Exercise pathophysiology in cardiac diseases

Incremental exercise

The incremental exercise test (see Chapter 5 for details) is considered the ''gold standard'' when studying the cardiovascular, pulmonary and metabolic adaptations to exercise in cardiac patients. This protocol allows the identification of indices of particular prognostic or interventional significance in cardiac disease, such as the lactate threshold (0L) and V'o2,peak, as well as indices derived from particular physiological system responses, such as the slope of the VO2-WR relationship and that of the relationship between minute ventilation (Ve) and carbon dioxide production (Vco2).

As discussed previously in Chapter 1, the V02 response in exercise is determined by the product of cardiac output (Co) and the arterio-venous oxygen content difference (C(a-vD02)) [2]. During incremental exercise, directly measured CO in normal subjects has been shown to increase as a curvilinear function of Vo2 [3], which contrasts with the linear characteristic seen for steady-state exercise (refer to Chapter 1). This effect is ascribed to CO dynamics which are faster than those of Vo2 [3]. It is of note that

Eur Respir Mori, 2007, 40, 93-107. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2007; European Respiratory Monograph; ISSN 1025-448X.

C(a-vDO2) increases linearly (rather than hyperbolically; refer to Chapter 1) with V'o2 when normalised to Vo2,peak both in normal subjects [2] and in CHF patients [4]. Finally, a linear correlation between peak CO and Vo2,peak has been reported in CHF patients [5].

As in normal subjects, arterial oxygen content (Ca,02) increases at higher WRs in CHF patients, because of an increase in haemoglobin (Hb) concentration [4], which promotes oxygen delivery to the exercising muscles. This certainly reflects exercise-induced haemoconcentration, due to an oncotic effect of increased intracellular metabolite levels in muscle, which accounts for ~20% of the increase in C(a-vD02) at peak exercise for CHF patients [4]. However, a contribution from splenic contraction cannot be excluded [6]. Indeed, a reduction of spleen size has been documented after exercise in healthy humans [6], and thalassaemic patients who have undergone splenectomy demonstrate less exercise-induced haemoconcentration than nonsplenec-tomised patients [7]. However, as arterial oxygen tension (Pa,o2) typically operates over the upper flat region of the oxygen dissociation curve during exercise in normal subjects (at least those of average fitness) and CHF patients, any increase in Pa,o2 will have little influence on Ca,o2 [4].

Therefore, femoral venous and mixed venous oxygen contents fall progressively throughout incremental exercise. This reflects the falling partial pressure of oxygen (PO2) that occurs with increasing WR, certainly up to 0L, with an additional contribution from the rightward shift in the oxygen dissociation curve (Bohr effect) at higher WRs [4, 6, 8]. However, while mixed venous Po2 continues to decline above 0L, any further fall in femoral venous Po2 becomes insignificant not only in normal subjects [9] but also in CHF patients [8] (fig. 1). This discrepant behaviour reflects a progressively greater contribution to the venous return from blood draining the exercising muscle at higher WRs. In CHF patients, the overall reduction in femoral venous Po2 and the Bohr effect account for 60 and 20%, respectively, of the C(a-vDo2) increase at peak exercise [4].

The nadir in the femoral venous Po2 response appears to be relatively fixed at around 2.39 kPa in normal subjects [10, 11], and has led to the concept of the "critical capillary Po2'' [10, 11]. This states that a Po2 gradient of 2.39 kPa is the lowest gradient able to guarantee oxygen flow from the capillary bed to the mitochondria. However, it should

18 H

Rest

0l o

15 Peak exercise

Fig. 1. - Schematic diagram of femoral venous partial pressure of oxygen (Po2;-) and oxygen saturation changes

(-----) during progressive exercise. 0L: lactate threshold. : critical capillary Po2 (2.39 kPa);------: upper

(2.66 kPa) and lower (2.12 kPa) limits. 1 mmHg=0.133 kPa.

be recognised that, according to the laws of diffusion, there must be, and there is, some oxygen flow below the value of 2.39 kPa. However, in an incremental exercise test, this flow is not enough to guarantee sufficient oxygen delivery for the increasing metabolic rate over the entire WR range. It should also be recognised that the measured femoral venous PO2 represents a mean value of a large number of muscle fibres whose local ratio of blood flow to metabolic rate vary significantly. Indeed, lower values of femoral venous Po2 have been reported during submaximal exercise performed with inhalational hypoxia [12]. Furthermore, the nadir in femoral venous Po2 is more variable in CHF [11]. In some heart failure patients, femoral venous PO2 actually increases with further increases in WR up to peak exercise, which is suggestive of an intramuscular mismatching of perfusion to metabolic rate. In the current authors' experience, this happens in at least 20% of patients and, more frequently in patients with severe heart failure.

The C(a-vDO2) at 9l is deserving of comment, especially in cardiac patients. At 0L, the C(a-vDO2) is relatively fixed, as both [Hb] and the fall in mixed venous Po2 are known and the metabolic acidosis has not yet begun. In a large CHF population, C(a-vDO2) at 0L is 12.3 + 1.3 mL-100 mL-1 in Class A patients (Fo^peak >20 mL-min-kg"1), 13.1+2.7 in Class B patients (Vo2,peak 15-20 mL-min-kg"1) and 13.4+2.6 in Class C patients (Vo2,peak <15 mL-min- kg"1; Class A=p<0.05 versus Class B and C) [13]. Accordingly, it is possible to estimate CO at 9l in CHF patients if simultaneous Vo2 measurements are made [13].

