ORIGINAL ARTICLE

Effects of age on aerobic capacity in heart failure patients under beta-blocker therapy: Possible impact in clinical decision-making?

Emmanuel Gomes Ciolac1, Edimar Alcides Bocchi2, Miguel Morita Fernandes da Silva2, Aline Cristina Tavares2, Iram Soares Teixeira-Neto2, Guilherme Veiga Guimarães2

1Exercise and Chronic Disease Research Laboratory, Physical Education Department, School of Sciences, São Paulo State University — UNESP, Bauru, Brazil
2Heart Institute (InCor) – Hospital das Clínicas da Faculdade de Medicina, University of São Paulo, Sao Paulo, Brazil

Address for correspondence: Dr Guilherme Veiga Guimarães, Rua Dr Baeta Neves, 98, São Paulo/SP, Brazil, CEP 05444-050,
tel/fax: +55 11 2661–5502, e-mail: gvguima@usp.br
Prof. Emmanuel Gomes Ciolac, Universidade Estadual Paulista – UNESP – Departamento de Educação Física,
Av. Engenheiro Luiz Edmundo Carrijo Coube 14-06, Bauru/SP, Brazil, CEP 17033-360, tel/fax: +55 14 3103–6082,
e-mail: ciolac@fc.unesp.br

Received: 13.02.2013 Accepted: 11.05.2013

Abstract Background: Heart failure (HF) is associated with impaired maximal aerobic capacity as indicated by decreases in peak oxygen uptake (peak VO2). Considering that aging by itself has a negative effect on this variable, the evaluation of maximum capacity is often questioned because current predicted peak VO2 is based on subjects without heart disease or β-blocker therapy. In contrast, if decline in predicted and attained peak VO2 were age-related, proportionally, loss of aerobic function (predicted peak VO2, %) would remain stable over time in these patients. The purpose of this investigation is to assess the effects of age on peak VO2 in HF patients taking β-blockers. Methods: We retrospectively evaluated 483 (132 female) patients (aged 20–88 years, LVEF 31 ± 11%) with non-ischemic (n = 362), ischemic (n = 74) and Chagas-related HF (n = 47) who had been submitted to an incremental cardiopulmonary exercise testing on a motorized treadmill. Linear regression was used to develop the equation to predict peak VO2, based on age. Results: Peak VO2 decreased 0.9 mL/min/kg per age-decade, maximum HR also decreased with aging and VE/VCO2 slope was similar among all decades. The predicted new β-blocker equation to peak VO2bb was 20.934 – 0.092 × age. Conclusions: Clinical interpretation of aerobic capacity impairment is influenced by aging in HF patients. This evidence must be considered when using peak VO2 for prognostic stratification and clinical decision-making in patients with HF under β-blocker therapy. (Cardiol J 2013; 20, 6: 655–661) Key words: aging, β-blocker therapy, cardiopulmonary exercise test, cardiorespiratory fitness, heart failure

Introduction

Chronic heart failure (HF) is an increasingly common disorder in population, which causes high mortality and morbidity, despite modern developments in medical therapy [1–4]. The primary symptoms of chronic HF are exertional fatigue and dyspnea due to a reduction in exercise tolerance [1]. Additional traits, as age, gender, weight, body surface area and muscle mass, can also be correlated to functional capacity in patients with HF [5, 6].

Indeed, performing the cardiopulmonary exercise testing (CPX) became increasingly important in order to provide objective and reproducible measurement of exercise limitation [1] and to identify individuals suffering from HF with poor prognosis [1, 6]. Among exercise variables, the strongest and most consistent predictors of death are peak oxygen consumption (peak VO2) [1, 4, 6], VO2 at the ventilatory threshold, percentage of age-predicted maximal heart rate (HR) and VE/VCO2 slope [6, 7].

These data have also influence on the chosen treatment. In the early 90’s, it was shown that patients with severe left ventricular dysfunction and peak VO2 < 14 mL/min/kg would benefit from cardiac transplantation [1, 8]. More recently, a lower cutoff for peak VO2 (< 12.5 mL/min/kg) has been identified as predictor of mortality in patients with HF, taking β-blocker agents [9].

