Cardiopulmonary Response to Exercise in Health and Disease

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Chapter 23

Cardiopulmonary Response to Exercise in Health and Disease

Objectives

After reading this chapter you will be able to:

• Describe why continual regeneration of adenosine triphosphate (ATP) is necessary to sustain exercise

• Explain how aerobic and anaerobic metabolic processes differ in their ability to generate ATP

• Explain how oxygen consumption and carbon dioxide production differ in aerobic metabolism of carbohydrates and fats

• Explain why the changes in respiratory, cardiovascular, and metabolic processes are different below than above the anaerobic threshold

• Explain how caloric expenditure is related to oxygen consumption

• Use exercise test data to differentiate cardiac and pulmonary limitations to exercise

• Explain why sedentary and athletically trained individuals differ in their ability to perform exercise

• Use exercise test data to differentiate obstructive and restrictive pulmonary limitations to physical activity

• Use exercise test data to prescribe appropriate physical activity in cardiopulmonary rehabilitation programs

Physiology of Exercise

Strenuous exercise greatly increases the body’s requirements for oxygen delivery and carbon dioxide elimination. Close coupling between increased metabolic activity and cardiopulmonary function is necessary to supply adequate oxygen to exercising muscles and maintain a normal blood acid-base balance. This coupling is schematically represented in Figure 23-1.

Figure 23-1 Ventilatory-cardiovascular-metabolic coupling. The gas-exchange pathway is a highly integrated series of steps.

Normal exchange of O₂ and CO₂ between muscle cells and the air requires the following:¹ (1) efficient alveolar ventilation, (2) pulmonary blood flow matched to ventilation, (3) adequate blood hemoglobin content, (4) adequate cardiac pump function, (5) systemic blood flow matched to tissue requirements, and (6) ventilatory control mechanisms sensitive to arterial blood gas changes. These factors normally interact in a finely coordinated fashion, responding precisely to the metabolic needs of exercising muscle.

Normally, respiratory and cardiac reserve capacities are so large that only great physiological impairment reduces daily functioning ability. Exercise testing is clinically important because it stresses all physiological systems, revealing their capacity to respond. Respiratory and cardiac impairments produce characteristically different patterns of response to exercise, allowing cardiovascular and pulmonary limitations to be differentiated. The purpose of this chapter is to provide a physiological basis for evaluating exercise performance, not to provide a definitive guide for interpreting exercise test results.

Metabolism during Exercise

The source of energy for skeletal muscle contraction is adenosine triphosphate (ATP). The structure of the ATP molecule is symbolized as follows:²

Adenosine−PO3−∼PO3−∼PO3−

The bonds between the PO3− radicals, designated by the symbol ~, are high-energy phosphate bonds. The process of metabolism breaks these bonds, releasing the energy needed to form and break cross-bridges between the muscle’s actin and myosin myofibrils, as described in Chapter 17; in this way, muscle fibers shorten and generate force. During exercise conditions, each high-energy bond stores about 7300 calories (7.3 kcal) per mole of ATP molecules.² The hydrolysis of the first PO3− bond produces 7300 calories, generating adenosine diphosphate (ADP) in the process. Hydrolysis of the remaining PO3− bond yields yet another 7300 calories and creates adenosine monophosphate (AMP) for a total energy release of about 14.6 kcal/mol.²

ATP stores in skeletal muscle are extremely small and can sustain strenuous muscular activity for only about 3 seconds.² Therefore ATP molecules must be reconstituted continuously during exercise through aerobic (with oxygen) and anaerobic (without oxygen) metabolic processes.

The energy required for sustained exercise is derived from internal and external mechanisms.³ Internal mechanisms include anaerobic production of ATP, O₂ release from hemoglobin, and dissolved O₂ uptake from plasma and tissue fluids. External mechanisms involve the delivery of atmospheric O₂ molecules to the tissues. Atmospheric O₂ is relatively unimportant for power surges of a few seconds and the first few minutes of exercise. Internal mechanisms are crucial for initiating exercise because of the delay involved in transporting atmospheric O₂ to the tissues. As exercise continues, energy production becomes primarily dependent on the adequate delivery of atmospheric O₂ to the tissues. As exercise intensity reaches maximum limits, internal anaerobic sources of energy become increasingly important.

