Treatment of hypertension with angiotensin‐converting enzyme inhibitors or angiotensin receptor blockers and resting metabolic rate: A cross‐sectional study

Abstract Hypertension in obese and overweight patients is associated with an elevated resting metabolic rate (RMR). The aim of this study was to determine whether RMR is reduced in hypertensive patients treated with angiotensin‐converting enzyme inhibitors (ACEI) and blockers (ARB). The RMR was determined by indirect calorimetry in 174 volunteers; 93 (46.5 %) were hypertensive, of which 16 men and 13 women were treated with ACEI/ARB, while 30 men and 19 women with untreated hypertension served as a control group. Treated and untreated hypertensives had similar age, BMI, physical activity, and cardiorespiratory fitness. The RMR normalized to the lean body mass (LBM) was 15% higher in the untreated than ACEI/ARB‐treated hypertensive women (p = .003). After accounting for LBM, whole‐body fat mass, age, the double product (heart rate x systolic blood pressure), and the distance walked per day, the RMR was 2.9% lower in the patients taking ACEI/ARB (p = .26, treatment x sex interaction p = .005). LBM, age, and the double product explained 78% of the variability in RMR (R 2 = 0.78, p < .001). In contrast, fat mass, the distance walked per day, and total T4 or TSH did not add predictive power to the model. Compared to men, a greater RMR per kg of LBM was observed in untreated hypertensive overweight and obese women, while this sex difference was not observed in patients treated with ACEI or ARBs. In conclusion, our results indicate that elevated RMR per kg of LBM may be normalized by antagonizing the renin‐angiotensin system.


INTRODUCTION
Resting metabolic rate (RMR) is increased in hypertension 1-3 likely due to increased sympathetic 4,5 and renin-angiotensin system (RAS) overactivation. 6 In overweight and obese hypertensives, the increased RMR is explained by an elevated myocardial oxygen consumption due to an increased resting double product (heart rate x systolic blood pressure), combined with differences in body composition. 1 Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin blockers (ARB) are a cornerstone in the treatment of hypertension, mainly when administered to patients with increased RAS activity as hypertensives with overweight or obesity. 7 Despite recent rodent studies showing that RMR is increased by angiotensin II acting on arcuate nucleus neurones, 8 it remains unknown whether the RAS system's counteraction is associated with reduced RMR. Moreover, sexual dimorphism in blood pressure regulation and metabolism exists in humans, 9,10 in part explained by sex differences in the RAS. 11 Therefore, this study aimed to determine whether resting metabolic rate is reduced in hypertensive patients treated with ACEI/ARB after controlling for the confounding effects of lean mass, fat mass, age, and physical activity. We hypothesized that ACEI/ARB treatment would be associated with lower RMR per kg of lean mass in hypertensive patients treated with ACEI/ARB compared with untreated hypertensives of similar age, BMI, and level of physical activity.

Patients
One hundred and seventy-four participants with overweight or obesity volunteered to participate in a study to reduce body weight with exercise and a low-calorie diet. As inclusion criteria, men and women had to be 18- In the untreated hypertensive group, four men and two women had type 2 diabetes treated with diet and exercise in three men, while the other man and the two women received metformin. Likewise, one man and one woman from the ACEI/ARB-treated hypertensives had diabetes treated with metformin. In addition, two men and five women from the untreated hypertensive group were on statins, as well as six men and one woman in the treated hypertensive group.

General procedures
A full description of the general procedures has been previously published. 1  The RMR was assessed for 30 minutes in a well-ventilated room while the subjects laid supine on a comfortable laboratory stretcher.
Participants were instructed to avoid talking and remain motionless.
Oxygen uptake (VO 2 ) and carbon dioxide production (VCO 2 ) were measured breath-by-breath for 20 minutes after an initial 10-minute habituation period using a face mask. For further analysis, the data were averaged every 20 seconds. All 20-second averages with VO 2 values deviating from the mean more than two SD were discarded.

Physical activity
Participants were equipped with a Garmin Vivofit activity tracker  The intra-and inter-assay coefficients of variation for these assessments are 7.0 % and 7.7 % for TSH and 4.7 % and 5.4 % for T 4 , respectively.

Statistical analysis
The sample size required to show a 10 % between-groups differ-

RESULTS
The general characteristics of the patients studied are shown in Tables 1 and 2. Age and BMI were similar in both sexes. Women had a higher percentage of body fat than men. Cardiorespiratory fitness was better in men than women, although the differences were  (Table 3). No significant differences were observed between treated and not treated hypertensives in insulin sensitivity or thyroid function ( Table 3).
The RMR in absolute values was larger in men than women (Table 3 and Figure 1). However, when expressed as kcal.d −1 . kg LM −1 , the values were marginally higher in women than men due to differences in the untreated group. Consequently, the RMR normalized to the wholebody lean mass was 15 % higher in the untreated hypertensive women (Table 3 and Figure 1). Multiple regression analysis showed that lean body mass, age and the double product explain 78 % of the variability in RMR (R 2 = 0.78, p < .001). In contrast, fat mass, the distance walked per day, and total T4 or TSH did not add predictive power to the model (Table 4).