Nevertheless, a progressive decline in cardiovascular system occurs with advancing age [10]. Age itself is an independent morbidity and mortality risk factor for a long list of diseases, hospitalization and length of hospitalization [11]. Physiological changes that occur during the aging process regarding quality of life and functional independence are muscle intrinsic abnormalities, low muscle mass or muscle perfusion [3], declining in muscle strength and in aerobic capacity, indexed as peak VO2 [5, 12, 13].

A few studies demonstrated that longitudinal rate of declining in peak VO2 is on average 8% to 10% per decade in the general population and, at the age of 60, it is approximately two-thirds of that at 20 [10, 14]. Recently it has been reported that peak VO2 decreases with age in HF patients, how­ever, these reports came from studies with patients classified as young, middle-aged and older, and the peak VO2 was assessed using either a treadmill or cycle ergometer CPX [15, 16]. On the other hand, there are no trials showing the effect of age by decade on peak VO2 in HF patients. It is possible that age can influence the peak VO2, as well as the cutoff point for cardiac transplant in patients suffering from HF. The purpose of this investigation is to assess the effects of age on peak VO2 in HF patients taking β-blockers.

Methods

Population and study design

A retrospective analysis was performed in consecutive patients with systolic HF referred to heart transplant, from 1999 to 2009. Inclusion criteria included clinical and pharmacological stability for at least 3 months prior CPX, age ≥ 20 years, left ventricular ejection fraction (LVEF) < 45%, New York Heart Association functional class I–III and no participation in regular physical activity (≥ 30 min 3 times a week). Patients with cardiac device system (pacemaker or implantable defibrillator), CPX interrupted due to hemodynamic or electrocardiographic complications, respiratory exchange ratio (RER) < 1.0, neuromuscular or respiratory limitations were excluded from the study.

A total of 655 clinically and pharmacologically stable HF patients underwent CPX during this period. One hundred seventy two patients were excluded from analysis because they were, either, under regular physical activity (n = 40), were under 20 years old (n = 25), had no optimized drug therapy (n = 10), or interrupted test due to hemodynamic or electrocardiographic complications (n = 40), respiratory limitations (n = 10), LVEF ≥ 45% (n = 10), atrial fibrillation (n = 20), and pacemaker or implantable defibrillator (n = 15). The final sample included 483 patients with systolic HF aged from 20 to 88 years, with stable dose of β-blocker for more than 3 months prior to the CPX. The patients were enrolled in six age groups ranging from 20 to 29, 30 to 39, 40 to 49, 50 to 59, 60 to 69 and ≥ 70 years old. Clinical characteristics are listed in Table 1.

Table 1. Baseline characteristics according to age decade.

	20–29 (n = 28)	30–39 (n = 67)	40–49 (n = 152)	50–59 (n = 143)	60–69 (n = 75)	≥ 70 (n = 18)
Sex (male/female)	19/9	49/18	114/38	96/47	60/15	12/6
Body mass index [kg/m2]	23 ± 4	26 ± 5	25 ± 4	26 ± 5*	27 ± 5*	27 ± 4
Hemoglobin [g/dL]	13.6 ± 1.4	13.7 ± 1.4	13.5 ± 1.8	13.6 ± 1.6	13.8 ± 1.3	13.7 ± 2.2
LVEF [%]	27 ± 8	30 ± 10	28 ± 11	30 ± 13	30 ± 12	25 ± 7
Heart rate rest [bpm]	86 ± 21	79 ± 15	76 ± 15*	75 ± 15*	76 ± 18*	79 ± 12
Etiology:
Idiophatic	23	48	114	107	62	10
Ischemic	3	13	23	22	8	5
Chagas	2	8	15	14	5	3
Medication [%]:
Beta-blocker	100	100	100	100	100	100
Diuretics	76	73	70	69	72	77
ACE-I/ARB	86	87	80	81	79	88
Digoxin	43	38	41	40	37	38
Aldosterone	46	40	39	37	40	42
Nitrate	2.5	2.1	3.2	3.3	2.8	2.1
Amrinone	1	1.8	2.1	2.0	1	1
Anticoagulants	0	1.5	2.3	2.5	1	0
aSignificant difference in relation to age group 20–29 (p = 0.01); LVEF — left ventricular ejection fraction; ACE-I — angiotensin converting enzyme inhibitor; ARB — angiotensin receptor blocker

The review board of the ethical committee at our institution had approved the study and it is in accordance with the declaration of Helsinki.

