Left ventricular perfusion occurs only during diastole because during systole the left coronary vessels are compressed by the surrounding cardiac muscle (see Chapter 2, p. 6). By contrast, since right ventricular pressure does not normally rise above 25 mmHg, the coronary vasculature supplying the right ventricle is not compressed at any stage of the cardiac cycle and coronary flow is continuous. The increased efficiency of coronary oxygen delivery is reflected in a lower density of coronary blood vessels in the right heart. However, this design feature has potentially disadvantageous results if left atrial pressure becomes chronically elevated and right ventricular pressure rises in response to this higher afterload.

Under these circumstances, right coronary perfusion during systole becomes progressively reduced and the metabolic demands of the right-side cardiac muscle cells are less efficiently serviced. Over time, the right ventricle will respond to the high afterload by muscle hypertrophy. This will exaggerate the coronary insufficiency, both by providing greater metabolic demand for oxygen delivery and by producing more coronary compression. As a result, chronic hypoxic damage to the muscle of the right heart, with an inability to increase contraction appropriately in response to increased filling (right cardiac failure) is a common long-term effect of elevated pulmonary blood pressure (see Chapter 12, p. 148).

REGIONAL MATCHING OF VENTILATION AND PERFUSION

Vertical variations

In a resting, upright individual, dramatic differences in both respiratory ventilation and pulmonary perfusion exist along the vertical axis of the lung. Resting inspiration is due to elevation of the ribs and lowering of the diaphragm, but the shape of the ribcage means that the increase in thoracic volume that occurs becomes progressively more pronounced towards the lung bases. The fact that the lung apices are around 10 cm higher than the heart means that the vessels there are perfused only when pulmonary arterial pressure exceeds this value (10 cm H₂O = 14 mmHg). Thus, there is only intermittent apical perfusion, especially during expiration when intra-thoracic pressure rises and compresses the capillaries. By contrast, the lung bases are gravitationally lower than the heart; therefore, the perfusion pressure for vessels in this region is several mmHg higher than that at heart level and perfusion is correspondingly greater.

Although both ventilation and perfusion rise towards the base of the lungs, the gravitational effect on regional blood flow is rather more powerful than the vertical variation in ventilation, with the result that the ratio of ventilation to perfusion is around 3 at the apices and around 0.5 at the bases. Exact matching of the two is achieved only over a relatively narrow region of lung corresponding to about the mid-sternal level (Fig. 8.1).

Figure 8.1 Ventilation/perfusion () ratio variation in the vertical lung. At rest, optimal matching ( = 1.0) occurs only over a relatively narrow region around the mid-sternal area.

Effects of intrapulmonary gas tensions

At rest, when tidal volume is around 400–600 ml, the lung does not expand sufficiently during inspiration to allow ventilation of all alveoli. Those at the end of the longest airways with greatest resistance and those that are subjected to the greatest external tissue forces receive little if any fresh air, so that the air within these regions accumulates carbon dioxide and becomes progressively depleted of oxygen. In terms of matching, it is clearly more efficient if the pulmonary blood flow bypasses these alveoli and is directed entirely to regions in which the concentration gradients for gas exchange are optimal.

To fulfil this purpose, hypoxia sensors exist within the pulmonary arteriolar walls that monitor the oxygen concentration in adjacent alveoli (the P_AO₂). We have seen previously that this receptor type is found in systemic arterioles, where it mediates a hyperpolarizing vasodilator response to hypoxia (Chapter 6, p. 68). In pulmonary arterioles, by contrast, hypoxia receptor activation causes muscle cell depolarization and vasoconstriction. The subcellular mechanisms that transduce this process are still the subject of debate; oxygen-sensitive potassium channels appear to be involved, but evidence exists also for release of some endothelium-derived vasoactive factor (Moudgil et al 2005). The terminal airways also possess receptors that detect locally inefficient ventilation – mainly by recognizing carbon dioxide build-up rather than oxygen depletion – and this dilates the airways and so helps re-oxygenate the under-ventilated alveoli. The interaction of arteriolar receptors for hypoxia and airway receptors for hypercapnia means that the regions of poor perfusion do not remain constant but oscillate in response to the oscillations in regional ventilation.

