INTRODUCTION

Systemic hypertension is a circulatory disorder frequently recognized in geriatric cats. A high incidence of hypertension has been noted in cats with chronic renal failure (61%) and in cats with hyperthyroidism (87%) (Kobayashi et al, 1990), but hypertension in absence of renal or thyroid dysfunction is also noted (Littman, 1994). Because untreated hypertension may result in serious neurologic, ocular, renal, and cardiac disease, treatment of cats with this disorder is imperative. However, the specific antihypertensive agent or agents used may also significantly impact vital organ function and long-term prognosis.

This review contains current concepts regarding epidemiology, etiology, pathophysiology, and diagnosis of feline hypertension and presents a discussion of therapeutic strategies aimed at not only reducing blood pressure, but reducing blood pressure in a way likely to preserve vital organ function.

EPIDEMIOLOGY, ETIOLOGY AND PATHOGENESIS

In general, hypertension is a disorder occurring in older cats. The average age of affected cats is reported as 15 years with a range of 5-20 years (Littman, 1994, Steele et al, 2002). While there appears to be an inverse correlation between arterial blood pressure and age (Bodey & Sansom, 1998), it is unclear whether the age related rise in pressure noted in seemingly healthy cats is a normal aging phenomenon or a result of early, subclinical disease. No gender or breed predilection has yet been identified for feline hypertension.

Although hypertension often occurs in association with renal dysfunction in cats, a specific cause and effect relationship between the renal disease and increased arterial blood pressure is not clearly understood. Renal vascular and renal parenchymal diseases are recognized causes of hyperreninemic hypertension in people (Pastan & Mitch, 1998). Expanded extracellular fluid volume is another mechanism by which hypertension may develop in patients with end stage renal disease (Pastan & Mitch, 1998). However, available data suggest that most cats with naturally occurring systemic hypertension and renal dysfunction have neither increased plasma renin activity nor increased plasma volume (Hogan et al, 1999; Henik et al, 1996). It is possible that some cats have primary (essential) hypertension and incur renal damage secondarily as a result of chronic glomerular hypertension and hyperfiltration.

Similarly, the causal relationship between hyperthyroidism and hypertension in cats is not well defined in spite of the high incidence of hypertension in thyrotoxic cats. Hyperthyroidism results in an increased number and sensitivity of myocardial b-adrenergic receptors and a subsequent heightened response to catecholamines. In addition, L-thyroxine has a direct positive inotropic effect. Consequently, hyperthyroidism tends to produce increases in heart rate, stroke volume, and cardiac output and an increased arterial blood pressure. While it is conceivable that the increase in blood pressure noted in cats with hyperthyroidism may result from a hyperthyroid-induced increase in cardiac output, no significant relationship is found between serum thyroxine concentration and arterial blood pressure (Bodey & Sansom, 1998). Moreover, some cats remain hypertensive following appropriate treatment of the hyperthyroid state. These observations suggest that at least some cats with hyperthyroidism and hypertension have hypertension independent of the hyperthyroid state. Other possible, yet unlikely, causes of hypertension in cats include hyperadrenocorticism, primary aldosteronism, pheochromocytoma, and anemia.

These observations, and the fact that feline hypertension may occur in the absence of renal or thyroid disease, suggest that cats, like people, may develop essential, or idiopathic, hypertension in which the primary pathologic process is within the resistance vessels of the systemic vasculature. In human patients with essential hypertension the pathophysiologic mechanism appears to involve increased vascular resistance due to endothelial dysfunction. The endothelial dysfunction has been verified in these patients by demonstrating impaired endothelium-dependent vasodilation in response to bradykinin (Panza et al, 1990; Panza et al, 1995) and impaired nitric oxide availability (Linder et al, 1990; Taddei et al, 1998). The vascular mechanisms responsible for essential hypertension in cats have not been completely elucidated. However, an increase in systemic arterial pressure can be induced in normal cats by inhibition of nitric oxide synthase (Brown et al, 1997) suggesting a possible role for nitric oxide in feline hypertension.