Exercise testing

All referred patients had undergone maximal exercise testing using a modified Naughton protocol and a metabolic cart. CPX had been carried out on a programmable treadmill (TMX425 Stress Treadmill; TrackMaster, Newton, KS, USA) in a controlled-temperature room (21–23oC) with monitoring of cardiac rhythm (CardioSoft 6.5; GE Medical Systems IT, Milwaukee, WI, USA) and blood pressure (Tango Stress BP; SunTech Medical Inc, Morrisville, NC, USA) as previously described [17]. The 12-lead electrocardiogram and HR had been monitored in the standing position before and throughout the exercise and recovery period. Ventilation (VE), oxygen uptake (VO2) and carbon dioxide output (VCO2) had been measured breath-by-breath using a computerized system (Vmax Encore29; SensorMedics Corp., Yorba Linda, CA, USA). The RER had been recorded at each average sample obtained during each stage of the protocol. The highest VO2 uptake level (1 min mean) at the end of exercise was considered the peak VO2, and the VE/VCO2 slope was calculated by automatic linear regression fitting with the breath-by-breath values obtained throughout the whole exercise. Patients had been instructed and encouraged to exercise to their maximum capacity.

The predicted peak VO2 was calculated according to normative values to age, sex and body weight by Wasserman et al. [18]. The percentage of predicted peak VO2 was determined by dividing the weight normalized peak VO2 by the predicted peak VO2 and then multiplying it by 100. Predicted maximum heart rate (HRmax) was determined by the equation HRmax = 164 – (0.7 × age), which was validated for patients receiving β-blocker therapy [19].

Statistical analysis

All data are reported as means ± standard deviation and the statistical program SPSS 13.0 for Windows (SPSS Inc, Chicago, IL, USA) was used to perform statistical analysis. The Kolmogorov-Smirnov test was applied to ensure a Gaussian distribution of the results. One-way analysis of variance (ANOVA) was used to analyze differences in the subject’s characteristics at baseline. Bonferroni post hoc analysis was used to determine significance of data that was indicated by one-way ANOVA. Pearson correlation was used to assess the relationship between age and both peak VO2 and HRmax, and between age and percent predicted for them. Linear regression was used to generate equation to predict peak VO2 from age for HF patients receiving β-blocker therapy. Then, we calculated the predicted peak VO2 using this linear regression for patients taking β-blocker agents (VO2bb). The significance level was set at p < 0.05.

Results

The comparisons of clinical characteristics of categorized patients by age decades are listed in Table 1. The percentage of subjects with non-ischemic HF etiology, as well as male subjects was greatest in all decades. The body mass index was significantly lower in the 20–29 year group when compared to patients in the 50’s and 60’s decades. The resting HR was significantly higher in the 20’s decade in relation to the 40’s, 50’s and 60’s. LVEF and HF pharmacological therapy were not different among the groups. All patients were taking β-blockers (carvedilol 80%, bisoprolol 15% and metaprolol 5%) at maximum tolerated dose at the discretion of the treating physician.

Cardiopulmonary exercise test data are shown in Table 2. None of the exercise tests were terminated secondary to electrocardiogram criteria and all patients stopped it by fatigue symptoms. The peak VO2 was significantly lower among patients in the 60’s and 70’s decades in relation to the 20’s, 30’s and 40’s. We also observed that peak VO2 decreased approximately 0.9 mL/kg/min by decade in this population. However, the percentage of the predicted peak VO2 and, the peak RER were similar in all groups, as well as their maximum and percentage of maximum HR. The other variable that was similar in all decades was VE/VCO2 slope.

Table 2. Cardiopulmonary exercise test variables according to age decade.

