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Keywords:

  • Aldosterone:renin ratio;
  • Blood pressure;
  • Feline;
  • Hyperthyroidism;
  • Plasma renin activity

Abstract

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. References

Background

Hypertension is present in some hyperthyroid cats at diagnosis or can develop after treatment for hyperthyroidism. Activation of the renin-angiotensin-aldosterone system (RAAS) could be involved in the pathogenesis of hypertension.

Hypothesis

Hyperthyroid cats that develop hypertension before or after treatment for hyperthyroidism will have greater RAAS activation than normotensive cats.

Animals

Ninety-nine hyperthyroid cats.

Methods

Retrospective case–control study. Plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were measured in untreated hyperthyroid hypertensive cats (HT-Pre group), initially normotensive hyperthyroid cats that develop hypertension after treatment (HT-Post group), and hyperthyroid cats that are normotensive (NT group). Data are presented as median [25th, 75th percentile].

Results

Baseline PRA was not significantly different among the 3 groups (HT-Pre group 1.50 [0.05, 2.37] ng/mL/h, HT-Post group 0.66 [0.17, 2.31] ng/mL/h, NT group 1.11 [0.57, 2.18] ng/mL/h; P = .44). PRA decreased significantly after treatment in the NT group (1.09 [0.53, 2.47] versus 0.22 [0.05, 0.76] ng/mL/h; P < .001) and the HT-Post group (0.71 [0.17, 2.33] versus 0.28 [0.07, 0.57] ng/mL/h; P = .006). Baseline PAC was not significantly different among the 3 groups (HT-Pre group 72.2 [40.0, 145.6] pg/mL, HT-Post group 69.7 [43.3, 142.6] pg/mL, NT group 109.0 [68.2, 184.6] pg/mL; P = .10). PAC decreased significantly after treatment in the NT group (114.4 [56.6, 204.1] versus 59.5 [32.4, 98.2] pg/mL; P < .001) but did not change significantly in the HT-Post group (61.2 [44.9, 124.0] versus 58.4 [42.0, 97.7] pg/mL; P = .59).

Conclusions and Clinical Importance

RAAS activation occurs in hyperthyroid cats, but is not associated with the development of hypertension. PAC is not influenced by changes in PRA in hyperthyroid cats that develop hypertension after treatment, perhaps indicating RAAS dysfunction in these cats.

Abbreviations
ARR

aldosterone:renin ratio

SBP

systolic blood pressure

CKD

chronic kidney disease

HT-Pre

hypertensive at diagnosis

HT-Post

hypertensive posttreatment

NT

normotensive

PAC

plasma aldosterone concentration

PRA

plasma renin activity

RAAS

renin-angiotensin-aldosterone system

TT4

plasma total thyroxine concentration

USG

urine specific gravity

Hypertension is present in 14–23% of cats at the time of diagnosis of hyperthyroidism.[1, 2] Twenty-three percent of initially normotensive hyperthyroid cats will also develop hypertension after treatment for hyperthyroidism and restoration of euthyroidism.1 The development of hypertension in hyperthyroidism or after treatment for hyperthyroidism could be secondary to the presence of underlying chronic kidney disease (CKD), as hypertension is present in at least 19% of cats with CKD.[1, 3, 4] Azotemic CKD is present in 11% of hyperthyroid cats,[2] and develops in a further 15–49% of hyperthyroid cats after treatment.[2, 5]

Although hypertension is associated with CKD in the cat,[1, 3, 4] the exact pathophysiologic mechanism(s) and interrelationship between the 2 conditions is still poorly understood.[6, 7] Stimulation of the renin-angiotensin-aldosterone system (RAAS) occurs in human patients with CKD,[8-10] and this has been correlated with the severity of hypertension.[10] RAAS activation, through the effects of angiotensin-II and aldosterone, causes volume expansion, vasoconstriction, and a resultant increase in blood pressure. In cats with CKD and hypertension, plasma renin activity (PRA) is similar to normal cats[6] or decreased compared with normotensive cats with CKD.2 However, plasma aldosterone concentration is higher in hypertensive cats with CKD compared with normal cats[6] and normotensive cats with a similar degree of renal dysfunction.[6, 11]

Hyperthyroidism causes RAAS activation in humans.[12-14] There is a decrease in systemic vascular resistance in the hyperthyroid state,[15] which decreases effective arterial filling volume and stimulates the release of renin as a compensatory response. Once euthyroidism is restored, systemic vascular resistance returns to normal and RAAS activation should decrease. However, if activation of the RAAS remains after restoration of euthyroidism, this could lead to the development of hypertension after treatment. Although concurrent hypertension is common in cats with hyperthyroidism, the pathophysiologic mechanisms for the development of hypertension in the cat are poorly understood. One preliminary study measured RAAS activation before and after treatment for hyperthyroidism in cats with and without hypertension;3 however, the group sizes were small and so it is difficult to draw any firm conclusions as to the role of the RAAS in the development of hypertension.