CLINICAL FEATURES OF FELINE HYPERTENSION

The clinical signs of feline hypertension usually arise as a result of damage to target organs, namely the brain, heart, kidneys, and eyes. As blood pressure rises, auto regulatory arteriolar constriction occurs in these highly vascular organs to protect capillary beds from the high pressure. Intense, sustained vasoconstriction may ultimately produce ischemia, infarction, and loss of capillary endothelial integrity with edema or hemorrhage. Cats with hypertension may present for blindness; polyuria/polydypsia; neurologic signs including seizures, ataxia, nystagmus, and rear limb paresis or paralysis; dyspnea; or epistaxis (Littman, 1994). Unusual behavior such as gazing and vocalizing have also been described (Stewart, 1998). Many cats have no obvious clinical signs and are diagnosed because of murmurs, gallop rhythms, or electrocardiographic abnormalities.

Hypertension is a widely recognized cause of left ventricular hypertrophy, left ventricular dysfunction, congestive heart failure, myocardial infarction, and arrhythmias in people (Frohlich et al, 1992; Houston, 1992). Impaired diastolic filling is a consistent and early feature of hypertensive heart disease and has been attributed to abnormal myocardial energy metabolism (Ren et al, 1994; Lamb et al, 1999). Left ventricular systolic dysfunction at rest occurs much later unless another cause of heart disease is also present (Frohlich et al, 1992).

In cats systemic hypertension is frequently associated with left ventricular hypertrophy, audible systolic murmurs, and electrocardiographic abnormalities. Left ventricular hypertrophy is typically mild in hypertensive cats, and asymmetric septal hypertrophy may occur (Nelson et al, 2002; Chetboul et al, 2003). Dilation of the ascending aorta is often noted radiographically or echocardiographically, but it is unclear whether this finding is consistently due to hypertension or whether it is simply an aging change in some cats. Hypertensive cats frequently have abnormal pulsed Doppler patterns of diastolic function that are consistent with impaired relaxation. And although age-matched, controlled studies have not been done, normalization of the pulsed Doppler filling patterns with antihypertensive therapy suggests that altered left ventricular diastolic function in hypertensive cats is due, at least in part, to hypertension. A wide variety of electrocardiographic abnormalities including ventricular and supraventricular arrhythmias, atrial or ventricular enlargement patterns, and conduction abnormalities may be found in cats with systemic hypertension. Tachyarrhythmias often resolve when the hypertension is appropriately treated. In contrast to hypertensive heart disease in people, cardiac disease secondary to hypertension rarely progresses to congestive heart failure in cats (Bonagura, 1994; Littman, 1994). However, thromboembolic complications (Littman, 1994) and aortic dissection (Wey & Atkins, 2000) have been observed.

Acute blindness is the most common clinical manifestation of systemic hypertension in cats. Blindness usually results from bilateral retinal detachment and/or hemorrhage. In one study of hypertensive cats 80% had hypertensive retinopathy characterized by hemorrhage of the retina, vitreous, or anterior chamber; retinal detachment and atrophy; retinal edema; perivasculitis; retinal artery tortuosity; and/or glaucoma (Stiles et al, 1994). The auto regulatory arteriolar vasospasm may also produce retinal ischemia. The time interval between onset of hypertension and appearance of retinal lesions appears to be highly variable (Stiles et al, 1994). Retinal lesions usually improve with antihypertensive therapy, and a small percentage (17%) of cats will regain vision after beginning treatment (Kirschner & Langston, 1994).

The central nervous system is prone to hypertension-induced damage because of the abundance of small vessels. In people hypertensive-induced damage to the brain may manifest as seizures, cerebrovascular accidents, encephalopathy, and dementia. In cats clinical signs due to hypertensive damage of the central nervous system are less common and more difficult to recognize than in people but include seizures, head tilt, depression, paresis or paralysis, and vocalizing.

Chronic hypertension may cause renal disease as a result of changes induced in the afferent glomerular arterioles (Ross, 1992). Focal and diffuse glomerular proliferation and glomerular sclerosis may also develop (Kashgarian, 1990). Once renal dysfunction is present, chronic systemic hypertension produces a sustained increase in glomerular filtration pressure which plays a pivotal role in progressive deterioration of renal function (Anderson & Brenner, 1987; Bidani et al, 1987). Proteinuria and hyposthenuria commonly caused by hypertension in people are uncommon in feline hypertensive patients (Kobayashi et al, 1990; Littman, 1994), but microalbuminuria is observed (Mathur et al, 2002).

