Candesartan Improves Maximal Exercise Capacity in Hypertensives: Results of a Randomized Placebo‐Controlled Crossover Trial

Abstract

Cardiac hypertrophy and remodelling in hypertension has been associated with impaired exercise capacity. The authors tested whether an angiotensin receptor blocker, candesartan, improved exercise peak oxygen volume (VO₂) in this population. A total of 154 untreated hypertensive patients, aged 40 to 66 years, with World Health Organization stage I or II hypertension and left ventricular hypertrophy, were randomized to receive placebo, candesartan (32 mg), each of these plus aspirin (300 mg/d), or the same preparations in a reverse order, for 3 weeks, with a 3‐week washout period between treatments. The authors measured maximal workload and oxygen reserve with an exercise test, 24 hour‐ambulatory blood pressure, and echocardiography at the end of each treatment. Hypertensive patients did not achieve the maximal workload (116 [99–133] W vs 132 (AMA style = no period on vs) [116–149] W; P=.01). This impaired exercise capacity was in a multiple regression analysis related to lower oxygen reserve (r=0.49, P<.001), and the lower oxygen reserve to higher left ventricular hypertrophy by echocardiography (β=−0.34), respectively. The use of candesartan alone or with aspirin resulted in an improvement of peak VO₂ and exercise tolerance, when compared with controls. Patients with hypertension and cardiac hypertrophy cannot achieve a predicted maximal workload. The use of an angiotensin receptor blocker in therapy may represent a useful treatment in these patients for its effect on exercise peak VO₂ and exercise tolerance. The use of aspirin did not affect outcome.

A reduction of functional capacity has been reported in hypertension. However, the reduced peripheral vasodilatation observed in the early stages of hypertension could also impair the blood supply to exercising muscles in mild hypertensive patients who present with a normal left ventricular (LV) mass. ¹ Considering that mild hypertension is defined as a systolic blood pressure (BP) 140 to 159 mm Hg and a diastolic BP 90 to 99 mm Hg, respectively, secondary preventive measures are the most widely used at this stage of the disease. The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) guidelines encourage lifestyle modification as definitive therapy for individuals with high‐normal and stage 1 hypertension in risk group A and risk group B and as adjunctive therapy for all persons with hypertension. ² Exercise capacity is dependent on sufficient oxygen supply to the heart ³ as well as to the skeletal muscles. ⁴ It may therefore be influenced by cardiovascular (CV) changes in patients with hypertension. ⁵ Cardiac hypertrophy and remodelling in patients with untreated hypertension has been associated with impaired exercise capacity, ⁶ , ⁷ but whether this relationship remains in hypertensive and target organ damage patients is less clear.

The benefit of medication intervention to reduce BP is well established, especially in high‐risk individuals. Angiotensin receptor blockers (ARBs) and angiotensin‐converting enzyme inhibitors (ACEIs) are useful agents in the treatment of high BP and congestive heart failure. ⁸ ACEIs produce an improvement in carbon monoxide at rest, an independent predictor of peak exercise oxygen uptake (VO₂) in patients with congestive heart failure. This is consistently inhibited by acetylsalicylic acid, supporting the concept that prostaglandins may be the mediators of this effect. ⁹ , ¹⁰ This may be a result of high concentration in the pulmonary vascular endothelium of the same enzyme that generates angiotensin II and degrades bradykinin. ACEIs not only reduce exposure of the lung vessels to angiotensin II, but also increase levels of bradykinin, nitric oxide, and prostaglandin I2. ¹¹ The use of ACEIs improves exercise capacity, although renin‐angiotensin system inhibition may be incomplete. It has been found that ARBs, which act more peripherally, do not affect kinase II, the ACE isoenzyme zinc‐metallopeptidase that converts angiotensin I to the potent vasoconstrictor angiotensin II and that degrades bradykinin into inactive products. Thus, the use of an ARB does not result in an increase in bradykinin. ¹² , ¹³ , ¹⁴ Candesartan is a long‐acting angiotensin II type 1 blocker that does not require biotransformation for its pharmacologic activity. ¹³ , ¹⁴

The aim of this study was to investigate whether the ratio (to be corrected for different age, sex, weight, and height) between achieved and predicted maximal workload during a bicycle exercise test was related to the BP level and the degree of CV remodelling in patients with predominant hypertension and electrocardiographic LV hypertrophy, whether candesartan improved the maximal exercise capacity in this population, and whether there was an involvement of different therapeutic targets.

