Clinical relevance of autonomic nervous system disturbances in pulmonary arterial hypertension

To the Editors:

We read with great interest the editorial by Naeije and van de Borne 1 on clinical relevance of autonomic nervous system disturbances in pulmonary arterial hypertension. This editorial applies to the study of Wensel et al. 2 investigating heart rate variability and baroreflex sensitivity in patients with severe pulmonary arterial hypertension (PAH).

In their editorial, R. Naeije and P. van de Borne discuss the cause of exercise hyperventilation in PAH, as well as in patients with congestive heart failure, and attribute it mainly to an increased chemosensitivity on the basis of some previous inert gases studies. In fact, three factors determine the ventilatory response to exercise, 1) the CO₂ production, 2) the ratio of physiological dead space (V_D) to tidal volume (V_T), V_D/V_T, 3) the arterial CO₂ tension or set point. By analysing each factor in quantitative terms, it is possible to determine the role of each in the high ventilatory response observed in patients during exercise without the help of a costly technique.

Computing V_D/V_T needs to measure arterial carbon dioxide tension (P_a,CO2). Using end tidal carbon dioxide tension (P_ET,CO2) as a substitute to P_a,CO2 may be misleading in patients. Indeed, whereas P_ET,CO2 is a few mmHg higher than P_a,CO2 at maximum exercise in normal subjects, P_a,CO2 becomes higher than P_ET,CO2 in patients with low perfusion in well ventilated areas of the lungs. Increase in both V_D/V_T and P_(a-ET),CO2 in proportion to the degree of exercise limitation has been previously shown in patients with chronic heart failure 3. The ventilatory response relative to CO₂ production increases when metabolic H⁺ production stimulates the carotid bodies to prevent lowering of pH, lowering therefore the P_a,CO2. In patients with low cardiac output, anaerobic threshold and excess H⁺ production occurs at a lower oxygen uptake (V'_O2) than in normal subjects. Patients with chronic heart failure have at maximal exercise not only higher V_D/V_T than healthy subject of similar age and sex but also higher carbon dioxide production relative to V'_O2. On the basis of arterial blood gases and gas exchange measured breath by breath, Wasserman et al. 3 attribute the excessive exercise ventilation in heart failure patients not only to an increase in V_D/V_T but also to regulation of arterial pH by the decrease in P_a,CO2. Arterial pH remains close to 7.4 at maximal exercise in the more limited heart failure patients whereas it remains above 7.3 in normal subjects.

It is likely that mechanisms similar to those observed in patients with chronic heart failure explain excessive ventilation during exercise in PAH. Without the help of arterial blood gases measurement during exercise showing overcompensation of metabolic acidosis, increased chemosensitivity as an explanation to the increased ventilation during exercise remains very speculative.

In the paper of Wensel et al. 2, baroreflex sensitivity in patients with pulmonary arterial hypertension was inferred from the slope of the relationship between systolic blood pressure and the heart beat interval to follow spontaneous blood pressure variations. In fact, these authors only analysed baroreceptor control of heart rate. This study by no means proves that the activating afferent baroreceptor input to vagal and sympathetic cardiomotor neurones is impaired. Moreover, variations of systolic blood pressure were spontaneous and therefore only small changes were observed and related to changes in heart rate. Heart rate is dominated by the activity of the cardioinhibitory parasympathetic nervous system and in humans there is tonic level of parasympathetic cardiac nerve firing and little if any sympathetic activity to the heart at rest 4. Investigating baroreflex needs testing through the full pressure range. Although we agree that this could be dangerous and unrealistic in patients with severe PAH, results with larger variations of pressure exploring the response to both activation and deactivation of baroreceptors by vasopressor drugs or application of neck pressure or suction could have been different. In animals and humans, it has been shown that the decrease in heart rate in response to a vasopressor drug is mediated by vagal efferents since it remains unchanged after cardiac sympathetic blockade. Only the tachycardia induced by nitroglycerine is attenuated by sympathetic blockade and therefore partly related to sympathetic efferents 4. Moreover dissociation between baroreflex control of microneurographic sympathetic activation and heart rate as previously shown in hypertensive patients cannot be ruled out 5. From the study of Wensel et al. 2, it can only be concluded that PAH is associated with decreased heart rate variability. Further studies are needed to test if it relates to decrease of the vagal tone and carries a prognostic value similar to what has been observed in heart failure and post-myocardial infarction patients.

Statement of interest

A statement of interest for B. Raffestin can be found at www.erj.ersjournals.com/misc/statements.dtl