Introduction

Pathophysiology and Incidence of Systemic Hypertension

Systemic hypertension (SH) occurs secondary to a number of diseases, including chronic kidney disease (CKD), hyperthyroidism, primary hyperaldosteronism, hyperadrenocorticism and phaeochromocytoma. Of these, CKD is the most commonly detected cause of SH, followed by pre- and post-treatment cases of hyperthyroidism. In up to 20% of cats with SH, no underlying cause is identifiable and hypertension is classified as idiopathic.¹ Cats with idiopathic SH are geriatric (>12 years of age) and subclinical renal disease is suspected to be the cause of hypertension in at least some of these cases.

Systemic hypertension is diagnosed in up to 40% of cats with CKD seen in primary care clinics, in up to 65% of CKD cases in the referral practice setting. Most cats with CKD and SH have creatinine concentrations of <300 µmol/L (3.4 mg/dL) (IRIS stage I–III). In humans with CKD, SH is associated with impaired renal sodium handling, excessive activation of the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system, structural changes to arterioles, endothelial dysfunction, oxidative stress and genetic factors. Investigations into RAAS activation in cats with SH and CKD have yielded heterogeneous results, and the pathogenesis of SH is yet to be fully elucidated.²

Measuring Blood Pressure in Clinics

The two indirect methods of blood pressure recommended for diagnosis of SH in conscious cats in clinics are Doppler sphygmomanometry and high definition oscillometry (HDO). However, only systolic blood pressure (SBP) readings are accurate using either of these methods. Thus, in clinical practice, diagnosis of SH in cats is on the basis of elevated SBP.

In the largest single study to measure SBP in 780 apparently healthy cats³ using the Doppler method, the median SBP was 120.6 (110.4–132.4) mm Hg. Factors independently associated with a higher SBP were increasing age category, being more nervous during assessment, being male, being neutered, and being a stray.

Minimisation of stress is critical to prevent stress-related “white-coat” hypertension in the clinic environment, which can result in large transient increases in BP. Standardised protocols minimise stress and help ensure accurate and consistent BP measurements are readily available,¹ and should include time for the cat to acclimatise in a stress-free environment, minimal use of restraint and use of a cuff width 30–40% of the circumference of the limb/tail where it is used. The International Renal Interest Society has standardised definitions of hypertension (www.iris-kidney.com/guidelines/staging.html) for cats with CKD that can also be applied to other causes of hypertension in cats (Table 1). The International Society of Feline Medicine (ISFM) consensus guidelines on hypertension include recommendations for frequency of BP monitoring in cats (Table 2).

Table 1. International Renal Interest Society (IRIS) classification of blood pressure substages

Table 2. ISFM Panel Recommendations for monitoring of systemic blood pressure (SBP)¹

Treatment Protocols

For cats with CKD, treatment for hypertension is usually initiated when the SBP is 160–179 mm Hg and ocular/cardiac/neurological TOD is detected or, in the absence of TOD if SBP is persistently160–179 mm Hg (as measured on >1 occasion on separate visits, ideally measured over one to two months), if SBP is ≥180 mm Hg and TOD is present or, in the

absence of TOD if SBB is persistently ≥180 mm Hg (as measured on >1 occasion on separate visits measured over one to two weeks). Amlodipine besylate, a second-generation dihydropyridine that blocks L-type calcium channels in vascular smooth muscle, is the first-choice antihypertensive agent in cats. Due to its long plasma half-life and slow receptor binding and dissociation that results in a relatively slow onset and waning of effect, the drug can be administered once daily orally. To manage SH it is recommended to aim for a target SBP of <160 mm Hg and to recheck SBP one to two weeks after commencing treatment.

