Systemic Hypertension in Cats

Diet has a major impact on the etiology and the therapy of feline cardiovascular diseases. As in humans and dogs, sodium intake in the diet can help modify cardiovascular function. More specifically, cats are dependent on a diet that provides sufficient taurine. Contrary to dogs, taurine is an essential amino acid for cats. The synthesis of bile acids in the cat is exclusively dependent on taurine, and the hepatic activity of the enzymes responsible for its synthesis from the sulfur amino acids, methionine and cysteine is extremely weak.

Valérie CHETBOUL
DVM, PhD, Dipl. ECVIM-CA (cardiology)

A qualified veterinarian since 1984 with a degree from the Alfort National Veterinary School (France), Professor Valérie Chetboul has taken training courses, obtained diplomas and carried out research projects in her favourite field, cardiology, in both Europe and the United States. In 1986, in collaboration with Professor Pouchelon, she opened the first echocardiography clinic for domestic carnivores. The growth of her field of specialization is illustrated by the creation of the Alfort Cardiology Unit and the first French Holter veterinary center (2000) and by an active collaboration with a cardiovascular surgical research unit in Paris (2002). Her involvement in the field of cardiovascular research was translated into her participation in the establishment of a National Health and Medical Research Institute center on the Alfort National Veterinary School campus (2005), attached to the University of Paris XII and dedicated to cardiology. She has published numerous articles in scientific referred journals with an international readership and has written several works, among which an ‘An Echo-Doppler Colour Atlas of Dogs and Cats’, which in 2002 earned her the Groulade Prize by the Veterinary Academy of France. She was editor-in-chief of the Journal of Veterinary Cardiology (2002-2006) and she is still editor of this journal. She has also given numerous papers at different international conferences, both in human and veterinary medicine. Her competence has been recognized by her peers, who in 2001 granted her the prestigious Award of the American College of Veterinary Internal Medicine.

Vincent BIOURGE
DVM, PhD, Dipl. ACVN, Dipl. ECVCN

Vincent Biourge graduated from the Faculty of Veterinary Medicine of the University of Liège (Belgium) in 1985. He stayed as an assistant in the nutrition department for 2 more years before moving to the Veterinary Hospital of the University of Pennsylvania (Philadelphia, USA) and to the Veterinary Medical Teaching Hospital of the University of California (Davis, USA) as a PhD/resident in clinical nutrition. In 1993, he was awarded his PhD in Nutrition from the University of California and became a Diplomate of the American College of Veterinary Nutrition (ACVN). In 1994, he joined the Research Center of Royal Canin in Aimargues (France) as head of scientific communication and then as manager of the nutritional research program. Vincent is now Scientific Director of Health Nutrition at the Research Center of Royal Canin. He has published more than 30 papers, and regularly present scientific papers as well as guest lectures at International Veterinary Medicine and Nutrition meetings. He is also a Diplomate of the European College of Veterinary Comparative Nutrition (ECVCN).

Introduction

Essentially, acquired cardiovascular disease in cats is due to either systemic hypertension (SH) or a cardiomyopathy (including more specifically taurine deficiency). This chapter will review separately and successively each of these pathological entities. An epidemiological, etiological, pathophysiological and diagnostic review will be conducted for and the potential etiological or therapeutic influence of the diet will be considered. While cardiomyopathies (especially hypertrophic forms) are the most commonly found cardiopathies in practice, it would appear justified to first consider SH, due to the key role dietary sodium plays in the development of cardiovascular diseases in general. Additional points of the nutritional management of cardiopathies will be handled in the third part of this chapter.

1. Systemic Hypertension in Cats

SH is defined as the chronic systolic and/or diastolic increase in systemic blood pressure (BP). It is now a well-recognized clinical phenomenon in domestic carnivores, especially cats older than ten years (Chetboul et al., 2003; Brown, 2006; Brown et al., 2007). Most clinicians consider a diagnosis of SH in cats when the systolic BP and diastolic BP is at least 160 and 100 mmHg respectively, measured in a calm animal and according to current recommendations (Stepien, 2004; Brown et al., 2007).

