Editorials

Vascular Structure and Function in Chronic Obstructive

Pulmonary Disease
A Chicken and Egg Issue?
There is an inverse relationship between FEV1 and cardiovascular risk in the general population (1), which is reflected in the
link between airway obstruction and cardiovascular events in
chronic obstructive pulmonary disease (COPD) (2, 3). In such
patients, cardiovascular mortality is increased two- to threefold
(35), independent of smoking and other risk factors (5). Although the mechanisms underlying the relationship between
COPD and cardiovascular disease are currently unknown, alterations in arterial stiffness and endothelial function are likely to
be important, since they both predict cardiovascular risk in a
number of diseases and healthy populations (6, 7). This is in
keeping with the accepted view that COPD is a precursor of
cardiovascular disease. However, there is growing evidence that
microvascular changes in response to cigarette smoking are important in early alveolar injury and the development of emphysema. Thus, is there a shared pathophysiologic mechanism
linking early pulmonary vascular changes and later cardiovascular disease?
Two studies in this issue of the Journal (pp. 12001207 and
pp. 12081214) provide further information on the relationship
between COPD and cardiovascular disease. Barr and colleagues
(8) report a relationship among FEV1, percentage of emphysema on computed tomography (CT), and endothelial function
in an unselected sample of ex-smokers studied in the Emphysema and Cancer Action Project (EMCAP). Endothelial function was determined by flow-mediated dilatation (FMD) (7), a
validated measure of endothelium-dependent nitric oxide vasodilatation. In fully adjusted regression models, a fall in FMD by
1 SD, indicating endothelial dysfunction, was associated with a
132-ml decrease in FEV1 and a 2.6% increase in CT percentage
of emphysema (both P , 0.05). These associations were independent of age and other confounders of endothelial function,
and were present across the spectrum of airway obstruction and
in subjects with nonobstructive post-bronchodilator spirometry.
The authors suggest that their findings could be explained in the
context of reduced expression of vascular endothelin growth
factor, and that endothelial dysfunction may be directly implicated in the pathogenesis of COPD. However, an equally likely
explanation is that factors associated with COPD, such as tissue
hypoxia, oxidative stress, and systemic inflammation, may lead
to endothelial dysfunction. An important finding in this study
is that the association between FEV1 and FMD was entirely
attributable to CT percentage of emphysema, suggesting that
anatomic emphysema, rather than airway obstruction, is responsible for impaired vascular function.
The concept that anatomic emphysema leads to pulmonary
vascular changes is not new. Alterations in vascular structure
and vessel compression secondary to emphysema are believed
to have a role in the pathogenesis of pulmonary hypertension in
COPD (9). Furthermore, pulmonary vascular endothelial dysfunction has been demonstrated at both ends of the COPD

Am J Respir Crit Care Med Vol 176. pp 11751177, 2007

Internet address: www.atsjournals.org

spectrum and is also implicated in the pathogenesis of pulmonary hypertension (10, 11). However, this does not answer the
question of how emphysematous changes in the lung are
associated with later degenerative disease in the extrapulmonary vasculature?
The study by McAllister and colleagues (12) in this issue of
the Journal also explored the relationship between emphysema
and systemic vascular function.
This cross-sectional analysis demonstrated a relationship
between emphysema severity by high-resolution CT scanning
and brachial artery pulse-wave velocity, an indicator of arterial
stiffness, independent of confounders such as age and smoking
and even airway obstruction. The authors speculate that this
relationship may be mediated by similar alterations in the
content and architecture of elastin in the lung and the vasculature. Such alterations may be genetically predetermined or
acquired as a result of increased activity of elastolytic enzymes.
Although this study provides new insights into the relationship
between emphysema and the systemic vasculature, its results
must interpreted with caution. The brachial artery is predominantly a muscular artery and, as such, is affected by a range of
factors influencing vascular smooth muscle tone. As the authors
comment, carotid-femoral (aortic) pulse-wave velocity, a measure of large elastic artery stiffness, would have been the ideal
choice when investigating the relationship between emphysema
and systemic vascular function. Furthermore, aortic pulse-wave
velocity is considered the gold-standard measure of arterial
stiffness and, in contrast to brachial pulse-wave velocity, is a
proven predictor of cardiovascular risk (6, 13).
Taken together, these studies offer further insight into the
effects of COPD, in particular the emphysematous form, on
vasculature structure and function, and suggest that the lungs
and vasculature are involved in similar or parallel pathologic
processes. Although the two groups investigated different aspects of the vascular function, the results are complementary
since it is widely accepted that endothelial function is an important factor influencing arterial stiffness (14). Moreover, both
studies suggest that anatomic emphysema, rather than FEV1, is
important when considering the effects of COPD on systemic
vascular function. Such conclusions are supported by recent
evidence of increased arterial stiffness and endothelial dysfunction in patients with COPD compared with matched control
subjects (15). Furthermore, the association of arterial stiffness
with osteoporosis could be interpreted as adding further to the
concept of a wide-scale alteration in connective tissue physiology in COPD.
Both studies raise a number of important questions. If the
effects of emphysema on vascular structure and function occur
independently of FEV1, does this mean that patients with
COPD and chronic bronchitis are less susceptible to cardiovascular disease? At least one report would argue against this
hypothesis (16). What is the role of systemic inflammation and
oxidative stress in the relationship between emphysema and vascular structure and function? Perhaps the most important question is whether any interventions to improve arterial stiffness