Aerobic Metabolism

Aerobic metabolism of carbohydrates (glucose), fats (fatty acids), and proteins (amino acids) provides the major energy source for ATP synthesis.² During exercise, stored glycogen in the muscles breaks down into glucose. Glucose breaks down into pyruvic acid, which reacts with O₂ in the cell’s mitochondria, forming ATP, CO₂, and water; thus the aerobic or oxidative process of ATP synthesis consumes O₂ and generates CO₂.

Aerobic metabolism of fatty acids also produces ATP molecules. For a given rate of ATP production, fat metabolism requires more O₂ than carbohydrate metabolism (Figure 23-2). This means carbohydrate metabolism uses O₂ more efficiently and requires less cardiovascular work per mole of ATP synthesis. However, fat metabolism generates less CO₂ per mole of ATP produced than carbohydrate metabolism (see Figure 23-2); in other words, fat metabolism requires less ventilatory work than carbohydrate metabolism in generating a given amount of energy.²

Figure 23-2 Aerobic and anaerobic metabolism. About midway between resting and maximal exercise, anaerobic metabolism supplements aerobic generation of ATP. HCO3− ions buffer anaerobically generated lactic acid; this lowers the HCO3− concentration, while generating CO₂. Aerobic metabolism generates ATP much more efficiently than anaerobic metabolism.

CONCEPT QUESTION 23-1

What is the theoretical benefit of a high-fat diet in patients with advanced chronic obstructive pulmonary disease (COPD)?

Anaerobic Metabolism and Lactic Acid Production

Anaerobic metabolic processes occur in the absence of O₂. An example of anaerobic metabolism is the breakdown of creatine phosphate (CP), which, similar to the ATP molecule, possesses a high-energy phosphate bond:

Creatine∼PO3−

The breakdown of this bond supplies the immediate energy for ATP resynthesis from ADP, as shown:

Creatine∼PO3−+ADP→creatine+ATP

However, this process produces only enough ATP to fuel muscle contraction for 8 to 10 seconds during heavy exercise.²

If the cardiovascular system does not supply enough O₂ for aerobic metabolism, glucose from muscle glycogen is metabolized in a process called anaerobic glycolysis. In this process, pyruvic acid is metabolized anaerobically into lactic acid and ATP (see Figure 23-2). The lactic acid subsequently diffuses into the interstitial fluid and blood, creating lactic acidosis, a form of metabolic acidosis. Increased blood lactic acid concentration indicates the presence of anaerobic metabolism, implying inadequate O₂ delivery to the tissues.

CONCEPT QUESTION 23-2

Why would a patient experiencing severe shock be likely to have increased blood levels of lactic acid?

Anaerobic Threshold

As exercise intensity increases, energy requirements gradually increase until aerobic metabolism alone can no longer meet the demand for ATP resynthesis. Consequently, the body must rely on anaerobic metabolism to generate additional ATP. The onset of anaerobic metabolism, the anaerobic threshold, normally occurs at about 50% to 65% of the body’s maximum oxygen consumption (V˙O₂max).³ Because fat cannot be metabolized anaerobically, less fat is used as exercise intensity increases.² The major energy sources at maximal exercise are aerobic and anaerobic glucose metabolism. For this reason, the body’s glucose stores limit exercise endurance. Sustained exercise such as marathon running may totally deplete glucose stores, explaining the reason some marathon runners suddenly fatigue or “hit the wall” after about 20 miles.

Figure 23-2 shows that aerobic metabolism produces ATP far more efficiently than anaerobic metabolism. In aerobic metabolism, one molecule of glucose produces 36 molecules of ATP compared with only two molecules of ATP in anaerobic glucose metabolism. In addition, anaerobic glucose metabolism generates two lactic acid molecules. Blood bicarbonate immediately buffers newly formed lactic acid, generating more CO₂, adding to the CO₂ already produced by aerobic metabolism (see Figure 23-2). This increased CO₂ production stimulates a proportional increase in ventilation.³

Respiratory Quotient and Respiratory Exchange Ratio

The respiratory quotient (RQ) is the ratio of CO₂ molecules produced to O₂ molecules consumed by the tissues (V˙CO2/V˙O2), as shown in Figure 23-1.² (In Figure 23-2, the RQ for glucose is about 1.0, whereas for fat, it is 0.71.) The fat RQ is lower because fat metabolism generates less CO₂ per ATP molecule than carbohydrate metabolism. At rest, the body metabolizes nearly equal amounts of fats and carbohydrates, yielding an RQ of about 0.85.² As exercise intensity increases, the RQ rises toward 1.0 as the metabolic substrate changes to glucose.

