心衰大动物模型 z-bo 2020-10-13 364

　　Introduction: The pre-clinical large animal model of heart failure (HF) plays an important role in the development and clinical approval of new therapies and new equipment. Facts have proved that the complex combination of these cardiovascular events and the risk factors that lead to heart failure makes it difficult for these patients to develop new treatments. This latest review introduces the history and latest research of HF pig, sheep and dog models, and outlines existing methods and physiological phenotypes. Through an overview of the latest equipment approved by the Food and Drug Administration and an overview of pre-clinical HF animal studies used to support research and development and safety and/or efficacy testing, large animal studies have achieved clinical success. The importance is also emphasized. HF animal studies are used to support development and safety and/or efficacy testing. It is very possible to use large-scale HF animal models to determine new mechanisms of potential clinical conditions, improve the physiological and economic translation of animal research, and successfully treat human HF that can be used for decades.

　　 The complexity of heart failure (HF) has been challenging the scientific community. Many aspects of the pathophysiological mechanisms driving HF have been studied in detail. However, the heterogeneity of the disease limits the treatment progress in this field. Not surprisingly, the prevalence of heart failure continues to increase at an alarming rate. An important feature of heart failure is the inability of the heart to provide enough blood for the body, which may lead to a decrease in the patient's quality of life. In the past thirty years, HF diagnosis has developed into two main categories: 1) Reduced emission rate (HFrEF) HF, which is characterized by a static emission rate (EF) ≤ 40%, commonly referred to as shrinkage. HF; and 2) Radiation-saving HF (HFpEF) with a static EF of 50% or higher is traditionally called extended HF. Recently, a third type of heart failure was introduced in the region, called intermediate frequency EF HF. It has a dormant EF in the range of 40% to 50%. Due to a combination of risk factors (lack of physical activity), comorbidities (obesity, hypertension, type 2 diabetes, chronic kidney disease), and disease modifiers (age, gender) related to heart failure, it is difficult to improve treatment options. meeting. The reasons for these difficulties are the lack of ideal animal models and the inability to reliably reproduce most of the common pathophysiological characteristics of human HF. Since the main determinants of myocardial function and energy expenditure (such as left ventricular (LV) wall tension, heart rate and blood vessel wall space) are similar to humans, it is suitable for large animal models of heart failure (pigs, sheep, etc.). The clinical benefits have changed. In addition to using large preclinical animal models of heart failure to discover new syndrome mechanisms and develop and/or test new treatment options for the treatment of heart failure, this highly prevalent cardiovascular system understands that you need to help improve your disease contact. The latest review outlines the existing methods and physiological phenotypes of several heart failure models developed in large animals.

　　HF caused by pressure overload:

