Frits Franssen
Obesity paradox versus cardiovascular risk reduction
Epidemiology
While traditionally been considered a wasting disease, there’s an increasing focus on the
impact of obesity, defined as a BMI ≥ 30 kg/m2 in patients with COPD. The worldwide
prevalence of obesity has more than doubled since 1980. According to WHO estimates, it is
projected that the number of obese adults will exceed 700 million by the year 2015 [1].
Studies on the epidemiology of obesity in subjects with COPD have been inconclusive,
reporting prevalences from 18% [2] to 54% [3]. In comparison with non-COPD populations
both reduced [4] and well as increased [3, 5] prevalences of obesity were observed in COPD.
Variations in disease-specific factors, including severity of airflow limitation [2] and smoking
status, and general lifestyle factors, such as dietary intake and level of daily physical
activities, may contribute to observed variability in obesity prevalence in COPD.
Functional effects
Aside from its effect on chronic diseases such as diabetes and heart disease, obesity is
associated with mechanical, metabolic and systemic alterations that may contribute to COPD
heterogeneity and to the development of co-morbidities such as cardiovascular disease. In
obese individuals without respiratory disease, several effects of excessive fat mass on the
respiratory system can be observed. Increased breathlessness during daily physical activities
[6] and a reduction in functional residual capacity (FRC) of the lungs [7] are the most
prominent effects.
Obese COPD patients have increased dyspnoea at rest and poorer health status compared
to normal weight patients [8], while static lung hyperinflation is reduced in obese COPD
patients [9], irrespective of the severity of disease [10]. Whether a central or peripheral
distribution of excessive fat mass influences the effects of obesity on lung function in COPD
is currently unknown.
The combined effects of obesity and COPD on exercise tolerance seem to depend on the
type of exercise (weight-bearing versus non weight-bearing) that is performed. While peak
cycling capacity is preserved in obese COPD patients compared to non-obese [9] and
dyspnea ratings are consistently lower during cycling in obese patients, the distance covered
during a 6-minute walk test (6MWT) is reduced and the degree of fatigue is increased in
obese patients [11]. Future studies need to clarify the influence of obesity on activities of
daily life in COPD.
Prognosis
In the general population, obesity is associated with a largely decrease in life expectancy [12,
13]. In the Copenhagen City Heart Study, the relative risk of all-cause mortality was 20-34%
increased in obese patients with mild-to-moderate COPD compared to normal BMI patients
with comparable disease severity [14]. However, the relative risk of all-cause mortality and
COPD-related mortality was 0.62 and 0.31, respectively, in obese patients with severe
COPD compared to normal weight patients with severe disease [14]. A possibly protective
role for obesity in patients with severe COPD was also observed in early studies on the
association between body weight and mortality [15, 16]. In the ‘Association Nationale pour le
Traitement a Domicile de l’Insuffisance Respiratoire Chronique’ (ANTADIR) network, the
prognostic value of obesity in hypoxemic patients with COPD treated with long-term oxygen
therapy, was clearly demonstrated [17]. During the 7.5 years follow up, the highest survival
and lowest hospitalization rates were observed in obese COPD patients. The 5-year survival
rates were 24%, 34%, 44%, and 59%, respectively, for patients with BMI’s < 20, 20 to 24, 25
to 29, and > 30 kg/m2.
This possible association between obesity and improved survival in COPD thus contrasts
with epidemiological data from the general population. Although not completely understood,
this phenomenon known as the “obesity paradox” is not unique for COPD [18]. One
explanation, for the prognostic advantage of obesity, concerns the relative reduction in static
lung volumes in obese COPD patients. During a three-year follow-up study, the inspiratory
capacity–to-total lung capacity ratio (IC/TLC), an index of static lung hyperinflation, was
found to be an independent predictor of increased respiratory and all-cause mortality in
patients with COPD [19]. Although the mechanism underlying the association between
hyperinflation and prognosis remains unclear, it can be speculated that increased IC/TLC in
obese patients with COPD [9] may contribute to a benefit in survival.
In addition, obesity is associated with significantly lower annual decline in FEV1 in men and
not in women [20]. Thus, there may be gender specific differences in the effect of obesity on
the progression of chronic airflow limitation. Furthermore, it is not yet clear whether
excessive fat mass or muscle mass contributes to the survival advantage in chronic diseases
[18].
Based on the evidence outlined above, it can be hypothesized that obesity exerts divergent
effects on COPD prognosis based on patient characteristics and disease severity. Obesity
may protect against mortality in advanced COPD patients, in which loss of fat-free mass is a
particularly important short-term risk factor for death [21]. By contrast, in earlier stage COPD,
the harmful long-term effects of obesity-related conditions such as low-grade systemic
inflammation and metabolic syndrome may result in increased cardiovascular and all-cause
mortality.
