swine in biomedical research...•dyslipidemia (increased ldl/hdl ratio) •increased plasma...
TRANSCRIPT
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SWINE IN BIOMEDICAL RESEARCH
M MICHAEL SWINDLE, DVM
PORCINE MODELS DEVELOPED/REFINED
• Teaching• Neonatal shunts-VSD, ASD• Interventional catheterization-Cryoablation, VSD
closure• Pacemaker testing• Fetal surgical models• Congestive heart failure• Cardiac hypertrophy• ECMO, CPB bypass0• Technical procedure development
Large White
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Yucatan
22 Kg Female
Ventral
Dorsal
Vaso Vasorum
Cardiac Conduction System
• Neurogenic rather than myogenic• Large numbers of adrenergic and cholinergic nerve
fibers• Nerve fibers in AV node and bundle branches• More proximal bifurcation of bundle branches, more
connective tissue, less elastic tissue• Large well differentiated subendocardial Purkinje
cells• Blood supply to conduction system similar
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Age vs Weight MatchingWeight
Different between breeds at same age
Index hemodynamics to body surface area
Age
Differences in hemodynamics at various stages of maturity even within the same breed
Heart weight: Body weight decreases with maturity
Atherosclerosis
High cholesterol / High fat diets
Endothelial / Intimal damage
Fatty streak lesion
Macrophage foam cells
Fibrous plaques (collagen, elastin)
Complicated lesions - inflammation, necrosis, calcification, neovascularization, hemorrhage
MENOPAUSE/AS MODELJ.A. Goodrich, DVM
Sexually mature Yucatan micropigs are ovariectomized and fed a 4% cholesterol diet free of plant phytoestrogens with 40% of the calories from fat for 6 months.
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DeploymentPre-stent
CFX
ImmediatePost-stent
CFX
• COURTESY OF MICHAEL STUREK
• University of Indiana
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Coronary Artery Restenosis
• Stent implantation
• 2-6 weeks for lesion
• Occlusion may lead to infarction and aneurysm
Spontaneous Diseases
• CardiomyopathiesGenetic hypertrophic
• EndocarditisBeta Hemolytic Streptococcal
AORTA
AV VALVE ATRIUM
GENETIC MODELS
Left Hypoplastic Heart Syndrome (LHHS)
Ventricular Septal Defect (VSD)
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VSD - FTT Syndrome
Reduced stroke volume is due to failure ofend-diastolic volume to increase adequatelyinstead of reduced contractility, increasedafterload or reduced preload.
Corin WJ, Swindle MM, et al: J Clin Invest, 1988
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INDICATIONS FORFETAL INTERVENTION
Correct congenital defect
Fetal drug delivery
Antenatal therapy may prevent postnatal complications
FETAL HYDROPS
• Life threatening condition associated with increase in fluid, heart failure and fetal arrhythmias.
