thus retaining ejection fraction). In addition, HFpEF does not show cardiac dilation, but has high filling pressure and pulmonary congestion, breathing difficulties and intolerance. For these reasons, exercise testing plays an important role in the diagnosis of patients. Myocardial remodeling HFpEF is characterized by abnormal left ventricular (LV) dilation, which may be caused by increased stiffness conditions, abnormal ventricular arterial action, increased vascular sclerosis, vascular endothelial dysfunction, heart rate, relaxation and/or impaired cardiovascular reserve function . The most important mechanism of diastolic dysfunction is ventricular muscle relaxation and/or changes in the passive characteristics of the ventricular wall. But not always interstitial fibrosis with left ventricular concentric remodeling/hypertrophy and atrial enlargement are related. These patients are generally older, mainly women, and exhibit a large number of comorbidities, including diabetes, hypertension, obesity, and renal insufficiency. HFpEF is a multifactorial disease. The heterogeneity of patients is not limited to the heart, but also involves complications that affect the entire cardiovascular system. The effective treatment strategy of HFPEF is hindered by the lack of appropriate animal models. There are only a few animal models, and the difficulty lies in replicating the clinical features of HFpEF animal models. Most of them are cardiac overload models that further develop into left ventricular concentric hypertrophy and diastolic dysfunction, but they rarely show the hemodynamic characteristics of human HFpEF. There is little evidence that the preclinical evaluation of potential new therapeutic targets is reliable. In this article, we present the currently available animal models, an overview of adoption research, including rodents and large animal models, as well as the strengths and weaknesses of these models.

　　HFpEF animal model: The main limitations of animal models are in mechanism research and pathophysiology. Most heart failure models are mainly HFrEF. Animal models of diastolic insufficiency 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, namely aging, diabetes and hypertension.

　　 The rodent model of HFpEF: Aortic stenosis and systemic hypertension: Hypertension is an important risk factor for some heart diseases, and it is also a major cause of HfpEF. Therefore, it is not surprising that many studies of HfpEF model increased afterload and left ventricular concentric hypertrophy (ie, transverse aortic coarctation or systemic arterial hypertension). Dahl/SS rats were selected from SD rats showing hypertension. Dahl/SS rats are characterized by sodium intake hypersensitivity and the most representative animal model of HfpEF. When fed a high-salt diet from 7 weeks of age, Dahl/SS rats developed renal failure, hypertension (> 175 mmHg) and left ventricular hypertrophy, and developed HfpEF between 12 to 19 weeks. At 12 weeks, Dahl/SS rats developed diastolic dysfunction, such as increased cavity stiffness (upper left end-diastolic pressure-volume transition (EDPVR) decreased end-diastolic volume). Between 16 and 20 weeks, Dahl/SS heart enlargement, end-diastole and EDPVR developed into age-matched controls. At the same time, the pump function curve tends to be controlled, and the ejection fraction drops, slowly turning into HfpEF. Although the master pump function is normal or enhanced at a certain point in time, the left ventricular end diastolic pressure (LVEDP) and lung wet weight increase, indicating the development of heart failure.

　　Deoxycorticosterone acetate (DOCA) salt-induced rat model represents a drug-induced hypertension model. One week after unilateral nephrectomy, at 7 weeks of age, DOCA was induced by intraperitoneal or subcutaneous injection. Within 4–5 weeks of chronic corticosterone treatment, it causes hypertension, renal hypertrophy, glomerular sclerosis, cardiac hypertrophy, and perivascular fibrosis. It is suitable for rats and mice. Isotonic saline is the only drinking solution that accelerates and aggravates the progression of hypertension. DOCA salt hypertensive rats develop myocardial inflammation, oxidative stress, fibrosis and diastolic dysfunction. Subsequently, related models were established, including exposure to lateral aortic constriction for 2 weeks until DOCA use, showing normal left ventricular systolic blood pressure and shortening fraction, hypertrophy, fibrosis and diastolic dysfunction (high LVEDP and EDPVR) and lungs The weight increase is consistent with HfpEF. Chronic stimulation of pro-hypertrophic drugs, such as angiotensin II and isoproterenol, is used as a model for systolic and diastolic dysfunction and left ventricular hypertrophy. Rats fed with Hypertensive Peptide II showed hypertension, left ventricular hypertrophy, fibrosis, and expression of natriuretic peptides. By increasing the time to left ventricular isovolumic relaxation/exacerbation (IVRT), myocardial performance indicators, without LV size, Changes in mass, or changes in ejection fraction, cause diastolic dysfunction. In the same way, 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. Moderate coarctation of the aorta can cause concentric left ventricular hypertrophy in the early stage, with significant ventricular compensatory function, and abnormal diastolic filling. These abnormalities became more exaggerated at 12 and 18 weeks. A major limitation of using aortic coarctation or hypertension models is that most patients with HFpEF continue to have symptoms of heart failure, even if blood pressure is controlled.