The respiratory exchange ratio (R) is the ratio between CO₂ elimination and O₂ uptake, measured from inhaled and exhaled gases at the mouth (see Figure 23-1).² In steady-state conditions, R equals RQ. The steady state is characterized by a CO₂ elimination rate that matches the CO₂ production rate; likewise, the lung’s O₂ uptake rate equals the tissue’s O₂ consumption rate in steady-state conditions. During short bursts of maximal exercise such as the 100-yard dash, RQ and R are different because tissue O₂ consumption and CO₂ production momentarily exceed the lung’s O₂ uptake and CO₂ elimination. Like RQ, R increases as exercise intensity increases; the onset of anaerobic metabolism further increases R as bicarbonate reacts with lactic acid and generates more CO₂

CONCEPT QUESTION 23-3

As exercise intensity increases, CO₂ production and alveolar ventilation increase steadily. Why does the rate of alveolar ventilation rise increase abruptly after anaerobic metabolism begins?

Exercise Testing Methods

Exercise tests in the laboratory involve treadmills or bicycle ergometers that provide the subject with graded exercise over a period of time. In a graded exercise test, the workload is progressively increased in a series of stages by increasing the treadmill speed (and its angle from the floor) or by increasing the

Clinical Focus 23-1 Arterial Carbon Dioxide Pressure during Exercise

In an exercise testing laboratory, a well-trained, long-distance runner undergoes an exercise test. At rest, she has a PaCO₂ of 40 mm Hg, R of 0.8, and minute ventilation of 6.5 L per minute. After 5 minutes of running on the treadmill, the following measurements are obtained:

V˙CO₂ = 960 mL/min

V˙O₂ = 1200 mL/min

Minute ventilation = 33 L/min

From these data, do you expect her PaCO₂ to be low, normal, or high?

Discussion

Because this athlete’s V˙E increased more than five times over the resting measurement, you may be inclined to predict a low PaCO₂. However, her R remained unchanged at 0.8, as the following calculation shows:

V˙CO2/V˙O2=960/1200=0.8

The increase in V˙E perfectly matched her increased metabolic CO₂ production and V˙O₂. Although her V˙E increased greatly, it was an appropriate increase, proportional to metabolic demands. In other words, this athlete was not hyperventilating, even at a V˙E of 33 L per minute. Therefore, her PaCO₂ is expected to remain unchanged. PaCO₂ remains remarkably constant in normal individuals during mild to moderate exercise.

bicycle’s pedal resistance. For example, the subject may exercise at a certain treadmill speed and angle for 3 minutes, after which the speed and angle are increased for the next 3 minutes, and so on. The subject exercises through a well-defined series of stages, each more difficult than the last, until maximum capacity is reached. During this time, a machine called a metabolic cart measures the inhaled and exhaled O₂ and CO₂ concentrations, tidal volume (V_T), respiratory rate, and minute ventilation.

To obtain these measurements, the subject breathes through a specially designed mouthpiece attached to the metabolic cart by large-bore tubes. Nose clips prevent breathing through the nose. The lips must be sealed tightly around the mouthpiece to prevent mixing of respiratory gases with atmospheric air. An electrocardiogram (ECG) machine measures the heart rate (HR) and ECG pattern during the exercise test. Depending on the data desired, various other physiological parameters may be measured. Table 23-1 lists physiological measurements grouped according to the invasiveness of the test and the monitoring equipment needed.