Finally, when making judgements on the incremental exercise protocol that is most appropriate for a specific CHF patient, several points should be kept in mind. The first is the need for a familiarisation test. This is underscored by a difference of up to 25% in Vo2,peak between the first and second test, simply because of a lack of patient confidence with the technique on the first test [14]. Secondly, the WR incrementation rate and hence time needed to reach peak exercise can influence outcome (refer to Chapter 1) [15]. However, these can be particularly difficult to predict in CHF. Recently, the current authors have shown that in a CHF population tested with different incremental protocols aimed at achieving peak exercise in 5, 10 and 15 min while, as expected, exercise time was longer and peak WR lower with the lowest WR incrementation rate (refer to Chapter 1), only peak exercise oxygen pulse, Vo2 at 9l and the V'e- Vco2 slope were independent of the WR incrementation rate (table 1) [16]. In contrast, Vo2,peak and peak fc, as well as the VO2-WR slope, were all influenced by the WR incrementation rate. Therefore, for comparison purposes, it is recommended that all tests should reach peak exercise in ~10 min and that the test duration should be reported. An additional point to be kept in mind relates to the conventional practice of reporting Vo2,peak as the mean over the final 20-30 s of the incremental phase of the test. In CHF, however, because of the presence of a low CO, Vo2,peak might be measured at the very beginning of the recovery phase. Finally, in cases of exercise" induced periodic breathing, which may persist until the end of the test, a mean value of Vo2,peak needs to be calculated over a longer interval (e.g. 1 min).

Constant WR exercise

Although constant WR protocols can provide valuable additional information to that obtained with an incremental test, with the exception of walking tests, they are not widely utilised in the clinical setting. Patients with CHF, like those with chronic obstructive pulmonary disease, have an impaired ability to utilise oxygen which, at the onset of exercise, depends in part on the kinetics of CO increase. Thus, in cardiac patients, Vo2 kinetics for constant WR exercise are slower the more severe the exercise impairment [17]. Several kinetic parameters have been used to evaluate Vo2 kinetics in

TABLE 1 - Cardiopulmonary exercise test responses for the three different endurance tests in heart failure patients

Test min

Peak WR

Exercise

VO2,peak

Peak /G

VO2-WR

Peak O2 pulse VE,peak

Ve-VOO2

SutiL-

W

time s

mL-min-kg"1

bpm

slope ml-min-W-1

mL-min-beat

L-min

slope

min-kg-1

Class C#

5

77¡26

323 + 35

11.8 + 2.0**

124 + 24**

*7.28+1.12

7.2 + 1.4

42 + 12**

38.8+ 7.0

8.0+ 2.9

10

76¡24

565 + 39

12.5 + 1.7

131+26

7.63 + 1.55

7.3 + 1.4

46 + 13

38.0+ 7.1

9.1 + 1.9

15

65 + 20*"

'899 + 96

12.3+ 2.0

126 + 23**

8.63 + 1.24**

* 7.5 + 1.5

42 + 13**

37.4+ 7

8.4+ 2.1

Class B"

5

111+28**

311+24

16.4+1.7**

* 125 + 23**

*8.18+0.97**

* 10.0 + 3.0

47 + 10***

32.4+ 5.8

12.1+2.1

10

106 + 24

583+43

17.4+1.3

134 + 20

9.14 + 1.22

10.0 + 2.9

54 + 10

32.3+ 4.7

11.7+1.5

15

97 + 27***

'860+62

17.6 + 1.7

132 + 23

9.81+1.04**

* 10.1+2.7

54 + 12

32.7+ 5.6

12.0+ 2.0

Class A+

5

154 + 41

318 + 31

21.9 + 2.3**

* 136 + 24**

*8.96+0.84**

* 12.6 + 2.8

54 + 12**'

28.9+ 4.2

16.2 + 2.7

10

154 + 30

600+58

23.2 + 2.0

146 + 24

9.74 + 1.19

12.6v3.0

61+13

28.9+ 3.5

16.4 + 2.0

15

150 + 32*

868 + 58

23.4+ 2.4*

151+23**

9.94+0.79

12.3 + 3.5

66 + 16**

28.9+ 5.5

16.3 + 2.7

Data are presented as mean±SD. WR: work rate; Vo2: oxygen uptake; fc: cardiac frequency; Ve: minute ventilation; Vco2: carbon dioxide production; 0l: lactate threshold. Class A: Vo2,peak >20 mL-min-kg"1; Class B: Vo2,peak 15-20 mL-min-kg"1; Class C: Vo2,peak <15 mL-min-kg"1. #: n=23; ": n=39; +: n=28. *: p<0.05 versus 10-min test; **: p<0.01 versus 10-min test; ***: p<0.001 versus 10-min test. Modified from [16] with permission.

CHF, including the Vo2 time constant (t) and, as long as the response is a close approximation to exponential, the VO2 half time (t1/2; refer to Chapter 1). Belardinelli et al. [18] have shown a good correlation between these kinetic parameters and Vo2,peak in CHF patients. It is also possible to characterise Vo2 kinetics in the recovery phase of the test [19]. Above 9l, Vo2 kinetics become more complex because of the additional and delayed "slow component'' (refer to Chapter 1). A useful index of the prominence of the Vo2 slow component, and one which has been used in CHF, is the Vo2 increment between the 3rd and the 6th min of the test [20]. As each of these indices correlates with exercise performance in CHF, this can remove the need for patients to undergo a symptom-limited incremental test [21].

The distance walked on the 6-min walking test (6MWT; refer to Chapter 7) allows the prediction of prognosis in patients with CHF, New York Heart Association functional class and left ventricular ejection fraction [22, 23]. The correlation between the distance walked on the 6MWT and Vo2,peak measured on a maximal incremental test ranges 0.54-0.90 [24]. Zugck et al. [25] have shown that the repeatability of the 6MWT in CHF is high. Changes in the distance walked on the 6MWT have also been utilised in CHF to assess the efficacy of interventions, such as cardiac rehabilitation [26].

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