University of Sydney, NSW 2006, Australia
* Corresponding author. Tel: +61 235 14579; fax: +61 235 16645. E-mail address: ajscoats{at}aol.com
This editorial refers to Exercise ventilation inefficiency and cardiovascular mortality in heart failure: the critical independent prognostic value of the arterial CO2 partial pressure
by M. Guazzi et al., on page 472
Chronic heart failure is a common condition with a poor prognosis. Major treatment advances have been achieved utilizing three main drug classes: the angiotensin-converting enzyme inhibitors (and the similarly acting angiotensin receptor antagonists), beta-blockers, and aldosterone antagonists. Despite our increased knowledge of the pathophysiology of the condition, the generation of symptoms and the causes of exercise intolerance remain confusing. Establishing accurate risk stratification has also proved difficult. While a logical measure such as left ventricular ejection fraction,1 reflecting as it does damage to the pumping action of the heart, remains a powerful predictor of mortality, other factors such as plasma norepinephrine2 are, through the combination of reflecting the severity of heart failure and by having a direct deleterious effect. These markers are, however, less accurate in predicting the objective exercise limitation. More recently, interest has turned to markers of increased risk, such as BNP levels, which are not, in themselves, thought to cause harm.3 Other measures which directly estimate exercise intolerance, such as peak oxygen uptake on progressive cardiopulmonary exercise testing, both document the exercise intolerance and are themselves predictive of mortality risk.
Other parameters that can be measured during a cardiopulmonary exercise test have also been shown to help our understanding of both mortality risk and the causes and extent of exercise intolerance. One of the most powerful of these has been an estimate of the ventilatory response to exercise, measured variously as the slope of the relationship between the rise in ventilation and the rate of carbon dioxide elimination (VE/VCO2 slope), a similar expression for ventilation when compared with oxygen consumption (VE/VO2) or other measures of maximal or submaximal ventilatory control. There has been confusion and controversy as to the extent to which abnormalities in dead space ventilation4 or abnormal ventilatory control mechanisms explain the increased VE/VCO2 slope in heart failure patients5,6 with convincing evidence presented for both. Either can cause a high VE/VCO2 slope. At the two extremes, there could be an abnormal dead space fraction which requires an increased minute ventilation to excrete the same volume of CO2 and therefore maintain CO2 pressures in the arterial blood, or an exaggerated or abnormal drive to ventilation which causes relative hyperventilation, thereby reducing arterial CO2 during exercise. The most obvious example of the latter is premature metabolic acidosis inducing ventilatory compensation, but can also include abnormally sensitive ventilatory control reflexes, mediated by both chemoreceptors and muscle ergoreceptors. The relative contribution of the two mechanisms has remained uncertain because several reports have shown that, on average, heart failure patients maintain normal or slightly reduced arterial CO2 tensions during exercise and that the degree of hypocapnia, where it does occur, is not related to measure of haemodynamic severity of heart failure. In contrast, other reports have demonstrated significant exercise hypocapnia in many patients and particularly in those with an exaggerated ventilatory response. Recently, we attempted to evaluate the relative contribution of these two mechanisms by measuring both arterial CO2 control during exercise and the influence of dead space ventilation on the VE/VCO2 slope.7 Both mechanisms appear to operate in mediating the exaggerated ventilatory response. Guazzi and colleagues8,9 have gone one step further and investigated the relative contributions of the two mechanisms in contributing to the prognostic impact of the VE/VCO2 slope, reasoning that understanding which mechanism is more closely related to prognosis may help explain the mechanism behind the adverse prognostic impact of the heightened ventilatory response. In an elegant study, they demonstrated that although both increased dead space ventilation and relative hyperventilation (evidenced by exercise-induced hypocapnia) are associated with increased mortality, it is the latter which more accurately predicts mortality and which carries the majority of the prognostic impact of the increased VE/VCO2 slope. These two recent studies put to rest the controversy in demonstrating that both mechanisms are important, in that both carry a prognostic value.
Further study of how lung function abnormalities and the heightened ventilatory control systems cause impaired survival should be our next target. For the latter, we are already well under way, for we know that increased chemosensitivity is in itself a powerful adverse prognostic marker,10 even when exercise tolerance is relatively preserved. Furthermore, we know that both the candidate reflex systems which are overactive (the chemoreflexes and the ergoreflexes) and which have been shown to contribute to the heightened ventilatory response are major sympatho-excitatory reflexes, giving a plausible mechanism whereby they could directly cause increased mortality. Of course, there may be more mechanisms in operation, such as the fact that increased central norepinephrine and angiotensin II can directly increase chemosensitivity, thereby helping to explain the adverse prognostic associations of chemoreflex hypersensitivity. Whatever the cause, further exploration of treatments designed to reduce this abnormal ventilatory drive, in an effort to reduce both the adverse symptomatic effect of abnormal ventilatory control and even perhaps reduce the sympathetic drive and mortality, may be a tantalizing novel therapeutic target.
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