The 1st objective of this study was to determine if RAAS activation was increased in hyperthyroid cats with concurrent hypertension at the time of diagnosis compared with initially normotensive hyperthyroid cats that develop hypertension after treatment and normotensive hyperthyroid cats. The 2nd objective was to evaluate the changes in RAAS activation that occur in initially normotensive hyperthyroid cats which develop hypertension after restoration of euthyroidism and compare these changes with those of hyperthyroid cats which remain normotensive. Activation of the RAAS was assessed by measurement of PRA and plasma aldosterone concentration.

Methods

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. References

Cat Selection

Records from 2 London-based first opinion practices (People's Dispensary for Sick Animals, Bow and the Beaumont Sainsbury Animal Hospital, Camden) between January 1, 1999, and March 30, 2011 were reviewed and newly diagnosed hyperthyroid cats identified. Diagnosis of hyperthyroidism was based on a plasma total thyroxine concentration (TT4) greater than the laboratory reference range (>55 nmol/L, 4.26 μg/dL).

Cats were excluded from further analysis if, at the time of diagnosis of hyperthyroidism, they had evidence of previous or concurrent azotemia (defined below) or if they were receiving antihypertensive medication (amlodipine).

Cats were treated for hyperthyroidism with antithyroid medication (carbimazole or methimazole) alone, or in combination with thyroidectomy and were reexamined at approximately 4 weekly intervals until euthyroidism was restored. Once stable, cats were examined every 8 to 12 weeks. Blood and urine samples were obtained approximately every 3–4 months.

Blood Pressure Measurement

Systolic blood pressure (SBP) measurements were made by an 8.1 MHz Doppler ultrasound probe using the protocol previously described.[3] Fundic examination by indirect ophthalmoscopy was performed in cats with an average SBP >160 mmHg to assess for evidence of hypertensive retinopathy.

Categorization of Hypertension, Azotemia, and Control of Hyperthyroidism

Cats were categorized as hypertensive at diagnosis (HT-Pre group) if they had a mean SBP >160 mmHg with evidence of hypertensive retinopathy at baseline. Cats were also classified as hypertensive at diagnosis (HT-Pre group) if they had a mean SBP >170 mmHg without evidence of hypertensive retinopathy at baseline, and hypertension was confirmed by repeat blood pressure measurement (SBP >170 mmg) at a 2nd visit within 1–2 weeks (and the clinician did not feel that white coat hypertension was a significant contributing factor). In cases for which concurrent hypertension was diagnosed at a 2nd visit within 1–2 weeks of diagnosis of hyperthyroidism, antithyroid medication was withheld until hypertension was successfully controlled by antihypertensive medication (amlodipine). This was deemed prudent, as blood pressure can increase after treatment for hyperthyroidism,1 which could exacerbate concurrent hypertension.

Hyperthyroid cats that were normotensive at the time of diagnosis were followed for a 6-month period after establishment of euthyroidism. Cats that developed hypertension within 6 months of initiation of treatment were classified as hypertensive posttreatment (HT-Post group). The visit at which the cat was diagnosed as hypertensive (ie, prior to initiation of treatment for hypertension) was defined as the posttreatment visit for the HT-Post group. Hyperthyroidism was not always well controlled (defined below) at the posttreatment visit for the HT-Post group. Cats that remained normotensive and well controlled (defined below) for a 6-month period after establishment of euthyroidism were classified as normotensive (NT group), and the time point at the end of the 6-month period was defined as the posttreatment visit for normotensive cats. Any cats that started renal care diet during the follow-up period were also excluded from the study.

Renal azotemia was defined as a plasma creatinine concentration >2.0 mg/dL (177 μmol/L) in conjunction with USG <1.035, or persistent azotemia on 2 or more consecutive occasions without clinical evidence of prerenal cause.

Hyperthyroidism was categorized as well controlled if cats appeared euthyroid on clinical examination (no tachycardia or weight loss) and had serial TT4 measurements <40 nmol/L (3.1 μg/dL) for a 6-month period.

