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SWINE IN BIOMEDICAL RESEARCH

M MICHAEL SWINDLE, DVM

SWINETECH@HOTMAIL.COM

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