BLOOD PRESSURE MEASUREMENT IN CATS

Patient size and temperament make noninvasive measurement of arterial blood pressure in conscious cats a challenge. Diagnosis and assessment of therapeutic response depend upon accurate and reproducible blood pressure measurement. It is important that the patient be minimally stressed and that proper technique be followed. Non-invasive blood pressure measurement in cats can be done using either a Doppler ultrasonographic flow probe or an oscillometric sphygmomanometer. Although inaccuracy of the oscillometric method in cats has been reported (Binns et al, 1995), a more recent study has validated this technique when used on the tail of conscious, unrestrained cats (Bodey & Sansom, 1998). If the Doppler method is used, only systolic pressure is reliably obtained. However, this is not an important limitation for diagnosis or treatment of feline hypertension because most hypertensive cats have combined systolic and diastolic hypertension (Kobayashi et al, 1990; Lesser et al, 1992). Furthermore, therapeutic management based on the level of systolic blood pressure appears to be both safe and medically justified (Stevo & Brunner, 1999).

With either the Doppler or the oscillometric method, measurement of blood pressure using the median coccygeal artery usually enables measurement to be done with minimal restraint and minimal stress. In addition, use of this site results in negligible vertical distance between the cuff and the heart. Cuff size should be 0.4-0.6 times the circumference of the measurement site. It is best to obtain a series of three to five readings from each cat on each occasion with at least 30 seconds between consecutive readings to allow recirculation. With either method the initial blood pressure value is often high, but subsequent values decrease and level off as the cat settles.

If blood pressure measurements cannot be obtained from the coccygeal artery, measurements from the forelimb (median artery) or rear limb (dorsal metatarsal artery) may be obtained with the cat positioned in lateral recumbency during measurement.

DIAGNOSIS OF FELINE HYPERTENSION

The presence of hypertension in cats may be inferred from characteristic retinal lesions. However, other causes of retinal detachment and/or hemorrhage exist, and diagnosis of hypertension should be confirmed with blood pressure measurement. Blood pressure should also be measured to verify or refute the presence of systemic hypertension in all cats with left ventricular hypertrophy, renal dysfunction, or hyperthyroidism as well as in cats greater than 7 years old with murmurs, gallops, or electrocardiographic abnormalities.

Hypertension in cats has been defined as an indirect systolic pressure of greater than 160 mmHg (Littman, 1994; Stiles et al, 1994) or 170 mmHg (Morgan, 1986) and diastolic blood pressure of greater than 100 mmHg (Littman, 1994; Stiles et al, 1994). However, arterial blood pressure will increase with age in cats and may exceed 180 mmHg systolic and 120 mmHg diastolic in apparently healthy, aged cats (cats > 14 years) (Bodey & Sansom, 1998). Therefore, the diagnosis of systemic hypertension may be made in a cat of any age with a systolic blood pressure > 190 mmHg or a diastolic pressure > 120 mmHg. Cats with clinical findings compatible with hypertension and systolic pressures between 160 and 190 mmHg should also be considered hypertensive, particularly if less than 14 years of age. In absence of clinical findings of hypertension, cats with a systolic blood pressure between 160 and 190 mmHg or diastolic pressure between 100 and 120 mmHg, should have blood pressure measurements repeated several times over the course of a day and, perhaps, on several days. Testing the urine for presence of microalbuminemia may also be helpful.

THERAPEUTIC STRATEGIES

Early recognition and treatment of cats with systemic hypertension is important. Although not all cats will manifest clinical signs, consequences of failing to intervene medically can be gleaned from the term "silent murderer" that is used to describe untreated hypertension in people. The primary goal of treatment is to prevent injury or further injury to the eyes, kidneys, heart, and brain. This is accomplished, not merely by reducing the arterial pressure, but by doing so in a way that improves circulation to the target organs.

Numerous pharmacologic agents are available for use as antihypertensive agents including diuretics, b-adrenergic antagonists, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), calcium channel antagonists, direct-acting arterial dilators, centrally acting a2-adrenergic agonists, and a1-adrenergic antagonists. Cats tend to become refractory to the antihypertensive effects of a-adrenergic blocking agents, such as prazosin, and also to the direct-acting arteriolar dilators such as hydralazine. In addition, long-term use of direct-acting agents often results in undesirable stimulation of compensatory neural and hormonal pathways. Diuretics, b-adrenergic blockers, or combinations thereof will effectively reduce arterial blood pressure in most hypertensive cats. However, b-blockers and diuretics do not reduce the vital organ damage associated with hypertension (Houston, 1992).

