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β1-Adrenoceptor Mediated Origin of the Heart Rate Performance Curve Deflection

HOFMANN, PETER1; WONISCH, MANFRED2; POKAN, ROCHUS3; SCHWABERGER, GÜNTHER4; SMEKAL, GERHARD3; VON DUVILLARD, SERGE P.5

Medicine & Science in Sports & Exercise: October 2005 - Volume 37 - Issue 10 - p 1704-1709
doi: 10.1249/01.mss.0000176308.70316.cc
Basic Sciences: Original Investigations
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Purpose: The deflection of the HR performance curve (HRPC) has been described as an objective marker of submaximal exercise performance. HR response to incremental cycle ergometer exercise is shown to be neither linear nor uniform and a physiological explanation of the deflection phenomenon is lacking. We hypothesized that differences in the β1-adrenoceptor site are the source of these differences. The aim of the study was to investigate the influence of the highly selective β1-adrenoceptor (β1-AR) antagonist bisoprolol (Bi) on the HRPC in young healthy male subjects with different HR response patterns.

Methods: Sixteen subjects were treated in randomized order with Bi or a placebo (Pl) in two separate trials. HR response during incremental cycle ergometer exercise was compared between the two trials. Blood lactate concentration (La) and ventilatory variables were measured throughout both tests.

Results: Bi changed the direction of the HRPC more in subjects with a regular, s-shaped response pattern under placebo than those with a nonregular or linear pattern. The influence of Bi on the HR at the second lactate turn point was significantly related (R = 0.78; P < 0.001) to the pattern of the HRPC in Pl conditions.

Conclusion: We suggest that differences between the subjects with regular s-shaped versus nonregular HRPC may be due to differences at the β1-AR site. The origin of the HRPC deflection is mediated in part by the β1-AR sensitivity.

1Institute of Sports Science, University of Graz, Graz, AUSTRIA; 2Department of Internal Medicine, Medical University of Graz, Graz, AUSTRIA; 3Institute of Sports Science, University of Vienna, Vienna, AUSTRIA; 4Institute of Physiology, Medical University of Graz, Graz, AUSTRIA; and 5Human Performance Laboratory, Department of Health and Human Performance, Texas A&M University—Commerce, Commerce, TX

Address for correspondence: Serge P. von Duvillard, Ph.D., Human Performance Laboratory, Department of Health and Human Performance, Texas A&M University–Commerce, P.O. Box 3011, Commerce, TX 75429-3011; E-mail: serge_vonduvillard@tamu-commerce.edu.

Submitted for publication January 2005.

Accepted for publication June 2005.

Usually, the HR response during incremental or ramplike exercise has been described to be linearly related to workload (2,10,37) and/or oxygen uptake (2,10,28). However, there is strong evidence that the mean HR response to incremental ergometer exercise is curvilinear at low and high workloads presenting a typical s-shape (9). In a large homogeneous group of young healthy male subjects, we could show three different individual patterns of HR response to incremental cycle ergometer exercise (21) present as 1) a regular s-shaped HR performance curve (HRPC); 2) a nonregular, linear HR response without any deflection of the HRPC above the first lactate turn point (LTP1); and 3) an inverted HR response (19–23). These three response patterns were also demonstrated in older healthy subjects (31) and in patients after myocardial infarction (33), which has some important consequences for training regulation presented previously (24,39). The different HR responses were related to left ventricular ejection fraction (LVEF) (20,29,33). The more linear or inverted the HR response was the more LVEF was diminished above the second lactate turn point (LTP2), which denotes an estimate of the maximal lactate steady state (3,5,19,38). The LVEF response was hypothesized to be one possible cause of the accelerated HR response to compensate for the loss of myocardial function; however, the phenomenon could only be described, but no physiological explanation of the HRTP could be given. Additionally, the response pattern was found to be independent of parasympathetic activity (32).

Using the HR response pattern to detect the HR deflection point is a method first introduced by Conconi and coworkers (13). Their original hypothesis suggested that an increase in workload above the anaerobic threshold (AT) (the term anaerobic threshold is used as a phenomenological description and is not addressing issues of metabolism in this paper) is at least in part independent of oxygen uptake and HR. They further proposed that because of anaerobic adenosine triphosphate (ATP) production, the work intensity above AT increases more than HR. However, these investigators provided no data on sympathetic or other neuroendocrine responses, lactate flux, or muscle oxygenation, and the unusual method of validation of their HR deflection point by means of venous blood lactate measures was critically discussed. Nonetheless, they maintained that the HR deflection point could be used to indirectly and noninvasively evaluate AT. Subsequently, presenting a modified method (14), they maintained their previously advanced hypothesis (13) that the deflection of the HR performance curve is caused by the activation of the anaerobic lactacid mechanisms of ATP production and thus muscular work is independent of aerobic metabolism, cardiocirculatory activity, and HR. Again, no data on lactate flux or muscle oxygenation were provided.

