In the name of GOD Animal models of cardiovascular diseases: myocardial infarction & hypertension 44
Presentation outline: Cardiovascular diseases Acute myocardial infarction Animal models for myocardial infarction Hypertension Animal models of hypertension 43
Cardiovascular diseases Coronary heart disease Congestive heart failure Hypertension Stroke
Cardiovascular diseases Major cause of morbidity & mortality 30% of total deaths worldwide 17.1 million in 2004 23.4 million in 2030 38% of total death in Iran In America: 2010: $503.2 billion dollars Ischemic heart disease
Ischemic heart disease First global cause of death in 2004 Remain the first cause of death in 2030 Acute myocardial infarction Restricted regional flow of blood in coronary vessels Deprivation of myocardial tissue from oxygen and nutrients
Impairment of coronary blood supply to the myocardium Thrombosis embolism other acute alterations of coronary atherosclerotic plaques The heart can survive a short period of ischemia and exhibit recovery upon reperfusion but If the ischemic period is too long, tissue injury and cell death will occur
Animal models for myocardial infarction
Animal models for myocardial infarction Better understanding of disease pathophysiology, and progression of ischemia to myocardial infarction New approaches to diagnosis and treatment of diseases Drug development
Animal models for myocardial infarction Various species Large animals: pig, dog, sheep Expensive Require substantial resources for housing and care In several countries, investigations in larger animals are limited due to ethical considerations Small animals: mice, rat, rabbit Small size Easy availability Low maintenance cost
Ideal animal model Mimic human diseases Easy to reproduce Chronically stable Suitable for measurements of cardiac size and function Sufficiently economical to allow therapeutic trials
Animal models for myocardial infarction In vivo animal models of MI Surgical procedure Pharmacologically-induced models Genetically modified mice Ex vivo models of MI Langendorff heart model In vitro models of isolated cardiac cells
Surgical procedure
Coronary artery ligation model Occluding of the coronary arteries via thoracotomy to induce MI Ligation of the left anterior descending (LAD) coronary artery to create anterior wall infarction Surgical procedure Under anesthesia the hearts of animals are exposed following a left thoracotomy at the forth intercostal space The pericardium is carefully broken, and the LAD is ligated with a suture placed just distally from tip of the left auricle Permanent ligation of the LAD Irreversible damage to the myocardium Stable and easily reproduced Extensively employed in studies on MI therapies
Pharmacologically-induced models Convenient procedure Does not require complicated surgery Isoproterenol, adriyamycin, and ergonovin Increases myocardial oxygen consumption Induces coronary artery spasm Reduce blood flow Drug safety Difficulty in accurately positioning the infarct region
Isoproterenol Synthetic β-adrenergic agonist Enhanced catecholamine levels: myocardial hyperactivity: an imbalance between oxygen supply versus demand Administration of isoproterenol in high doses infarct-like necrosis of the heart muscle, which morphologically resembles acute myocardial infarction in humans
A single subcutaneous administration of ISO at a dose of 85-150 mg/kg body weight on two subsequent days ISO get auto oxidize into reactive oxygen species (ROS) Alters membrane permeability Increase the level of cardiac specific enzymes, low density lipoprotein (LDL), cholesterol Decreases the endogenous antioxidant enzyme levels widely used animal model Assessment of cardio protective activity of natural as well as synthetic compounds
Cardiovascular effects of acute myocardial infarction Cardiac structural and hemodynamic changes Echocardiographic parameters Left ventricular structural and functional abnormalities including increased systolic and diastolic left ventricular internal diameter, decreased EF and FS Hemodynamic parameters Reduction of LVSP, + dp/dt, -dp/dt and cardiac output, and elevation of LVEDP Increased serum levels of Cardiac troponin I Creatine kinase-mb (CK-MB) Lactate dehydrogenase (LDH)
Ex vivo models of MI Langendorff heart model German physiologist Oskar Langendorff Isolated heart model Excellent model for understanding the consequences of acute as well as chronic myocardial ischemia Advantages over in vivo MI models Easy to understand the pathophysiological changes and well controlled environmental conditions and elimination of hemodynamic and neurohumoral hindrances
Hypertension One billion individuals worldwide Major risk factor Myocardial infarction and heart failure Primary or essential hypertension: idiopathic Secondary hypertension Less than 20% of cases of hypertension