Etiology and Pathogenesis

BP is the lateral force the blood exercises on each surface unit of the arterial vascular wall (Guyton & Hall, 1996). BP depends on heart rate (HR) and total peripheral resistance (TPR).

BP = HR x TPR

The increase in BP can therefore result in a higher HR (due to an increase in the heart inotropism or blood volume) or a rise in TPR (during vasoconstriction, structural modification of the vessels or blood hyperviscosity). The circumstances that may lead to SH are therefore multiple.

Contrary to humans, in which primary or essential SH is the most common form, feline SH is most often secondary to another disorder (Figure 1), most commonly renal or endocrine dysfunction (hyperthyroidism) (Kobayashi et al., 1990; Syme et al., 2002; Chetboul et al., 2003). Essential SH is rare in the feline species. However, more routine measures of BP in veterinary medicine associated with the aging of the animal population suggest a greater frequency. At the moment it is difficult to establish, but SH may affect up to 18 - 20% of cats (Elliott et al., 2001; Maggio et al., 2000). Just like in humans, BP tends to rise with age in normal cats (Samson et al., 2004).

Figure 1. Etiology of systemic arterial hypertension in cats.

The main cause of feline SH (Figure 1) is chronic kidney disease (CKD). Studies show that 20 - 60% of feline renal patients are hypertensive (Kobayashi et al., 1990; Stiles et al., 1994). There are many pathogenic mechanisms linking the kidneys and SH to varying degrees of sodium and water retention and hyperactivity of the renin-angiotensin-aldosterone system, as evidenced by:

• Hormonal alterations (plasma renin activity, aldosteronema, plasma aldosterone/renin ratio)
• Histological and immunohistochemical analysis of the kidneys of animal patients (Taugner et al., 1996; Jensen et al., 1997; Mishina et al., 1998; Pedersen et al., 2003).

SH in cats is also a frequent complication of untreated or poorly controlled hyperthyroidism, affecting a highly variable proportion of animals according to the studies. Between 20% and almost 90% of cats with hyperthyroidism are reported to be hypertensive in the literature (Kobayashi et al., 1990; Stiles et al., 1994). The true prevalence of pathologic SH is probably overestimated due to the sensitivity of the cat to stress. SH in cats with hyperthyroidism is most often moderate and reversible with the treatment of the underlying endocrinopathy. The origin of SH in the event of hyperthyroidism (Feldman & Nelson, 1997) is multifactorial, including an increase in heart rate induced by the thyroidal hormones, an inotropic and chronotropic action directly and indirectly mediated by the receptors coupled to adenylate cyclase, and hyperactivation of the renin-angiotensin-aldosterone system via stimulation of the b juxta-glomerular receptors that initiate increased synthesis of renin.

Other less common causes of SH in cats include diabetes mellitus or more rarely obesity, hyperadrenocorticism, pheochromocytoma, hyperaldosteronemia, or even drugs such as glucocorticoids, phenylpropanolamine, erythropoietin and cyclosporine A (Maggio et al., 2000; Chetboul, 2003; Senello et al., 2003; Brown, 2006; Brown et al., 2007). Predisposing factors include (Brown, 2006) rapid sodium chloride infusion (classic example of a cat with CKD), which may accelerate the expression of subclinical SH or lead to a sharp increase in BP that was initially within the upper limits of normal.

