Osteoporos Int. 2013 Jul;24(7):2123-6.

Soft tissue calcification in the Ossabaw miniature pig: experimental and kinetic modeling studies.

Wastney M, Lee W, Jackson GS, Alloosh M, Sturek M, Lachcik P, Peacock M, Martin B, Weaver CM.

Department of Nutrition Science, Purdue University, Stone Hall, Rm 210, 700 W State Street, West Lafayette, IN 47907-2059, USA.

 

Abstract

Calcium (Ca) deposition into vascular tissue was measured in Ossabaw miniature pigs with and without metabolic syndrome (MetS) using Ca tracer kinetics and coronary atherosclerosis measured with intravascular ultrasound. Pigs with MetS had higher Ca uptake into coronary arteries than lean pigs.

INTRODUCTION: Ca deposition into arteries is a common disease in humans. The Ossabaw pig develops MetS when fed an atherogenic diet. The aim of this study was to measure Ca deposition into arteries of lean vs. MetS pigs.

METHODS: Male pigs were fed for 5 months with chow diet (healthy, lean; n = 7) or atherogenic diet (n = 8) consisting of chow supplemented with 2 % cholesterol, 43 % kcal from fat, and 20 % kcal from fructose. Pigs were verified to have MetS by obesity, insulin resistance, impaired glucose tolerance, dyslipidemia, and hypertension. Two pigs received 50 nCi of 41Ca i.v. and blood was drawn frequently for 24 h, and 2, 3, 6, 8, 10, 15, 20, and at sacrifice at 28 days after injection. Peripheral arteries were biopsied four times per pig over the 28th day and coronary artery sampled at sacrifice. Tissues were analyzed for 41Ca:Ca. A compartmental model was used to estimate rates of Ca deposition into the arteries.

RESULTS: The MetS swine had higher 41Ca and atherosclerosis in coronary arteries than lean pigs.

CONCLUSIONS: This pig model is a suitable model for studying vascular calcification in humans.

PMID: 23224107

 

Supplement:

Vascular calcification is a concern the in progression of cardiovascular disease.  This is common in people with chronic kidney disease.  Recently, the risk of calcium supplementation for vascular calcification and heart attacks has been hotly debated.  Methodological limitations have impeded our understanding of development of the disease and interventions that could prevent or ameliorate vascular calcification.  In humans, the classical approach is to evaluate vascular wall coverage of plaque by computed tomography (CT).  The disease has to be quite advanced to be able to detect coronary artery calcification by CT scans.  Sampling cardiovascular tissue in humans is not feasible.  A few investigators have used animal models to study development of atherosclerosis or to determine efficacy of interventions.  However, the animal models used, typically rodents and rabbits, have had serious limitations.  Rabbits do not exhibit the same type of lesions that are characteristic in humans.  Most of the cholesterol in rabbits and rats is transported as high-density lipoproteins, in contrast to the low-density lipoproteins associated with cardiovascular risk in humans.  Both mice and rats are generally resistant to diet-induced atherosclerosis as they lack plasma cholesteryl ester transfer protein (CEPT), a regulator of both lipoprotein metabolism and development of atherosclerosis.  Genetically-modified strains such as the ApoE-knock out mouse have been created which develop widespread plaque and calcification of aorta and coronary arteries.  Still, the plaques do not rupture or lead to subsequent vessel occlusion, a critical event of human atherosclerosis.

Ossabaw miniature swine-1

Swine are a superior animal model of human atherosclerosis as they have a similar circulating cholesterol composition to humans, they develop spontaneous atherosclerosis with advancing age, diet can influence the disease process as in humans, and they are more physiologically similar to humans.  We developed a new approach for studying early calcification of the arteries using the Ossabaw miniature swine and 41Ca metabolism.  Ossabaw pigs develop obesity, hypertension, and insulin resistance when fed an atherogenic diet that progresses from metabolic syndrome to type II diabetes and coronary artery disease.  The pigs evolved on the uninhabited island of Ossabaw Island where they acquired a “thrifty genotype”, capable of accumulating great fat stores due to seasonal availability of food resulting in periods of feasting and fasting.

To be able to monitor early uptake of calcium into the soft tissue of the coronary arteries in very small amounts, long before calcification could be detected by CT scans or even by histology, we used a rare, long-lived isotope of calcium, 41Ca, which can be detected by Accelerator Mass Spectrometry at concentrations of 10-18M (2).  We measured uptake of 41Ca into coronary arteries of 41Ca and expanded our kinetic model of calcium metabolism to include deposition into the heart.

Connie M. Weaver-2

We proved that calcium uptake into coronary arteries could be determined early in the disease process by this sensitive method.  The pigs made to be obese on the atherogenic  diet took up significantly more 41Ca than lean pigs fed the regular diet.

This model can be used to evaluate interventions for prevention and therapies for treatment of atherosclerosis.  Our first application is to evaluate whether dietary calcium supplementation promotes coronary artery calcification in the Ossabaw pig model.

References:

1. Neeb ZP, Edwards JM, Alloosh M, Long X, Mokelke EA, Sturek M.  Metabolic syndrome and coronary artery disease in Ossabaw compared with Yucatan swine.  Comparative Med. 60(4): 300-315, 2010.

2. Jackson GS, Weaver CM, Elmore D.  Use of accelerator mass spectrometry for studies in nutrition.  Nutr Res Rev  14:317-334, 2001.

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