The HR deflection point method (6), also termed HR threshold (HRT) (7,19,20) or HR turn point (HRTP) (24,31,33), has been critically discussed in the literature (1,6,7,25), especially concerning the basic physiological mechanisms relating HR and muscle anaerobiosis (6). Earlier studies demonstrated that the pattern of HR response was related to neither pH nor blood lactate concentration (La). Moreover, parasympathetic receptor blockade did not alter the principal pattern, but rather increased HR at rest and submaximal workload but not maximal workload (23,32). The plasma catecholamine response was not significantly different between two groups of subjects with a different HR response pattern (23). As exercise-induced tachycardia is known to be mediated solely through β1-adrenoceptor (β1-AR) stimulation by neuronal released norepinephrine, the magnitude of the response is dependent on β1-AR sensitivity (8). Exercise testing has been shown to be a precise indicator of human cardiac β1-AR sensitivity. The reduced maximal HR in response to exercise stress is in agreement with in vivo observations of decreased β1-AR responsiveness in aging (8). From this, we followed the hypothesis that a highly selective β1-AR antagonist is able to deduce differences in the receptor site and its influence on the HRPC deflection.

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METHODS

Subjects.

Sixteen young healthy male sports students (age 24.3 ± 3.6 yr, height 183.1 ± 5.8 cm, body mass 77.6 ± 7.8 kg) participated in the study. Subjects signed a written informed consent, were considered trained, and had a maximal oxygen consumption (V̇O2max) of 57.3 ± 6.2 mL·kg−1·min−1. Subjects were randomly selected from a large group of sports students according to the HR response pattern (eight regular and eight nonregular) obtained during routine diagnosis at the beginning of their education. These routine diagnostic tests were performed 1–4 yr before the study. As only 6–7% of young healthy male subjects present a nonregular HRPC, a great number of tests had to be performed to get sufficient data to randomly select subjects with a nonregular HRPC (22). Standard medical screening was performed before starting the study. The study protocol was approved by the local clinical ethics committee and was in accordance with the Declaration of Helsinki.

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Experimental design.

Subjects underwent two incremental cycle ergometer exercise tests to voluntary exhaustion. Three hours before each exercise test, subjects received an oral placebo or 5 mg of the highly selective β1-AR antagonist bisoprolol in a random order. The 5-mg dose of bisoprolol was chosen because of the high selectivity for β1-AR and because it invokes only low receptor-blocking action on β2-AR (16,18). Furthermore, it represents a clinically relevant dose to reduce HR by about 10%. Acute administration was chosen to avoid receptor adaptation.

All exercise tests were performed on an electronically braked cycle ergometer (Ergoline 900, Siemens, Germany). Subjects sat quietly on the ergometer for 1 min to obtain resting values. Exercise was started at a power output of 40 W and increased by 20 W every minute until voluntary exhaustion. Cycling cadence was held constant at 70 rpm.

A 12-lead ECG was recorded throughout the entire testing time and the data were stored on computer (Schiller AT10, Schiller, Austria). Blood pressure was measured at rest, during exercise, and recovery.

Blood samples (20 μL) were collected from the hyperemic ear lobe at rest, after each load step, and during recovery, and La was measured enzymatically (Ebio Plus, Eppendorf, Germany).

HR was measured continuously, stored at 5-s intervals, and transferred to a computer immediately after the end of the recovery period for additional HR deflection analysis (Sporttester PE4000, Polar Electro, Finland).

Respiratory gases were measured in breath-by-breath mode and analyzed via an indirect open-air circuit system, and 10-s means were stored for analyses (MetaMax I, Cortex Biophysik, Germany). Gas analyzers were calibrated with gases of known concentration before each test according to manufacturer’s guidelines.

To define the different phases of energy supply (19) and to define the region of interest (ROI) for the analysis of the HRPC, the LTP concept (15) was used (20–22). The first LTP (LTP1) was calculated as the first increase in La above baseline values. The intersection point between two linear regression lines satisfying the conditions of least error squares was calculated by a computer-aided method. Between LTP1 and Pmax (ROI) the second lactate turn point (LTP2) was calculated applying the same method.

The HRTP was calculated using the same method as described for LTP2. The ROI was defined by LTP1 and Pmax (Fig. 1). The deflection of the HRPC (kHR) was calculated according to Pokan et al. (29). The direction and the degree of the HRPC deflection were calculated by second-degree polynomial representation of the HRPC within the ROI satisfying the conditions of least error squares. The slopes of the tangents at the points of LTP1 and Pmax were calculated as well as the differences in angles as kHR = (T1 – T2) × (1 + T1 × T2)−1 (28). Figure 1 represents the principle of the determination as presented earlier (21,22,24).