　　 Aortic valve stenosis or chronic pressure overload caused by systemic hypertension can eventually lead to heart failure. Over time, the continuous myocardial activity required to overcome the chronic rise in afterload undergoes structural, physiological, and molecular changes that can lead to pathological heart remodeling. trigger. In addition, the vascular dysfunction of many organs including the heart, brain, skeletal muscle and kidney system may also be adversely affected, leading to further cardiovascular dysfunction. The heart enters the compensatory phase to maintain normal function (usually measured by EF). It is characterized by left ventricular hypertrophy, increased myocardial sclerosis, decreased myocardial relaxation, increased left ventricular filling pressure, pulmonary congestion, and decreased cardiac reserve. Patients transitioning to the functional compensation stage usually show symptoms and signs similar to HFpEF. Taking into account the fact that many patients with heart failure suffer from hypertension and/or aortic stenosis, it is necessary to strengthen the understanding of how these pathological mechanisms contribute to the development of the disease. Many large animal models of heart failure caused by overload have been developed. Many of these models incorporate features such as obesity, type 2 diabetes, and chronic kidney disease into the overall design to address clinical syndromes, traditional HF physiological features (pulmonary congestion, respiratory distress, etc.) and movement disorders. More completely imitate. Resistance). Therefore, surgical techniques such as transthoracic aortic constriction, renal bandage and renal microembolization have been used in pigs, sheep and dogs to establish animal models of heart failure caused by pressure overload. .. Endocrine interventions based on high-salt diets (such as deoxycorticosterone acetate) are also used. Transthoracic aortic fusion attempts to rebuild aortic stenosis by constricting the aorta, resulting in increased local myocardial afterload. The severity of each condition depends on the location of the aortic contraction (for example, ascending and descending aorta). Similar to what is observed in aortic stenosis, the aortic area increases the aortic pressure gradient of the left ventricle, induces concentric left ventricular hypertrophy, increases myocardial stiffness, and impairs myocardial relaxation. However, aortic fusion cannot reproduce aortic valve calcification and fibrosis. It also does not significantly increase the stiffness of blood vessels along the length of the aorta, which is common in human aortic stenosis. Kidney dressing, renal microembolism, and transplantation of deoxycorticosterone acetate pellets cause systemic hypertension through neurohumoral activation. Although effective, these methods cannot be used because they cannot integrate the genetic factors that usually cause high blood pressure and cannot use superphysiological doses of salt. .. Considering these general advantages and disadvantages, the next section will introduce the existing large-scale HF animal models caused by pressure overload, and focus on the physiological and molecular phenotypes associated with each animal. guess. Aortic coagulation model: In the absence of comorbidities, several different studies examined the aortic band in pigs. A systolic blood pressure gradient of 60-70 mmhg is used to shrink the ascending aorta of a 45-day-old Yorkshire pig, which can cause heart pressure overload. In these animals, traditional signs of heart failure include less than half of the aortic nodule animals with 100-2000 ml of ascites. At the same time, signs of left and right ventricular hypertrophy were observed, accompanied by diastolic dysfunction, manifested as increased end-diastolic pressure (EDP), depending on the severity of the disease. A systolic pressure gradient of 50 or 70 mmHg was used to induce chronic pressure overload in 3- and 8-month-old Yucatan minipigs to induce HF, which lasted for 6 months in the ascending aorta. In this model, typical symptoms of experimental heart failure include increased levels of left ventricular natriuretic peptide mRNA and increased lung weight. The molecular and physiological phenotypes of these animals are most reminiscent of HFpEF. This includes overall central petal enlargement, normal resting EF, diastolic dysfunction (increased end-diastolic pressure-volume relationship, impaired early and late diastolic tension, cardiomyocyte calcium therapy, etc.). will. Changes), fibrosis increases extracellular matrix (ECM) regulation, mitochondrial dysfunction, and changes in gender differences in disease symptoms. The model also showed obvious signs of vascular dysfunction in the coronary vessels including the brain and surrounding vascular beds.

　　Other models of HF developed using the porcine aortic area include the study by Ishikawa et al. A custom rubber band with an inner diameter of 12 cm was attached to the ascending aorta (10 to 13 kg) of Yorkshire pigs, and Ishikawa et al. followed it for 3 to 5 months. These animals did not show historical experimental signs of heart failure, but had EF retention, diastolic dysfunction (increased end-diastolic pressure-volume relationship, increased EDP during pacing), and left ventricular hypertrophy. And showed increased fibrosis. Yarbrough et al. Use an inflatable cuff on the ascending aorta of Yorkshire pigs. Inflate the cuff for 5 weeks every week to gradually contract the ascending aorta. The final measurement results include diastolic dysfunction (increased LVEDP and tau), increased fibrosis, local myocardial stiffness and ECM regulation biomarkers (MMP-7 and -14, TIMP-1 and -4). The accompanying pressure gradient is shown as 66 mmHg. Related to the level. This more acute model of myocardial overload cannot provide traditional indicators of heart failure.

　　 A recent attempt to study the heterogeneity of heart failure by combining a Western diet (10 months) with chronic pressure overload (6 months; 70 mmHg systolic pressure gradient) using aortic stenosis. The HFpEF working group of the National Heart, Lung, and Blood Institute recently listed it as a multipoint model for studying the heterogeneity of HFpEF. These animals exhibit classic experimental markers of HF, such as increased lung weight and many HF-related diseases. Genetic characteristics induced by genes. Obvious inflammation and metabolic abnormalities (obesity, insulin resistance, dyslipidemia) have been observed clinically and molecularly, which are considered to be the main causes of HFpEF. The molecular and physiological phenotypes are concentric left ventricular hypertrophy, normal EF, diastolic dysfunction (increased end-diastolic pressure-volume relationship, impaired early and late diastolic tension), changes in ECM composition, and mitochondrial dysfunction. It can also cause HFpEF.