　　 Diabetes: About 1/3 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 manifestation of diabetes. Because young diabetic patients mainly exhibit diastolic abnormalities, and HFREF rarely occurs in middle-aged obese individuals with diabetes. Insulin resistance, type 2 diabetes, and hyperinsulinemia have a series of pleiotropic effects on the myocardium, including stimulating hypertrophy, increasing oxidative stress and inflammation/fibrosis, and inducing harmful changes in cardiomyocyte function and extracellular matrix. Many models of type 2 diabetes summarize the characteristics of HFPEF patients, including ob/ob mice lacking leptin, db/db mice deficient in leptin receptors, and their altered leptin balance leads to obesity due to bulimia, hyperglycemia, and hyperglycemia. Insulinemia and diabetes complications. In db/db mice, the left ventricular mass and wall thickness increase at 9 weeks of age, which leads to cardiac hypertrophy, which is related to the smaller 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 showed hemodynamic changes such as increasing LVEDP and EDPVR, and decreasing dp/dtmin to extend diastole. At this age, transthoracic echocardiography confirmed a decrease in systolic function and an increase in IVRT. A decrease in E/A clearly indicates diastolic dysfunction. Application of angiotensin II in db/db mice for 4 weeks induces the expression of myocardial hypertrophy and fibrosis markers, but does not affect the heart structure or cause HFpEF. The ob mouse is an animal model of obesity and diabetes, showing that heart lipid accumulation may lead to diastolic dysfunction. Ob/ob mice develop cardiac hypertrophy and triglyceride accumulation, similar to left ventricular diastolic dysfunction. This animal model gradually developed into diabetic cardiomyopathy with impaired contractility and relaxation.

　　 Obesity: The global increase in the incidence of obesity heralds the continued increase in the burden of cardiovascular disease. This is especially true for HFpEF, because the prevalence of obesity is 41–46 %, which 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 crosses between rats, including one of the two most important mutations in the leptin receptor. Zucker rat, originally a genetic model of obesity and hypertension. Obese Zucker rats showed left ventricular mass and early diastolic dysfunction with prolonged IVRT. In contrast, obese diabetic Zucker (ZDF) rats did not increase left ventricular mass even with mild hypertension and significant diastolic dysfunction.

　　 Cardiovascular and Metabolic Syndrome: Dahl/SS obese rats are obtained by crossing Dahl/SS and Zucker rats as a new metabolic syndrome model. At 15 weeks of age, female Dahl/SS/obese rats developed left ventricular diastolic dysfunction, significant left ventricular hypertrophy, fibrosis, and increased cardiac oxidative stress and inflammation. The recently discovered HFpEF model is obese ZSF1 rats. ZSF1 rats are crosses of non-hypertensive lean female Zucker diabetic obese rats and spontaneous hypertensive heart failure-prone male rats (SHHF/MCC). The two rats share a common genetic background. The 20-week-old ZSF1 obese rat is a powerful metabolic syndrome model because it displays hypertension, obesity, type 2 diabetes, insulin resistance, hyperinsulinemia, hypertriglyceridemia, hypercholesterolemia, and heart failure. This cardiometabolic risk model develops diastolic dysfunction, such as long-term τ, upward displacement of EDPVR, and elevated arterial elasticity. For the first time, an important human characteristic diagnosis-exercise intolerance appeared in an animal model. At the same time, there was left ventricular hypertrophy and left atrium dilation, and there was no sign of renal failure after 20 weeks. In male obese ZSF1 rats, the increase in myocardial stiffness seems to be mainly due to changes in myofilaments without obvious interstitial fibrosis.

　　Aging: The prevalence of HFpEF in female patients increases with age. Naturally aging mice (SAMP8) tend to provide a good model of heart function associated with aging. At 6 months of age, the animal model showed a significant decrease 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 powerful inbred line. Male mice showed diastolic dysfunction within 12 months, while female mice did not observe this phenomenon.

　　 HFpEF large animal model: Rodents have inherent limitations due to their size, heart structure and function compared with larger mammalian species, especially the human heart. Therefore, the experimental models of human heart failure have also been summarized in large animal models, which are particularly useful in elucidating several important pathophysiological aspects of diastolic dysfunction and HFpE. Aortic stenosis: Studies have revealed that the existing myocardial blood flow reserve is impaired, especially in the coronary arteries with impaired vascular endothelial function during exercise, which promotes apoptosis during abnormal energy metabolism, exhausted myocardial perfusion and exaggerated exercise Of oxygen consumption, all of which are possible contributions to diastolic dysfunction in this model. Cardiac dysfunction is often variable. Although abnormalities at the level of cardiomyocytes still exist, they are not always obvious in vivo. In their study, the increase in left ventricular fibrosis was due to increased collagen stability, not its expression, and collagen content was related to myocardial stiffness.

　　Obesity, metabolic syndrome and diabetes animal models: There are few large animal models of HFpEF induced by obesity and metabolic syndrome (such as high-fat diet or combined with experimental diabetes). However, in type 2 diabetic rhesus monkeys, despite varying degrees of diastolic dysfunction, LV histology was performed on 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. The pig model of obesity and metabolic syndrome showed coronary microvascular dilatation and coronary resistance microvascular remodeling, which is related to the reduction of coronary blood flow and myocardial ischemia. In the pre-atherosclerotic type 2 pig model of diabetes mellitus, small coronary arteries show a reduction in the bioavailability of nitric oxide and endothelin-1 response. Unfortunately, there is no cardiac function research, so further research is needed to evaluate the impact of these coronary vascular abnormalities on cardiac function.

　　 Animal model of aging: As the age increases, the known hardening of the cardiovascular system, and the incidence of patients increases. Therefore, old dogs are used to study the effect of age on functionality. Aging does not have a major impact on the structure and function of the left ventricle. However, aging and renal inclusion led to impaired diastolic function, although myocardial fibrosis was similar to the control level. It suggests that high blood pressure is an inducement that is not age. Compared with young dogs, it was observed that the LV dilatation of elderly dogs was reduced, and with the increase of LVEDP, the left ventricular end-diastolic volume decreased. Ejection fraction and left ventricular quality are not affected. This model reflects several aspects of HFpEF and may be useful in future studies.

　　 Conclusion: Researchers need to determine the risk factors or risk factor combinations that lead to multifactorial diseases. Therefore, it is very important to choose an appropriate model, which will help to better understand and discover new knowledge about the disease.