Methods

This study was approved by the hospital ethics committee and all patients gave written consent before starting the study. Study received no support from pharmaceutical companies.

Patients

A total of 154 untreated patients, aged 40 to 66 years (mean age 53±13 years), with World Heart Organization (WHO) stage I and stage II hypertension and electrocardiographic LV hypertrophy were studied. We measured maximal workload and oxygen reserve by an exercise test. In addition, 24 hour‐ambulatory BPs and LV mass index by echocardiography were measured according to American Heart Association recommendations. ¹⁵ The study population consisted of consecutive patients referred to our institution for functional evaluation of hypertension during a single‐blind run‐in period of 21 days (Table I).

Table I.

 General Characteristics of Study Population

Patients, No.	154
Age, mean ± SD, y	52±13
Male, %	61
Female, %	39
Weight, kg	66±2
BMI, kg/m2	29±3
24‐h SBP, mm Hg	166±4
24‐h DBP, mm Hg	97±3
Heart rate, bpm	72±2
Smoking status, %
Current smokers	35.9
Former smokers	25.7
Never smoked	38.4
Diabetes, %	2.2
VO2max, mL/min/kg	16.8±4.0
Oxygen reserve, ratio	3.8±0.3

Abbreviations: BMI, body mass index; bpm, beats per minute; DBP, diastolic blood pressure; SBP, systolic blood pressure; SD, standard deviation; VO₂max, maximum oxygen consumption.

They were randomized in a crossover and placebo‐controlled study to receive placebo, candesartan (32 mg), successively each of these plus aspirin (300 mg/d), or the same preparations in a reverse order, each for 3 weeks, with a 3‐week wash‐out period between treatments. ¹⁶ , ¹⁷ Patients and investigators were blinded to the protocol (Figure 1).

Figure 1.

 Study design. A indicates aspirin; C, candesartan; Pl, placebo.

Patients and Study Profile

Participants were free of other CV disease with the exception of uncomplicated stage I and stage II hypertension. All hypertensive patients had either newly diagnosed hypertension or did not receive antihypertensive medication for ≥3 months before enrollment in the study. Arterial BP was determined at each of 3 separate clinical visits by the same investigator. BP from the 3 visits were averaged, and participants with a mean systolic BP >150 mm Hg and diastolic BP >90 mm Hg, respectively, were considered hypertensive.

Patients who tested positive for coronary artery disease on the first exercise test were excluded from this study (Figure 2). Clinical evaluation, 24 hour‐ BP determinations, and echocardiography were performed within a 3‐week period in each patient, and stress tests were obtained in the run‐in and at the end of each treatment period at the same time of the day (Figure 2).

Figure 2.

 Study profile.

Cardiopulmonary stress tests were performed 6 hours after dosing. After 1 hour of resting, an automatic BP device that measured ambulatory BP using the cuff oscillometric method was applied to the left arm and worn for 24 hours. Oscillometric BPs were measured every half hour during daytime and every hour at night (10 pm to 7 am). For each patient, median values for daytime, night‐time, and 24 hours were calculated. ¹⁸

Electrocardiographic Data

Data were collected by means of a Novacode electrocardiogram program and coded according to the Minnesota code. ¹⁹ Presence of probable LV hypertrophy was defined by means of code 3.1 (left: R amplitude >26 mm in either V5 or V6, or R amplitude >20.0 mm in any of leads I, II, III, and aVF, or R amplitude >12.0 mm in lead aVL measured only on second‐to‐last complete normal beat) and one of the following codes: 5.1 (T amplitude negative 5.0 mm or more in lead II, in lead aVF when QRS in mainly upright), 5.2 (T amplitude negative or diphasic with negative phase at least 1.0 mm but not as deep as described in 5.1), or 5.3 (T amplitude flat, negative, or biphasic [negative–positive type only] with <1.0 mm negative phase in lead II; not coded in lead aVF).

Echocardiographic Methods and Measurements

Echocardiographic results were recorded after the first cardiopulmonary exercise test, between the first and second study week. All examinations were performed with the patients in the standard left lateral position and in expiratory apnea or during quiet breathing, using phased array echocardiographs with M‐mode, 2‐dimensional, and Doppler capabilities. The parasternal acoustic window was used to record ≥10 consecutive beats of 2‐dimensional and M‐mode recordings of the internal diameter and wall thickness at or just below the mitral valve leaflet tips. ²⁰

Measurements were obtained using a computerized review station with digitizing tablet and monitor screen. LV internal dimensions and septal and posterior wall thicknesses were measured at end‐diastole and end‐systole according to the American Society of Echocardiography recommendations ²¹ for up to 3 cycles. When optimal M‐mode beam orientation through the left ventricle could not be obtained, correctly oriented 2‐dimensional linear dimensions were measured ¹⁵ (Table II).