Blood and Urine Sampling and Processing

Blood and urine samples were collected as part of a geriatric screening and healthcare program with the consent of the owner. The Ethics and Welfare Committee of the Royal Veterinary College approved the diagnostic protocol. Jugular venous blood samples were collected and placed in heparinized and EDTA coated tubes, and urine samples collected by cystocentesis. Samples were kept at 4°C before sample processing which occurred within 6 hours of sample collection. Blood samples were placed in a refrigerated centrifuge at approximately 2000 × g for 10 minutes to enable separation of plasma from cellular components. Heparinized plasma was submitted to a single external laboratory4 for biochemical analysis including TT4 measurement. Surplus heparinized and EDTA plasma was stored at −80°C until batch analysis of PRA and plasma aldosterone which occurred up to 11 years later.

Measurement of Plasma Renin Activity and Plasma Aldosterone Concentration

Plasma renin activity was measured by a commercially available radioimmunoassay5 validated previously for use in cats.[11] The assay was performed according to the manufacturer's instructions with half the volume of EDTA plasma and reagents recommended for the angiotensin-I generation phase of the assay, except that incubation of samples at 37°C was performed by an incubator rather than a water bath. Half the recommended volumes were used to reduce the amount of plasma required to perform the assay.

Plasma aldosterone concentration was measured by a commercially available radioimmunoassay6 according to the manufacturer's instructions. This assay has also previously been validated for use in cats.[16]

Statistical Analysis

Statistical analyses were performed by a computerized statistical software package.7 Results are reported as median [25th, 75th percentile] and statistical significance was defined as P ≤ .05 unless otherwise stated. For the purposes of statistical analysis, any PRA measurement ≤0.05 ng/mL/h was assigned a value of 0.05 ng/mL/h. Any plasma aldosterone concentration ≤11 pg/mL (assay lowest limit of detection) was assigned a value of 11 pg/mL.

The Kruskal–Wallis test was used to compare clinicopathologic variables, including PRA and plasma aldosterone concentration among groups (HT-Pre, HT-Post, and NT groups) at baseline (time of diagnosis of hyperthyroidism). The Mann-Whitney U-test was used to make pairwise comparisons among the groups to identify significant differences. Bonferroni correction was applied to correct for multiple comparisons, therefore statistical significance was defined as P < .017. Treatment effect was assessed by the Wilcoxon signed rank test for each group. The Fisher's Exact test was used to compare the proportion of animals treated by thyroidectomy and antithyroid medication between the HT-Post and NT groups. Correlations between clinicopathologic variables at baseline were assessed by Spearman's correlation coefficient.

Results

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. References

Ninety-nine hyperthyroid cats were eligible for inclusion in the study. All cats were not azotemic at baseline. Twenty-two cats were hypertensive at the time of diagnosis of hyperthyroidism (HT-Pre group), nine of which had hypertensive retinopathy. Twenty-four cats developed hypertension within the 6-month follow-up period after documentation of euthyroidism (HT-Post group). In the HT-Post group, 6 cats (27%) were treated by thyroidectomy and 16 cats (73%) were treated with antithyroid medication. Thirty-six cats in the NT group were followed for 6 months after establishment of euthyroidism, of which 20 cats (56%) had been treated by thyroidectomy and 16 cats (44%) had been treated with antithyroid medication. There was no significant difference in the proportion of cats treated with thyroidectomy and antithyroid medication between the HT-Post and NT groups (P = .267). Seven out of 24 (29%) cats in the HT-Post group also developed azotemia within 240 days after establishment of euthyroidism, and 3 of 53 (6%) normotensive cats developed azotemia within 240 days after establishment of euthyroidism. Four of 24 cats (17%) in the HT-Post group had low plasma TT4 at the posttreatment time point, and 7 out of 53 (13%) normotensive cats had low plasma TT4 at the posttreatment time point; however, concurrent thyroid stimulating hormone concentrations were not available in these cases to confirm if iatrogenic hypothyroidism was present.

Cats that were hypertensive at the time of diagnosis of hyperthyroidism were significantly older than cats that remained normotensive posttreatment (Table 1, P < .001); however, there was no significant difference in age between the other groups. The age of 5 of the cats (1 hypertensive at diagnosis, 1 hypertensive posttreatment, and 3 normotensive) was unknown. There were also significant differences in SBP among all 3 groups at baseline (Table 1, P < .017 for comparisons among all groups). There were no other significant differences in clinicopathologic variables at baseline among the 3 groups (Table 1).

