Lapis ISSN 2398-2969

Arteriosclerosis

Contributor(s): Michelle Ward, Michelle Campbell-Ward, Aidan Raftery, Sarah Pellett

Introduction

  • Arteriosclerosis refers to thickening and hardening of arterial walls.
  • This condition is rare in rabbits and is even more rarely diagnosed.  
  • Rabbits are widely used for the study of human atherosclerosis because of their unique feature of lipoprotein metabolism. Rabbits are also sensitive to cholesterol in the diet. 
  • Cause: as a result of proliferative or degenerative changes. This leads to a loss of arterial elasticity and subsequently impaired circulation.
  • Lesions can occur in all major arteries, eg carotid/coronary/renal, but are most pronounced in the descending thoracic aorta and aortic arch. 
  • Arterial wall thickening may be due to calcium deposits (usually termed spontaneous arteriosclerosis) or cholesterol/lipid deposits (referred to as atherosclerosis). 
  • Signs: generally non-specific; referable to the organ supplied by the affected artery.
  • Diagnosis: radiography, serum cholesterol, serum ionized calcium, urinalysis, BP measurement, cardiac assessment.
  • Treatment: no specific treatment available.
  • Prognosis: likely to be poor.

Our understanding of this disease in the rabbit is based almost entirely on laboratory rabbit research. The incidence and clinical characteristics of arteriosclerosis in pet rabbits are largely unknown.

Presenting signs

  • Often an incidental finding. 
  • When clinical signs are present, they are generally non-specific; lethargy, anorexia and weight loss.
  • May be referable to the organ/part of the body supplied by the affected artery.

Acute presentation

  • Uncommon. 
  • Theoretically, may present acutely if circulatory function to one or more organs is disrupted.

Age predisposition

  • Generally incidence increases with age. 
  • Been observed as early as 6 weeks of age.

Sex predisposition

  • Cholesterol concentrations show greater seasonal variation in experimental female rabbits than in males, with some sources suggesting female rabbits are less prone to diet-induced atherosclerosis because of the atheroprotective effect of 17-β-estradiol. Other sources suggest cholesterol levels are lower in pregnant and lactating female rabbits than in non-pregnant, non-lactating ones.
  • Male rabbits are preferable for use in atherosclerosis research because of the varying cholesterol concentrations in females, possibly affected by estrogen.
  • No information is available in relation to sex predisposition in pet rabbits.

Breed predisposition

  • Can occur in any breed and in wild rabbits but there appears to be significant breed predispositions. 
  • Spontaneous arteriosclerosis:
    • Low incidence (10%) in Dutch rabbits Dutch in the US and the Danish Country strain of albino rabbit in Europe.
    • High incidence (>40%) in laboratory strains of New Zealand White rabbits New Zealand White.
  • Some laboratory strains of rabbits have been specifically bred as research models with a predisposition to develop atherosclerosis:
    • Watanabe Heritable Hyperlipidemic Rabbit analogous to human familial hypercholesterolemia.
    • St Thomas.
    • Houston RT.
    • Genetically modified (transgenic and knock-out) rabbits.

Public health considerations

  • None.

Cost considerations

  • Costs associated with obtaining a diagnosis are variable depending on the location and nature of the disease process. Plain radiography alone may provide a diagnosis but for complete evaluation of many patients serum biochemistry Blood biochemistry: overview and echocardiography may also be considered.
  • Expensive imaging techniques, eg computed tomography Computed tomography or magnetic resonance imaging Magnetic resonance imaging, are frequently used in human medicine in the diagnosis of arteriosclerosis. Their use in veterinary practice is currently limited but they may be employed for investigation of vascular disease of rabbits in the future. 
  • Treatment costs are minimal as therapy is largely supportive. 

Special risks

  • The cardiovascular system of rabbits with arteriosclerosis will be less able to tolerate and buffer insults, particularly if there is concurrent hypertension and/or cardiac insufficiency Heart: disease. As a result, there is a higher risk of anesthetic and surgical complications. 
  • Thorough pre-anesthetic evaluation of the pulmonary, cardiac and renal systems is recommended. 
  • Drug selection and dosage calculations must account for the patient's individual needs. 
  • During anesthesia Anesthesia: overview particular care must be taken to maintain adequate ventilation and to monitor blood pressure Blood pressure measurement Blood pressure measurementand tissue oxygenation Anesthetic monitoring: pulse oximetryAnesthetized rabbit 03.
  • Studies in human patients suggest that the risk of peri- and post-operative thromboembolism is higher in patients with arteriosclerosis.