FIGURE 1— Calculation of the degree and the direction of the deflection (kHR) of the HR performance curve (HRPC) according to Pokan et al. (

FIGURE 1— Calculation of the degree and the direction of the deflection (kHR) of the HR performance curve (HRPC) according to Pokan et al. (

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Statistical analysis.

Data are presented as means ± SD. Statistical analysis was performed using Winstat software (Calmia Corp.). Where appropriate, significance of differences was calculated by paired sample t-tests or ANOVA using Tukey (HSD) post hoc tests. Pearson product correlation coefficients were calculated where appropriate. Significance was set at P < 0.05.

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RESULTS

The HRPC was highly reproducible (R = 0.89, P < 0.001) and was not significantly different between pre and placebo tests, but was significantly different in the β1-AR antagonist treatment. An HRTP could be determined in all subjects in the placebo treatment independent of the direction of the deflection of the HRPC. However, an HRTP could not be determined in the β1-AR antagonist treatment in four subjects because the deflection changed into a linear time course of the HRPC.

Bisoprolol significantly reduced oxygen uptake and power output at maximal workload and at LTP2 but not at LTP1. La was not significantly different between treatments (Fig. 2). Mean values for the degree and the direction of the deflection of the HRPC (kHR) were found at 0.34 ± 0.42 (range, −0.37 to 1.00) for placebo and −0.25 ± 0.34 (range, −1.17 to 0.17) for β1-AR antagonist treatment, and they were significantly related (R = 0.49; P < 0.05). Mean values of HR, power output, La, and V̇O2 at rest, at LTP1, LTP2, HRTP, and maximal performance are depicted in Table 1. Power output at LTP2 was significantly reproducible between treatments (R = 0.88; P < 0.001).

FIGURE 2— HR and La during incremental cycle ergometer exercise in young healthy male subjects during placebo and β1-adrenoceptor antagonist (bisoprolol) treatment.

FIGURE 2— HR and La during incremental cycle ergometer exercise in young healthy male subjects during placebo and β1-adrenoceptor antagonist (bisoprolol) treatment.

TABLE 1

TABLE 1

Power output and oxygen uptake at the LTP2 and the HRTP were not significantly different in each of the treatments and were significantly related (placebo: R = 0.852; P < 0.001, N = 16; β1-AR antagonist: R = 0.891; P < 0.001; N = 12).

As expected, HR was significantly reduced at rest and at all workload levels by the β1-AR antagonist treatment (Fig. 2), however, the HR response pattern was significantly influenced. The magnitude of influence was significantly related to the degree and the direction (kHR) of the deflection of the HRPC. The more kHR was positive (regular HR response pattern) in placebo, the greater was the decrease of HR at LTP2 in the β1-AR antagonist treatment (Fig. 3). HR at LTP2 decreased to a greater extent than HR at LTP1 and HRmax, which indicated a complete change in the HR response pattern from a regular to a nonregular pattern (Fig. 4A). This change was negligible in cases where a nonregular HR response was present in the placebo treatment (Fig. 4B).

FIGURE 3— Relationship between the degree and the direction of the deflection (kHR) of the HR performance curve and the change in HR (dHR Pl-Bi) at the second lactate turn point (LTP2) induced by selective β1-adrenoceptor antagonist treatment.

FIGURE 3— Relationship between the degree and the direction of the deflection (kHR) of the HR performance curve and the change in HR (dHR Pl-Bi) at the second lactate turn point (LTP2) induced by selective β1-adrenoceptor antagonist treatment.

FIGURE 4— Examples of the influence of highly selective β1-adrenoceptor antagonist treatment on a regular (A) and a nonregular (B) HR performance curve (HRPC) response pattern. The change of the deflection is indicated by kHR.

FIGURE 4— Examples of the influence of highly selective β1-adrenoceptor antagonist treatment on a regular (A) and a nonregular (B) HR performance curve (HRPC) response pattern. The change of the deflection is indicated by kHR.

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DISCUSSION

A single dose of 5 mg of the highly selective β1-AR antagonist bisoprolol administered 3 h before exercise was effective in decreasing HR at rest and at all workloads, as has been described earlier (16). The key finding of the study was that dependent on the time course of the HRPC, the change due to β1-AR antagonist treatment was altered depending on whether the HRPC was regular. A regular HR response pattern could be converted into a nonregular pattern, whereas the nonregular pattern was not significantly affected. The β1-AR treatment influenced the magnitude of drop in the HR at the LTP2; the more the HRPC was regular, the more augmented was the change. The overall pattern as shown for bisoprolol in Figure 2 was presented earlier for propranolol (35) and metoprolol (26) treatment. These authors did not, however, differentiate individual response patterns of the HRPC. Additionally, parasympathetic blockade had no influence on the principal pattern of the HRPC (32).