According to Poiseuille's law of fluid flow, arterial blood pressure is determined by the product of systemic vascular resistance and cardiac output. Because the reduction of arterial pressure that results from administration of diuretics and b-adrenergic antagonists comes about from a reduction of cardiac output, these agents reduce arterial pressure by a mechanism that reduces flow to the target organs, thereby compromising perfusion of the myocardium, kidneys, and brain (Houston, 1992). In contrast, calcium channel antagonists, ACE inhibitors, and ARBs decrease arterial pressure by reducing vascular resistance, a mechanism likely to improve organ perfusion. The calcium channel antagonists, particularly those lacking myocardial depressive effects, and the ACE inhibitors have, in fact, been shown to have favorable effects on renal function and coronary and cerebral perfusion in hypertensive people (Houston, 1992; Anderson et al, 1986). The centrally acting a-adrenergic agonists are also antihypertensive agents that reduce blood pressure by reducing vascular resistance, and these agents have also been shown to maintain target organ function (Houston, 1992). Diuretics and b-blockers reduce cardiac output, stroke volume, coronary blood flow, and renal blood flow while increasing renal vascular resistance. Furthermore, these agents do not consistently reduce left ventricular hypertrophy. In contrast, the calcium channel blockers, ACE inhibitors, ARBs, and centrally acting agents have the opposite effects.

Amlodipine is a long-acting antihypertensive agent belonging to the dihydropyridine subclass of calcium channel blocking agents (Aristizabal et al, 1994). This agent relaxes vasculature smooth muscle by blocking calcium influx. Its primary vasodilating effect is in the systemic resistance vessels although the coronary arteries are also affected. This agent is safe and effective, even in cats with renal dysfunction, when used at an oral dose of 0.2 mg/kg once daily (Snyder, 1998). Once daily administration of amlodipine reduces arterial pressure for an entire 24 hour period (Snyder, 1998). Furthermore, cats do not appear to become refractory to the therapeutic effects of this agent with long-term treatment.

ACE inhibitors such as enalapril and benazepril are also a good choice for treatment of feline hypertension. However, these agents are often ineffective as mono-therapy in cats (Steele et al, 2002, Mathur et al, 2002). The ACE inhibitors may be best used in combination with amlodipine.

In cats, refractory to amlodipine or ACE inhibitors alone, a combination of these agents often safely provides adequate blood pressure control. The author has achieved successful long-term control of arterial hypertension by adding a modest dose of enalapril or benazepril (1.25-2.5 mg/cat/day) to amlodipine. A slight improvement in renal status may be observed in some cats receiving this combination of drugs. Experimental data indicate that the combination of these two classes of antihypertensive agents not only increases the effectiveness of blood pressure reduction, but also maximizes end-organ protection (Raij & Hayakawa, 1999). Finally, the Joint National Committee has recently advocated the use of low-dose combination therapy with amlodipine and ACE inhibitor for human patients citing increased effectiveness with reduced likelihood of toxicity (Joint National Committee, 1997). The angiotensin receptor blocking agent, irbesartan, used with amlodipine is effective in some cats refractory to ACE inhibitor/amlodipine.

Aggressive treatment with pharmacologic agents that rapidly lower blood pressure is indicated for cats with neurologic signs. Amlodipine and ACE inhibitors have a gradual onset of action, requiring two to three days to reach peak hypotensive effect. In contrast, sodium nitroprusside is a potent hypotensive agent with a rapid onset of action that may be administered intravenously for acute management of hypotensive crises. However, safe administration of this drug requires careful dose titration using an infusion pump (1.5-5 mg/kg/min IV infusion) and continuous blood pressure monitoring. Hydralazine may be used as an alternative to nitroprusside when rapid reduction of blood pressure is needed. This drug is typically administered orally every twelve hours beginning with a dose of 0.5 mg/kg and increasing, if necessary, up to 2.0 mg/kg every 12 hours. Caution is advised when using rapidly acting, potent antihypertensive agents to treat a hypertensive crisis. A rapid, precipitous drop in blood pressure may cause cerebral ischemia and worsening neurologic signs (Calhoun & Oparil, 1990).

References

References are available upon request.