Table 1. Selected clinicopathologic variables at time of diagnosis of hyperthyroidism for cats that are hypertensive at the time of diagnosis of hyperthyroidism (HT-Pre group), cats that develop hypertension within 6 months of starting treatment (HT-Post group), and cats that remain normotensive for a 6-month period after establishment of euthyroidism (NT group). The Kruskal–Wallis test was used to compare the 3 groups at baseline for each variable. Sig. – significance
VariableHT-Pre Group Median [25th, 75th percentiles]nHT-Post Group Median [25th, 75th percentiles]nNT Group Median [25th, 75th percentiles]nSig.
  1. Groups bearing different letters in superscript were significantly different from one another (P < .017).

Age (years)16.5 [15.0, 17.7]a2115.0 [13.1, 17.0]ab2313.8 [12.0, 15.0]b50<0.001
Systolic blood pressure (mmHg)183.0 [176.2, 205.4]a22159.0 [152.9, 173.5]b24148.8 [131.8, 160.8]c53<0.001
Plasma total thyroxine concentration (nmol/L)150.5 [100.4, 197.5]22130.0 [92.3, 170.8]24113.0 [71.3, 176.0]530.26
Plasma creatinine concentration (mg/dL)1.13 [0.97, 1.28]201.13 [0.88, 1.34]211.06 [0.96, 1.21]400.59
Plasma potassium concentration (mmol/L)4.05 [3.67, 4.30]204.00 [3.65, 4.10]213.85 [3.63, 4.18]400.58
Plasma sodium concentration (mmol/L)154.9 [153.0, 155.9]20153.7 [152.0, 155.0]21154.4 [152.0, 155.6]400.38

There was no significant difference in the PRA among the 3 groups at baseline (HT-Pre group 1.50 [0.05, 2.37] ng/mL/h, n = 9, HT-Post group 0.66 [0.17, 2.31] ng/mL/h, n = 19, NT group 1.11 [0.57, 2.18] ng/mL/h, n = 39; P = .44, Fig 1). PRA decreased significantly after treatment for hyperthyroidism in both the HT-Post (0.71 [0.17, 2.33] versus 0.28 [0.07, 0.57] ng/mL/h, n = 18; P = .006, Fig 2) and NT groups (1.09 [0.53, 2.47] versus 0.22 [0.05, 0.76] ng/mL/h, n = 32; P < .001, Fig 2). There was also no significant difference in the PRA after treatment for hyperthyroidism between the HT-Post and NT groups (P = .57).

image

Figure 1. Box and whisker plots showing plasma renin activity (PRA) in hyperthyroid cats at baseline. Nine cats were hypertensive at the time of diagnosis of hyperthyroidism (HT-Pre group), 15 cats developed hypertension within 6 months of treatment for hyperthyroidism (HT-Post group) and 39 cats remained normotensive for a 6-month period following documentation of euthyroidism (NT group). The Kruskal Wallis test indicated that there were no significant differences between the groups (P = .44).

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image

Figure 2. Box and whisker plots showing plasma renin activity (PRA) in hyperthyroid cats before and after treatment of hyperthyroidism. Thirty-four cats remained normotensive for a 6-month period following documentation of euthyroidism (NT group), and the posttreatment visit is taken at the end of this 6-month period. Eighteen initially normotensive cats developed hypertension within 6 months of treatment for hyperthyroidism (HT-Post group). The posttreatment visit is taken as the time of diagnosis of hypertension, prior to initiation of any antihypertensive therapy. PRA decreased significantly following treatment in both the HT-Post and NT groups (P = .006 and P < .001, respectively). Unshaded boxes represent data from the pretreatment time point, whereas boxes with diagonal shading represent data from the posttreatment time point.

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Plasma aldosterone concentration was not significantly different among the three groups at baseline (HT-Pre group 72.2 [40.0, 145.6] pg/mL, n = 21, HT-Post group 69.7 [43.3, 142.6] pg/mL, n = 24, NT group 109.0 [68.2, 184.6] pg/mL, n = 47; P = .10, Fig 3). Plasma aldosterone concentration decreased significantly after treatment for hyperthyroidism in the NT group (114.4 [56.6, 204.1] versus 59.5 [32.4, 98.2] pg/mL, n = 30; P < .001, Fig 4), whereas plasma aldosterone concentration did not change after treatment for hyperthyroidism in the HT-Post group (61.2 [44.9, 124.0] versus 58.4 [42.0, 97.7] pg/mL, n = 18; P = .59, Fig 4). There was no significant difference in the plasma aldosterone concentration between the HT-Post and NT groups after treatment (P = .44).