The individual pattern of the HRPC was highly reproducible even though 1–4 yr passed between pre and placebo tests, indicating a relatively stable pattern of the HR response to incremental ergometer exercise described earlier (4,34). Other authors reported a poor reproducibility of the HR deflection (6), which may be explained by methodological differences and different subgroups of subjects investigated.

As plasma catecholamine response was shown not to be related (30) and not significantly different (23) between groups of subjects with different HRPC response during incremental cycle ergometer exercise, the response to a highly selective β1-AR antagonist treatment may be explained by differences on the receptor site itself and in receptor sensitivity (8). Exercise testing is described as being a precise indicator for human β1-AR sensitivity (8). We suggest that β1-AR in subjects with a regular HRPC are more sensitive to catecholamines at low workload levels and may be termed “early responders.” This response is indicated by a distinct increase in HR between LTP1 and LTP2 when catecholamine levels are still low, but receptors may become saturated above LTP2 when a sharp increase of catecholamines is present (23,27). Although both epinephrine and norepinephrine increase markedly above the lactate threshold (27,35), the HR response is diminished, which contributes to the well-described deflection of the HRPC (9,13,14,21–24), also termed exhaustion phase (9), thus preserving the left ventricular function (20,29). Sensitivity of β1-AR appears to be lower in subjects with a nonregular HR response pattern showing a slow increase in HR up to the LTP2. As catecholamines increase sharply above LTP2, HR increases with an augmented response that may be defined “late responders.” This increase in HR in association with higher workloads may lead to the previously described diminished LVEF above LTP2 (20,29). Similar to the catecholamine response (23,30), La was not significantly different between subjects presenting a different HR response pattern (20,22,23). So from this point of view, the original hypothesis proposed by Conconi et al. (13) suggesting that because of anaerobic ATP production at work intensities above AT work load increases more than HR has to be withdrawn. The hypothesis of a β1-AR–mediated cause of the HR deflection holds true for the young healthy subjects investigated, but one should keep in mind that for the great number of patients presenting a nonregular HR response (33) in addition to a downregulation of the β1-AR (36), other additional pathophysiological influences may be the cause. A limitation of the study is that catecholamine data were not measured directly and older data from a previous study were used for comparison. However, as the catecholamine data are from the same homogeneous group of young healthy men (23,30), we may expect the data to be representative for the investigated group in this study.

The HRTP is shown to be significantly related to LTP2 (19,20,22), ventilatory threshold (12), and the maximal lactate steady state (19). Wonisch et al. (38) reported this relationship even under long-term β1-AR blockade. However, several authors failed to support these results (6). Contrary to Hambrecht et al. (17), the relationship between different individual threshold concepts was the same in placebo and selective β1-AR treatment in our study. These differences may be explained by methodological differences, as these authors determined the first but not the second LTP. Power output and oxygen uptake were slightly but significantly lower in the β1-AR treatment in our study.

An HRTP could not be determined in four of our subjects as the time course of the HRPC was linear after the β1-AR treatment. This has been described earlier (6,22,24) and is one of the main criticisms of the HRTP method.

Because the pattern of the HRPC is relatively stable and reproducible (4,34), one may suggest genetic differences at the β1-AR between subjects with a different HRPC and β1-AR antagonist treatment response to incremental exercise. The Gly389Arg β1-AR polymorphism described in the literature does not support a major functional role in humans although in vitro studies have revealed that this polymorphism alters the functional responsiveness to isoprenaline (11). In this study, exercise load was terminated at 100 W, which may be too low to detect a significant influence. The Gly389Arg β1-AR polymorphism may explain the differences in the HR response pattern and should be evaluated in further studies.

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CONCLUSIONS

In conclusion, we suggest that the different HR response pattern seen in young healthy male subjects is dependent on differences in β1-AR sensitivity. A metabolic origin of the HR deflection as proposed by Conconi et al. (13,14) should be questioned in light of these results. As the changes in catecholamines are significantly related both to the HRTP and the LTP2 (23), we further suggest that the catecholamines are the link between both the HR and the LTP phenomenon, although effects on blood flow and blood flow distribution may also be involved.

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Keywords:

LACTATE TURN POINT; HR TURN POINT; β1-ADRENOCEPTOR ANTAGONIST; CYCLE ERGOMETER EXERCISE

©2005The American College of Sports Medicine