Role of Sodium

In Rodents

An excess in dietary sodium (Na) is well known in some animal species to be directly responsible for SH or at least a predisposing factor to its expression. A diet with a very high salt content [8% Na on a dry matter basis (DMB)]; (by comparison, commercially available diets for cats do not exceed 2% Na DMB) for a period of eight weeks leads to increased BP not only in spontaneously hypertensive rats but also in the initially normotensive Wistar-Kyoto rat (Yu et al., 1998). In the abovementioned rats, these changes were accompanied by the development of interstitial fibrotic lesions in the kidneys (glomeruli, tubules) and the arteries of the left myocardium (Yu et al., 1998). These changes paralleled the increased tissue expression of the gene coding for transforming growth factor-beta 1 (TGFb1). Likewise, in a murine model of renal failure induced by nephron reduction, it has been shown that excessive sodium intake is accompanied by a rise in systemic BP (Cowley et al., 1994).

The genetic models of SH include the salt-sensitive Dahl rat, which develops SH as well as disproportionate fibrotic and hypertrophic lesions in the arteries and left myocardium after the administration of a salt-enriched diet (2 - 8% Na DMB) (Zhao et al., 2000; Siegel et al., 2003; Charron et al., 2005).

In Humans

It has been demonstrated that excessive salt intake in humans can also be deleterious and a direct cause of increased BP, although there is great heterogeneity in responses depending on the individual (Weinberger et al., 1986; 1996; 2001). Thus, in people who are said to be sensitive to salt – less than 25% of the normotensive population (Weinberger et al., 1986, 1996) – the increase in dietary salt intake (from 230 mg (10 mmol)/day to 34.5 g (1500 mmol) over a period of 15 days) is accompanied by an abnormally large rise in BP that may exceed 30% of the baseline value (Luft et al., 1979; Weinberger et al., 1996; 2001). This abnormal sensitivity to salt is said to be a mortality factor independent of the BP value (Weinberger et al., 2001). Inversely, in some hypertensive diseases, sodium restriction may help reduce BP in a manner comparable to that of an anti-hypertensive drug (Weinberger et al., 1986; Luft & Weinberger, 1997). The effect on BP of salt intake in humans is however highly variable, depending on various factors including genetic context, age, consumption of other electrolytes or even the concomitant intake of some drugs (Luft & Weinberger, 1997). The genetic predisposition to salt sensitivity is said to play a major role in humans, as demonstrated in African American people or people with non-insulin dependent diabetes mellitus.

In Healthy Cats

Compared with humans or rats, there are fewer data on the influence of dietary sodium in the genesis of SH in cats. To the authors’ knowledge no case of salt-sensitivity has been truly described comparable to those depicted in humans or rats. In the feline species, it has even been shown that a relatively high sodium level in a normotensive animal is accompanied by an increase in water consumption and urine output (Devois et al., 2000; Luckschander et al., 2004). Thus, in healthy young cats (average age 2.5 years, n=10) the administration of a diet with a moderate sodium chloride (NaCl) content (1.02% Na and 2.02% Cl DMB) for a period of two weeks does not change the systolic BP value (measured with the Doppler method), which remains within reference intervals comparable to what is obtained with a control diet (0.46% Na and 1.33% Cl DMB). In the same study, compared with the control diet, the diet with the higher salt content resulted in only a significant increase in water consumption (in excess of 50%) and urinary osmolarity associated with a reduction in urine density.

While supplementary data (high-salt diet given over a longer period to several animals) are needed to complete the results, the National Research Council (NRC) has estimated that there is now sufficient scientific evidence to conclude that a value of 1.5% Na DMB in a dry food providing 4000 kcal/kg could be considered as being risk-free, in healthy cats (NRC 2006). This level equates to an intake of 3.75 g of sodium per 1000 kcal.

What About Cats Whose Renal Function Is Impaired?

Six different studies of healthy dogs and cats as well as animals with renal failure (presenting maximum azotemia equivalent to stage III CKD according to the IRIS classification) show no influence of a moderate rise in sodium ingestion (up to 3.2 g of sodium per 1000 kcal of metabolizable energy (ME)) on BP (Greco et al., 1994; Buranakarl et al., 2004; Luckschander et al., 2004; Kirk et al., 2007).