DISCUSSION
This study shows that hypertensive overweight or obese women have a greater RMR than men. Treatment of hypertensive overweight and obese patients with ACEI/ARB is associated with a slightly lower RMR.
However, the observed differences between treated and untreated patients were reduced to 2.9 % and were not statistically different after accounting for between-groups differences in total lean mass, fat mass, age, the double product, and physical activity (distance walked per day).
Nevertheless, significant sex by treatment interaction remained, indicating that in hypertensive overweight or obese women antagonizing angiotensin II might reduce RMR.

Untreated hypertensive women have a slightly higher RMR than untreated men
Previous studies in healthy humans have reported similar lean body mass normalized RMRs in men and women. [16][17][18][19] In addition, a small study reported a reduction of lean body mass normalized RMR in hypertensive women after a 10 % weight loss, while it remained unchanged in normotensive women. 20 In the present cohort, hypertensive women had higher RMR-normalized to lean body mass than men, which does not seem mediated by the larger fat mass of women than men, since when fat mass was included as a covariate, the differences in RMR persisted. Several factors are implicated in the regulation of RMR, among which the sympathetic nervous system (SNS) and RAS play important roles. 8,21 The SNS increases brown adipose tissue heat production and facilitates the action of thyroid hormones. 22 SNS overactivity promotes ATP consumption by stimulating futile cycles and increasing Na + -K + pump and SERCA energy expenditure. 22 Besides, sympathetic overactivity increases resting heart rate and blood pressure, contributing to elevating RMR by increasing the heart's energy consumption. 1 One of the mechanisms that could explain a larger RMR per kg of whole-body lean mass in women is a potentially higher SNS activity in hypertensive obese women. 4,[23][24][25] Besides, greater SNS responsiveness to the cold pressor test measured as increased MSNA has been reported in 60-year-old women compared to men of similar age. 26 Although insulin increases MSNA, 27 were similar in men and women, regardless of ACEI/ARB treatment (Table 3).
Angiotensin II, which is increased in obesity, 29 has been shown to stimulate sympathetic activity. 30 In the present investigation, no significant differences in RMR per kg of LM were observed between men and women after treatment with ACEI/ARB, indicating that inhibition of angiotensin II might normalize RMR in hypertensive women.
Part of ACEI/ARB's effect is likely due to the reduction of the double product, which has been shown to contribute to increased RMR observed in untreated hypertensives. 1 In agreement, the heart mass has predictive value for the RMR in women. 31 Besides, a sex difference in the action ACEI/ARB treatment in RMR is also supported by the significant sex x treatment interaction reported in The resting metabolic rate was logarithmically transformed; N = 78; Sex: Men = 1, Women = 2; hypertension (HTA) treatment with ACEI/ARB = 1, otherwise = 2; a Represents reference level (Men = 1 and treated with ACEI/ARB = 1).
sex differences in the balance between angiotensin II (vasoconstrictive and pro-inflammatory) and its metabolite angiotensin 1-7 (antiinflammatory and vasodilatory). Experiments with mice indicate that obesity increases the hypertensive arm of the RAS (AngII/AT1R) but decreases angiotensin 1-7 and ACE2 in males, while opposite effects were observed in females. 32 In contrast, our data indicate that women with overweight and hypertension have an elevated RMR, which is normalized by antagonizing angiotensin II action.
In agreement with previous studies, 18,19 basal thyroid hormone concentrations were not associated with resting metabolic rate in this cohort and did not contribute to explaining the increased resting metabolic rate of untreated hypertensive women in the present investigation.

Antagonizing angiotensin II and RMR
Angiotensin II binds to two G-protein Coupled Receptors (GPCRs), angiotensin type 1 (AGTR1) and type 2 (AGTR2) receptors. In rodents, two isoforms of the AGTR1 termed AGTR1a and ANGTR1b receptors are expressed. 33,34 Stimulation of AGTR1a in neurones of the arcuate nucleus by angiotensin II increases both blood pressure and RMR in rodents. 6,35 Likewise, in rats overexpressing the human renin gene RMR is increased. 36 In theory, this action of angiotensin II could be mediated through the AGTR1 in humans, 8 but experimental evidence is lacking. The fact that treatment with ACEI/ARB is associated with normalized RMR in hypertensive women with overweight or obesity supports a thermogenic effect of angiotensin II in humans. In men, ACEI/ARB treatment was not associated with lower RMR may be related to the greater degree of adiposity in women than men (48 vs 38 %), which may facilitate a greater activation of RAS in women. Nevertheless, to definitively establish the role played by adiposity on the effects of ACEI/ARB treatment in RMR, new longitudinal studies will be required in lean and obese hypertensives.
Hypertension is associated with insulin resistance. 2 However, no association was observed in the present cohort between insulin sensitivity and blood pressure status after accounting for differences between treated and untreated patients in physical activity or cardiorespiratory fitness. 1

Limitations
The main limitation of this study relies on its cross-sectional nature and the small sample size. In addition, although the groups were wellmatched by blood pressure, age, BMI, physical activity, and cardiorespiratory fitness, women had a higher percentage of body fat than men. These results will need confirmation with longitudinal studies to establish whether ACEI/ARB treatment may lower more RMR in women than men. In so doing, the information reported in the present investigation may be helpful to estimate the appropriate sample size.

CONCLUSIONS
In summary, hypertensive overweight or obese women have a greater RMR per kg of lean body than men. This sex difference is not observed in men and women treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Our results indicate that elevated RMR per kg of lean body mass may be normalized by antagonizing the RAS.