	20–29 (n = 28)	30–39 (n = 67)	40–49 (n = 152)	50–59 (n = 143)	60–69 (n = 75)	≥ 70 (n = 18)
HRmax	129 ± 29	124 ± 27	123 ± 23	117 ± 24	116 ± 27	114 ± 19
% HRmax	89 ± 19	88 ± 20	93 ± 17	93 ± 19	97 ± 22	103 ± 17
peak VO2	18.8 ± 6.5	17.5 ± 5.7	16.7 ± 5.0	16.2 ± 4.5	14.9 ± 4.2a, b	13.0 ± 2.4a,b,c
% VO2pred	46 ± 14	43 ± 13	44 ± 11	48 ± 11	48 ± 12	46 ± 8
peak VO2bbd	18.5 ± 0.27	17.7 ± 0.27	16.8 ± 0.25	15.9 ± 0.26	15.0 ± 0.27	13.9 ± 0.45
% VO2predbb	101 ± 35	99 ± 32	100 ± 30	102 ± 30	99 ± 28	94 ± 18
RER	1.06 ± 0.05	1.05 ± 0.05	1.07 ± 0.06	1.07 ± 0.07	1.06 ± 0.06	1.03± 0.02
VE/VCO2slope	35 ± 15	35 ± 13	35 ± 8	36 ± 10	35 ± 9	35 ± 9
HRmax — maximum heart rate [bpm]; % HRmax — percent-predicted HRmax; peak VO2 — peak oxygen consumption [mL/kg/min]; % VO2pred — percent-predicted peak VO2; peak VO2bb — peak VO2 estimated by 20.934 – 0.092 × age [mL/kg/min]; % VO2predbb — percent-predicted peak VO2 using predicted peak VO2bb; RER — respiratory exchange ratio; significant differences between age group: a20–29, b30–39, and c40–49; dsignificant differences among all decades

The linear regression analysis of peak VO2 vs. age is shown in Figure 1. The intercept and slope were 20.93 ± 0.95 and –0.092 ± 0.018, respectively. So, the equation for estimated peak VO2bb to HF patients in β-blocker therapy is 20.934 – 0.092 × age for whole population.

Figure 1. Linear regression equation of peak exercise oxygen consumption (peak VO2) versus age. Dashed line represent 95% confidence interval of the mean. From these data, a new equation was proposed: VO2bb = 20.934 – 0.092 × age.

Table 2 shows the results of the new β-blocker prediction equation for peak VO2bb using a computerized system in HF patients receiving β-blockers therapy underwent treadmill exercise testing. The peak VO2bb was not significantly different from the peak VO2 measured in all age-decades. However, the peak VO2bb was significantly different among all groups. The Figure 2 shows the interrelation between age, HRmax and peak VO2.

Figure 2. Interrelation among age, peak exercise oxygen consumption (peak VO2) and maximum heart rate (HRmax).

The correlations between age and peak VO2 (r = 0.21, p < 0.0001), and HRmax (r = 0.16, p = 0.0007) were weak although statistically significant (Fig. 3). The analysis for VE/VCO2 slope did not show correlation with age (r = 0.01, p = 0.6).

Figure 3. Relationship between age and: A. Peak exercise oxygen consumption (peak VO2); B. Maximum heart rate (HRmax). There was a significant correlation between age and both A and B. Dashed lines represent 95% prediction interval.

Discussion

The primary finding of the present study was that peak VO2 decreased 0.9 mL/kg/min for every 10-year increment in age in HF patients taking β-blockers. Additionally, our results show that aerobic function (% predicted) did not differ among young, middle-aged and older patients with HF. The other finding in this investigation is that the new β-blocker equation for predicted peak VO2bb in this specific population between 20 and 88 years old corresponds to 20.934 – 0.092 × age. To the best of our knowledge, this is the first study to determine an equation to predict peak VO2 and compare the effects of age on physical capacity among different decades in HF patients under­- going a CPX performed on a treadmill in all cases.

Two previous studies that have investigated the effect of age in HF patients showed a reduction in aerobic capacity [16, 17]. However, these authors analyzed these effects within broad aged groups and the exercise testing was completed using both treadmill and upright cycle ergometer. In spite of methodological differences, the decrease in value of peak VO2 was 1.0 mL/kg/min for every 7 years [16], which was similar to the findings in our study. The functional capacity is associated with age and begins to decline after age 30, with a more exponential decrease in cardiorespiratory fitness and muscle strength after the age of 50 in apparently healthy individuals [20, 21]. This represents a decline in peak VO2 on average of 8% to 10% per decade [10–12]. Hence, age itself is an independent predictor for peak VO2. In previous specific investigations about aerobic capacity and aging in HF [16, 17] it was reported that physiologic reserve in HF is very reduced, which is supported by our results. Progressive decline in peak VO2 reflects the degree of disease’s severity and provides prognostic information in patients with HF [22].

