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Ocular lesions associated with systemic hypertension in cats: 69 cases (1985–1998) Federica Maggio, DVM; Teresa C. DeFrancesco, DVM, DACVIM; Clarke E. Atkins, DVM, DACVIM; Stefano Pizzirani, DVM; Brian C. Gilger, DVM, MS, DACVO; Michael G. Davidson, DVM, DACVO

Objective—To characterize clinical and clinicopathologic findings, response to treatment, and causes of systemic hypertension in cats with hypertensive retinopathy. Design—Retrospective study. Animals—69 cats with hypertensive retinopathy. Procedure—Medical records from cats with systemic hypertension and hypertensive retinopathy were reviewed. Results—Most cats (68.1%) were referred because of vision loss; retinal detachment, hemorrhage, edema, and degeneration were common findings. Cardiac abnormalities were detected in 37 cats, and neurologic signs were detected in 20 cats. Hypertension was diagnosed concurrently with chronic renal failure (n = 22), hyperthyroidism (5), diabetes mellitus (2), and hyperaldosteronism (1). A clearly identifiable cause for hypertension was not detected in 38 cats; 26 of these cats had mild azotemia, and 12 did not have renal abnormalities. Amlodipine decreased blood pressure in 31 of 32 cats and improved ocular signs in 18 of 26 cats. Conclusions and Clinical Relevance—Retinal lesions, caused predominantly by choroidal injury, are common in cats with hypertension. Primary hypertension in cats may be more common than currently recognized. Hypertension should be considered in older cats with acute onset of blindness; retinal edema, hemorrhage, or detachment; cardiac disease; or neurologic abnormalities. Cats with hypertensioninduced ocular disease should be evaluated for renal failure, hyperthyroidism, diabetes mellitus, and cardiac abnormalities. Blood pressure measurements and funduscopic evaluations should be performed routinely in cats at risk for hypertension (preexisting renal disease, hyperthyroidism, and age > 10 years). Amlodipine is an effective antihypertensive agent in cats.(J Am Vet Med Assoc 2000;217:695–702)

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ystemic hypertension in cats has been diagnosed with increasing frequency during the past several years, perhaps because of increased recognition of the disease and longer life spans of cats. Hypertension in cats, generally defined as systolic pressure > 160 to 170 From the Clinica Veterinaria Europa, Viale Europe 64, Florence, Italy 50126 (Maggio, Pizzirani), and the Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27606 (DeFrancesco, Atkins, Gilger, Davidson). Portions of this study were presented at the 1999 Meeting of the European College of Veterinary Ophthalmologists, Lyon, France, Sep 23, 1999. The authors thank Marlina Nasution for assistance with statistical analyses. Address correspondence to Dr. Davidson. JAVMA, Vol 217, No. 5, September 1, 2000

mm Hg, is most commonly associated with, and attributed to, chronic renal failure.1-8 Less commonly, it has been described in cats with hyperthyroidism,2,3 diabetes mellitus,2 and chronic anemia,5 and those fed a high-salt diet.9 Primary or essential hypertension, the most prevalent form of the disease in humans, is considered rare in cats.6,10 Although a primary, age-related form of hypertension has been postulated in cats,2,11 the extremely common coexistence of renal disease in affected cats, which may be caused by hypertension, has made conclusions difficult. As a result, the prevalence of the various causes of hypertension in cats with ocular disease has not been well characterized. Retinal lesions, generally referred to as hypertensive retinopathy and characterized by intraretinal and subretinal edema, hemorrhage, and detachment, are a commonly described complication of systemic hypertension,2,5,8,9,11,12 reported in 80 to 100% of hypertensive cats.7,8 Because of the difficulty in recognizing hypertension in cats in its early stages, blindness from complete retinal detachment has historically been the most common complaint at referral or evaluation. Recently, a new antihypertensive agent, amlodipine besylate, has effectively lowered blood pressure in cats with hypertension7,8; however, responses of associated retinal lesions have not been reported. The purposes of the study reported here were to characterize clinical and clinicopathologic findings, response to treatment, and causes of systemic hypertension in cats with hypertensive retinopathy. Criteria for Selection of Cases Cats with hypertensive retinopathy were included in the study. Hypertensive retinopathy was defined as systemic hypertension (sustained, indirect systolic blood pressure > 170 mm Hg) and concurrent retinal vascular tortuosity, retinal effusion, hemorrhage or detachment, or hyphema. Cats with other possible causes for these ocular lesions were excluded. Procedures Medical records from all cats with a diagnosis of hypertensive retinopathy at the Veterinary Teaching Hospital of North Carolina State University and the Clinica Veterinaria Europa between 1985 and 1998 were reviewed. Medical records were reviewed for signalment, history, physical examination findings, ophthalmic examination findings, laboratory test results, and radiographic or ultrasonographic findings. Ophthalmic examination and blood pressure determination—A complete ophthalmic examination was performed on each cat with hypertensive retinopathy and included slit-lamp biomicroscopy and fundic Scientific Reports: Retrospective Study