The recommended dose rate for cats is 0.125–0.5 mg/kg once daily orally, and most cats are administered 0.625 mg to 1.25 mg/cat at diagnosis. A recent study investigating factors influencing the dose of amlodipine required to change SBP in cats with SH identified that cats with a higher SBP at presentation needed a higher dose of amlodipine to decrease SBP to target levels.⁴ Plasma amlodipine concentrations were directly related to the dose of amlodipine administered. The decrease in SBP was directly and independently associated with the SBP at diagnosis and the plasma amlodipine concentration. Based on these results, the authors proposed a starting dose for cats with SBP of ≥200 mm Hg of 1.25 mg per cat once a day.⁴

For cats with SH that have SBP≥160 mm Hg after >1 week of amlodipine therapy, treatment options include doubling the dose of amlodipine (from 0.25–0.5 mg/kg once daily) or combining amlodipine with a RAAS inhibitor, either an angiotensin-converting enzyme inhibitor (ACEi) (e.g., benazepril), or an angiotensin II receptor blocker (ARBs; e.g., telmisartan). The antihypertensive effect of benazepril in cats is relatively mild, thus benazepril is not recommended for first-line therapy of SH in cats.

Telmisartan selectively antagonizes the angiotensin II, subtype 1 (AT1) receptor, the latter which mediates the adverse effects of angiotensin II on the cardiovascular system and kidneys. A field trial evaluating the effect of telmisartan on SB in healthy conscious cats found that doses of telmisartan of 1–3 mg/kg/day administered orally as a single dose or split into two equal doses resulted in a significant reduction of SBP and was well tolerated.⁵ In cats administered placebo, mean±SBP was 131±15 mm Hg at baseline and 124±14 mm Hg after 14 d. For cats administered 1 mg/kg telmisartan once daily, mean baseline SBP was 130±15 mm Hg and after 14 d was 105±10 mm Hg, while for cats administered 1 mg/kg telmisartan twice daily, baseline SBP was 131±19 mm Hg and after 14 d was 91±18 mm Hg. Further studies are required to determine dose and efficacy of telmisartan for treatment of feline SH.

Gingival hyperplasia is a dose-dependent adverse event associated with amlodipine administration in humans. Recently, it was described in a cat administered 2.5 mg of amlodipine daily, and resolved after the drug was withdrawn.⁶

Cats with SH should be monitored after stabilisation at least every three months. Drug dosages should be decreased in cats showing clinical signs of hypotension (e.g., weakness) or if SBP <120 mm Hg.

References

1.  Taylor SS, Sparkes AH, Briscoe K, Carter J, Cervantes Sala S, Jepson RE, Reynolds BS, Scansen BA. ISFM Consensus Guidelines on the diagnosis and management of hypertension in cats. Journal of Feline Medicine and Surgery. 2017;19:288–303.

2.  Jepson RE, Syme HM, Elliott J. Plasma renin activity and aldosterone concentrations in hypertensive cats with and without azotaemia and in response to treatment with amlodipine besylate. Journal of Veterinary Internal Medicine. 2014;28:144–153.

3.  Payne JR, Brodbelt DC, Luis Fuentes V. Blood pressure measurements in 780 apparently healthy cats. Journal of Veterinary Internal Medicine. 2017;31:15–21

4.  Bijsmans ES, Doig M, Jepson RE, Syme HM, Elliott J, Pellingand L. Factors influencing the relationship between the dose of amlodipine required for blood pressure control and change in blood pressure in hypertensive cats. Journal of Veterinary Internal Medicine. 2016;30:1630–1636.

5.  Coleman AE, Brown SA, Sartk M. Evaluation of orally administered telmisartan for the reduction of indirect systolic arterial blood pressure in awake, clinically normal cats. Journal of Feline Medicine and Surgery. 2018; doi: 10.1177/1098612X18761439.

6.  Desmet L, van der Meer J. Antihypertensive treatment with telmisartan in a cat with amlodipine-induced gingival hyperplasia. Journal of Feline Medicine and Surgery Open Reports. 2017; doi: 10.1177/2055116917745236.