According to the available scientific information, blood pressure in healthy cats or cats with moderate CKD is not affected by the sodium levels required to stimulate water consumption and urine output in cats. (© Royal Canin).

Pathophysiological Consequences

Most of the organic consequences of SH appear for systolic BP values in excess of 180 mmHg (Brown, 2006), more particularly during the sharp rise in pressure (30 mmHg or more in less than 48 hours).
- The kidneys are one of the preferred targets of SH (Brown, 2006). Untreated SH can lead to the development of nephroangiosclerotic lesions, which themselves have the potential to accentuate the initial hypertension.
- The heart, and specifically the left ventricle, is another main target organ of SH. In a study conducted in association with Toulouse National Veterinary School on 58 hypertensive cats (Chetboul et al., 2003), 85 % presented with an abnormal echocardiograph. In 59% of the cases, the alteration was concentric hypertrophy of the left ventricular wall (Figure 2 & Figure 3A), symmetric or not. There was no correlation between the degree of parietal hypertrophy and blood pressure values nor the age of the animals. Eccentric hypertrophy and septal hypertrophy localized in the subaortic region (Figure 3B & Figure 3C) were found in a lower but similar proportion (13% each). Dilatation of the left atrium was associated with the left ventricular remodelings in less than one third of cases (28%). Feline SH has also been shown to accompany modification of the proximal aorta (dilatation, twisting contours) (Nelson et al., 2002).

Figure 2. Example of marked symmetrical concentric hypertrophy of the left ventricle in a cat with renal failure and systemic arterial hypertension. (© Unit of Pathologic Anatomy, ENVA).

Figure 3. The three main types of left ventricular remodeling associated with systemic arterial hypertension in cats.

- Ocular lesions are common in hypertensive animals (Maggio et al., 2000; Chetboul et al., 2003; Samson et al., 2004), affecting up to 50% of hypertensive cats and 80% of hypertensive cats with renal failure. These lesions mainly correspond to alterations in the vascularization of the fundus termed ‘hypertensive retinitis’ (Figure 4): abnormal twisting and dilatation of blood vessels in the retina, localized or diffuse preretinal or retinal hemorrhages, and partial or total detachment of the retina potentially leading to permanent blindness in the absence of early treatment. SH may also cause hyphema, anterior uveitis due to vasculopathy of the ciliary bodies or even glaucoma caused by an obstruction of the iridial angle by blood.

Figure 4. Sudden blindness in a cat, caused by hypertensive retinopathy. (© Valérie Chetboul).

- A sharp and marked rise in BP may lead to the appearance of cerebral lesions (edema or hemorrhage) classified as hypertensive encephalopathy (Brown et al., 2005; Brown, 2006). Hypertensive encephalopathy causes various nervous problems ranging from simple behavioral modifications (hypernervosity, anxiety, complaining mewing), ataxia and disorientation, to more serious signs (torpor (Figure 5), convulsions or coma). For reasons that are not yet apparent, cats suffer from hypertensive encephalopathy more often than dogs.

Figure 5. Exhaustion and torpor in a cat with systolic arterial hypertension (systolic arterial pressure = 290 mmHg). (© Valérie Chetboul).

Diagnosis

Diagnostic Step n°1: Suspicion

In practice, SH must be suspected when the cat has a disorder that is a known cause of SH (especially CKD or hyperthyroidism). Other suspicious circumstances include:

1. When one or more (physical or functional) symptoms are suggestive of SH (Table 1).
2. Identification of left cardiomegaly or left ventricular remodeling by radiograph or ultrasound imaging, respectively.

The diagnosis of SH can also be established during the routine measurement of BP despite the absence of other signs based on clinical observation, etiology, radiograph or ultrasound. However, an increase in BP alone, should be carefully interpreted (do not hesitate to repeat the BP measurement in the absence of clinical signs or biochemical modifications).

