Rebecka S. Hess, DVM, DACVIM
Atherosclerosis is a vascular disease characterized by intimal lesions called atheromas or fibrofatty plaques. An atheroma is a raised focal plaque within the intima comprised of a lipid core and covered by a fibrous cap. The lipid core consists mainly of cholesterol and cholesterol esters, which form cholesterol clefts, but it is also characterized by foam cells, necrotic cell debris, fibrin, and plasma proteins. Foam cells are formed when lipid globules accumulate in the cytoplasm of macrophages or smooth muscle cells.1-4 Atherosclerosis is a leading cause of mortality and morbidity in human beings 4,5 Some of the risk factors for atherosclerosis in human beings include dyslipidemia, increased age (> 40 years of age), male gender until age 55 (after menopause woman are at the same risk as men), diabetes mellitus, hypertension, and cigarette smoking.4
Hyperlipidemia is one of the main risk factors for atherosclerosis in human beings,4 and has been associated with atherosclerosis in hypothyroid dogs.1 Spontaneous atherosclerosis in dogs has been reported mainly in association with hypothyroidism, and is thought to develop due to hypercholesterolemia.1
Atherogenic dyslipidemia in human beings is characterized by increased concentration of small dense LDL, decreased concentration of high-density lipoprotein (HDL), increased plasma triglyceride concentration, and increased apolipoprotein B concentration. The pathophysiology by which small dense LDL increases the risk for atherosclerosis has been studied extensively. Several proposed mechanisms by which small dense LDL may increase the risk of atherosclerosis are increased ability of small dense LDL to penetrate the subintimal space, greater susceptibility of small dense LDL to oxidation, increased binding of small dense LDL to intimal proteoglycans, increased toxicity of small dense LDL to endothelial cells, small dense LDL stimulation of production and secretion of plasminogen activator inhibitor 1 and thromboxane by endothelial cells, and increased binding of small dense LDL to scavenger receptors, which contributes to formation of foam cells.
Diabetes mellitus, hypothyroidism, and hyperadrenocorticism (HAC) were examined retrospectively as possible risk factors for atherosclerosis in dogs, because all three endocrinopathies are associated with hypercholesterolemia. The case group included 30 dogs with histopathological evidence of atherosclerosis. The control group included 142 dogs with results of a complete necropsy, and no histopathological evidence of atherosclerosis.6
Serum was assessed subjectively for lipemia in all dogs included in the study. Lipemia was noted in 12 dogs (40%) in the case group and in 10 dogs (7%) in the control group. Mean serum cholesterol concentration in the group of dogs with atherosclerosis was 578 ± 330 mg/dl, which was significantly higher than mean serum cholesterol concentration of 199 ± 64 mg/dl in the group of dogs with no histopathologic evidence of atherosclerosis (p<0.0001). Serum cholesterol concentration was abnormally high (> 359 mg/dl) in 19 dogs (63%) with atherosclerosis and one dog (1%) with no histopathologic evidence of atherosclerosis. It is therefore concluded that serum cholesterol concentration is significantly higher in dogs that develop atherosclerosis than in dogs that do not have atherosclerosis.
In the group of 30 dogs with atherosclerosis, 15 dogs with hypothyroidism had a mean serum cholesterol concentration of 554 ± 388 mg/dl, 7 dogs with no endocrinopathy had a mean serum cholesterol concentration of 351 ± 181 mg/dl, 3 dogs with concurrent hypothyroidism and diabetes mellitus had a mean serum cholesterol concentration of 826 ± 361 mg/dl, 2 dogs with HAC had a mean serum cholesterol concentration of 609 ± 484 mg/dl, 2 dogs with diabetes mellitus had a mean serum cholesterol concentration of 651 ± 479 mg/dl, and 1 dog with concurrent HAC and diabetes mellitus had a serum cholesterol concentration of 426 mg/dl. Difference between serum cholesterol concentration in dogs with hypothyroidism and dogs with no endocrinopathy approached significance (p=0.053). Statistical analysis for the other groups of dogs was not possible due to small sample size.