Effects of hypertension on cardiac functions Left ventricular hypertrophy Atrial fibrillation, ventricular arrhythmias and sudden cardiac death Three- to four-fold increase in the risk of stroke, Three- to four-fold increase in the risk of stroke, coronary heart disease, and peripheral arterial diseases
Effects of hypertension on vascular functions Changes in vascular endothelial functions: endothelial dysfunction Augmented vascular contractile responses to various vasoconstrictor agents Increased contraction responses to phenylephrine, potassium chloride, angiotensin II Impairment of relaxation response to vasodilator agents Decreased endothelium-dependent relaxation to Ach Unchanged endothelium-independent relaxation to sodium nitroprusside (SNP)
Animal models of hypertension Provided valuable information regarding many aspects of HTN Etiology Pathophysiology Complications Treatment The choice of animal model Research question Limitations Technical expertise
Animal models of HTN Renovascular Renal parenchymal Pharmacologically induced Genetic models
Etiology of HTN is heterogeneous Primary ( essential ) Etiology: unclear Interaction of multiple genetic and environmental factors Secondary to a defined process Renal artery stenosis
Ideal animal model for HTN research Human-like cardiovascular anatomy, hemodynamics, and physiology Develop the human HTN characteristics and complications Allow studies in chronic stable HTN Allow measurement of relevant hemodynamic and biochemical parameters
Renovascular HTN Goldblatt First animal models of HTN HTN in dogs by unilateral clamping of the renal artery 2-kidney, 1-clip (2K-1C) 2-kidney, 2-clip (2K-2C) 1-kidney, 1-clip (1K-1C)
2K-1C Model Both native kidneys: left intact Constricting clip (to resemble a clinical stenosis): placed on 1 renal artery In the absence of damage to the contralateral kidney Classic renin dependent model 2K-1C HTN Decreased renal arterial pressure in the clipped kidney Increase in plasma renin activity (PRA)
1K-1C Model unilateral nephrectomy placement of a constricting clip on the renal artery of the remaining kidney resembles patients who have only a solitary kidney and a significant renal artery stenosis in that kidney
Stimulation of the renin angiotensin aldosterone system Initial elevation of blood pressure Renin-angiotensin system (RAS) dependent In the absence of renal excretion or fluid loss Retention of water and salt Volume-overload form of hypertension
2K-2C Model Both renal arteries are constricted Less often used
Renal Parenchymal HTN Reduced Renal Mass Salt-Induced Model Clinically, the most common secondary cause of HTN is a loss of renal function from any cause The animal model that most closely approximates this clinical condition is the reduced renal mass model a renal mass reduction of >85% is required unilateral nephrectomy followed by surgical removal of two-thirds of the remaining kidney By itself, this degree of renal mass reduction results in only a slight BP increase compared with sham-operated, normotensive control animals A further increase in BP is provoked by the administration of excess salt in the drinking water or in the food PRA is low and the HTN is salt-dependent
Pharmacologically Induced HTN Deoxycorticosterone Acetate-Salt Induced Model Resembles the clinical situation of aldosterone excess Unilateral nephrectomy followed by administration of DOCA along with excess salt (usually, 0.9% NaCl drinking water)
Genetic Models of Hypertension Inbred Rat Models Discovery of individual animals spontaneously having high BP without any surgical or pharmacological intervention Genetic homogeneity is achieved by sibling mating of these hypertensive rat strains over several generations Spontaneously Hypertensive Rats (SHR) Dahl salt-sensitive rats
Spontaneously Hypertensive Rats Develop HTN and target organ damage similar to human essential HTN Pathophysiological changes are similar to those found in human essential HTN The pathogenesis of HTN in the SHR appears to be heterogeneous: CNS, neurohumoral, renal, and cellular abnormalities Screening of potential pharmacologic antihypertensive agents, and in the investigation of genetic determinants of high BP
Dahl salt-sensitive rats Requires administration of increased dietary sodium for BP elevation High-salt diets (8% NaCl enriched diet) Develop severe HTN
Conclusions No model mimics all traits of human hypertension choice of the animal model for HTN research research question Limitations technical expertise Models with an unknown etiology of HTN, such as genetic models (eg, SHR, Dahl) provide an opportunity to search for new mechanisms and new genes in HTN Models with a relatively known etiology of HTN, such as DOCA-salt models and Goldblatt models more useful in studying the neurohumoral mechanisms and the effects of elevated BP on target organs