Diagnostic Step n°2: Confirmation Via BP Measurement

The Doppler method (Figure 6 & Figure 7) is currently recommended by the majority of authors due to its speed and simplicity compared with oscillometry (Jepson et al., 2005). In addition, the Doppler method is strongly correlated with the values obtained by the gold standard reference method of direct catheterization (Binns et al., 1995). The only drawback of this technique is the occasional difficulty determining the diastolic BP value, which is negated by experienced operators. Several rules must however be followed to ensure that the values measured are as repeatable and reproducible as possible and to limit anxiety-induced hypertension ("white coat effect"), which can lead to the erroneous diagnosis of pathological SH.

Figure 6. Example of equipment used to measure blood pressure by the Doppler method. 6A: machine - 6B: manometer - 6C: occlusive cuff - 6D: transducer (8-10 MHz). (© Valérie Chetboul).

Figure 7. Blood pressure measurement by the doppler method in a cat. (© Valérie Chetboul). 7A: Positioning of the cuff at the base of the tail and distal application of gel. 7B: Inflation of the cuff after location of the blood flow. The animal is lying on its sternum (measurement taken at heart level).

Rules to Be Followed to Measure Blood Pressure in Cats (Stepien et al., 2004; Snyder et al., 2006; Brown et al., ACVIM consensus statement, 2007)

1. The following recommendations help limit “white coat hypertension” and avoid erroneous diagnosis of pathological hypertension.

• Conduct the test in a separate room that is calm, in the presence of the owner.
• Wait until the heart rate is stable or the cat calms down before conducting a test or registering the results.
• Eliminate the first BP values, then take 3 - 5 additional measures, if possible at 30 - 60 seconds intervals to calculate the average.
• Do not hesitate to repeat the test within 48 hours, in the event of clinical or etiological suspicion, or 15 - 30 days, in less urgent circumstances in borderline cases (cat showing stress and BP values above the upper limits: 160 mmHg in systole, 100 mmHg in diastole).

2. The following rules help increase the reliability of the technique.

• The same people, trained in the technique and the use of the equipment should always conduct BP tests at any given clinic or in any given team.
• The ambient temperature in the room should not be too low, to avoid the appearance of peripheral vasoconstriction, which could cause the BP value to be higher than expected or even make it difficult to get a measurement.
• Use the appropriate cuff (if it is too small BP may be overestimated; if it is too big the BP may be underestimated).
• The average BP value, the name of the tester, the test site and the number of measurements taken should be noted, to ensure maximum rigor in longitudinal monitoring.

Diagnostic Step n°3: Determination of the Cause

When SH is identified in a cat the veterinarian must begin with a simple blood test (urea, creatinine and T4 measurement) to confirm or rule out CKD and hyperthyroidism. If the results are normal, a complete medical evaluation must be conducted before concluding primary SH. This examination includes a CBC, biochemical profile, urine analysis and even an abdominal ultrasound to check for an adrenal mass. Finally, it also advised to analyse the urine protein to creatinine ratio (UPC) as proteinuria can be a negative pronostic factor (Jepson et al., 2007).

Medical Treatment

Anti-hypertensive drugs that can be administered to cats are listed in Table 2. Amlodipine besylate is by far the anti-hypertensive of choice in cats. It is a documented drug in the species with efficacy in most cases without the additional need of other anti-hypertensive treatments (Henik et al., 1997; Elliott et al., 2001; Snyder et al., 2001; Tissier et al., 2005). Amlodipine is a long-action calcium inhibitor of the dihydropyridine group that acts against the opening of the voltage-dependant slow calcium channels. Its long action (contrary to that of nifedipine) limits the secondary effects of sudden hypotension (tachycardia, exhaustion, malaises). Amlodipine also has few negative effects on inotropism and conduction. Amlodipine is not recommended in cats with hepatic failure.