TABLE 23-1

Measurements during Graded Exercise Testing

Level of Rest	Measurements
Group 1	No mouthpiece
	Patient response and symptoms
	Heart rate
	Blood pressure
	ECG
	SaO₂ by oximetry
Group 2	Mouthpiece, oxygen, and carbon dioxide analyzer
	Respiratory rate
	Tidal volume
	Minute ventilation
	End-tidal gas measurements
	V˙O₂ and O₂ pulse
	V˙CO₂
	Respiratory exchange ratio
Group 3	Arterial line
	Blood gas values: PaO₂, PaCO₂, and pH
	HCO3− and lactate
	V_D/V_T
Group 4	Right-sided heart catheter
	Pulmonary artery pressures
	Cardiac output
	Mixed venous PO₂ and SO₂

ECG, Electrocardiogram; SaO₂, arterial oxygen saturation; V˙O₂, oxygen consumption per minute; O₂ pulse, oxygen consumption per heartbeat; V˙CO₂, carbon dioxide production per minute; PaO₂, arterial oxygen pressure; PaCO₂, arterial carbon dioxide pressure; pH, measure of blood H⁺ concentration; HCO₃^–, blood bicarbonate; V_D/V_T, dead space-to-tidal volume ratio; PO₂, oxygen pressure; SO₂, oxygen saturation.

Modified from Martin L: Pulmonary physiology in clinical practice: the essentials for patient care and evaluation, St Louis, 1987, Mosby.

Physiological Changes during Exercise

Oxygen Consumption, Cardiac Output, and Blood Pressure

Figure 23-3 represents the exercise performance of a normal person. V˙O₂ increases linearly with the work rate from rest to maximal exercise. The slope of V˙O₂ increase is about the same for all normal people; it is unaffected by training, age, or gender.¹ Because V˙O₂ depends primarily on the amount of work done by exercising muscle, V˙O₂ can be predicted from the work rate.^2,3

Figure 23-3 Breath-by-breath physiological changes during exercise from rest to maximal exertion in minute ventilation (V˙E), carbon output (V˙CO₂), oxygen uptake (V˙O₂), ventilatory equivalent for carbon dioxide (V˙E/V˙CO₂), ventilatory equivalent for oxygen (V˙E/V˙O₂), end-tidal PCO₂ (P_ETCO₂), end-tidal PO₂ (P_ETO₂), arterial blood lactate, bicarbonate, and pH. *BTPS,* Body temperature and pressure, saturated; *STPD,* standard temperature and pressure, dry. (From Mason RJ, et al, editors: *Textbook of respiratory medicine,* ed 4, St Louis, 2005, Saunders.)

As exercise intensifies, contracting muscles consume ever greater amounts of ATP, which means aerobic ATP regeneration requires an increasingly greater O₂ supply from the blood flow. Cardiac output rises to meet this demand by increasing stroke volume (SV) and heart rate. SV increases to its maximum value within the first half of the tolerable work rate range (at about 45% of the maximum V˙O₂).³ From that point on, SV remains fairly constant; the only way the heart can increase its output further is to increase its rate of contraction. The early increase in SV is the result of an increased ejection fraction rather than greater diastolic filling; sympathetic nervous stimulation and circulating epinephrine increase systolic ejection.³ Heart rate increases linearly with O₂ requirements until the maximum heart rate (HR_max) is achieved (Figure 23-4).

Figure 23-4 Changes in heart rate, systemic blood pressure, and SaO₂ during exercise from rest to maximal exertion. *AT,* Aerobic threshold. (From Martin L: *Pulmonary physiology in clinical practice: the essentials for patient care and evaluation,* St Louis, 1987, Mosby.)

As cardiac output increases with exercise, systolic blood pressure rises significantly (often ≥200 mm Hg). Diastolic pressure changes little, if at all, in normal, healthy people because the peripheral vasculature dilates significantly in response to increased O₂ demand, which greatly reduces vascular resistance.2,3 Thus, the pulse pressure (systolic – diastolic) increases significantly, forcing open all of the capillaries in working skeletal muscle. In heavy exercise, up to 80% of the cardiac output is diverted to skeletal muscle, making possible greatly increased O₂ delivery and V˙O₂ rates.

HR_max is age related and does not change with fitness. The predicted HR_max for adults is as follows:⁴

HRmax=220−Age(years)

HR_max, and thus, cardiac output are reduced in older persons because their hearts are less responsive to beta-adrenergic stimulation.⁴ An unconditioned person and a conditioned athlete of the same age have the same HR_max, but the conditioned athlete has a much greater SV and therefore a much higher cardiac output at HR_max. For a given amount of submaximal exercise, a conditioned person’s HR is much lower than the HR of a sedentary person. This explains why a sedentary person reaches the HR_max sooner and at much lower exercise intensity than an athlete. Because the unconditioned person’s cardiac output is lower at the HR_max, maximum O₂ delivery and V˙O₂ are also lower.