image

Figure 3. Box and whisker plots showing plasma aldosterone concentration in hyperthyroid cats with and without hypertension at baseline. Twenty-one cats were hypertensive at the time of diagnosis of hyperthyroidism (HT-Pre group), 23 cats developed hypertension within 6 months of treatment for hyperthyroidism (HT-Post group) and 47 cats remain normotensive for a 6-month period following documentation of euthyroidism (NT group). The Kruskal Wallis test indicated there were no significant differences between the groups (P = .10).

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image

Figure 4. Box and whisker plots showing plasma aldosterone concentration in hyperthyroid cats before and after treatment of hyperthyroidism. Thirty-one cats remain normotensive for a 6-month period following documentation of euthyroidism (NT group), and the posttreatment visit is taken at the end of this 6-month period. Eighteen initially normotensive cats develop hypertension within 6 months of treatment for hyperthyroidism (HT-Post group). The posttreatment visit is taken as the time of diagnosis of hypertension, prior to initiation of any antihypertensive therapy. Plasma aldosterone concentration decreased significantly in the NT group (P < .001); however, plasma aldosterone concentration did not change significantly following treatment in the HT-Post group (P = .59). Unshaded boxes represent data from the pretreatment time point, whereas boxes with diagonal shading represent data from the posttreatment time point.

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Pretreatment plasma aldosterone: renin ratio (ARR) was not significantly different among the 3 groups at baseline (HT-Pre group 55.9 [35.2, 421.8], n = 8, HT-Post group 94.3 [33.4, 252.4], n = 19, NT-group 73.3 [36.4, 159.6], n = 33; P = .88). There was also no significant difference in ARR between the HT-Post and NT groups after treatment (P = .89).

Plasma sodium concentration decreased significantly with treatment (P = .017, Table 2) in the NT group, although this change is unlikely to be clinically relevant. In contrast, plasma sodium concentration did not change significantly in the HT-Post group (P = .65, Table 2). Four cats in the NT group were mildly hypernatremic at baseline. There was no significant difference in plasma sodium concentration between the HT-Post and NT groups after treatment (P = .16).

Table 2. Selected clinicopathologic variables before and after treatment for hyperthyroidism in cats. Cats were divided into 2 groups; NT group – cats remained normotensive for a 6-month period after establishment of euthyroidism, and the end of this 6-month period was taken as the posttreatment visit, HT-Post group – cats that develop hypertension within 6 months of starting treatment, with the date of diagnosis of hypertension taken as the posttreatment visit. The Wilcoxon signed rank test was used to compare selected variables before and after treatment for hyperthyroidism. Sig. – significance
VariablePretreatment Median [25th, 75th percentiles]Posttreatment Median [25th, 75th percentiles]nSig.
Systolic blood pressure (mmHg)
HT-Post group158.6 [151.7, 168.0]185.2 [179.7, 196.8]220.001
NT group151.2 [133.5, 163.3]147.2 [135.6, 152.9]360.19
Plasma creatinine concentration (mg/dL)
HT-Post group1.09 [0.83, 1.38]1.79 [1.34, 2.90]150.002
NT group1.07 [0.91, 1.28]1.50 [1.35, 1.94]21<0.001
Plasma potassium concentration (mmol/L)
HT-Post group4.00 [3.70, 4.10]4.07 [3.90, 4.30]150.038
NT group3.80 [3.65, 4.23]3.90 [3.60, 4.01]210.39
Plasma sodium concentration (mmol/L)
HT-Post group153.8 [152.0, 155.0]154.0 [150.0, 156.0]150.65
NT group154.8 [151.4, 155.8]153.0 [150.5, 153.5]210.017
Plasma total thyroxine concentration (nmol/L)
HT-Post group134.0 [101.9, 212.3]25.8 [4.8, 73.2]140.001
NT group96.0 [67.8, 132.5]17.5 [6.8, 25.6]28<0.001

Plasma potassium concentration increased significantly with treatment (P = .038, Table 2) in the HT-Post group, although this change is likely to be of minimal clinical relevance. Plasma potassium concentration did not change significantly with treatment in the NT group (P = .39, Table 2). There was no significant difference in plasma potassium concentration between the HT-Post and NT groups after treatment (P = .084).