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evaluation by use of indirect ophthalmoscopy. Systolic arterial blood pressure was measured by use of an indirect method without sedation with a Doppler device,a as described.13 The cuffb,c was placed at the base of the tail, on the hind limb above the tarsus, or on the forelimb above the carpus. The transducer was placed distally over the coccygeal artery at the base of the tail, over the anterior tibial artery, or over the ulnar artery on the palmar side of the foot. Blood pressure was measured with minimal manual restraint during a 5- to 10minute period until multiple similar readings were obtained, and the most consistent 3 or 4 readings were used to determine the mean value. Systolic blood pressure measurements that exceeded 300 mm Hg (the upper detection limit of the sphygmomanometer) were included in calculation of the mean as having a measurement of 300 mm Hg. Laboratory analyses—Complete blood count, serum biochemical and electrolyte analyses (n = 65), and serum thyroxine (T4) radioimmunoassay (58) were performed on most cats to identify any underlying cause of hypertension. Cats were defined as having azotemia if concentration of creatinine was > 1.8 mg/dl or BUN concentration was > 35 mg/dl, despite apparently normal hydration. Hyperthyroidism was defined as resting serum T4 concentration > 4.0 g/dl or T4 concentration > 2.0 g/dl after suppression by administration of triiodothyronine (T3). Other laboratory testing included urinalysis (46 cats), examination of serum for FeLV (25 cats), feline immunodeficiency virus (FIV; 21 cats), and Cryptococcus neoformans (3 cats) antigens, and examination of serum for antibodies against feline coronavirus (5 cats), Toxoplasma gondii (ELISA; 9 cats), and Dirofilaria immitis (5 cats). Serum renin concentrations were measured in 2 cats and serum aldosterone concentrations in 2 other cats. Other tests—In 34 cats with cardiac anomalies that were detected by physical examination, a complete cardiac evaluation with electrocardiography, echocardiography, and thoracic radiography was performed. Abdominal ultrasonographic examination was performed in 15 cats and abdominal radiography in 4 cats. A computed axial tomographic scan of the head was performed on 3 cats; CSF analysis was performed on 1 of these cats. Estimated median survival time was calculated by use of a Kaplan-Meier technique and a statistical software package.d Data were reported as mean ± SD, where appropriate. Results Sixty-nine cases of hypertensive retinopathy were diagnosed during the study period (62 cases from North Carolina State University and 7 cases from Clinica Veterinaria Europa); mean age of affected cats was 14.8 ± 2.1 years (range, 7 to 20 years). Sixty-four of 69 (92.7%) cats were > 10 years of age. Three cats were sexually intact females, 40 were spayed females, 1 was a sexually intact male, and 25 were castrated males. Breeds were Domestic Shorthair (n = 31), Domestic Longhair (15), Siamese (11), Persian (7), Himalayan (3), Burmese (1), and Maine Coon (1). 696

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The primary complaint in 47 (68%) cats was sudden or progressive blindness (duration, 1 week to 2 years) or profound ocular abnormalities diagnosed by the referring veterinarian (retinal detachment, vitreal or retinal hemorrhage, or hyphema). The remaining 22 cats were evaluated for a variety of clinical signs including nasal discharge or epistaxis (n = 2), cardiac murmur (2), iris color change (1), weight loss (3), recumbency (1), neoplasia (2), neurologic signs (7), and history of hypertension and chronic renal failure (4). Partial or complete blindness and pupillary light reflex deficits in 1 or both eyes were detected in 49 cats (93 eyes). Ocular lesions were bilateral in 61 of 69 cats, but were often not of equal severity in the 2 eyes. The most common ocular lesion was partial to complete retinal detachment in 86 of 138 (62.3%) eyes; 36 (52.2%) cats had bilateral retinal detachment. In these eyes, the subretinal fluid was generally serous in nature with various amounts of hemorrhage, and resulted in bullous detachment (Fig 1). A mild to moderate degree of generalized retinal vascular tortuosity was also common in eyes with detachments. Subretinal, intraretinal, or vitreal hemorrhages were detected in 78 eyes, and 52 eyes had both retinal detachment and retinal or vitreal hemorrhage or hyphema. Mild retinal lesions without retinal detachment were characterized by multifocal intraretinal edema (8 eyes), multifocal intraretinal or vitreal hemorrhage (13 eyes), or edema and hemorrhage (13 eyes). These subclinical lesions, which were not associated with vision loss or pupillary light reflex deficit, were seen in only 13 cats in which retinal detachment or hyphema were not evident in the other eye. Twelve eyes had hyphema, and in 10 eyes this was attributed to retinal detachment with anterior migration of vitreal hemorrhage, whereas in 2 eyes hyphema appeared to result from iris hemorrhage. Large areas of diffuse retinal degeneration were evident at the time of diagnosis of retinopathy in 13 eyes. In these eyes, the retinal degeneration was attributed to hypertension as a result of coexisting retinal effusion or hemorrhage in the affected or opposite eye. Three eyes (2 cats) had secondary glaucoma. Neurologic signs were noticed at referral in 14 cats, including disorientation (n = 3), vestibular signs (2), ataxia (1), seizures and stupor (3), tremors (2), cervical ventroflexion (1), and paraparesis (2). Six additional cats developed neurologic signs after referral; 5 of these historically had poor control of hypertension. Computed axial tomography scan findings in 3 cats with neurologic signs were interpreted as normal. On physical examination, the majority (54%) of cats had some auscultatory abnormality, including systolic heart murmurs (n = 37), cardiac gallop (5), and sinus tachycardia (4). Two cats developed systolic heart murmurs some time later. Of 34 cats undergoing cardiac evaluation (thoracic radiography, echocardiography, or both), 29 (85%) had evidence of cardiomegaly. One cat had pleural effusion, presumably secondary to congestive heart failure. Mean indirect systolic blood pressure in affected cats was 232.8 ± 37.7 mm Hg (range, 170 to > 300 mm Hg). Values exceeded 300 mm Hg in 3 cats. Abdominal radiography or ultrasonography was performed on 19 JAVMA, Vol 217, No. 5, September 1, 2000