When hypoxic vasoconstriction affects small regions of the lung during normal air breathing, it helps optimize the efficiency of gas exchange. If, however, one were to breathe air that contained less oxygen than usual, then there would be widespread vasoconstriction and an increase in total pulmonary vascular resistance that would increase right heart workload. We shall look at this situation further when we examine the circulatory effects of high altitude in Chapter 12 (p. 143).

CHANGES IN PULMONARY EFFICIENCY WITH EXERCISE

Even at peak workloads, pulmonary gas exchange is usually unimpaired and arterial oxygen saturation remains unchanged from rest. One factor in this maintenance of optimal gas exchange is that, with a normal resting cardiac output, equilibrium between alveolar air and plasma is reached about one-third of the way along a typical pulmonary capillary. Thus, full oxygen saturation of blood can be maintained when cardiac output rises around threefold without any additional adjustments being needed. At higher work intensities, additional mechanisms must be employed to maintain gas exchange. These involve increasing the efficiency of matching between perfusion and ventilation.

The increased respiratory drive that automatically accompanies motor cortex activation increases minute ventilation proportionately to exercise intensity. This both expands regions of the lung that are partially collapsed at rest, removing external compression of the microcirculatory vessels, and causes pulmonary arteriolar dilation due to elevation of P_AO₂ in these areas.

In addition, the increased depth of breathing results in greater intrathoracic negative pressure during inspiration, which increases right atrial filling, right stroke volume and pulmonary arterial pressure. This produces more efficient perfusion of lung areas that are gravitationally above the heart. Collectively, these factors transform the variable regional relationship to one that is virtually independent of vertical position (Fig. 8.2). In addition, distribution of blood flow over a greater number of pulmonary capillaries reduces the velocity of flow through each of these and so increases the time for oxygen loading.

Figure 8.2 Ventilation/perfusion ratio variation in the vertical lung during intense whole-body exercise. Note that now, by contrast with the situation at rest, there is optimal matching throughout the lung.

Figure 8.3 adds the contributions of pulmonary circulation and lungs to our flow chart of the exercise response.

Figure 8.3 Expansion of Figure 7.3, with the factors discussed in this chapter denoted in red.

Although the processes outlined above are able in most individuals to preserve optimal uptake of oxygen, even at the highest work intensities, there is one population in whom pulmonary gas exchange does limit work capacity under normoxic conditions. In a proportion of elite athletes with work capacities of the order of 70 ml O₂/min/kg, arterial oxygen saturation falls from the normal of 96–97% to as low as around 90% at peak exercise (Stewart & Pickering 2006). It appears that these individuals generate cardiac outputs during exercise which are so high that, even with optimal matching, there is not enough time for equilibration of oxygen between alveolar air and bloodstream. In addition, they can be predicted to be relatively more susceptible to any circumstances that limit inspired oxygen levels, such as those associated with ascent to high altitude (see Chapter 12, p. 144). Some sports scientists have made the case that these athletes should be classified as having an abnormal arterial oxygenation response to exercise. A more realistic interpretation would be that they simply have an extremely efficient cardiovascular response.

Case history

Robert A, a 42-year-old, non-obese man (76 kg) sought advice on an exercise training programme because he habitually became out of breath during quite moderate exertion. He thought that this might be due to lack of fitness. He had no history of major illness and appeared normal at rest, with no signs of breathlessness or cyanosis. At rest, resting heart rate was 74 beats/min and blood pressure 124/86 mmHg. Vital capacity was 4.8 l, tidal volume 750 ml, respiratory frequency 14 breaths/min. An attempt was made to measure his resting cardiac output by CO₂ Fick; end-expiratory PCO₂ was 26 mmHg and systemic venous CO₂ (PvCO₂) as measured by CO₂ rebreathing was 47 mmHg. Since this combination of values gave a calculated cardiac output far outside the normal range, a nitrous oxide rebreathing technique was used instead and gave a cardiac output of 5.6 l/min. Measurement of arterial oxygenation using a transcutaneous pulse oximeter on the earlobe showed saturation of 87% when breathing room air and 100% when breathing pure oxygen.