　　 Compared with the pig model, in the sheep stress-induced heart failure model, the onset of systolic dysfunction usually precedes the onset of diastolic dysfunction. Acute and chronic models of canine heart failure caused by pressure overload have been widely used for more than 40 years. Over time, the use of dog models has declined. This is due to extensive collateral circulation in dogs. This is completely different from the collateral circulation of other large animals (such as humans and pigs).

　　Heart failure caused by myocardial infarction:

　　Myocardial cell death associated with abnormal cardiac insufficiency is the main feature of myocardial infarction (MI), which may eventually lead to HF. This catastrophic event occurs due to partial or complete blockage of one or more coronary arteries, thereby blocking blood flow in various areas of the heart muscle. Correctly identifying the different types of myocardial infarction caused by ischemia is very important for optimizing patient treatment and seeking translation studies that mimic the development of acute myocardial infarction and subsequent heart failure. This is an important consideration. In this regard, the general definition of MI is driven by MI, including biomarkers (such as cardiac troponin levels), pathological features (such as edema, reduced glycogen content, and mitochondrial abnormalities), and electrocardiogram (such as electrocardiogram). It has recently been updated based on major clinical forecasts. For example, the new ST-segment elevation), echocardiography, radionuclide imaging, or magnetic resonance imaging (such as free myocardial wall rupture or mitral regurgitation). The structural, functional and metabolic characteristics of the heart after myocardial infarction indicate rupture of the contractile apparatus, mitochondrial damage, endothelial dysfunction and increased cell death. Consistent with the progression of HF, MI-induced HF animal models showed early ischemia, subsequent reductions in cardiac output and EF, ventricular dilatation associated with normal or reduced wall thickness, and ischemic fibrosis. This will be a feature. , The neurohormonal system is activated, and the reserve capacity of the heart is reduced. Experimental models of MI-induced HF include ischemia/reperfusion (I/R), irreversible coronary artery occlusion caused by coronary artery ligation or coronary artery stenosis, and coronary microembolism. .. Each technique includes clinical features, including the central and peripheral changes observed in patients with HFrEF caused by myocardial infarction. The molecular mechanisms leading to reperfusion injury are sudden arrhythmia, calcium overload, oxidative stress caused by myocardial spectacles, and microvascular and endothelial dysfunction. This method is most commonly used in the left anterior descending coronary artery (LAD) or left circumflex coronary artery (LCx) of the reversible ligation or inflatable angiogenic balloon. Although dogs have historically been used in I/R studies, the extensive coronary collateral circulation in the dog's heart significantly reduces the use of this model. In pigs and sheep, the advantage of the I/R method is that it can predict size and use similarities similar to human coronary arteries, such as the overall anatomy and lack of existing collateral vessels. Including infarction in situ. The weakness of the pig and sheep I/R model is the obvious susceptibility to arrhythmia, and the difficulty of imaging the heart due to the different anatomical structure of the gastrointestinal tract, which depends on irrigation. included. Irreversible coronary artery blockage can be achieved by suture ligation or enamel contraction agent without reperfusion. Coronary artery suture ligation is a direct method of acute myocardial infarction. Ameloid constrictor can simulate myocardial infarction caused by coronary artery stenosis. Finally, coronary microembolism is a continuous infusion of microspheres that can be performed quickly and/or over time. The accumulation of atherosclerotic plaque in the coronary microcirculation increases the incidence of microembolism by 20% to 79%, which may also be caused by PCI. Destroying the rupture of coronary atherosclerotic plaque, erosion or calcification nodules can release harmful substances and accumulate in the distal coronary microcirculation, causing vasoconstriction, inflammation and potential microinfarction. sexual. Currently, in the absence of obvious coronary artery occlusion, there is clinical evidence that atherosclerosis leads to reduction of myocardial blood flow, and the occurrence of myocardial infarction is classified as myocardial infarction without coronary heart disease. Atherosclerotic plaque rupture followed by coronary microembolism can impair myocardial contractility and increase inflammation mainly mediated by tumor necrosis factor-α. Persistent embolism can lead to recurrence of thrombus and possibly myocardial infarction. This technology can simulate the chronic effects of myocardial ischemia, which gradually increases over time, but due to its limited ability to control multiple embolisms and the degree of obstruction of the entire coronary vascular tree. , The consistency and repeatability of infarction may be high. difficult. In addition, this model can cause myocardial infarction and remodeling of the site, leading to variability and differences in the evaluation process.　　