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Figure 1—Photographs of the ocular fundi of cats with systemic hypertension and associated retinal lesions. A—Preretinal hemorrhage near a major retinal venule (arrow) and focal intraretinal edema (arrowhead). B—Multifocal intraretinal and subretinal edema (arrows) and mild retinal vascular tortuosity. C—Complete infundibular retinal detachment with substantial serous subretinal fluid and focal intraretinal hemorrhage (arrow). D—Diffuse retinal degeneration and vascular attenuation. Notice the substantial tapetal hyperreflectivity (arrows) and focal hemorrhage (arrowhead). E—Multifocal intraretinal edema (arrows). F—Same eye as (E), 2 weeks after treatment with amlodipine besylate (0.625 mg, PO, q 24 h). Notice substantial resolution of edema.

cats; in 9 cats, small hyperechoic kidneys were detected, whereas renal calculi were found in 1 cat, and a renal cyst was detected in 1 cat. Two cats were seropositive for FIV infection; results of all other serologic tests were unremarkable. Serum T4 concentrations were obtained in 58 of the 69 cats, and hyperthyroidism was diagnosed in 5 cats on the basis of increased resting serum T4 concentration (n = 3) or T4 concentration after suppression by administration of T3 (2). Primary hyperaldosteronism was diagnosed in 1 cat with ventroflexion of the neck (serum potassium concentration, 2.8 mg/dl [reference range, 3.5 to 4.7 mg/dl]; serum aldosterone concentration, 563 pg/ml [reference range, 70 to 140 pg/ml]). Diabetes mellitus was diagnosed in 2 cats with serum glucose concentrations of 452 and 425 mg/dl [reference range, 72 to 144 mg/dl], respectively. Fifty-four of the 69 cats with retinopathy had 1 or more abnormal findings for renal function, including abnormally high serum concentrations of creatinine, BUN, or both (Table 1), and some cats had ultrasonographic or physical findings indicating the kidneys were small and irregular in shape. Abnormally high serum creatinine concentration was detected in 44 cats (mean, 3.3 ± 1.9 mg/dl; range, 1.9 to 12.7 mg/dl [reference range, 1.0 to 1.8 mg/dl]) and increased BUN JAVMA, Vol 217, No. 5, September 1, 2000

concentration was detected in 40 cats (mean, 69.9 ± 75.9 mg/dl; range, 36 to 511 mg/dl [reference range, 19 to 35 mg/dl]). Among these 54 cats with evidence of renal dysfunction were 4 of the 5 cats with hyperthyroidism, 1 cat with primary hyperaldosteronism, and 1 of 2 cats with diabetes mellitus. Twenty-two other cats had either a history of preexisting renal insufficiency or failure that preceded the diagnosis of hypertension, or had moderate to profound azotemia and historical findings suggestive of preexisting renal failure. Thirty-nine cats had no evidence of endocrinopathy, and had no historical or clinical findings suggestive of chronic renal failure. Serum creatinine and BUN concentrations were unavailable in 1 of these 39 cats. Among 38 of these cats, 26 cats had mild azotemia that was confirmed at time of referral (Table 1). Five of these 26 cats had a mild increase in BUN but had serum creatinine concentration within reference range; 5 cats had serum creatinine concentrations slightly greater than reference range but had BUN concentration within reference range. Twelve cats did not have abnormal findings for tests of renal function. Among these 39 cats without obvious antecedent disease, serum T4 concentrations were evaluated in 34 cats and found to be within reference range. Serum sodium to potassium ratio was determined in 37 cats and found to be within refScientific Reports: Retrospective Study

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Table 1—Systolic blood pressure and measurements of renal function in 68 cats with hypertensive retinopathy and various clinical findings

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Clinical finding Hyperaldosteronism Diabetes mellitus Hyperthyroidism Chronic renal failure Mild azotemia Normal renal function

No. of cats

Systolic blood pressure (mm Hg)

Serum creatinine (mg/dl)

1 2 5 22 26 12

230 190 ⫾ 0 223.1 ⫾ 24.9 232.5 ⫾ 40.8 240.1 ⫾ 39.8 230 ⫾ 34.3

2.1 1.8 ⫾ 0.5 1.8 ⫾ 0.2 (4) 4.4 ⫾ 2.4 (20) 2.3 ⫾ 0.6 (24) 1.6 ⫾ 0.1

BUN (mg/dl)

Urine specific gravity

40 37 ⫾ 7.1 43 ⫾ 4.9 (4) 88.3 ⫾ 106.9 (20) 47.2 ⫾ 20 (25) 26.4 ⫾ 4.5

1.023 1.022 ⫾ 0.010 1.025 ⫾ 0.010 (3) 1.016 ⫾ 0.006 (15) 1.022 ⫾ 0.010 (15) 1.030 ⫾ 0.09 (10)

