Figure 3. Individual NMD in the 7 patients that had measurements
at admission (NMD 1) and follow-up (NMD 2). The horizontal bar
represents the mean NMD at that time point. NMD improved from
5.0 ± 2.6% to 13.3 ± 4.5% on follow-up (p = 0.02).
calcium channel blockers, or angiotensin converting enzyme
inhibitors.
DISCUSSION
Patients hospitalized for AECOPD had severe vascular dysfunction as evidenced by markedly reduced FMD and NMD.
Upon recovery, both FMD and NMD improved significantly.
Not only were both FMD and NMD dramatically lower than
normal individuals (32) but FMD in our cohort was significantly lower than that reported for other systemic diseases with well-known vascular complications (16, 21). To
our knowledge this is the first report showing impaired vascular function in patients with hospitalized AECOPD that
improves following resolution of the acute exacerbation.
Vascular dysfunction has previously been shown in stable
COPD (23, 24, 33). Sabit et al. showed that COPD patients
had evidence of vascular stiffness as measured by aortic pulse
wave velocity (34), and that the severity of airflow obstruction, age, IL-6 level, and arterial blood pressure were independent predictors of vascular stiffness. Barr et al. found that
FMD was impaired in a group of former smokers and that the
magnitude of impairment was more severe in those COPD
patients with lower FEV1 and more emphysema evident on
chest CT imaging (24). Two other studies have shown that
COPD patients had lower FMD and NMD when compared to
normal controls and that NMD was lower in COPD patients
compared to non-smoking controls but not to smokers without COPD (23, 33). Our data is consistent with previously
reported impairments in both FMD and NMD in COPD, but
our data highlights the effect of an acute exacerbation on vascular function.
Our study is unique in that we studied FMD and NMD
in subjects during an acute severe exacerbation that resulted
in hospitalization. This may have important clinical implications since patients hospitalized with AECOPD have been
reported to have high incidences of pulmonary embolism
or cardiac events. Venous thromboembolism (VTE) occurs
5 times more commonly in COPD and can be an unexpected
cause of AECOPD in up to 25% of these patients (25). In a
recent autopsy study of 46 patients who died within 24 hours
of hospitalization for AECOPD, patients were found to have
died from congestive heart failure (CHF) in 37% and VTE in
21% (4).
Systemic inflammation has been shown to be greater during AECOPD (9, 12) and the severity of FMD and NMD
impairment correlates with inflammatory markers even in
stable COPD (23, 34). This led to our premise that vascular
function as measured by FMD and NMD would be further
impaired during an exacerbation. The magnitude of vascular
impairment in our patients both during exacerbation and at
resolution was worse than most of the previously published
reports on FMD in COPD (23, 24). This may be due to differences in technique (forearm occlusion vs. upper arm occlusion), our patient population being more severely obstructed,
or our patients not achieving full resolution of their exacerbation. Acute hypercapnia can result in vasodilatation which
may impair the capacity of the vessel to respond to stimuli
such as FMD or NMD. However, in our patients there was
no significant difference in the baseline brachial artery diameter during AECOPD compared to AECOPD resolution,
thus making it unlikely that the impaired FMD and NMD
was due to arterial vasodilatation from hypercapnia.
Flow mediated dilation is a response to nitric oxide released by the vascular endothelium resulting from distention
of the vessel following sudden return of flow to the previously obstructed vessel. FMD reflects endothelial function;
while NMD reflects endothelium independent function (i.e.,
vascular smooth muscle), which could be due to atherosclerosis or impaired vascular smooth muscle function (28). In
our study FMD and NMD, both of which are risk factors
for cardiovascular disease, were markedly impaired suggesting abnormalities in both endothelial and vascular smooth
muscle function (19). Others have also shown that there is
impairment in both FMD and NMD in patients with stable COPD (23, 24). Cardiovascular disease occurs at a 2–3-
fold increased risk in COPD patients (1–3, 35), and both cardiovascular disease and COPD are associated with increased
markers of inflammation (7).
It is possible that the increased systemic inflammatory
state associated with COPD leads to an accelerated development of cardiovascular disease in this patient population.
Patients hospitalized for AECOPD are at increased risk for
mortality during and after the admission (36–38). The increased inflammatory state associated with AECOPD may
even further accelerate cardiovascular diseases and place patients at an increased risk of death due to cardiac events. This
heightened risk is theoretically temporary because once the
exacerbation is treated; vascular function returns to baseline,
although still impaired compared to the normal state.
Limitations of this study include a small sample size,
which limited statistical power and prevented multivariate
analysis. FMD can be impaired in advanced age and two of
our subjects (both had FMD during hospitalization and one
during follow-up) were above age 70. However, there still
was an improvement in the FMD following resolution of the