Pathogenesis

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Diagnosis

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Treatment

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Prevention

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Sequelae

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Further Reading

Publications

Refereed papers

  • Recent references from PubMed and VetMedResource.
  • Fan J, Kitajima S, Watanabe T et al (2015) Rabbit models for the study of human atherosclerosis: from pathophysiological mechanisms to translational medicine. Pharmacol Ther 146, 104-119 PubMed.
  • Beaufrère H (2013) Atherosclerosis: Comparative pathogenesis, lipoprotein metabolism, and avian and exotic companion mammal models. J Exotic Pet Med 22 (4), 320-335 VetMedResource.
  • Reusch B (2005) Investigation and management of cardiovascular disease in rabbits. In Pract 27 (8), 418-425 VetMedResource.
  • Orlandi A, Francesconi A, Marcellini M et al (2004) Role of ageing and coronary atherosclerosis in the development of cardiac fibrosis in the rabbit. Cardiovasc Res 64 (3), 544-552 PubMed.
  • Galle J, Quaschning T, Seibold S et al (2003) Endothelial dysfunction and inflammation: what is the link? Kidney Int Suppl (84), S45-S49 PubMed.
  • Haarbo J, Leth-Espensen P, Stender S et al (1991) Estrogen monotherapy and combined estrogen-progestogen therapy attenuate aortic accumulation of cholesterol in ovariectomized cholesterol-fed rabbits. J Clin Invest 87 (4), 1274-1279 PubMed.
  • Rosenfeld M E, Khoo J C, Miller E et al (1991) Macrophage-derived foam cells freshly isolated from rabbit atherosclerotic lesions degrade modified lipoproteins, promote oxidation of low-density lipoproteins, and contain oxidation-specific lipid-protein adducts. J Clin Invest 87 (1), 90-99 PubMed.
  • Wójcicki J, Rózewicka L, Barcew-Wiszniewska B et al (1991) Effect of selenium and vitamin E on the development of experimental atherosclerosis in rabbits. Atherosclerosis 87 (1), 9-16 PubMed.
  • Chobanian A V, Lichtenstein A H, Nilakhe V et al (1989) Influence of hypertension on aortic atherosclerosis in the Watanabe rabbit. Hypertension 14 (2), 203-209 PubMed.
  • Daugherty A, Zweifel B S & Schonfeld G (1989) Probucol attenuates the development of aortic atherosclerosis in cholesterol-fed rabbits. Br J Pharmacol 98 (2), 612-618 PubMed.
  • Kobayashi M, Ishida F, Takahashi T et al (1989) Preventive effect of MK-733 (simvastatin), an inhibitor of HMG-CoA reductase, on hypercholesterolemia and atherosclerosis induced by cholesterol feeding in rabbits. Jpn J Pharmacol 49 (1), 125-133 PubMed.
  • Kritchevsky D, Tepper S A, Davidson L M et al (1989) Experimental atherosclerosis in rabbits fed cholesterol-free diets. 13. Interactions of  proteins and fat. Atherosclerosis 75 (2-3), 123-127 PubMed
  • La Ville A E, Seddon A M, Shaikh M et al (1989) Primary prevention of atherosclerosis by lovastatin in a genetically hyperlipidaemic rabbit strain. Atherosclerosis 78 (2-3), 205-210 PubMed.
  • Ostlund-Lindqvist A M, Lindqvist P, Bräutigam J et al (1988) Effect of metoprolol on diet-induced atherosclerosis in rabbits. Arteriosclerosis (1), 40-45 PubMed.
  • Watanabe Y, Ito T, Shiomi M et al (1988) Preventive effect of pravastatin sodium, a potent inhibitor of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase, on coronary atherosclerosis and xanthoma in WHHL rabbits. Biochim Biophys Acta 960 (3), 294-302 PubMed.
  • Zhu B Q, Smith D L, Sievers R E et al (1988) Inhibition of atherosclerosis by fish oil in cholesterol-fed rabbits. J Am Coll Cardiol 12 (4), 1073-1078 PubMed.
  • Carew T E, Schwenke D C & Steinberg D (1987) Antiatherogenic effect of probucol unrelated to its hypocholesterolemic effect: evidence that antioxidants in vivo can selectively inhibit low density lipoprotein degradation in macrophage-rich fatty streaks and slow the progression of atherosclerosis in the Watanabe heritable hyperlipidemic rabbit. Proc Natl Acad Sci USA 84 (21), 7725-7729 PubMed.
  • Rosenfeld M E, Tsukada T, Gown A M et al (1987) Fatty streak initiation in Watanabe Heritable Hyperlipemic and comparably hypercholesterolemic fat-fed rabbits. Arteriosclerosis (1), 9-23 PubMed.
  • Rosenfeld M E, Tsukada T, Chait A et al (1987) Fatty streak expansion and maturation in Watanabe Heritable Hyperlipemic and comparably hypercholesterolemic fat-fed rabbits. Arteriosclerosis (1), 24-34 PubMed.
  • Subbiah M T R, Yunker R L, Rymaszewski Z et al (1987) Cholestyramine treatment in early life of low-density lipoprotein receptor deficient Watanabe rabbits: Decreased aortic cholesteryl ester accumulation and atherosclerosis in adult life. Biochim Biophys Acta 920 (3), 251-258 PubMed.
  • Bell F P & Schaub R G (1986) Chlorpromazine inhibits arterial ACAT and reduces arterial cholesterol and cholesteryl ester in cholesterol-fed rabbits. Arteriosclerosis (1), 42-49 PubMed