Data are mean ⫾ SD values. Values in parentheses indicate No. of cats tested, if less than No. of cats in that group.

erence range (ratio, < 45) in 35 cats and slightly increased in 2 cats (ratio, 46.6 and 53.4). Serum alkaline phosphatase and alanine transferase activities were evaluated in 37 cats and were within the reference range for 35 cats, and slightly increased in 2 cats. Follow-up blood pressure information and results of ocular examination were available in 48 cats (mean follow-up interval, 383.7 ± 475.4 days; range, 3 to 2,520 days). Indirect blood pressure measurements were generally reevaluated within a 5- to 10-day period after initiation of treatment. Among these 48 cats, a positive response to treatment, defined as a decrease in systolic blood pressure ≥ 20% or to < 170 mm Hg, was found in 41 cats. Mean interval until blood pressure decreased was 32 days (range, 1 week to 6 months). Relapse, defined as blood pressure that increased > 20% from the previous value, occurred in 15 cats; mean time to relapse was 40.1 weeks (range, 1 week to 7 years). Information on survival was available for 50 cats; cats lived for 3 days to 84 months after diagnosis of retinopathy. Estimated median survival time for all 69 cats was 730 days (95% confidence interval, 600 to > 1,095 days). Median survival interval for the 17 cats confirmed to be dead or euthanatized was 365 days and median length of observation for the 9 cats that were still alive was 270 days. Various antihypertensive drugs were used for treatment of 62 cats (Table 2). Prior to 1995, cats were generally treated by administration of 1 to 3 medications, including diuretics, β-blockers, angiotensin converting enzyme (ACE) inhibitors, or diltiazem. After 1995, amlodipine besylate was used as a single agent in almost all cats. Response to the 4 different treatment regimes varied (Table 3). Recommendations were also made to all owners to feed a low-salt diet.e Six cats were treated for hyphema by topical administration of corticosteroid suspension. Thirty-six cats were treated with amlodipine as the sole agent, and 2 cats received amlodipine and captopril (or benazepril) or propranolol, or both. Among cats treated with amlodipine, 31 of 32 cats in which follow-up blood pressure measurements were available had a positive response with reduction in systolic pressure to 150 to 210 mm Hg at intervals of 1 to 6 weeks; 28 of 32 cats became normotensive. Seven of these cats relapsed, which was attributed to changing from treatment with amlodipine to treatment with atenolol in 2 cats and reduction in dose of amlodipine in 1 cat. 698


Table 2—Antihypertensive drugs used in treatment of 62 of 69 cats with hypertensive retinopathy Drug Atenolol Propranolol Enalapril Captopril Benazepril Furosemide Spironolactone-thiazide Diltiazem Amlodipine besylate

No. of cats 12 11 6 4 1 9 3 7 38

Dosage 6.25–12.5 mg, q 24 h 2.5–10 mg, q 8 h–q 12 h 1.25–2.5 mg, q 24 h–q 48 h 3.125–6.25 mg, q 8 h–q 12 h 2.5 mg, q 24 h 3.0–12.5 mg, q 8 h–q 12 h 4 mg, q 12 h 2.5–7.5 mg, q 8 h 0.625–1.25 mg, q 12 h–q 24 h

Reinstitution of a standard dose of amlodipine in 3 cats or an increase to twice daily dosing in 4 cats resulted in a positive response in all instances. Among cats treated with amlodipine, 18 of 26 cats with results for follow-up ophthalmic examinations had improvement in retinal lesions in 1 or both eyes characterized by lessening of the amount of subretinal edema (Fig 1), resorbing retinal hemorrhage, or partial to complete retinal reattachment. In this group, 20 of 46 eyes with retinal detachment had either substantially less subretinal fluid, partial to complete retinal reattachment, or both. Fourteen of 26 eyes that had retinal edema or hemorrhage but no detachment had partial to complete resolution of retinal lesions. In the amlodipine-treated cats, 30 eyes were assessed as blind on initial evaluation, and of these, 4 eyes (3 cats) with complete retinal detachment had retinal reattachment and some degree of visual recovery following treatment. Two of these cats still had vision 4 and 11 months after diagnosis. Among all 69 cats, 24 eyes (13 cats) subsequently developed large, focal to diffuse areas of retinal degeneration in the areas of retinal detachment, determined by follow-up evaluation. Among these 13 cats, 7 cats had early improvement in ocular signs, and 6 cats failed to improve. Discussion Clinical manifestations of hypertension are attributable to effects on the arterial system, and consequently, the target organs (eyes, kidneys, heart, and brain) are those with a rich arterial and arteriolar supply. Ocular lesions associated with hypertension typically result from failure in vascular autoregulation of the retinal arteries. In response to increases in blood pressure, retinal arterioles undergo vasoconstriction, leading to compensatory hypertrophy and hyperplasia JAVMA, Vol 217, No. 5, September 1, 2000

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Table 3—Summary of responses to various treatments for hypertensive retinopathy in 69 cats

␤-blocker,* ACE inhibitor,† diuretic,‡ or diet ␤-blocker plus diuretic, ACE, or both Diltiazem Amlodipine besylate