Table II.

 Echocardiographic LV Measurements

LV mass, g	168±54
LV mass/BSA, g/m2	84±25
IVS, cm	1.1±0.2
LVID, cm	5.5±0.5
PWT, cm	1.1±0.1
RWT, ratio	0.36±0.05

Abbreviations: BSA, body surface area; IVS, interventricular septal thickness; LV, left ventricular; LVID, LV internal dimension; PWT, posterior wall thickness; RWT, relative wall thickness. Values are expressed as mean ± standard deviation.

Cardiopulmonary Exercise Stress Testing

Cardiopulmonary exercise stress tests were performed in the run‐in and at the end of each treatment period by each patient on a bicycle ergometer. Before each test, oxygen and carbon dioxide analyzers and a flow mass sensor were calibrated by use of available precision gas mixtures and a 3‐L syringe, respectively. To stabilize gas measurements, patients were asked to remain still on the ergometer for at least 3 minutes before commencing exercise.

We utilized an individualized ramp test with the ramp rate set to elicit a test duration of approximately 10 minutes. After a 1‐minute warmup period at 0 W workload, we increased in steps of 20 W or 25 W every 2 minutes according to the predicted maximal workload:

• • In men: 358×height (m)−1.59×age (years)+0.66×weight (kg)−398
• • In women: 157×height (m)−1.52×age (years)+0.66×weight (kg)−126. ²² , ²³

The pedalling rate was kept constant at 55 to 65 revolutions per minute. Electrocardiography was continuously monitored during the test, and cuff BP was manually recorded every 2 minutes. Respiratory gas exchange measurements were obtained breath‐by‐breath with use of a computerized metabolic cart. Peak VO₂ was recorded as the mean value of peak VO₂ during the last 320 seconds of the test and expressed in milliliters per kilogram per minute.

Patients were asked to identify the primary reason for stopping and to score their perceived level of exertion by pointing to a number on the 6‐ to 20‐point range on the Borg scale at the end of each minute of exercise. All patients were encouraged to exercise to their maximal ability.

Hemodynamic and gas exchange measurements obtained from both tests were analyzed. Maximal exercise BP and heart rate were measured immediately after termination of exercise test.

Exercise‐induced changes in BP and heart rate were determined by subtracting resting BP and heart rate values from those obtained at maximal exercise.

Oxygen Reserve

Oxygen reserve was calculated as the ratio between VO₂ at maximal exercise and at rest. The ratio between achieved and predicted peak VO₂ was determined by use of a sex‐, age‐, height‐, and weight‐adjusted protocol‐specific formula outlined by Wassermann et al. ²⁴

Statistical Analysis

All data are expressed as mean ± standard deviation. Statistical analysis was performed by analysis of variance followed by the Student–Newman–Keuls test. We performed simple linear regression analyses calculating the regression quotient (r) and stepwise, backward multiple linear regression analyses calculating the standardized regression coefficient for each parameter (β) and the adjusted coefficient of determination for the model (adj R ²). In all linear multiple regression analyses we started out with our CV parameters together with basic characteristics like age and sex, subtracting one at a time until all were significant. Since many of the parameters were highly dependent on sex, this was taken into account using multiple regression analyses including sex. A value of P<.05 was considered statistically significant.

Results

Achieved Maximal Workload Compared With Predicted

In this study, hypertensive patients did not achieve the maximal workload as predicted by age, sex, and weight and height (116 [99–133] vs 132 [116–149] W; P=.01). They also had lower oxygen reserve than predicted (4.9 [4.3–5.5] vs 6.5 [5.5–7.6]; P=<.01) (Table III). In simple regression analyses, the ratio between achieved and predicted maximal workload was negatively related to 24‐hour median systolic BP and LV mass while positively related to oxygen reserve (Table IV), suggesting that patients with higher BP, LV hypertrophy, and lower oxygen reserve could not achieve the predicted maximal workload. However, neither resting systolic BP before exercise nor “echo” LV mass index were significantly related to the ratio between achieved and predicted maximal workload. In multiple regression analyses, a lower ratio between achieved and predicted maximal workload was independently associated with lower oxygen reserve (β=0.64) (adj R ²=0.52, P<.001). The maximal voluntary ventilation and the alveolar capillary membrane conductance did not increase with angiotensin receptor blockade.