  • Hough J L & Zilversmit D B (1986) Effect of 17 beta estradiol on aortic cholesterol content and metabolism in cholesterol-fed rabbits. Arteriosclerosis (1), 57-63 PubMed.
  • Sugano M, Nakashima Y, Matsushima T et al (1986) Suppression of atherosclerosis in cholesterol-fed rabbits by diltiazem injection. Arteriosclerosis (2), 237-241 PubMed.
  • Tawara K, Ishihara M, Ogawa H et al (1986) Effect of probucol, pantethine and their combinations on serum lipoprotein metabolism and on the incidence of atheromatous lesions in the rabbit. Jpn J Pharmacol 41 (2), 211-222 PubMed.
  • Chobanian A V, Brecher P & Chan C (1985) Effects of propranolol on atherogenesis in the cholesterol-fed rabbit. Circ Res 56 (5), 755-762 PubMed.
  • Willis A L, Nagel B, Churchill V et al (1985) Antiatherosclerotic effects of nicardipine and nifedipine in cholesterol-fed rabbits. Arteriosclerosis (3), 250-255 PubMed.
  • Spence J D, Perkins D G, Kline R L et al (1984) Hemodynamic modification of aortic atherosclerosis. Effects of propranolol versus hydralazine in hypertensive hyperlipidemic rabbits. Atherosclerosis 50 (3), 325-333 PubMed.
  • Rouleau J L, Parmley W W, Stevens J et al (1983) Verapamil suppresses atherosclerosis in cholesterol-fed rabbits. J Am Coll Cardiol (6), 1453-1460 PubMed.
  • Henry P D & Bentley K I (1981) Suppression of atherogenesis in cholesterol-fed rabbits treated with nifedipine. J Clin Invest 68 (5), 1366-1369 PubMed.
  • Kita T, Brown M S, Watanabe Y et al (1981) Deficiency of low-density lipoprotein receptors in liver and adrenal gland of the WHHL rabbit, an animal model of familial hypercholesterolemia. Proc Natl Acad Sci USA 78 (4), 2268-2272 PubMed.
  • Kritchevsky D, Tepper S A, Czarnecki S K et al (1981) Experimental atherosclerosis in rabbits fed cholesterol-free diets. Part 9. Beef protein and textured vegetable protein. Atherosclerosis 39 (2), 169-175 PubMed.
  • Falcone D J, Hajjar D P & Minick C R (1980) Enhancement of cholesterol and cholesteryl ester accumulation in re-endothelialized aorta. Am J Pathol 99 (1), 81-104 PubMed.
  • Kramsch D M, Aspen A J & Apstein C S (1980) Suppression of experimental atherosclerosis by the Ca++-antagonist lanthanum. Possible role of calcium in atherogenesis. J Clin Invest 65 (5), 967-981 PubMed
  • Chan C T, Wells H & Kramsch D M (1978) Suppression of calcific fibrous-fatty plaque formation in rabbits by agents not affecting elevated serum cholesterol levels. The effect of thiophene compounds. Circ Res 43 (1), 115-125 PubMed
  • Kramsch D M & Chan C T (1978) The effect of agents interfering with soft tissue calcification and cell proliferation on calcific fibrous-fatty plaques in rabbits. Circ Res 42 (4), 562-571 PubMed.
  • Ross A C, Minick C R & Zilversmit D B (1978) Equal atherosclerosis in rabbits fed cholesterol-free, low-fat diet or cholesterol-supplemented diet. Atherosclerosis 29 (3), 301-315 PubMed.  
  • Roberts D C K, West C E, Redgrave T G & Smith J B (1974) Plasma cholesterol concentration in normal and cholesterol-fed rabbits. Atherosclerosis 19 (3), 369-380 VetMedResource.
  • Kritchevsky D, Kim H K & Tepper S A (1973) Effect of colestipol (U-26,597A) on experimental atherosclerosis in rabbits. Proc Soc Exp Biol Med 142 (1), 185-188 PubMed.
  • Adams W C, Gaman E M & Feigenbaum A S (1972) Breed differences in the responses of rabbits to atherogenic diets. Atherosclerosis 16 (3), 405-411 PubMed.
  • Kritchevsky D, Kim H K & Tepper S A (1971) Influence of 4,4-(isopropylidenedithio)bis(2,6-di-t-butylphenol)(DH-581) on experimental atherosclerosis in rabbits. Proc Soc Exp Biol Med 136 (4), 1216-1221 PubMed.
  • Garbarsch C, Matthiessen M E, Helin P & Lorenzen I (1970) Spontaneous aortic arteriosclerosis in rabbits of the Danish Country strain. Atherosclerosis 12 (2), 291-300 PubMed.
  • Kritchevsky D (1970) Role of cholesterol vehicle in experimental atherosclerosis. Am J Clin Nutr 23 (8), 1105-1110 PubMed.
  • Schenk E A, Gaman E & Feigenbaum A S (1966) Spontaneous aortic lesions in rabbits I. Morphologic Characteristics. II. Relationship to experimental atherosclerosis. Circ Res 19 (1), 80-95 VetMedResource.
  • Constantinides P, Booth J & Carlson G (1960) Production of advanced cholesterol atherosclerosis in the rabbit. Arch Pathol 70, 712-724 PubMed
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  • Maegraith B G & Carleton H M (1939) Aortic arteriosclerosis in rabbits. J Pathol Bacteriol 48 (1), 33-40 Wiley Online Library.
  • Kesten H D (1935) Early incidence of spontaneous medial degeneration ("arteriosclerosis") in the aorta of the rabbit. Arch Pathol 20, 1-8 CAB Direct.
  • Miles A B (1907) Spontaneous arterial degeneration in rabbits. JAMA XLIX (14), 1173-1176 JAMA Network.