　　Arrhythmic heart failure:

　　The pathological interaction between arrhythmia and heart failure has been confirmed. In confirmed cases of heart failure, the incidence and/or mortality of arrhythmia and heart failure increase. Recently, cardiomyopathy caused by arrhythmia has been proposed as a more comprehensive method to study the various effects of electrophysiological pathology on the overall HF syndrome. With or without EF, sudden cardiac death is an important cause of death in HF, and the role of tachycardia in the occurrence of HF has always been the focus of attention. In particular, supraventricular arrhythmias such as atrial fibrillation (AF) can triple the risk of HF. As with the human syndrome, in the myocardial animal model induced by arrhythmia, the development of HF involves ventricular dilation and wall thickness reduction, followed by cardiac output and EF over time. Continue to decrease, the neuroendocrine system is activated, and calcium homeostasis is significantly impaired. The experimental model of arrhythmia is characterized by a chronic rapid pacing cycle, which is mainly manifested in the anatomical position of the pacemaker. In tachycardia models, a pacemaker is implanted in the right or left ventricle, while animal models of atrial fibrosis usually stimulate pathological pacing of the myocardium from the atrial position. Interestingly, the model of heart failure caused by arrhythmia includes the nearly complete recovery of myocardial function and structure after the pacing stimulation. The following are some important considerations for these techniques: 1) Changes in the structure and function of the myocardium within the same heart. Proximity to the pacemaker makes a big difference. 2) The occurrence of heart failure is directly related to the frequency and duration of pacing. In addition, atrial pacing has been shown to be unable to maintain chronic atrial fibrosis for more than 2-8 weeks, usually requiring the use of traditional cardiac drugs, such as beta-blockers and cardiac glycosides.

　　Transformation effect of HF large animal model: an important part of clinical success?

　　Large-scale preclinical animal models of cardiovascular disease are essential. Although the preclinical loss rate is only 35%, this high failure rate still occurs, and the high level of success in animal studies may be "stupid". .. Some are related to the clinical inability of animal studies to perform clinical translation, including overly optimistic conclusions drawn from animal studies with methodological flaws, which cannot fully reflect animal models of human diseases. Factors have already been proposed. A large-scale pathophysiological animal model is also needed to improve the transformation ability through the following ways: 1) promote clinical delivery, support imaging and testing of equipment; 2) valuable toxicology and provide biodistribution information; 3) provide relevant physiological input Guide clinical risk calculations and omics-based assessments useful in precision medicine. Supporting data for large animal models is usually an important aspect of the process of exempting new drugs and new devices from research and testing, and has been approved by the FDA. The FDA evaluates, regulates, and approves various medical products, including intra-arterial balloon pumps (IABP), axial flow pumps, left atrium to femoral ventricular assist devices, and mechanical circulation assist devices for patients with heart failure. .. These devices mechanically support the myocardium, provide short-term systemic hemodynamic support, and minimize myocardial load in the case of ischemic events complicated by cardiogenic shock or high-risk PCI. In a pig model of acute myocardial infarction or ventricular arrhythmia, the effect of tandem heart on hemodynamics and cardiac morphology was studied.

　　Conclusion: Preclinical large animal models play an important role in the development and clinical approval of new cardiovascular therapies, and they are still expanding. The physiology and economics of animal research are increasingly using large-scale HF animal models to discover new mechanisms of heart failure, provide the safety and effectiveness of new therapies, and successfully treat human heart failure to provide value for improving profitability Information has important potential.