Plasma creatinine concentration increased significantly with treatment in both the HT-Post group (P = .002, Table 2) and the NT group (P < .001, Table 2). There was no significant difference in plasma creatinine concentration between the HT-Post and NT groups after treatment (P = .34).

Plasma TT4 concentration decreased significantly with treatment in both groups as expected (Table 2); however, 6 cats in the HT-Post group were not well controlled (TT4 <40 nmol/L) at the posttreatment time point. There was no significant difference in SBP at the posttreatment time point between the well-controlled (n = 6) and poorly controlled cats (n = 18) in the HT-Post group (P = .53). There was also no significant difference in plasma TT4 concentration between the NT-group and the HT-Post group after treatment (P = .13).

Pretreatment PRA was significantly positively correlated with pretreatment plasma aldosterone concentration (rs = 0.41, n = 60; P = .001) and plasma TT4 concentration (rs = 0.456, n = 67; P < .001). Pretreatment PRA was also significantly negatively correlated with plasma creatinine concentration (rs = −0.552, n = 53; P < .001). PRA was not correlated with systolic blood pressure (rs = −0.129, n = 67; P = .30). Plasma aldosterone concentration was negatively correlated with plasma potassium concentration (rs = −0.289, n = 75; P = .012).

In the NT group, there was a weak positive correlation between posttreatment PRA and posttreatment plasma aldosterone concentration (rs = 0.44, n = 31; P = .014) and posttreatment plasma TT4 concentration (rs = 0.41, n = 27; P = .036). There was also a moderate negative correlation between posttreatment PRA and posttreatment SBP (rs = −0.51, n = 33; P = .002) in the NT group, and posttreatment PRA tended towards a significant negative association with posttreatment plasma creatinine concentration (rs = −0.35, n = 28; P = .067). Posttreatment plasma aldosterone concentration in the NT group was significantly, but weakly, negatively correlated with posttreatment plasma potassium concentration (rs = −0.48, n = 30; P = .007). In the HT-Post group, posttreatment PRA was strongly positively correlated with posttreatment plasma TT4 concentration (rs = 0.74, n = 12; P = .006).

Discussion

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. References

The results of this study suggest that there is upregulation of the RAAS in hyperthyroid cats, and that this is reversed by effective treatment for hyperthyroidism. PRA decreased significantly after treatment which suggests that there was increased PRA in the hyperthyroid state. Elevated PRA occurs in human patients with hyperthyroidism.[12] Changes in PRA and plasma aldosterone concentrations that occur after treatment for hyperthyroidism might be an unknown adverse effect of antithyroid medication; however, these changes were demonstrated in both medically and surgically treated hyperthyroid cats (data not shown), hence it would seem more likely that the changes in RAAS activity after treatment are a consequence of restoration of euthyroidism, rather than an effect of treatment per se.

The PRA of hyperthyroid cats with and without hypertension at baseline was not significantly different. Equally, there was no significant difference in PRA between hyperthyroid cats that remained normotensive after treatment and cats that developed hypertension within 6 months of treatment. Under normal physiologic conditions, it would be anticipated that the HT-Pre and HT-Post groups, with higher systolic blood pressure at baseline, would have lower PRA than normotensive cats; however, PRA was not significantly different among these groups. This could indicate that PRA is inappropriately high in the HT-Pre and HT-Post groups, as we would expect these cats (with higher SBP) to have lower PRA than the NT group.

It has been reported that hypertensive cats with CKD have higher plasma aldosterone concentrations (and lower PRA) than normotensive cats with CKD,[11] and it is also interesting to note that hypertensive cats with CKD have lower plasma potassium concentrations than normotensive cats with CKD.[3] Primary hyperaldosteronism is known to cause hypertension in cats[17]; however, the plasma aldosterone concentrations reported in hypertensive cats with CKD in previous studies[6, 11] are much lower than those seen in primary hyperaldosteronism.