No. of cats

Improved a blood pressure

Improved a ocular signs

14

3/6

1/6

10

3/7

6/7

7

4/5

3/5

38

31/32

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Treatment

Comments No improvement to partial improvement in most cats 7 cats had relapses with increased blood pressure and worsening of ocular signs 4 of 5 cats had relapses with progression to blindness 7 of 13 cats with vision at referral had vision 5–22 months after treatment

*Atenolol, propranolol. †Analapril, captopril, benazopril. ‡Furosemide, spiranolactone-thiazide. a Value indicates No. of cats with improvement/No. of cats for which results were available. ACE ⫽ Angiotensin converting enzyme.

of the smooth muscle layer. With chronic vasoconstriction, vascular smooth muscle cells have diminished contractile function, develop fibrous changes, and allow insidious leakage of plasma into the arteriolar wall, causing hyalinization with smooth muscle necrosis. Progressive degenerative changes in the vessel wall lead to rupture of the endothelial and muscle cells, with leakage of blood and serum into the surrounding retinal tissue, and account for the effusive lesions (edema, hemorrhage, retinal detachment) characteristic of hypertensive retinopathy.14 Although the choroid is not an autoregulatory vascular bed, hypertension-induced injury to this arterial system may cause occlusion of the choriocapillaris, leading to necrosis and atrophy of the retinal pigment epithelium and outer retinal ischemia. Hypertensive choroidopathy is characterized clinically by localized to complete retinal detachment from exudation from the choriocapillaris into the subretinal space.15,16 Prior studies have documented that ocular lesions are the most commonly detected complication of systemic hypertension in cats.2,8,12 However, the prevalence of ocular lesions in hypertensive cats is not well defined, because funduscopic examination and blood pressure measurements are often not performed in cats that may have early-stage hypertension (ie, those with chronic renal failure or hyperthyroidism). Ocular lesions were the reason for referral in most cats in the study reported here, likely reflecting the associated vision loss that is often readily apparent to the owner. Similar to previous reports,2,8,11 ocular lesions seen in the cats in the study reported here were often severe, and approximately one half of the cats had complete retinal detachment and blindness in both eyes at referral, whereas only approximately 20% (14 of 69 cats) had vision in both eyes. In a prospective study of hypertensive cats with chronic renal failure or hyperthyroidism, a number of cats with early hypertensive retinal lesions including vascular tortuosity, multifocal retinal edema, intraretinal hemorrhage, and small foci of serous retinal detachment were reported.12 Similar early-stage retinal lesions were the sole finding in 34 eyes in our study, and were seen in only 13 cats in which retinal detachment or hyphema were absent from the opposite eye. The subclinical retinal lesions were seen in cats evaluated for signs referable to other organ systems, and these cats subsequently received a JAVMA, Vol 217, No. 5, September 1, 2000

funduscopic examination at the request of the attending clinician. Retinal findings in our study differed from those typically identified in humans with hypertensive retinopathy.17 Prearteriolar occlusion, vascular narrowing, cotton-wool spots (caused by ischemia of the axons of the nerve fiber layer14), and retinal vascular tortuosity in the absence of other abnormalities were not detected in any of the cats in the study reported here. It is possible that these lesions developed in the earlier stages of retinopathy in these cats and were not detected because the lesions had become chronic by the time of initial funduscopic examination. Alternatively, the choroid, and not the retina, may be the predominant and most important affected ocular vascular bed within the posterior segment of the eye in cats with systemic hypertension. The prevalence of exudative retinal detachment, characterized by large amounts of subretinal fluid, identified in hypertensive cats in our study and others,2,5,9,11,12 supports this contention and suggests that the term “hypertensive choroidopathy” may be more accurate when bullous retinal detachment is evident. Indeed, the requirement for a relatively high blood flow to the choroid in cats, particularly in the tapetal choroid, compared with humans, may predispose the vascular system to ischemic injury.18,19 Interestingly, in humans with hypertensive ocular disease, choroidal vascular changes predominate when acute or profound increase in blood pressure is present, whereas a more gradual onset of hypertension results in retinal vascular changes.20 Whether this is true for cats is not known. Twenty of 69 cats in the study reported here had a variety of neurologic signs, with some cats developing neurologic signs after referral and inadequate treatment for control of hypertension. Although an extensive diagnostic work-up was not performed in all of these cats to rule out other causes of neurologic signs, the findings were compatible with, and may have resulted from, hypertensive encephalopathy caused by alterations in the brain vasculature similar to those in the retina and choroid. Prevalence of neurologic signs in our study was somewhat lower than that of another retrospective study of hypertensive cats in which 11 of 24 cats had neurologic abnormalities.2 Reasons for this difference are not clear, but may reflect different populations of cats that were evaluated in the 2 studies (ie, Scientific Reports: Retrospective Study