However, our results demonstrated that the mean percent-predicted peak VO2 value for all groups was 45.8%, which may suggest that these patients are already in their comfort zone, considering age-decades. On the other hand, when new β-blocker equation for predicted peak VO2bb was used this reduction disappears. The peak VO2bb calculated by equation did not differ from the actual peak VO2 measured, so the percentage of predicted peak VO2bb is around 100%. This finding itself indicates that both aerobic capacity and aerobic function, when adjusted by the equation, are in closer relationship with age than disease’s severity in patients with HF. Moreover, VE/VCO2 slope did not change among the age-decades, reinforcing the theory that the fall in peak VO2 is not related to worsening of HF.

The results of the present study are according to our previous investigation, which showed a cutoff point for peak VO2 of 12.5 mL/kg/min in HF patients undertaking β-blockers as better midterm prognosis [8].

The effects of physiologic aging are associated to declining in exercise capacity, HRmax and peak VO2 [11]. Although it was reported that the decline in peak VO2 seems to be primarily by reduction in HRmax [23], there was no significant difference in HRmax during age-decades among the groups.

The β-blocker therapy has become a primary pharmacologic intervention in patients with HF [24]. Previous report has shown that the maximal age-predicted HR depends on optimization of β-blocker dosing in HF patient [2, 25]. In our study, the HR in maximal effort evaluation was 93.8 ± 4.9% of the predicted in the whole sample, estimated by the specific equation to predict HRmax in patients receiving this therapy [18]. Despite the tendency to HR decline during age-decades, the percentage of β-blocker predicted HRmax in middle-aged and older tends to be higher, which may suggest reduced in chronotropic reserve over the years in HF patients taking β-blockers [26].

Limitations of the study

This is a retrospective study using selected patients with HF referred to heart transplant of a single center. All patients underwent a single treadmill CPX to assess aerobic capacity. Even though data collection is not planned and statistical analysis is exploratory, all patients underwent testing on the same equipment and by the same team, which eliminates the differences in data collection and conduction. Considering the high morbidity and mortality in this population, the functional capacity decrease is probably higher over time, since decompensated patients or with excessive limitation cannot be evaluated by exercise testing. However, our results are applicable to clinical setting where peak VO2 is an important prognostic parameter. Since present guidelines recommend cardiac rehabilitation for stable HF patients, excluding from analyses patients undergoing regular physical activity is a limitation. However, the inclusion of small number of patients undergoing regular physical activity could bias study results. Future studies focused in analyzing how age affects stable HF patients compliant to exercise/cardiac rehabilitation guidelines are thus necessary. The number of patients between 20–29 and ≥ 70 years was relatively small in comparison to the other groups, but the analysis showed that the sample size was sufficient to detect difference. Values of peak VO2 are lower for women than men [27], however we did not analyze it separately due to the small number of women in the sample. Finally, the new equation for predicted peak VO2 in HF patients undertaking β-blockers is based on treadmill only and cannot be extrapolated to upright cycle ergometer exercise test.

Clinical implication

The present finding shows an inverse and decreased association between aerobic capacity and aging in HF patients taking β-blockers. This association derives from patients who underwent a treadmill CPX. The finding suggests that a reduction in peak VO2 higher than 0.9 mL/kg/min per decade may indicate a significant worsening in aerobic capacity and may not reflect the expected decline in aerobic function in HF patients. The similarity between measured and calculated peak VO2 in all age-decades suggests that there is no functional physiologic reserve associated to aging in HF. Peak VO2 is used for clinical decision-making regarding the need for cardiac transplantation in all age-decades. However, the cutoff value was determined in middle-aged HF patient predominantly. Therefore, we may speculate that age-decades difference in peak VO2 could be an important factor for clinical decision-making in patients with HF.

Conclusions

In summary, this investigation suggests that age-adjusted peak VO2 may describe more accurately the degree of aerobic capacity impairment in HF patients. This evidence should be considered when using the peak VO2 for prognostic stratification and clinical decision-making in patients with HF.

Acknowledgements

This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP # 2010/08554-7). Emmanuel G Ciolac was supported by Fundação de Amparo à Pesquisa during this Project (FAPESP # 2012/02409-0). Guilherme V Guimarães was supported by Conselho Nacional de Pesquisa (CNPq # 304733/2008-3).

Conflict of interest: none declared

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