In this study, plasma aldosterone concentration decreased after treatment for hyperthyroidism in normotensive cats (paralleling changes in PRA), but did not change significantly in cats that developed hypertension (despite a decrease in PRA). It could be that this represents a basal nonsuppressible rate of aldosterone secretion in hypertensive cats, which is not related to PRA and represents a form of primary hyperaldosteronism; however, this is not supported by the results of this study, in which the plasma aldosterone concentration was not different in hypertensive cats than normotensive cats at baseline. Plasma aldosterone concentration was also not significantly different between the NT and HT-Post groups after treatment for hyperthyroidism. In addition, ARR, which is elevated in human patients with primary hyperaldosteronism,[18] was not increased in hypertensive hyperthyroid cats compared with normotensive hyperthyroid cats in this study. It could also be that the lack of a change in plasma aldosterone concentration after treatment for cats that developed hypertension represents a basal noninducible level of aldosterone, which does not respond to the increased PRA in hyperthyroidism. Secretion of aldosterone by the adrenal gland might be autonomous of control by angiotensin II (and perhaps potassium and ACTH) in cats with hypertension, and could be related to the presence of adrenocortical hyperplasia, which was reported in 95% of geriatric cats in one preliminary study.8 Dynamic testing of adrenal gland function in cats with hypertension would be required to test this hypothesis. It could be that the discordance between PRA and plasma aldosterone concentration in hypertensive cats reflects RAAS dysfunction, which might in turn contribute to the development of hypertension. Alternatively, discordance between PRA and plasma aldosterone concentration in hypertensive hyperthyroid cats might not be directly involved in the pathogenesis of hypertension, but could be associated with another as yet unidentified pathophysiologic process which leads to the development of hypertension.

Cats in the HT-Post group had significantly higher baseline SBP than cats in the NT group, although the baseline SBP for the majority of cats in both groups was below the threshold recognized by our clinic as being associated with target organ damage (<170 mmHg). Hyperthyroid cats that develop hypertension after treatment might have an underlying predisposition toward a higher SBP in the hyperthyroid state, which might be related to the apparent RAAS dysfunction that was observed in this group. It could also be that cats in the HT-Post group develop hypertension after treatment for hyperthyroidism, because the RAAS is not able to respond appropriately to the increase in systemic vascular resistance that occurs after restoration of euthyroidism.

The results of this study suggest that RAAS activation in hyperthyroid cats is not associated with the development of hypertension, and thus do not support the premise that RAAS activation is the primary pathophysiologic mechanism for the development of hypertension in hyperthyroid cats. However, RAAS activation in hyperthyroid cats might still be harmful as it could contribute to cardiovascular injury, renal injury, or both.[19]

Although 14% of hyperthyroid cats are reported to be hypertensive at the time of diagnosis,[2] hypertension is also known to be common in cats with CKD,[3] which in turn is also reported to be present in at least 11% of hyperthyroid cats.[2] Thus, it is possible that hypertension in some hyperthyroid cats may be a comorbid condition, rather than a direct consequence of hyperthyroidism itself. The pathogenesis of hypertension in cats with “comorbid” hypertension could be different to that of cats with “hyperthyroidism-induced” hypertension, which might also have influenced the results of this study.

In this study, each cat acted as its own control so that the changes in PRA and plasma aldosterone concentration that occur before and after treatment for hyperthyroidism could be identified. The conclusions of this study would be strengthened by the inclusion of a comparator group of normal cats in which RAAS activity was measured. The reference range for PRA in normal cats has been reported to be <0.05–1.8 ng/mL/h[11] and 0.28–2.96 ng/mL/h (derived by a different PRA assay to this study)[7]; however, the diets of cats included in the aforementioned studies were not standardized. PRA and plasma aldosterone concentration are affected by dietary change in cats,[11] and so it is likely that there will be differences in the individual PRA and plasma aldosterone concentration that are because of differences in the sodium content of the diet, which might confound the comparison between hypertensive and normotensive cats. Comparison of measured PRA and aldosterone in hyperthyroid cats with a normal group or reference range would therefore be uninformative unless the diets were standardized. This study did not attempt to control the diet of cats which were included in the study, other than to exclude cats which were fed renal care diet, as these diets tend to have lower sodium content than maintenance diets. Although differences in the diets fed to each cat will confound the analysis in this study, the diets fed to individual cats are unlikely to change with treatment in a way that would bias the results significantly. Treatment for hyperthyroidism might, however, be expected to alter the appetite of an individual cat such that total dietary intake of sodium might decrease.

The results of this study could have been confounded by the exaggerated white coat effect that has been reported in hyperthyroid cats,9 as this could have resulted in some normotensive hyperthyroid cats (without evidence of concurrent hypertensive retinopathy) being classified as hypertensive at the time of diagnosis. In this study, blood pressure measurements were obtained in a controlled environment by an experienced operator, which is reported to minimize the effect of white coat hypertension on blood pressure measurements in hyperthyroid cats.9 However, it is still possible that some of the 13 cats in the HT-Pre group without concurrent hypertensive retinopathy may not have been truly hypertensive, which might have confounded the results of the cross-sectional analysis.