Table III.

 Maximal Exercise Blood Pressure, Heart Rate, Oxygen Reserve, and LV Mass at Various Treatment Steps

	Pl	Pl+Asp	Can	Can+Asp
Maximal SBP, mm Hg	202±4	203±4	192±5a	190±4a
Δ SBP	55±4	56±3	58±5	58±4
Maximal DBP, mm Hg	99±5	92±2	85±3a	78±2a
Δ DBP	5±5	5±4	6±3	6±4
Maximal heart rate, bpm	161±4	166±2	170±5a	176±3a
Δ HR	84±4	84±3	96±4a	98±4a
VO2 rest/mass, mL/kg/min	4±3	4±2	4±4	4±1
LV mass, g	170±4	170±8	169±2a	169±3a
Oxygen reserve, ratio	3.8±0.3	3.5±0.2	3.3±0.1a	3.3±0.1a
Perceived effort, Borg scale	19±0.3	19±0.2	19±0.4	19±0.2

Abbreviations: bpm, beats per minute; Can, candesartan; DBP, diastolic blood pressure; HR, heart rate; LV, left ventricular; SBP, systolic blood pressure; VO₂, peak exercise oxygen uptake. Δ=change with exercise. ^aDifference from placebo (Pl) and from Pl plus aspirin (Asp) is significant at P<.01. Values are expressed as mean ± standard deviation.

Table IV.

 Correlations to Maximal Workload, Oxygen Reserve, and the Ratio Between Achieved and Predicted Maximal Workload

			Oxygen		Achieved/Predicted
	Maximal Workload a		Reserve		Maximal Workload
	β	P Value	r	P Value	r	P Value
Age, y	0.39	<.001	−0.28	.08	−0.22	NS
24‐h SBP, mm Hg	−0.32	<.001	−0.37	<.05	−0.31	.048
LV mass, g	−0.05	NS	−0.09	NS	−0.36	.048
LV mass/BSA, g/m2	−0.30	<.001	−0.22	NS	−0.26	.048
Oxygen reserve, ratio	0.52	<.001	–	–	0.49	<.001

Abbreviations: BSA, body surface area; LV, left ventricular; NS, not significant; SBP, systolic blood pressure. ^aβ and P values from multiple regression analyses also including sex.

Table V shows that the ARB candesartan was effective. Peak exercise VO₂ and exercise tolerance time were increased and the dead space volume to tidal volume ratio were decreased. Aspirin did not abolish these effects.

Table V.

 Functional Capacity at the Various Treatment Steps

	Pl	Pl+Asp	Can	Can+Asp
Oxygen consumption at peak exercise, mL/min/kg	15±3.5	14±5.6	17±3.2a	17.1±3.1a
Dead space/tidal volume ratio	0.21±0.03	0.22±0.06	0.18±0.04a	0.18±0.04a
Exercise tolerance time(s)	514±186	515±132	580±169a	602±26a

Abbreviation: Can, candesartan. ^aDifference from placebo (Pl) and from Pl plus aspirin (Asp) is significant at P<.01. Values are expressed as mean ± standard deviation.

VO₂ and Oxygen Reserve:  On placebo and at any treatment step, women (n=60) had, compared with men (n=94), lower VO₂ at rest (3.4 [2.7–4.2] mL/kg/min vs 4.2 [3.9–4.4] mL/kg/min; P<.05) and at maximal exercise (18 [15.5–22] mL/kg/min vs 23 [21–25] mL/kg/min; P<.001), respectively, but similar oxygen reserve (5.9 [3.6–8.6] vs 6.3 [5.0–6.3]; P=not significant). In multiple regression analyses, lower oxygen reserve uptake at maximal exercise was related to higher median 24‐hour systolic BP (β=−0.29) independently of female sex (β=−0.62) and older age (β=−0.28) (adj R ²=0.40; P<.001). Oxygen reserve was, in simple regression analyses, negatively correlated to median 24‐hour systolic BP. In men, oxygen reserve was negatively correlated to echo LV hypertrophy (r=−0.53, P<.01). In multiple regression analyses, lower oxygen reserve was related to higher LV hypertrophy (β=−0.34), female sex (β=−0.37), and older age (β=−0.28) (adj R ²=0.54; P<.001), respectively.

