Dyspnoea is the cardinal manifestation of heart failure and remains its most perplexing feature. Those afflicted with chronic heart failure typically report both symptoms of dyspnoea and exercise intolerance, but does dyspnoea actually limit activities of daily living? It is maddeningly difficult to know if patients with heart failure stop exercising because they are short of breath or because they are limited for some other reason and incidentally report dyspnoea as an accompanying symptom. Although it may seem obvious that dyspnoea impairs quality of life in heart failure, it is time to question the obvious.
Our thinking about dyspnoea in heart failure has long been heavily influenced by observations in patients with acute heart failure, particularly those who present with acute pulmonary oedema. This syndrome is characterized by abrupt and marked increases in cardiac filling and pulmonary venous pressures, which are accompanied by overwhelming dyspnoea at rest. Classically, patients exhibited pink frothy sputum upon coughing, the result of the transudation of fluid from the pulmonary capillaries into the alveoli. The presentation was so dramatic that it seemed reasonable to surmise that oxygen transport was impaired, and that the resulting hypoxaemia was responsible for the sensation of dyspnoea.
However, most patients with acute heart failure following myocardial injury are not hypoxaemic, even though they are generally dyspnoeic. Furthermore, acute interventions may lead to relief of dyspnoea, but without any improvement in alveolar fluid, pulmonary rales, or oxygenation. Interestingly, when bedside cardiology was in its heyday, the most reliable objective finding that presaged the relief of dyspnoea in patients with acute pulmonary oedema was not measures of respiratory rate, blood oxygenation, or pulmonary function, but rather the cessation of diaphoresis. Dyspnoea was relieved when sympathetic drive dissipated, even though pulmonary function had not changed.
Understanding dyspnoea became more difficult when we tried to decipher the genesis of the symptom in patients with chronic heart failure. An obvious explanation for dyspnoea in these individuals was that an increase in pulmonary venous pressures led to congestion-mediated changes in pulmonary compliance, alterations in alveolar fluid content, and impaired alveolar gas diffusion. Yet, many patients with chronic heart failure had markedly increased left ventricular filling pressures at rest (pulmonary wedge pressures >30 mmHg), but they did not complain of dyspnoea and did not exhibit tachypnoea, possibly because alveolar fluid transudation was prevented by heightened pulmonary lymphatic drainage. Additionally, in certain patients (i.e. those with mitral stenosis), the increase in pulmonary vascular resistance that accompanied progression of the disease led to a decrease in pulmonary blood flow and lessening of dyspnoea. As pulmonary artery pressures rose, exercise tolerance worsened, but patients often noted that dyspnoea was no longer a troublesome symptom and that fatigue had become the primary symptom that limited activities of daily living. Accordingly, an enhancement of transpulmonary blood flow could precipitate a rush of blood volume into the lungs, resulting in pulmonary oedema. These studies pointed to a role for pulmonary blood flow in the genesis of dyspnoea.
Subsequent efforts to understand dyspnoea relied on cardiopulmonary exercise testing with simultaneous measurements of gas exchange and invasive assessments of cardiac pressures and blood flows. Studies of patients with chronic heart failure and left ventricular systolic dysfunction concluded that pulmonary venous congestion was not a critical factor in the genesis of dyspnoea. Patients with chronic heart failure experienced an excessive ventilatory response to CO2, but this was not related to exercise-induced increases in pulmonary venous pressures and could not be alleviated by pulmonary venous decongestion.[6,7] Instead, the studies suggested a role for a low cardiac output as a mechanism for dyspnoea, based on the belief that a decrease in cardiac output (leading to poor pulmonary perfusion and ventilation–perfusion mismatching) might cause exercise-induced tachypnoea.[8,9] This hypothesis, however, did not explain why many patients with heart failure had substantial effort-induced symptoms but normal cardiac output responses to exercise.
Later studies proposed that the excessive ventilatory response to exercise in patients with chronic heart failure and systolic dysfunction might be related to increases in pulmonary vascular resistance and impairment of right ventricular systolic function. However, pulmonary vascular resistance typically declines with the onset of exercise (as vascular beds in pulmonary segments are recruited), although the respiratory rate increases. Importantly, the calculation of pulmonary vascular resistance assumes linearity in a system that is inherently non-linear. The pathophysiological basis of 'pulmonary vascular resistance' is poorly understood; its existence is related to transient shifts in vascular tone and capacitance rather than to structural changes in small pulmonary vessels.