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AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 176

and endothelial function will be effective in reducing cardiovascular and overall mortality in patients with COPD. Further
studies, in particular large-scale longitudinal studies, to describe the natural history of the association between COPD and
cardiovascular disease are now needed to answer these important questions.
Conflict of Interest Statement: Neither author has a financial relationship with a
commercial entity that has an interest in the subject of this manuscript.

RAMSEY SABIT, M.R.C.P.

DENNIS J. SHALE, M.D.
Cardiff University
Llandough Hospital
Penarth, United Kingdom
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DOI: 10.1164/rccm.200709-1428ED

Of Contagion and Inherited Susceptibility: An

Epidemiologic Tribute to George W. Comstock
In this issue of the Journal (pp. 12811288), van der Eijk and
colleagues venture into the past with modern analytic tools (1).
Taking prior analyses a step further, it is also a tribute to the
late George W. Comstock, one of the most preeminent epidemiologists of the 20th century in general and tuberculosis specifically (2).
The Prophit survey was an exceptionally well-designed twin
study, identifying cases with a twin sibling among a tuberculosis
population. Among the 101 twin pairs meeting the inclusion
criteria, 39 of the co-twins also had tuberculosis. The influence
of zygosity on the risk of tuberculosis in the co-twin, and thus
heredity, was the research question in the original survey, the
reanalysis by Comstock (3), and the current analysis (1). The
original and both reanalyses found a higher concordance of tuberculosis among monozygotic than dizygotic twins. The original study explained this finding with a greater exposure and a
higher incidence of sputum smearpositive tuberculosis among
the former compared with the latter. Comstock used a thenemerging multivariate analysis technique allowing adjustment
for potential confounders and found that monozygotes had an
approximately threefold elevated risk of developing tuberculosis compared with dizygotes even after this adjustment. van der
Eijk and colleagues obtained identical results as Comstock using
a standard multivariate logistic regression model. However, accounting for effect modifiers, zygosity vanished as a risk factor:

all apparent genetic susceptibility turns out to be just a masked

difference in exposure risk.
That a different analytic strategy gives the opposite results
begs for an explanation. Bias or confounding factors distort
study findings and may suggest a spurious association if in fact
there is none or if they mask one that exists. The very rationale
for Comstock to reanalyze the data was his acute awareness of
this potential pitfall. For example, if sex emerges as a risk factor
for a condition, the risk for which also increases continuously
with age, sex as a putative risk factor might be solely attributable to an age difference between the two sexes. Finding a crude
risk difference by sex in this setting is then said to be confounded by age. Confounders are addressed by either scrutinizing
sex differences within appropriately sized age groups (stratified
analysis) or, as is common now, using standard logistic regression analysis for adjustment.
Standard logistic regression averages out the strata effects of
a confounder. It will thus be inappropriate if sex differences go
in one direction in some age groups but in the opposite in
others, age being here an effect modifier. To prevent missing
such an age effect requires adding so-called interaction terms
in the logistic model. Several interactions with zygosity were
identified by van der Eijk and colleagues. These include age,
sputum smear status in the index case, and other factors that
potentially influence intensity of exposure. Among twins with