Other sources of information

  • Delaney M A, Treuting P M & Rothenburger J L (2018) Lagomorpha. In: Pathology of Wildlife and Zoo Animals. Eds: Terio K A, McAloose D & St.Leger J. Elsevier, UK. pp 481-497.
  • Orcutt C (2014) Cardiovascular Disease. In: BSAVA Manual of Rabbit Medicine. Eds: Meredith A & Lord B. British Small Animal Veterinary Association, UK. pp 205-213.
  • Orcutt C J (2006) Cardiovascular Disorders. In: BSAVA Manual of Rabbit Medicine and Surgery. 2nd edn. Eds: Meredith A & Flecknell P. British Small Animal Veterinary Association, UK. pp 96-102.
  • Huston S M & Quesenberry K E (2004) Cardiovascular and lymphoproliferative diseases. In: Ferrets, Rabbit and Rodents: Clinical Medicine and Surgery. 2nd edn. Eds: Quesenberry K E & Carpenter J W. Saunders, USA. pp 211-220.   
  • Harcourt-Brown F (2002) Textbook of Rabbit Medicine. Butterworth Heinemann, UK.
  • Jayo J M, Schwenke D C & Clarkson T B (1994) Atherosclerosis Research. In: The Biology of the Laboratory Rabbit. 2nd edn. Eds: Manning P J, Ringler D H & Newcomer C E. Academic Press, USA. pp 367-380. 
  • Lindsey J R & Fox R R (1994) Inherited diseases and Variations. In: The Biology of the Laboratory Rabbit. 2nd edn. Eds: Manning P J, Ringler D H & Newcomer C E. Academic Press, USA. pp 293-319.


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