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all hypertensive cats vs hypertensive cats with retinopathy). There is little published information regarding cardiovascular damage in systemically hypertensive cats.2,6,21 Hypertension results in left ventricular hypertrophy primarily by causing increased cardiac afterload; in cats with hyperthyroidism and hypertension, increased adrenergic stimulation and cardiac contractility may also be contributory. Ventricular hypertrophy and remodeling can ultimately lead to secondary valvular insufficiency and systolic murmur.6,22,23,f Cardiovascular abnormalities were common in the cats examined in our study. Heart murmurs, gallops, or both were detected in the majority (54%) of cats, as was cardiomegaly (85%). These findings compare favorably with those of 24 cats with hypertensive retinopathy described by Littman et al2 (prevalence of heart murmurs, 54%; prevalence of cardiomegaly, 64%). Likewise, mean heart rate detected in our study (188 beats/min) were comparable to that detected in the study by Littman et al2 (174 beats/min). One cat in our study appeared to have congestive heart failure, presumably secondary to chronic hypertension. Heart failure appears to be uncommon in cats with hypertension, but has been reported.2 It is important to recognize that other disease processes (eg, hyperthyroidism) may have affected cardiovascular findings. Hyperthyroidism was diagnosed in 5 cats in our study and was presumed to be at least contributory to hypertension, although 4 of the 5 cats also had concurrent chronic renal failure. With hyperthyroidism, increased β-adrenergic activity can result in tachycardia, increased myocardial contractility, systemic vasodilation, and activation of the renin-aldosteroneangiotensin system, resulting in hypertension. In 1 study, mild to moderate increases in systolic blood pressure were detected in 34 of 39 (87%) hyperthyroid cats.3 Fifty-three of 69 cats in our study had resting T4 concentration within reference range; however, a single evaluation of serum T4 concentration cannot definitively exclude a diagnosis of hyperthyroidism.24 Additionally, serum T4 concentrations were not evaluated in 11 cats, so hyperthyroidism may have been present but was not diagnosed. However, the prevalence of hyperthyroidism was not substantially different in our study (5/69), compared with results of a study of hypertensive cats (3/19).2 Additionally, in a large population of 131 hyperthyroid cats,25 obvious ocular signs such as blindness were not reported, and in a prospective study, using funduscopic examination, only 1 of 13 hyperthyroid cats had retinal lesions.12 Taken together, these findings suggest that hyperthyroidism is not a common cause of hypertension-associated ocular disease and most cats with hyperthyroidism do not develop overt retinopathy. Diabetes mellitus was diagnosed in 2 cats, and hyperaldosteronism was diagnosed in 1 cat; both of these diseases have been suggested to cause systemic hypertension in cats.2 Although diabetes mellitus was effectively ruled out by detecting serum glucose concentration within reference range in almost all cats, aldosterone concentrations were measured in only 2 cats. However, primary hyperaldosteronism is rare in 700


cats26 and characteristic changes in sodium to potassium ratio were not detected in other cats in our study in which serum biochemical evaluation was performed. A clear association exists between chronic renal failure and systemic hypertension in cats27,28 and because of the high prevalence of renal failure in hypertensive cats reported to date,2,5,7,8,g chronic renal failure has historically been considered the predominate cause of hypertension. In a previous study, all 24 hypertensive cats had some degree of renal failure.2 Most cats with retinopathy in our study had 1 or more abnormal findings for tests of renal function. However, conflicting information is available on the prevalence of retinal lesions in cats with chronic renal failure. Mild to moderate increases in systolic blood pressure were reported in 61% of 28 cats with chronic renal failure.3 However, only 6 of these cats had systolic blood pressure > 160 mm Hg, and only 1 cat had systolic blood pressure > 200 mm Hg; none of these cats were blind. Likewise, only 3 of 74 cats with chronic renal failure in another study29 had retinal detachment, although blood pressure measurements were not taken in that study, and details of ophthalmic examinations, or whether they were routinely performed, were not given. Conversely, prospective evaluation with funduscopic examination in cats with chronic renal failure found that 12 of 23 cats subsequently developed some form of hypertensive retinopathy.12 Determining whether renal dysfunction preceded, followed, or developed independently of hypertension could not definitively be determined in cats in our study. In experimental studies, hypertension may either cause or exacerbate renal dysfunction by causing arterial lesions similar to those in the retina. Renal disease attributable to hypertension is estimated to account for approximately 30% of all cases of end-stage renal failure in humans.30 Alternatively, hypertension may be secondary to chronic renal failure through a variety of pathophysiologic mechanisms primary involving the renin-angiotensin-aldosterone system and sodium retention.4,6,28 It is noteworthy that secondary hypertension from chronic renal disease is more common in humans with glomerular disease, compared with chronic interstitial nephritis,31-33 whereas chronic interstitial nephritis is by far the most common type of renal disease associated with renal failure in cats.29 In the study reported here, 22 (31.9%) cats had chronic renal failure prior to diagnosis of hypertension and onset of ocular lesions. These cats had moderate to severe increases in serum creatinine and BUN concentrations. Although it is reasonable to attribute hypertension to renal dysfunction in these cats, it is also plausible that in some instances, chronic low-level hypertension may have preceded renal dysfunction, and progression of the hypertension subsequently led to the development of clinically apparent ocular disease. Because hypertension27 and chronic renal failure29 are diseases seen in older cats, it is also possible that these diseases coexisted independently in this population. Twenty-six (37.7%) cats in our study had subclinical renal failure at the time of diagnosis of retinopathy, with only mild azotemia. Ten of these 26 cats had only mildly increased concentrations of BUN or creatinine, JAVMA, Vol 217, No. 5, September 1, 2000

