DIFFERENTIAL CARDIOVASCULAR PHYSIOLOGY AND PATHOLOGY IN SELECTED LINEAGES OF MINIATURE SWINE AND COMPARISON TO HUMAN

Scientific Poster
Differential Cardiovascular Physiology and Pathology in Selected Lineages of Miniature Swine and Comparison to Human - SciPos104

Abstract

The miniature swine has been increasingly recognized as a valid alternative to canine and non-human primates in regulatory toxicity. This poster presents the results of cardiovascular assessments in the Yucatan, Hanford, and Sinclair miniature swine conducted during clinical investigations and control toxicity testing. Anatomic parameters were obtained at necropsy. Blood vessels diameter, velocity, and flow were obtained by Doppler ultrasonography. Cardiac electrophysiology was obtained using clinical ECG and surgical monitor units. Macroscopic lesions and histopathology assessments were conducted on heart and kidneys. Data were compared to published measurements of adult human illustrating similarities or differences (for practicality, male data are reported here). Across the three lineages, heart-to-body weights ratio ranged from 0.41 to 0.50 and were higher than human (0.42). The geometric corrections for heart rate adjustment to body size ranged from 219 to 349 and were comparable to human (241), indicating that heart volume and function were well adjusted to the reduction in body size. The miniswine hearts showed a coronary artery distribution comparable to human. The right coronary internal diameters ranged from 1.44 to 1.79 mm and were comparable to human (3.9 mm) when adjusted to body surface area (weight range: 51-85 kg). External femoral blood flows at rest averaged 93 mL/min and were slightly lower than human (260 mL/min) when adjusted to body size. Electrophysiological heart segments duration (e.g. RR ranged from 360 to 662 msec) and their ratio (QT/RR) were proportional to human and well-adjusted to body size. Macroscopic lesions were nonexistent. Histopathology findings were rare and limited to sub-level myocardial inflammation with low incidence in the Hanford lineage. In conclusion, the similarities between the cardiovascular systems make these three lineages of miniature swine suitable animals to model the human counterpart. In addition, the differences will aid investigators select a relevant lineage of miniature swine if specific cardiovascular parameters are required.

Authors

Stricker-Krongrad A.1, Madsen T.J.1, Hanks B.C.1,2, Brocksmith D.2, Liu J.1, Brown L.D.1,2, Bouchard G.F.1,2
¹Sinclair Research Center, LLC, Auxvasse, MO, USA; ²Sinclair Bio Resources, LLC, Auxvasse, MO, USA

Introduction

The use of the swine in biomedical research has been increasing over the past decades(i) and our understanding of swine physiology and pathophysiology is increasing, including cardiophysiology(ii, iii). The three most popular lineages of miniature swine are depicted in Figure 1. They are currently used in non-clinical pharmacology and toxicology studies with great success, due to their relatively small size and comparability to human physiology(iv).

Objective

This poster presents the results of cardiovascular assessments in the Yucatan, Hanford, and Sinclair miniature swine conducted during clinical investigations and control toxicity testing.

Hypothesis

Cardiovascular differences will aid investigators in selecting a relevant lineage of miniature swine if specific parameters are required.

Methods

Blood vessels diameter, velocity, and flow were obtained by Doppler ultrasonography. Cardiac electrophysiology was obtained using clinical ECG and surgical monitor units. Macroscopic lesions and histopathology assessments were conducted on heart and kidneys.

Data were compared to published measurements of adult human illustrating similarities or differences.

Results

The use of the miniature swine in biomedical research has been increasing over the past decade and the three most popular lineages of miniature swine are depicted in Figure 1. They are currently used in non-clinical pharmacology and toxicology studies with great success, due to their relative small size and comparability to human physiology. A comparison of human and swine similarities and differences focusing on the cardiovascular system and related functions is indicated in Table 1.

Figure 2 shows a “typical” QRS complex in limb lead II from a pig (top). The miniswine represents a category II animal (most mammals but primates and carnivores) whereas human represent category I animals (primates and carnivores)(v). The differences in configurations of the QRS complexes between category I and II animals arise principally from differences in pathways of ventricular activation, and those in turn arise from differences in distribution of Purkinje fibers within the ventricular freewalls and from anastomotic branches between the left and right main bundles observed in animals of category II(vi). Notice that different configurations to the QRS complexes are underlined by differences in the Electro-Mechanical Window (EMw), leading to shorter QT and longer EMw in the miniswine when compared to primates.

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Discussion

Across the three lineages, heart-to-body weights ratio ranged from 0.41 to 0.50 and were higher than human (0.42). The geometric corrections for heart rate adjustment to body size ranged from 219 to 349 and were comparable to human (241), indicating that heart volume and function were well adjusted to the reduction in body size. The miniswine hearts showed a coronary artery distribution comparable to human. The right coronary internal diameters ranged from 1.44 to 1.79 mm and were comparable to human (3.9 mm) when adjusted to body surface area (weight range: 51-85 kg). External femoral blood flows at rest averaged 93 mL/min and were slightly lower than human (260 mL/min) when adjusted to body size.

Electrophysiological heart segments duration (e.g., RR ranged from 360 to 662 msec) and their ratio (QT/RR) were proportional to human and well-adjusted to body size. The effects of known antiarrhythmic drugs have been tested in the minipig and have demonstrated that the miniature swine can be used for prediction of drug-induced QT interval prolongation. The similarities between their cardiovascular systems make these three lineages of miniature swine suitable animals to model the human counterpart. The fundamental cardiac conduction differences lie in the nerve fiber content of the swine heart (the bundle being richer in nerve trunks). This results in increased sensitivity when evaluating the effects of drugs or exercise on cardiac electrophysiology in the miniswine.

Macroscopic lesions of the heart and the kidneys were nonexistent. Histopathology findings were rare and limited to sub-level myocardial inflammation with low incidence in the Hanford lineage.

References

  1. McAnulty, PA et al. (2012). The Minipig in Biomedical Research, CRC Press, Inc., Boca Raton, FL.
  2. Stanton, HC & HJ Mersmann. (1986). Swine in Cardiovascular Research, Vol. 1 & 2, CRC Press, Inc., Boca Raton, FL.
  3. Smith, AC, B Knick, M Swindle & PC Gillette. (1997). A technique for conducting non-invasive cardiac electrophysiology studies in swine. J Invest Surg, 10(1-2): 25-30.
  4. Larry D. Brown, DVM, PhD, Alain Stricker-Kongrad, MS, PhD & Guy F. Bouchard, DVM, MS (2013). Current Protocols in Toxicology – Minipig: Applications in Toxicology. In press.
  5. Hamlin RL (2010). QRS in pigs versus in dogs. J Pharmacol Toxicol Methods. 62(1):4-5
  6. Bharati, S, M Levine, K Shoei, S Huang, B Handler, GVS Parr, R Bauernfeind & M Lev. (1991). The conduction system of the swine heart. Chest 100(l): 207-212.
  7. Kano M, Toyoshi T, Iwasaki S, Kato M, Shimizu M, Ota T. (2005). QT PRODACT: Usability of Miniature Pigs in Safety Pharmacology Studies: Assessment for Drug-induced QT Interval Prolongation. J Pharmacol Sci 99, 501-511.

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