Maximal Workload:  In multiple regression analyses, lower maximal workload was related to lower oxygen reserve (β=0.44), independent of female sex (β=−0.58) and older age (β=−0.25) (adj R ²=0.67, P<.001) and higher median 24‐hour systolic BP (β=−0.27), independent of female sex (β=−0.71) and older age (β=−0.38) (adj R ²=0.54; P<.001).

Clinical Implications:  Figure 3 shows mean values of peak VO₂, change (Δ) in peak VO₂/Δ work rate. Compared with placebo, the use of aspirin plus placebo and candesartan resulted in a similar improvement of peak VO₂ (from 13.2±2.0 mL/min/kg while taking placebo to 15.3±3.0 and 15.2±3.0 mL/min/kg while taking aspirin + placebo and while taking candesartan; P<.01). Aspirin and the ARB combination promoted a further increase in peak VO₂ to 16.6±3.0 mL/min/kg. Angiotensin receptor blockade caused a significant Δ peak VO₂/Δ work rate increase in the absence of significant changes in ventilation. Combination of the 2 drugs resulted in significantly greater exercise tolerance.

Figure 3.

 Cardiopulmonary exercise data with different drug treatments. VO₂ indicates oxygen uptake; WR, walk rate.

Discussion

Study Findings

Comparison With Previous Studies:  Not many studies have assessed the prognostic value of cardiopulmonary exercise test parameters in different‐aged hypertensive patients. ²⁵ There may be a belief that since older persons have lower exercise capacities, the discriminatory power of cardiopulmonary exercise testing is reduced. It has been shown, however, that values obtained during cardiopulmonary testing (peak VO₂ and oxygen reserve ratio) have good reproducibility in elderly patients with heart failure. ²⁶

Prognostic Rationale:  Our study demonstrates that patients with hypertension and LV hypertrophy have impaired exercise capacity as they cannot achieve the maximal workload predicted by age, sex, and weight and height. Impaired exercise capacity was associated with a greater degree of LV hypertrophy in hypertensive patients. Peak VO₂ is an indirect estimate of cardiac output at maximal exercise. This raises the possibility that hypertensive patients have a limited ability to exhibit a full hemodynamic response to maximal bicycle ergometer exercise. Our data support the results from previous reports of impaired peak VO₂ and reduced exercise capacity in patients with WHO stage I and II hypertension. ¹ Our finding that impairment of peak VO₂, as well as maximal workload, were related to elevated BP and to LV hypertrophy has also been demonstrated by Missault and colleagues ²⁷ in middle‐aged hypertensive men. There was a lack of correlation between resting systolic BP before exercise and the achieved/predicted maximal workload. This suggests that the relation to 24‐hour systolic BP as a measure of BP‐associated CV changes is indirect. This is supported by the multiple regression analyses. According to Olsen and colleagues, ²⁸ one possible mechanism linking systemic vascular hypertrophy to impaired exercise capacity is consistent with a change in the coronary and noncoronary circulations that can reduce myocardial blood flow reserve in hypertensive patients. It is well documented that antihypertensive medication can improve exercise capacity, ²⁹ , ³⁰ , ³¹ but it remains uncertain whether this improvement is due to regression of CV remodelling, as suggested by Tanaka and colleagues. ⁶ In fact, these authors demonstrated that the peak VO₂ increases in parallel with the decrease in peripheral vascular remodelling and with the reduction in BP.

Clinical Implication:  The use of an ARB yielded a better physical performance and exercise VO₂ in hypertensive patients, presenting exercise limitation (baseline peak VO₂ was 13.4±4.0 mL/min/kg), compared with placebo or placebo plus aspirin. Guazzi and colleagues ³² have demonstrated that a combination of an ARB, losartan, and the ACEI enalapril yielded a better physical performance and exercise VO₂ in cardiac heart failure patients with an exercise limitation compared with either drug alone. The use of 2 drugs also produced an additive inhibitory effect on plasma neurohormones, suggesting that neurohumoral modulation is more effective with multiple drug therapy than with losartan or enalapril alone. Vescovo and colleagues ³³ have demonstrated, however, that the 2 drug categories have comparable efficacy for improving physical work and peak VO₂ in cardiac heart failure. Guazzi and colleagues ³² reported a significant variation in the ratio of Δ peak VO₂ to Δ work rate had been observed with candesartan. This parameter reflects the quantity of oxygen utilized per unit increase in work rate and has been proposed as an index of aerobic work efficiency. ³⁴ Hollenberg and colleagues ³⁵ demonstrated that ACEIs did not affect the ratio of peak VO₂ to work rate changes and oxygen pulse. This may be due to the fact that during exercise, angiotensin production is maintained by pathways that are an alternative to the converting enzyme. Guazzi and colleagues have demonstrated that concomitant treatment with aspirin limits improvement in peak VO₂ when used with enalapril but not with losartan. This supports a prostaglandin‐mediated influence of ACEIs. ¹⁷