Cholesterol and lipoprotein concentrations have been investigated in dogs with hypothyroidism, diabetes mellitus, and HAC.7,8 Dogs with hypothyroidism have been shown to have increased very low-density lipoproteins (VLDL), LDL, and HDL,7,8dogs with diabetes mellitus have been shown to have increased VLDL and HDL,7 and dogs with HAC have been shown to have increased LDL.7 Additional studies are needed to determine whether dogs with a specific pattern of hyperlipidemia are at increased risk for spontaneous atherosclerosis.
The mean age of dogs with atherosclerosis was 9.0 ± 3.9 years. Fifteen breeds of dogs were included in the group of dogs with atherosclerosis, and mixed breed dogs were observed most commonly. There was 1 miniature schnauzer (with diabetes mellitus, HAC, and a serum cholesterol concentration of 426 mg/dl) in the case group and none in the control group. There were 2 Shetland sheepdogs in the case group, and 2 in the control group. One of the Shetland sheepdogs in the case group had HAC and a serum cholesterol concentration of 267 mg/dl, and the other did not have any of the 3 endocrinopathies examined. The Shetland sheepdog with no endocrinopathy had a serum cholesterol concentration of 650 mg/dl. The case group included 11 intact males, 10 neutered females, 8 neutered males, and one intact female dog.
In human beings, genetic factors that predispose to hyperlipidemia increase the risk for atherosclerosis.7,8 In dogs, miniature schnauzers9 and Shetland sheepdogs10 have been shown to be at increased risk for primary hyperlipidemia. In this study, the single miniature schnauzer with atherosclerosis had diabetes mellitus, HAC and a serum cholesterol concentration of 426 mg/dl, making a diagnosis of primary hyperlipidemia unlikely. One of the Shetland sheepdogs with atherosclerosis had HAC and a serum cholesterol concentration of 267 mg/dl, also making the diagnosis of primary hyperlipidemia unlikely. However, another Shetland sheepdog with atherosclerosis had no detectable endocrinopathy and a serum cholesterol concentration of 650 mg/dl. Additional studies are needed to determine if genetic susceptibility to hyperlipidemia in dogs is associated with increased risk for spontaneous atherosclerosis.
Most dogs with atherosclerosis had an endocrinopathy (23/30, 77%). Eighteen of 30 dogs (60%) with atherosclerosis had hypothyroidism, 6 (20%) had diabetes mellitus, and 3 (10%) had HAC. In the age-matched control group of dogs with no histopathologic evidence of atherosclerosis, 5 of 142 dogs (3.5%) had hypothyroidism, 5 dogs (3.5%) had HAC, and 1 dog (1%) had diabetes mellitus.
Dogs with atherosclerosis were about 53 times more likely to have diabetes mellitus and approximately 51 times more likely to have hypothyroidism compared to dogs with no histopathologic evidence of atherosclerosis. The results of this study suggest that the prevalence of diabetes mellitus and hypothyroidism in dogs with atherosclerosis is similar. Dogs with atherosclerosis were not found to be more likely to have HAC than dogs that did not have atherosclerosis.
It is possible that diabetes mellitus and hypothyroidism increase the risk for development of atherosclerosis in dogs, because they are associated with hypercholesterolemia.
Clinical signs in the 30 dogs with atherosclerosis included lethargy (29), anorexia (17), thin hair coat or alopecia (12), polyuria and polydipsia (10), vomiting (10), obesity (8), hind limb paresis (6), panting (6), weight loss (6), diarrhea (4), polyphagia (3), and seizures (3). A clinical diagnosis of diabetes mellitus was made 1 week to 3 years before the time of necropsy, in 6 diabetic dogs with atherosclerosis, and 1 week to 17 months before necropsy in 3 dogs with HAC and atherosclerosis. Most hypothyroid dogs with atherosclerosis (13/18, 72%) were diagnosed with hypothyroidism at the time of necropsy.
Duration of clinical signs and hypercholesterolemia may be associated with development of atherosclerosis. However, the diagnosis of hypothyroidism was confirmed at necropsy in most of the dogs in the case group and duration of clinical signs and hypercholesterolemia was not known in these dogs. Therefore, investigation of the association between duration of clinical signs and development of atherosclerosis was not possible in this study.