Carbon Dioxide Production, Respiratory Exchange Ratio, and Minute Ventilation

The increased metabolic activity of exercising muscles raises not only the V˙O₂ but also the V˙CO₂. Before the anaerobic threshold is reached, V˙CO₂ increases linearly and parallel with V˙O₂. Thus, R remains constant. The ventilation rate and depth rise to accommodate the increase in V˙CO₂, producing a linear increase in V˙E parallel with V˙CO₂ and V˙O₂ (see Figure 23-3, before anaerobic threshold).

Although it is generally accepted that increased V˙CO₂ during exercise is the stimulus for the higher V˙E, some evidence suggests that a neurally mediated, muscle-derived signal plays a role. Apparently, peripheral muscle receptors send signals to the central nervous system, increasing blood pressure, HR, and ventilation. These signals are enhanced by muscle ischemia but are not present in ischemia alone without exercise.⁵ Thus, muscle movement appears to be partly responsible for the increased V˙E of exercise.

The ventilatory response to exercise was discussed in Chapter 11. The immediate hyperpnea of exercise has long been a controversial subject and remains incompletely understood.³ The abrupt increase in V˙E at the onset of exercise (phase I) occurs long before any chemical or humoral change can occur in the body. Rather than being geared to a chemoreceptor reflex mechanism, the abrupt increase in ventilation appears to be a response to anticipated future metabolic demand. Evidence points to a sophisticated internal respiratory controller that integrates multiple afferent and efferent signals to predict the level of metabolic activity that will occur and then adjusts ventilation before the fact.⁶ A study of children with congenital central hypoventilation syndrome revealed that passive leg motion induced by a motor-driven ergocycle increased V˙E, although these children had no V˙E response to inhaled CO₂.⁷ Increased V˙E occurred immediately with the first breath after the onset of pedaling motion in children with congenital central hypoventilation syndrome and normal controls. This study supports the idea that muscle or joint receptors play a role in exercise hyperpnea.

Normal people increase V˙E by increasing both V_T and respiratory rate. Early in exercise, a higher V_T produces most of the increase in V˙E. After about 60% to 70% of the vital capacity is reached, V_T plateaus, and increased respiratory rate is responsible for additional V˙E increases.⁸

Figure 23-5 shows that dead space-to-tidal volume ratio (V_D/V_T) decreases as exercise progresses. The initial steep reduction in V_D/V_T reflects early increases in V_T with respect to the fixed anatomical dead space. V_D/V_T decreases from normal values of 0.3 to 0.4 at rest to 0.15 to 0.2 in exercise, in part due to a larger V_T but also because of significant blood flow diversion to previously underperfused upper lung zones.^3,8 As the respiratory rate begins to account for more of the increase in V˙E, the decline in V_D/V_T is less steep.

Figure 23-5 Changes in arterial blood gases, blood lactate, and V_D/V_T ratio during exercise from rest to maximal exertion. (From Martin L: *Pulmonary physiology in clinical practice: the essentials for patient care and evaluation,* St Louis, 1987, Mosby.)

Events Occurring after Anaerobic Threshold

As shown in Figure 23-3, the anaerobic threshold is the point at which the V˙CO₂ slope becomes steeper than the V˙O₂ slope, indicating an increase in CO₂ generation rate. This increase in CO₂ generation is due to the bicarbonate buffering of anaerobically produced lactic acid.^3,4 The increased generation of CO₂ stimulates ventilation, and the V˙E slope rises in parallel with the V˙CO₂ slope, maintaining a constant PaCO₂. In the end, the amount of CO₂ exhaled per minute increases with respect to the amount of O₂ taken up by the lungs, and R increases. The new V˙E slope has two phases. For some time, immediately after an aerobic threshold (AT) appears, the V˙E slope rises to match the increased V˙CO₂ slope. This short phase is referred to as isocapnic buffering, in which ventilation increases in concert with CO₂, momentarily compensating for the evolving lactic acidosis (see Figure 23-3).