Consequently, recent studies of exertional dyspnoea have ignored the dynamics of the central circulation entirely, and instead have postulated the existence of a heightened 'ergoreflex', based on the premise that peripheral chemoreceptors in muscle register local metabolic by-products during exercise and initiate a neural reflex that drives hyperventilation.[12,13] Such a hypothesis explains why everyone (including those without heart failure) experiences exertional dyspnoea; healthy people experience the sensation at much higher workloads than those with heart failure. Yet, in healthy people, exertional dyspnoea is not related to central congestion, abnormalities in gas exchange, or haemodynamic derangements. Therefore, exertional dyspnoea in heart failure might simply be related to an exaggerated ergoreflex, potentially triggered by a reduction in skeletal muscle mass. According to this hypothesis, changes in cardiac filling pressures during exercise may be a clinically unimportant epiphenomenon, which are associated with (but do not cause) exercise-induced hyperventilation.
The study by Obokata et al. in the present issue of the European Heart Journal adds to the current morass of conflicting perspectives about the factors that limit exercise capacity in chronic heart failure. In an elegant series of carefully executed measurements, the investigators report the first observations of gas exchange measurements and exercise haemodynamics in patients with chronic heart failure associated with a preserved ejection fraction (HFpEF).
As expected, the patients studied by Obokata et al. exhibited rapid shallow breathing on exercise, as pulmonary wedge pressures increased. The increase in exercise pulmonary wedge pressures correlated with maximal exercise capacity and ventilatory abnormalities when the analysis included the data from patients with HFpEF together with those of controls without cardiac dyspnoea. However, this is exactly what we might expect if both controls and patients are plotted on the same graphs. If controls are included in the analysis, any abnormalities that are unique to HFpEF would appear to be related to impaired exercise tolerance or ventilatory abnormalities (even if they are not), since patients with non-cardiac dyspnoea do not have these derangements. To understand whether these exercise abnormalities are truly important in HFpEF, we must look only at the strength of the relationships among those with HFpEF. Yet, in the HFpEF patients studied by Obokata et al., the relationships between exercise haemodynamics and ventilatory abnormalities are unimpressive. The correlation coefficients are quite modest and often seem to be influenced by a few outlier measurements (see figure 1C and D of their paper).
The observations by Obokata et al. extend our knowledge about exercise haemodynamics and ventilatory abnormalities to patients with HFpEF. Yet, their findings do not shed light on the pathogenesis of dyspnoea in patients with chronic heart failure. Instead, the scattered nature of their reported associations indicates that there are critical determinants of dyspnoea in patients with chronic heart failure that they did not assess. These are likely to include (but are not limited to) peripheral abnormalities, particularly derangements in skeletal muscle metabolism and mass, which can trigger the activation of chemoreceptors that are responsible for exercise-related tachypnoea.[12–14]
Mechanisms that have been postulated to contribute to exertional dyspnoea and hyperventilation in chronic heart failure.
Therefore, despite the promulgation of diverse hypotheses over the last several decades (Figure 1), we do not understand the genesis or clinical importance of exertional dyspnoea in patients with chronic heart failure. We know that heart failure leads to hyperventilation at low workloads, resulting in ventilatory inefficiency. However, it is not clear whether changes in ventilation frequency limit exercise capacity. It is possible that patients with heart failure have both effort intolerance and exercise-induced hyperventilation, but that these two phenomena are not related to each other. Many patients with heart failure continue to exercise despite the experience of dyspnoea, until they feel that their legs can no longer carry them. So do patients with chronic heart failure stop exercising with dyspnoea or because of dyspnoea? If we were able to suppress the sensation of dyspnoea, would patients with heart failure be able to exercise longer? Many investigators who have closely evaluated patients with chronic heart failure believe this is unlikely.
Our inability to answer these simple questions highlights how little we know about the factors that influence the capacity of patients with heart failure to perform and enjoy activities of daily living. We have spent several decades prolonging the lives of patients with heart failure, but we have spent little time studying the symptoms that bring them to medical attention in the first place. Since heart failure has become not only the major cause of cardiac death but also the major cause of cardiac disability, this is a conundrum that we can no longer ignore.
Eur Heart J. 2018;39(30):2822-2824. © 2018 Oxford University Press
Copyright 2007 European Society of Cardiology. Published by Oxford University Press. All rights reserved.