The effect of treatment for hyperthyroidism on PRA and plasma aldosterone concentration in the HT-Pre group was not assessed in this study, because the results would be confounded by the concurrent treatment for hypertension, thus making interpretation of the data difficult. In addition, relatively few posttreatment samples were available for cats in this group, which would have limited the statistical power of any comparison. PRA and plasma aldosterone concentration were not measured in the HT-Pre group after treatment for hypertension and before the initiation of antithyroid treatment, because assessment of the effect of amlodipine treatment on RAAS activity was not an objective of this study; however, future studies to investigate this are warranted.

In this study, samples were stored at −80°C until batch analysis of PRA and plasma aldosterone concentration, which occurred up to 11 years after sampling; however, the effect of prolonged storage on PRA and plasma aldosterone concentration is unknown. Storage of samples at −80°C for 40 days did not result in a significant change in PRA in one previous study;[11] however, the effect of more prolonged storage has not been reported. Ideally, this would be investigated by determination of the PRA and aldosterone concentration in the same samples before and after prolonged storage for several years; however, this would require a long-term study and was not practical. In this study there was no significant correlation between storage time and PRA or plasma aldosterone concentration (data not shown), and storage time was not a significant predictor of either PRA or plasma aldosterone concentration after adjustment for other clinicopathologic variables that were associated with PRA or plasma aldosterone concentration in linear regression analyses (data not shown). In addition, both PRA and plasma aldosterone concentration decreased after treatment for cats in the NT group, even though these samples had been stored for around 6 months less than the baseline samples. If storage of samples at −80°C caused a significant decrease in the measured PRA and aldosterone, it would be expected that PRA and plasma aldosterone concentration would increase after treatment, which was not the case in this study. These data would suggest that prolonged storage does not have a significant effect on the measured PRA and plasma aldosterone concentration; however, further studies to investigate the effect of long-term storage of samples at −80°C on PRA and aldosterone are warranted.

Finally, as cats eating renal diets were excluded from the study, relatively few cats that developed azotemia after treatment for hyperthyroidism were included in the study. Although CKD can be present without azotemia, it is possible that different results might have been obtained if there had been a larger number of cats included with azotemic CKD, as RAAS activity is increased in the more advanced stages of CKD.[11] Further studies to evaluate the changes in the RAAS in hyperthyroid cats with azotemic CKD that develop hypertension and that remain normotensive are required.

In summary, this study found no evidence of increased RAAS activation in hyperthyroid cats that are hypertensive at the time of diagnosis, or those that develop hypertension after treatment for hyperthyroidism when compared with normotensive hyperthyroid cats. In hyperthyroid cats that developed hypertension after treatment, discordance between plasma aldosterone concentration and PRA was evident at the post-treatment time point, which could indicate RAAS dysfunction in these cats that might in turn contribute to the development of hypertension.

Acknowledgment

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. References

Conflict of Interest Declaration: Authors disclose no conflict of interest.

Footnotes
  1. 1

    Morrow LD, Adams VJ, Elliott J, Syme HM. Hypertension in hyperthyroid cats: Prevalence, incidence, and predictors of its development. J Vet Intern Med 2009;23:700 (abstract).

  2. 2

    Syme HM, Markwell PJ, Elliott J. Aldosterone and plasma renin activity in cats with hypertension and/or chronic renal failure. J Vet Intern Med 2002;16:354 (abstract).

  3. 3

    Jepson RE, Elliott J, Syme HM. The role of the renin-angiotensin-aldosterone system in the development of systemic hypertension in cats treated for hyperthyroidism. J Vet Intern Med 2005;19:424 (abstract).

  4. 4

    Idexx Laboratories, Wetherby, UK

  5. 5

    GammaCoat Plasma Renin Activity, Diasorin, MN

  6. 6

    Coat-a-Count, Siemens, Camberley, UK

  7. 7

    SPSS for Windows 17.0, SPSS Inc, Chicago, IL

  8. 8

    Keele SJ, Smith KC, Elliott J, Syme HM. Adrenocortical morphology in cats with chronic kidney disease and systemic hypertension. J Vet Intern Med 2009;23:1328 (abstract).

  9. 9

    Stepien R, Rapoport G, Henik R, et al. Effect of measurement method on blood pressure findings in cats before and after therapy for hyperthyroidism. J Vet Intern Med 2003; 17: 754 (abstract).

References

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. References