Treatment of the primary disorder, when known, is a priority. In cats with hyperthyroidism, normalization of BP may be achieved in association with the restoration of euthyroidism without use of anti-hypertensives (Snyder & Cooke, 2006). In an emergency (sudden blindness or major tachyarrhythmia), it will be necessary to quickly reduce BP with the administration of amlodipine (calcium inhibitor) or b blockers (propranolol, atenolol), which have the advantage of directly targeting the action sites of thyroidal hormones on the cardiovascular system (Table 2).

Adapting the Sodium Content in Food

Based on the data on excess dietary sodium from animal SH models or human medicine (see above), it is often accepted that the ingestion of sodium must be severely reduced in hypertensive cats. While excessive and sudden sodium intake (1.3%/DMB or more) must be avoided in the event of feline SH (Snyder & Cooke, 2006), no study has yet shown the benefit of sodium restriction in cats in terms of blood pressure values or life expectancy.

Contrary to preconceived ideas, too low an intake of dietary sodium in cats can be rather harmful, as shown by Buranakarl et al (2004). For one week, three groups of cats were given the same dry food differentiated only by sodium content: 0.34%, 0.65% and 1.27% as fed, (0.5 g, 1.4 g and 2.8 g per 1000 kcal, respectively). One group of healthy cats (control group, n=7) was compared with two groups of cats with experimental renal disease by renal infarct (ligature of the branches of the renal artery) associated either with contralateral nephrectomy ("remnant kidney (RK) model", n=7) or contralateral "wrapping" (wrapping or WA model, n=7).

In the two groups of cats with renal failure, in spite of the prescription of amlodipine (0.25 mg/kg/24 hours PO) systemic, systolic, diastolic and average BP (measured by radiotelemetry) were higher than in the control group, significantly in the RK group and to a lesser degree in the WA group. However, no influence of dietary sodium was observed in the three groups of cats, on heart rate, blood pressure variability (shown by a retained baroreflex also in sick animals) or the systemic BP value (systolic, diastolic and mean). In other terms, and contrary to the data published in rats (Cowley et al., 1994), the high sodium diet characterized by 2.8 g Na/1000 kcal was not responsible for a rise in BP in either the healthy control cats, which concurs with the data obtained for healthy dogs (Krieger et al., 1990; Greco et al., 1994) or cats with renal failure. Likewise, the lower sodium diet did not induce a lower systemic BP in the two groups of sick cats nor in the control group. This latter diet was shown to have no beneficial anti-hypertensive protector effect in cats with renal disease.

In the same study (Buranakarl et al., 2004), the lowest sodium intake (0.5 g/1000 kcal) was also associated with:

• A significant reduction in the glomerular filtration rate in control cats compared with the values obtained in the same group with the other two diets. The same observation was made in the WA group;
• Activation of the renin-angiotensin-aldosterone system (RAAS) in cats with renal disease which was greater in the WA group than in the RK group. This activation was characterized by aldosteronemia and a higher serum aldosterone/renin ratio compared with the control group. These hormonal modifications were reduced with NaCl supplementation. This diet was also associated with an increase in the arginine-vasopressin plasma concentration in the RK group;
• Hypokalemia in healthy cats and even more in cats with renal disease, associated with an increase in the excreted potassium fraction (very marked in the WA model) linked to a large degree to hyperaldosteronism, which is potentially harmful (risk of hypokalemic nephropathy and progressive renal lesions).

This cat shows a typical posture signifying general muscle weakness, with drooping of head and neck, that may be encountered with severe hypokalemia in patients with CKD, as well as in hypokalemia due another cause. (© Malik).

To summarize, the data presented above demonstrate that major restriction of sodium is not recommended in hypertensive cats or in cats with CKD that have hypertensive tendencies. Excessive restriction risks stimulating the renin-angiotensin-aldosterone system, a pressure system par excellence. This aggravates the reduction in the glomerular filtration rate and favors hypokalemia due to increased kaliuresis. The same recommendation applies to healthy cats.

Lastly the prescription of a low calorie diet has not been shown to have a hypotensive effect in obese cats (Snyder & Cooke, 2006), although few data are available on this subject.