Discussion

This case provides an opportunity for detailed reasoning about the coordination of respiratory function and the pulmonary circulation. First and most basically, Robert’s arterial oxygen saturation was far lower than the 97–98% expected. This is likely to explain his low exercise tolerance, but what was the underlying reason? There was no obvious indication of abnormal cardiovascular or respiratory function. However, one dramatically abnormal set of data existed – while PvCO₂ was normal at 47 mmHg, end-expiratory CO₂, which should be identical to arterial CO₂ (PaCO₂) and, therefore, around 6 mmHg lower (41 mmHg), was in fact over 20 mmHg lower. This large blood–air difference could occur only if CO₂ was being expired more rapidly than normal by hyperventilation. Comparison of ventilatory and cardiovascular flows confirms this. Cardiac output was 5.6 l/min and, with a normal ratio of 1.0, minute ventilation would be expected to be similar in magnitude. In fact, however, minute ventilation was (0.75.14) or 10.5 l/min.

This degree of hyperventilation might be expected as a result of peripheral chemoreceptor activation, since Robert’s arterial oxygen saturation of 87% equates to a PaO₂ of around 60 mmHg – but what was the cause of the poor oxygenation? It could be because a proportion of the pulmonary vasculature was not perfused and the entire right cardiac output supplied a reduced volume of lung. This would increase the velocity of capillary blood flow and so reduce the time available for oxygen uptake. Alternatively, a proportion of the alveoli might not be ventilated, so that blood passing through some pulmonary capillaries remained unoxygenated. These possibilities can be distinguished by breathing pure oxygen. If the limitation is time for oxygen uptake, then this would be overcome by increasing the diffusional concentration gradient. On the other hand, dilution of normal arterial blood by deoxygenated blood returning from unventilated lung would persist regardless of efficiency of oxygen uptake in the remaining areas. In Robert’s case, the data clearly indicated presence of an unperfused area of lung.

Subsequent radiological investigation showed that he had a long-standing thrombus lodged in his left pulmonary artery, so that his entire cardiac output was routed through the right half of his lung. With this knowledge it is easy to see why Robert’s resting minute ventilation was around twice normal – he had to inspire twice as much as normal in order to provide adequate blood oxygenation. It is also clear why he became breathless during exercise. The need to move twice as much air as normal in and out of the lungs would cause respiratory muscle fatigue at lower levels of exercise. As well, routing all of the right cardiac output through only half of the pulmonary capillaries increases capillary transit speed and so lowers the safety margin for equilibration of oxygen between air and plasma when cardiac output rises with exercise. If PaO₂ falls far enough to activate hypoxia receptors, then there will be further respiratory muscle fatigue.

PRACTICAL CONSEQUENCES OF LOW PULMONARY ARTERIAL PRESSURE

In addition to the functional considerations that we have examined in the previous sections of this chapter, the fact that pulmonary pressures and resistance are so much lower than those in the systemic circulation has two practical implications for the experimental physiologist.

Kinetic pressure

In Chapter 3 (p. 28), we saw that intravascular pressures measured in the moving bloodstream can have a component that is due to the kinetic energy of fluid movement, depending on the orientation of the catheter tip. The value of this kinetic pressure is around 5 mmHg at rest, which is only a minor contribution to the total pressure in the systemic circulation. It is, on the other hand, a substantial proportion of pulmonary arterial pressure and very different values for pulmonary blood pressure would be recorded if a catheter had an end-opening or a side-opening tip. Remember also that the magnitude of the kinetic pressure component rises dramatically as cardiac output rises. If one is interpreting data on pulmonary pressures, especially during exercise, it is, therefore, important to know which catheter type was used, and it is equally important for the catheter type to be standardized between experiments where one wishes to compare pulmonary pressures.

Pulmonary wedge pressure

If a pressure-sensing catheter with an open tip is introduced into the pulmonary artery through the right heart, it can be advanced down the arterial tree until it is wedged in one of the small arteries. Under these circumstances the catheter tip is sealed off from the arterial pressure upstream and the pressure recorded is that in the vessels downstream. But there is hardly any vascular resistance between the recording site and the final entry of pulmonary veins into the left atrium, so the pressure measured actually approximates left atrial pressure.

Recording of this so-called wedge pressure is the only practicable way in which mechanical function in the left heart can be measured, because it is not technically possible to pass a catheter retrogradely up the aorta and back into the heart. In practice, the catheter used for recording wedge pressure (called a Swann-Ganz catheter) has a small balloon just behind the tip that can be inflated so as to guarantee that the wedged tip is isolated from the pressure upstream (Fig. 8.4).