Location of Atherosclerosis
Atherosclerosis was noted in various organs, but most commonly in the coronary arteries (20 dogs), blood vessels of the thyroid glands (10 dogs), kidneys (10 dogs), aorta (9 dogs), spleen (8 dogs), and stomach, intestine, or pancreas (8 dogs).
Prevalence of Atherosclerosis in Dogs
While many dogs with diabetes mellitus or hypothyroidism have hypercholesterolemia, spontaneous atherosclerosis in dogs remains rare, and was identified in only 30 of 6,300 dogs (0.5%) that were reviewed in this study. It is unknown whether the degree and duration of hypercholesterolemia, a specific pattern of lipoprotein distribution, or other factors increase the risk of some dogs with hypercholesterolemia for development of spontaneous atherosclerosis.
Atherosclerosis Without Hypercholesterolemia or Endocrinopathy
Seven of 30 dogs with atherosclerosis had no evidence of diabetes mellitus, hypothyroidism, or HAC. Nine of 30 dogs with atherosclerosis had normal serum cholesterol concentration, and 4 of these 9 dogs also did not have an identifiable endocrinopathy. These data suggested that some dogs develop spontaneous atherosclerosis for reasons that are not related to an endocrinopathy or secondary hypercholesterolemia.
Renal glomerular disease increases the risk for atherosclerosis in human beings.11-13 Glomerular disease is characterized by many factors that increase the risk for atherosclerosis including hypercholesterolemia, hyperlipidemia, hypertension, increased platelet aggregation, and hypercoagulability.11,12,14 These potentially atherogenic characteristics have also been described in dogs with naturally-occurring glomerular disease.15
A retrospective mortality prevalence case-control study was therefore performed to investigate whether glomerulopathy is observed more commonly in dogs with spontaneous atherosclerosis compared to dogs that do not have atherosclerosis.16 It was hypothesized that dogs with atherosclerosis are more likely to have concurrent glomerulopathy than dogs that do not have atherosclerosis.16 37 dogs with histopathological evidence of atherosclerosis, and 279 control dogs with results of a complete necropsy and no histopathological evidence of atherosclerosis were frequency matched on age and year of necropsy.16 The 279 control dogs included 142 dogs with a final necropsy diagnosis of neoplasia, 71 dogs that were randomly chosen from the hospital population, and 66 dogs that had a diagnosis of diabetes mellitus, hypothyroidism, or hyperadrenocorticism. Dogs with atherosclerosis had significantly more glomerulopathy than dogs in the neoplasia control group (p<0.0001), dogs in the random diagnosis control group (p=0.0078), and dogs in the endocrine control group (p=0.0019). Dogs with atherosclerosis also had significantly higher serum cholesterol concentration than dogs in the neoplasia control group (p<0.0001), dogs in the random diagnosis control group (p<0.0001), and dogs in the endocrine control group (p=0.0086). It was therefore concluded that glomerulopathy is more prevalent in dogs with atherosclerosis compared to dogs without atherosclerosis.16
Atherosclerosis and Cardiovascular Disease
One of the main complications of atherosclerosis in human beings is cardiovascular disease.5 Impaired left ventricular function, which is reversible with levothyroxine supplementation has been documented in hypothyroid dogs.17 Atrial fibrillation, also has been associated with spontaneous canine hypothyroidism.1 One of these studies suggested that atrial fibrillation may be associated with coronary atherosclerosis,1 but, the pathophysiology of cardiac dysfunction in canine hypothyroidism is likely multifactorial and is not well understood.17 In the present study, 20 of 30 dogs with atherosclerosis had atherosclerosis of the coronary arteries. The relevance of this finding to clinical cardiovascular disease in dogs with atherosclerosis is not known. Future studies are needed in order to determine whether spontaneous atherosclerosis is associated with impaired cardiovascular function in hypothyroid dogs. Future studies are also needed to investigate a possible association between spontaneous atherosclerosis and impaired cardiovascular function in diabetic dogs.
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