The Autonomous Nervous System: A Novel and Potentially Modifiable Risk Factor for Chronic Obstructive Pulmonary Disease in the Population?

It is well known that the autonomic nervous system (ANS) plays a crucial role for maintaining homeostasis in several organ systems, including the cardiovascular and respiratory systems (1). In the respiratory system, activation of the sympathetic arm leads to bronchodilation, whereas activation of the parasympathetic arm causes bronchoconstriction and increased mucus production (2). Most obvious in a clinical context, inhaled medications that target pulmonary autonomic receptors have been commonly used to treat asthma as well as chronic obstructive pulmonary disease (COPD) for several years.

Emerging evidence suggests that clinical dysfunction of the cardiovascular branches of the ANS, such as seen in orthostatic hypotension, raises the risk of atherosclerotic cardiovascular disease (CVD) (3). CVD is in turn a very common comorbidity in COPD. As could be expected, studies have shown that dysfunction of the ANS may also be involved in COPD (4–6). An abnormal blood pressure response during standing predicts incident COPD in the population (7); however, studies associating ANS function with COPD in the general population have been sparse, especially for nonsmokers.

A marker of subclinical ANS dysfunction that may be assessed in an epidemiological study is heart rate variability (HRV), which has been used in several previous studies. In brief, HRV assesses the cardiovascular autonomic function by assessing the variation in time between heartbeats. Higher HRV is associated with lower mortality and reduced risk of adverse events (8). There have been indications that HRV is associated with COPD exacerbations (9); however, there is limited knowledge about these relationships in healthy middle-aged individuals.

In an important study presented in this issue of AnnalsATS, MacDonald and colleagues (pp. 1435–1444) used data from the ARIC (Atherosclerosis Risk in Communities) study to examine whether better cardiovascular autonomic function, indicated by higher HRV and appropriate control of orthostatic blood pressure, is associated with a reduced risk of incident COPD hospitalization and lower mortality due to chronic lower respiratory disease (10). Their findings suggest that individuals with better cardiovascular autonomic function (i.e., greater HRV and better orthostatic blood pressure control) indeed have a lower risk of COPD hospitalization over a median of nearly 27 years of follow-up. Of importance, these results were particularly consistent among participants without baseline airflow obstruction. Moreover, including incident coronary artery disease in their models did not significantly change the results, indicating that ANS dysfunction is a risk marker for COPD independently of the development of CVD, in line with previous findings in population-based cohorts (7).

As is also presented in the article with insightful reasoning by the authors, there are a number of potential mechanisms that may underly the results.

First, one must question the direction of the association between autonomic dysfunction and COPD. It cannot be excluded that autonomic dysfunction is a marker of an already-present subtle abnormality in pulmonary function. Pulmonary stretch receptors do contribute to HRV, and it may be that decreased HRV indicates early pulmonary disease that is not detected by standard dynamic spirometry (11, 12).

Naturally, markers of abnormal ANS function in one organ system (here, the cardiovascular system) may reflect an overall autonomic dysfunction, which would also be present in the respiratory system. An imbalance in sympathetic and parasympathetic activity could lead to bronchoconstriction and increased mucus production. In parallel to this, one hypothesis may also involve the inflammatory reflex, in which autonomic dysfunction with altered neurohormonal activation modulates inflammatory pathways involved in COPD pathogenesis (13).

In relation to COPD hospitalizations, the endpoint of the study by Macdonald and colleagues, impaired cardiovascular autonomic function may impede the ability to respond to physiological stress during a COPD exacerbation. Thus, individuals with autonomic dysfunction may have a higher likelihood of being hospitalized for COPD. For example, if inadequate sympathetic overactivity is already present, there may be inadequate additional reserves for coping with a COPD exacerbation (6). Supporting this hypothesis, as is also stated by the authors, are previous data showing that patients may be more susceptible to hospitalization for acute exacerbations of COPD when assigned to metoprolol compared with placebo (9, 14).

Finally, even though the authors adjusted for incident coronary artery disease in their models, it may still be the case that abnormal cardiovascular autonomic function is simply an indicator of exposure to other risk factors associated with both incident CVD and COPD (i.e., a common underlying cause). As one obvious example given by the authors, ambient particulate matter ⩽2.5 μm in aerodynamic diameter, a measure of air pollution and a known risk factor for COPD, has been shown to impair HRV (15).

The study by MacDonald and colleagues represents, to the best of my knowledge, the first analysis to investigate HRV as a risk factor for COPD hospitalizations in a community-based cohort. HRV can be safely applied and measured by various devices that are already present in the market (smartwatches, phones, and more). Thus, as also advocated by the authors, HRV may eventually serve as a screening tool in identifying concealed-risk individuals (i.e., nonsmokers with no airway obstruction) who are still at risk of developing COPD. However, significantly more data are needed before such screening procedures can be recommended and implemented.

The relationship between ANS function and respiratory disease may be complex and likely multifactorial, and, as such, an epidemiological study like the current one comes with a number of limitations, including the well-known healthy cohort effect and potential residual confounding. In relation to the specific research question, the ARIC study was designed for assessing cardiovascular outcomes, meaning that the authors had to rely on the International Classification of Diseases, Ninth and Tenth Revision codes for defining events, rather than more sophisticated measurements of COPD exacerbations. They only had access to hospitalization data, meaning that the probably much larger numbers of milder events of COPD (that are likely to be diagnosed and treated by general practitioners) were not included in the analysis. Including these milder COPD events may have enhanced the power of the current study.

In conclusion, it has become clear that autonomic dysfunction may be more important than previously thought for a number of common diseases, and the important results from MacDonald and colleagues provide further insights here. The current results emphasize the need for further research of risk factors in hidden-risk subjects for COPD, such as never-smokers, who represent a significant proportion of all COPD cases (16). Importantly, the function of the autonomic nervous system may be improved by interventions such as physical activity (17). If further data are in line with the current results, ideally randomized controlled studies should investigate whether improving the autonomic nervous system function in turn leads to reduced incidence and severity of COPD.