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1 to 2 weeks, chronic subclinical hypertensive changes in the vasculature of the posterior segment that preceded detachment may have complicated visual recovery. Approximately one-half of the cats with early clinical signs (multifocal retinal edema, retinal hemorrhage) and control of hypertension with amlodipine had either lack of progression or partial resolution of retinal lesions. Early recognition of hypertensive retinopathy, prior to retinal detachment and vision loss, likely offers the best prognosis for vision after antihypertensive treatment. Hypertension should be considered in older cats with sudden onset of blindness, effusive retinal lesions, hyphema, neurologic signs, and cardiac disease. Cats with hypertensive retinopathy or choroidopathy should be evaluated for renal dysfunction, hyperthyroidism, and cardiac abnormalities. Amlodipine besylate is the present treatment of choice for hypertension in cats and improves ocular lesions in most instances. Because hypertension is presently difficult to detect in cats until profound ophthalmic, neurologic, or renal injury is evident, indirect blood pressure measurements and funduscopic evaluations should be performed routinely in cats at risk for its development, including patients with preexisting renal disease and hyperthyroidism. Because a primary or essential form of hypertension appears to exist in older cats, it also seems prudent to perform routine blood pressure measurements, or, if a Doppler unit is not available, funduscopic examinations, in cats > 10 years of age. a

Ultrasonic doppler flow detector, model 811, Parks Medical Electronics Inc, Aloha, Ore. b Neonatal blood pressure cuff, No. 11, size 3 cm, Nippon Colin, Colin Corp, 2007–1 Hayashi, Komaki–City, Aichi Pref, 485 Japan. c North American Drager, 2-tube velcro cuff/bladder, size “newborn,” Telford, Penn. d PROC Lifetest, SAS Institute, Cary, NC. e Feline k/d Prescription Diet, Hill’s Pet Products Inc, Topeka, Kan. f Nelson IL, Riedesel EA, Ware WA. Echocardiographic and radiographic changes associated with systemic hypertension in cats (abstr). J Vet Intern Med 1999;13:246. g Elliot J, Rawlings JM, Markwell PJ, et al. Incidence of hypertension in cats with naturally occurring chronic renal failure (abstr). J Vet Intern Med 1999;13:251.

References 1. Ross JA. Hypertension and chronic renal failure. Sem Vet Med Surg 1992;7:221–226. 2. Littman MP. Spontaneous systemic hypertension in 24 cats. J Vet Intern Med 1994;8:79–86. 3. Kobayashi DL, Peterson ME, Graves TK, et al. Hypertension in cats with chronic renal failure or hyperthyroidism. J Vet Intern Med 1990;4:58–62. 4. Jensen J, Henik RA, Brownfield M, et al. Plasma renin activity and angiotensin I and aldosterone concentrations in cats with hypertension associated with chronic renal disease. Am J Vet Res 1997;58:535–540. 5. Morgan RV. Systemic hypertension in four cats: ocular and medical findings. J Am Anim Hosp Assoc 1986;22:615–621. 6. Henik RA. Diagnosis and treatment of feline systemic hypertension. Compend Contin Educ Pract Vet 1997;19:163–178. 7. Henik RA, Snyder PS, Volk LM. Treatment of systemic hypertension in cats with amlodipine besylate. J Am Anim Hosp Assoc 1997;33:226–234. 8. Snyder PS. Amlodipine: a randomized, blinded clinical trial in 9 cats with systemic hypertension. J Vet Intern Med 1998;12:157–162. 9. Turner JL, Brogdon JD, Lees GE, et al. Idiopathic hypertenScientific Reports: Retrospective Study

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but not both. As a result of these confounding factors, definitive conclusions regarding the cause of hypertension cannot be made in this population. Because of the modest azotemia, renal damage in some these cats may have been a secondary phenomenon. Twelve (17.4%) cats in our study had BUN and creatinine concentrations within reference ranges, and did not have evidence of endocrinopathy. For 38 of 69 (55.1%) cats, a cause of hypertension was not apparent and hypertension may have been primary in many instances. Interestingly, in 8 of these 38 cats for which long-term follow-up was available and hypertension was controlled by treatment, progression of the azotemia was not apparent (even after 7 years in 1 instance). Other causes of hypertension in cats (pheochromocytoma, renal arterial stenosis, hyperadrenocorticism, hyperaldosteronism) were not definitively ruled out in all cats. However, given the absence of compatible clinicopathologic findings in these cats, their response to antihypertensive treatment, and the apparent rarity of these disorders in cats, it seems unlikely that these diseases were present. Because the study period was 13 years in duration, several antihypertensive treatment regimes were used in these cats. In addition, the severe nature of the retinal lesions and the many causes of hypertension made assessment of response of the ocular lesions to treatment difficult. Nevertheless, certain general observations were made. Treatment with either β-blocking agents (alone or in combination with ACE inhibitors) or diltiazem alone often induced acute reduction in systolic blood pressure and at least partial improvement in ocular signs in most cats. However, recurrence of ocular signs was common, and improvement in ocular lesions was temporary in most cats. Amlodipine besylate was reported as an effective antihypertensive agent in cats in an uncontrolled clinical study7 and placebo-controlled clinical trial.8 In the study reported here, treatment with amlodipine as a single agent resulted in exceptional, rapid reductions in blood pressure in 31 of 32 cats, and 28 of 32 cats became normotensive without clinically evident adverse effects. Recurrence of hypertension was detected in 7 of these cats, but adjustments in dosage of amlodipine provided effective control. After reduction in blood pressure, improvement in ocular signs was evident in 18 of 26 cats, whereas substantial change in the severity of ocular lesions was not detected in 8 cats. Visual recovery with retinal reattachment developed in 4 eyes that had complete bullous retinal detachment at referral. However, retinal degeneration was a common later finding in cats with retinal reattachment, and many cats in this group failed to maintain substantial visual function for long periods. Recovery of visual function in cats with retinal reattachment is dependent on several factors, perhaps most importantly duration of detachment prior to treatment and overall physiologic state of the retina at the time of detachment. Normal retinal morphologic characteristics and function can be restored in cats with experimental retinal detachment and reattachment, even after several weeks.34 Although the cats in the study reported here generally had acute vision loss that was treated within