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Fetal / Maternal Blood Levels (Moricizine)
Swine Sheep
Maternal Level (mg/ml) 0.61 0.95
Fetal Level (mg/ml) 1.04 0.68
Fet / Mat Ratio 1.71 0.71
FETAL MODEL SUMMARY
• Antenatal therapy is indicated in life threatening conditions
• Fetal intervention may be performed in pigs and is valuable in the study of pharmacologic agents
• It is possible to treat human fetuses with antiarrhythmics administered to the mother
FUTURE DIRECTION IN RESEARCH
Tissue engineering with medicated gel delivered by catheter device
Intrauterine delivery of therapeutic agent to close the VSD
Gene therapy
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Induced Models
Neonatal Shunts - PDA, ASD, VSDAortopulmonary shuntsCoarctation of the aortaAneurysm modelsPressure & volume overload modelsGrowing heart modelMyocardial infarct/coronary arteryValvular replacement
Ventricular HypertrophyConcentric
Left Ventricular wall thickness
Systemic blood pressure
Pressure overload models induced by surgical banding
Eccentric
Left ventricular end diastolic diameter
Cardiac output
Volume overload models induced by arteriovenous fistulas or valvular regurgitation
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DILATEDCARDIOMYOPATHY
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Creation of the AAA in the Animal Model
AAA CreationPig # 3
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Pig Vs. Human ElectrophysiologyPaced and IntrinsicPulse Duration 0.5 msec
Pig HumanThreshold Voltages (V)
Atrium 0.27-1.21 0.46-2.29Right Ventricle 0.23-0.51 0.27-0.61Left Ventricle 0.31-0.69 0.43-0.95
Threshold Current (mA)Atrium 0.47-2.87 0.81-6.78Right Ventricle 0.43-1.21 0.74-1.36Left Ventricle 0.72-1.44 0.70-1.47
Intrinsic Amplitudes (mV)p wave 2-6 2-5R wave 6-15 7-18
Treatment of Arrhythmias
• PharmacotherapyClass I Membrane Stabilizing Agents
Class II Beta Blockers
Class III Inhibit Repolarization, Prolong Refractory Period
Class IV Calcium Channel Blockers
• Defibrillation
• Cardiac Pacing
• Surgery
• Transvenous Catheter AblationDirect Current
Radiofrequency
Cryothermia
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Renal Diseases• Vesicoureteral reflux
• Intrarenal reflux
• Hypertension
• Hydronephrosis
Ferrer et al, Transplantation, 2008
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PANCREAS
DUODENUM
Diabetes/Transplant/Metabolic Syndrome
CARDIOMETABOLIC SYNDROME
• Intra-abdominal obesity
• Insulin resistance
• Impaired glucose tolerance
• Dyslipidemia (increased LDL/HDL ratio)
• Increased plasma triglyceride
• Hypertension
• Females predisposed
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DERMAL TOXICOLOGY
• Anatomy-relatively hairless, fixed skin, epidermal thickness, comparable histology, apocrine rather than eccrine sweat glands, fatty subcutis, pH 6-7 higher
• Physiology—Similarities in cellular turnover time, permeability, transdermal absorption, dermal metabolism
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SKELETAL SYSTEM
• Epiphyseal closure
• Domestic Pig 3-4 years
• Hanford 2-4 years
• Yucatan 2-3 years
• Yucatan micro/Gottingen1.5-2 years
• Temporomandibular & Stifle (knee) joint similar to humans
• Bone remodeling & regeneration rate of 1.2-1.5 µm/day (human 1.0-1.5)
MUSCLE CHARACTERISTICS
• Predominance of Type II B muscle fibers Lesser extent of Type IIA, IIC, and IIX fibers
SKELETAL & CARTILAGE MODELS
• Nutritional osteopenia
• Bone defect models: mandibular and cranial models have critical sized defects of 25 mm
• Femoral-Tibial joint cartilage defects have a critical size of 5-7 mm
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SPINAL MODELS
• C7, T14-15, L6-7, S4, Cy20-23
• Miniature breeds may have one less thoracic and/or lumbar vertebra.
• Scoliosis and kyphosis models
• Intervertebral disc degeneration
NATURAL ORIFICE TRANSLUMINAL ENDOSCOPIC SURGERY
•froMASS
GENERAL
HOSPITAL
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SUMMARY OF PORCINE MODELS
• No perfect animal model exists: General surgery• Cardiovascular—myocardial infarction,
atherosclerosis, arrhythmias, heart failure• Gastrointestinal/Digestive—oral studies, motility&
emptying time different, first pass metabolism• Renal—comparable anatomy and physiology• Dermal—transdermal absorption, wound healing• Hepatic—P4502D & 2C19 low, sulfation usually
absent, biotransformation both similar and different• Genetic—Pig genome project, ventricular septal
defect, cystic fibrosis, Alzheimer’s, retinitis pigmentosa, atherosclerosis, psoriasis, xenotransplant