The prognostic and decisional impact of peak VO₂ and oxygen reserve in hypertensive patients is summarized in Figure 4. A threshold of peak VO₂ ≤ 16 mL/kg/min identifies high‐risk patients, whereas a cutoff value of ≥25 mL/kg/min categorizes patients with a fairly good long‐term prognosis. A peak of VO₂ ranging from 18 mL/kg/min to 23 mL/kg/min indicates a moderate risk of cardiac events. In this subset of patients, the oxygen reserve ratio ≤4.3 allows the identification of those with the worst outcome. A high‐risk rate is present in patients with a peak VO₂ ≤ 16 mL/kg/min. ³⁶

Figure 4.

 Proposed algorithm for efficient prognostic stratification according to peak oxygen consumption (VO₂) and oxygen reserve in mildly and moderately hypertensive patients. Prognostic value of cardiopulmonary exercise test.

Improvement in oxygen diffusion from capillaries and the ability of mitochondria to utilize oxygen, or, more likely, a better working muscle perfusion, are potential mechanisms for the increased ratio of Δ peak VO₂ to Δ work rate that was observed in our patients who took an ARB. According to Little and colleagues, ³⁷ the lack of increase in oxygen pulse with candesartan is in favor of reduced vasoconstriction and facilitated blood flow redistribution to exercising muscles, ³⁸ rather than of increased stroke volume or oxygen arterial‐venous difference as a cause of the increased Δ peak VO₂/Δ work rate. It is relevant that medical treatment could be optimized in cases with peak VO₂ ≤ 16 mL/min/kg, ³⁹ to identify patients with a better short‐term survival and guarantee priority to patients who, despite tailored therapy, do not have improved peak VO₂.

Compounds, such as positive inotropic agents, can increase peak VO₂ in a magnitude similar to or greater than an ARB with inconveniences such as neurohumoral activation. Conversely, the use of ARBs reduces morbidity and mortality in hypertensive patients. ⁴⁰ Although the prognostic significance of our results has to be explored in larger trials of longer duration, candesartan appears to be an intriguing therapeutic intervention to improve outcomes in patients with critical exercise limitation. Persistence over the time of the short‐term benefit remains to be explored.

ARBs may represent an alternative to ACEIs for hypertension, or even an advancement, because of similar efficacy for exercise performance but less exposure to the counteracting activity of aspirin. ⁴¹ This may have implications for patients with coronary artery disease.

Limitations of the Study:  Compared with normal volunteers, hypertensive patients had lower measures of maximal VO₂ and heart rate at maximal exercise. This appears most marked when hypertension and LV hypertrophy coexist. This is particularly true in patients who require high work loads to achieve maximal exercise levels. Performance during exercise testing may also be affected by the degree of familiarity with the exercise test procedure. Thus, unfamiliarity with the exercise protocol may induce anxiety and affect BP changes. It can also result in submaximal exercise performances. A previous report ⁴² describing an association between exaggerated exercise BP and LV hypertrophy did not include a learning exercise test.

Finally the simplicity, accuracy, and easy measurability of a reduced oxygen reserve (ratio) should be taken into account in a hierarchic selection of prognostic parameters. Further studies are required to verify the usefulness of the oxygen reserve (ratio) to monitor the effectiveness of medical therapy, and serial cardiopulmonary exercise testing should be performed to investigate whether a reduced oxygen reserve (ratio) with long‐term therapy may predict a more favorable prognosis.

Conclusions

Hypertensive patients had lower measures of peak VO₂, oxygen reserve, and heart rate at maximal exercise than predicted by age, sex, and weight and height. In this crossover and placebo‐controlled study in patients with mild to moderate hypertension, candesartan monotherapy, as expected, produced a significantly lower arterial BP than placebo or placebo plus aspirin at week 3 of treatment, while a combination of candesartan and aspirin yielded better physical performance and exercise VO₂ compared with either drug alone. An ARB may represent an alternative in hypertensive patients for its efficacy on exercise peak VO₂ and exercise tolerance because of similar efficacy of the ACEI for exercise performance and less exposure to the counteracting activity of aspirin.