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sion in a cat with secondary hypertensive retinopathy associated with a high-salt diet. J Am Anim Hosp Assoc 1990;26:647–651. 10. Brown SA, Henik RA. Diagnosis and treatment of systemic hypertension. Vet Clin North Am Small Anim Pract 1998;28:1481–1494. 11. Sansom J, Barnett KC. Ocular disease associated with hypertension in 16 cats. J Small Anim Pract 1994;35:604–611. 12. Stiles J, Polzin DJ, Bistner SI. The prevalence of retinopathy in cats with systemic hypertension and chronic renal failure or hyperthyroidism. J Am Anim Hosp Assoc 1994;30:564–572. 13. Kittleson MD. Measurement of systemic arterial blood pressure. Vet Clin North Am Small Anim Pract 1983;13:321–335. 14. Garner A, Ashton N, Tripathi R, et al. Pathogenesis of hypertensive retinopathy, an experimental study in the monkey. Br J Ophthalmol 1975;59:3–44. 15. MacCumber MW, Flower RW, Langham ME. Ischemic hypertensive choroidopathy. Fluorescein angiography, indocyanine green videoangiography, and measurement of pulsatile blood flow. Arch Ophthalmol 1993;111:704–705. 16. Hayreh SS, Servais GE, Virdi PS. Fundus lesions in malignant hypertension. VI. Hypertensive choroidopathy. Ophthalmology 1986;93:1383–1400. 17. Dodson PM, Lip GYH, Eames SM, et al. Hypertensive retinopathy: a review of existing classification systems and a suggestion for a simplified grading system. J Hum Hypertens 1996;10:93–98. 18. Wolbarsht ML, Stefansson E, Landers MBD. Retinal oxygenation from the choroid in hyperoxia. Exp Biol 1987;47:49–52. 19. Hill DW, Houseman J. Retinal blood flow to tapetal and pigmented fundus in the cat. Exp Eye Res 1980;30:245–252. 20. de Venecia G, Jampol LM. The eye in accelerated hypertension. II. Localized serous detachments of the retina in patients. Arch Ophthalmol 1984;102:68–73. 21. Lesser M, Fox PR, Bond BR. Assessment of hypertension in 40 cats with left ventricular hypertrophy by Doppler shift sphygmomanometry. J Small Anim Pract 1992;33:55–58.

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22. Labato MA, Ross LA. Diagnosis and management of hypertension. In: August JR, ed. Consultations in feline internal medicine. Philadelphia: WB Saunders Co, 1991;1196–1202. 23. Dukes J. Hypertension: a review of the mechanisms, manifestations, and management. J Small Anim Pract 1992;33:119–129. 24. Peterson ME, Graves TK, Cavanagh I. Serum thyroid hormone concentrations fluctuate in cats with hyperthyroidism. J Vet Intern Med 1987;1:142–146. 25. Peterson ME, Kintzer PP, Cavanagh PG, et al. Feline hyperthyroidism: pretreatment clinical and laboratory evaluation of 131 cases. J Am Vet Med Assoc 1983;183:103–110. 26. Eger CE, Robinson WF, Hustable CRR. Primary aldosteronism (Conn’s syndrome) in a cat: a case report and review of comparative aspects. J Small Anim Pract 1983;24:293–307. 27. Bodey AR, Sansom J. Epidemiological study of blood pressure in domestic cats. J Small Anim Pract 1998;39:567–573. 28. Bartges JW, Willis AM, Polzin DJ. Hypertension and renal disease. Vet Clin North Am Small Anim Pract 1996;26:1331–1345. 29. DiBartola SP, Rutgers HC, Zack PM, et al. Clinicopathologic findings associated with chronic renal disease in cats: 74 cases (1973–1984). J Am Vet Med Assoc 1987;190:1196–1202. 30. Cusi D, Tripodi G, Casari G, et al. Genetics of renal damage in primary hypertension. Am J Kidney Dis 1993;21:2–9. 31. Ishii M, Ikeda T, Takagi M. Elevated plasma catecholamines in hypertensives with primary glomerular diseases. Hypertension 1983;5:545–551. 32. Weidmann P, Maxwell MH, Lupu AN. Plasma renin activity and blood pressure in terminal renal failure. N Engl J Med 1971;285: 757–762. 33. Weidmann P, Maxwell MH. The renin-angiotensin-aldosterone system in terminal renal failure. Kidney Int 1975;8:219–234. 34. Anderson DH, Stern WH, Fisher SK, et al. Retinal detachment in the cat: the pigment epithelial-photoreceptor interface. Invest Ophthalmol Vis Sci 1983;24:906–926.

JAVMA, Vol 217, No. 5, September 1, 2000