Figure 8.4 Recording of pulmonary intravascular pressure using a Swann-Ganz catheter. Initially, pulmonary arterial pressure was recorded as 20/10 mmHg. At the arrow, the catheter balloon was inflated, sealing off the pressure-sensing catheter tip from the arterial inflow. Note the cessation of arterial pulsation and its replacement by typical atrial pulse waves with an absolute mean pressure around 4 mmHg.

IMPLICATIONS OF DEVELOPMENTAL CHANGES IN PULMONARY PERFUSION

Before birth, all foetal gas exchange takes place in the placenta where foetal venous and maternal arterial bloodstreams are separated only by thin membranes. As well, the foetal lungs are filled with relatively hypoxic amniotic fluid, so that the pulmonary microcirculation is compressed externally and is also constricted by activation of airways hypoxia receptors. At this time, therefore, the pulmonary circulation not only has no functional role, but also is a site of much higher vascular resistance than is the situation after birth. This creates higher systolic pressures in the fetal right atrium and ventricle, and pulmonary arteries than those in the corresponding parts of the left circulation. To prevent massive overwork of the right-side myocardium, most of the right cardiac output has to be short-circuited around the pulmonary circuit.

The shunting takes place in two ways (Moore 2003). The embryonic heart has only one atrium and one ventricle, which by around 8 weeks’ gestation has been partitioned into left and right sides by formation of intervening walls. The inter-atrial wall grows from both upper and lower extremities of the common atrium, with the two leaves overlapping each other but not fusing. This forms a valve (called the foramen ovale) by which a proportion of the venous blood returning to the right atrium can flow directly into the left atrium. The second shunting pathway is a short, muscular blood vessel that runs between the aortic arch and the pulmonary artery and is known as the ductus arteriosus. This vessel is maintained in a dilated state during fetal life by cells in its wall synthesizing large amounts of relaxant prostaglandins. In consequence, all of the relatively small right stroke volume of blood that was not shunted through the foramen ovale flows from pulmonary artery to aorta, bypassing the pulmonary microcirculation.

At birth, both of these shunts cease to function as a result of the baby beginning to breathe. Expansion of the lungs with air removes both the compressive forces and the effect of hypoxia receptor stimulation. The consequent reduction in pulmonary vascular resistance reverses the pressure gradients between the atria, sealing the foramen ovale, and across the ductus arteriosus, which now carries oxygenated blood from aorta to pulmonary artery. Because the process of prostaglandin synthesis that held the ductus open before birth is efficient only in a hypoxic environment, perfusion by oxygenated blood causes ductus closure and terminates the shunt.

Over the next few days after birth, both shunts normally become sealed permanently by growth of new tissue. Nonetheless, this is not absolute in a surprisingly high percentage of the population. The foramen ovale does not seal completely in up to 30% of individuals and, in a much smaller percentage of people, the ductus arteriosus fails to close completely. The residual hole is usually small and may not have any noticeable effect on cardiorespiratory efficiency. Lack of symptoms is particularly likely in the case of the foramen ovale because left atrial pressure is usually higher than that in the right atrium so the shunt is normally held shut. However, if pulmonary vascular resistance rises then there is the potential for right–left shunting and reduced pulmonary perfusion.

With any persistent ductus arteriosus and with some cases of persistent foramen ovale, there is chronic left–right shunting resulting in right heart overload. Intense exercise may not be advisable in such individuals and will certainly not be associated with entirely normal cardiorespiratory responses to exercise. The presence of these abnormalities is very likely to cause systolic murmurs and so, even though they are rare, checking for murmurs is a sensible safeguard in any naïve subject being admitted to an exercise study. The Case History in Chapter 12 (p. 151) returns to this theme.

Key points

The low pulmonary resistance is responsible for several important properties of the right-side circulation. While these save metabolic energy under normal circumstances they can result in inefficient cardiorespiratory function if pulmonary resistance is increased.

At rest, the matching of ventilation and perfusion varies dramatically in different regions of the lung.

With increasing intensity of aerobic exercise this variation progressively disappears.

Shunting between right- and left-side circulations is an essential feature of the foetal circulation and persistence of these after birth is relatively common, and may interfere with exercise capacity.

References

Moore KL, Persaud TVN. Before we are born, 6th edn, Saunders: Philadelphia, 2003. Chapter 15

Moudgil R, Michelakis ED, Archer SL. Hypoxic pulmonary vasoconstriction. Journal of Applied Physiology. 2005;98:390-403.