Metabolic syndrome
Patients with COPD are at high risk of hospitalization and death from cardiovascular disease
[22] and at increased risk of diabetes [23]. Although the mechanisms responsible for this
association remain largely unknown, obesity is associated with abnormal metabolic and
inflammatory responses that may contribute to increased cardiovascular morbidity in COPD.
Metabolic syndrome is a cluster of risk factors (i.e. hypertension, dyslipidemia, diabetes) for
cardiovascular disease [24]. Central obesity is one of the key factors in the pathogenesis of
this syndrome, in addition to physical inactivity, nutrition, aging, genetics, a proinflammatory
state and hormonal changes play a role [25].
Several studies have investigated the prevalence of metabolic syndrome in patients with
COPD. In a small study of patients with severe COPD referred for pulmonary rehabilitation,
47% of patients fulfilled the diagnostic criteria for metabolic syndrome. This percentage was
significantly higher compared to the age and gender matched control subjects, in whom the
prevalence of metabolic syndrome was only 21% [26]. Similar results were reported in a
larger study including patients with chronic bronchitis and COPD [27]. Although the
prevalence of metabolic syndrome does not appear to vary based on the severity of lung
disease, it is associated with increased circulatory levels of high-sensitivity C-reactive protein
(hs-CRP) and interleukin-6 (IL-6) and with physical inactivity. These associations were
independent of lung function impairment [27]. Future studies should focus on whether
patients with COPD and the metabolic syndrome indeed have an increased risk of
developing co-morbidities including cardiovascular diseases and diabetes and whether this
contributes to increased cardiovascular and all-cause mortality in these patients.
Adipose tissue dysfunction
Low-grade systemic inflammation is considered a hallmark of COPD [28, 29] and may
explain the increased cardiovascular morbidity and metabolic syndrome noted in patients
with COPD. Indeed, increased levels of pro-inflammatory cells and mediators have been
reported in the circulation of COPD patients, including increased plasma concentrations of
fibrinogen, CRP, TNF-α and circulating leukocytes [28]. Increased levels of IL-6 [30, 31], IL-8
[32], IL-10 [31], IL-18 [33] have also been reported. Although it is often hypothesized that
inflammation in the systemic compartment is the result of spill over of the inflammatory
process in the airways, lung parenchyma and pulmonary vasculature, evidence from crosssectional studies indicates no correlation between pulmonary and circulatory inflammatory
markers in stable COPD [32, 34]. In addition, it is becoming more and more evident, that
systemic inflammation is not a characteristic of all patients with COPD. In the ECLIPSE
study, only 16% of patients had persistent systemic inflammation during follow-up [35].
Interestingly, patients with systemic inflammation were more obese, had more respiratory
symptoms and lower health related quality of life, worse exercise tolerance and reported
more cardiovascular disease [35]. These ECLIPSE data suggest a systemic origin of
inflammation and are in line with previous observations suggesting that adipose tissue is a
potential source. Increased levels of systemic inflammation had been earlier reported in
relation with excessive fat mass in COPD patients. Specifically, TNF-α, IL-6 and leptin
plasma levels have been shown to be significantly increased in overweight/obese patients
compared with normal weight patients, while plasma adiponectin concentrations were
reduced [29]. The likelihood of having elevated CRP is three times higher in obese patients
compared to normal weight patients, after adjusting for relevant confounders [36], with
abdominal fat mass being positively associated with plasma CRP levels in patients with
COPD [37].
Few studies examined adipose tissue inflammation in COPD. Significant differences in
subcutaneous adipose tissue mRNA expression of proinflammatory IL-6, TNF-α, CD68
(macrophage cell surface receptor) were reported among cachectic, normal-weight,
overweight and obese patients with moderate-to-severe COPD [38]. However, there was no
difference in serum levels of IL-6, TNF-α and high-sensitivity CRP (hsCRP) [38]. In another
study, gene expression of proinflammatory CD40, mitogen-activated protein kinase 4 (MKK4)
and c-Jun NH2-terminal kinases (JNK) was increased in subcutaneous adipose tissue in
underweight and muscle wasted COPD patients with resting hypoxia, compared to less
severe patients with overweight and preserved muscle mass [39]. Upregulation of CD40,
MKK4 and JNK was inversely related to arterial oxygen tension (PaO2), BMI and adipocyte
diameter. However, since no healthy control groups matched for body composition were
included, a COPD-specific effect on adipose tissue inflammation could not be assessed.
Furthermore, given comparable levels of circulating hsCRP and IL-6 levels in the
underweight hypoxemic patients and the overweight normoxemic patients, a link between
white adipose tissue inflammation and systemic inflammation could not be proven. Recently,
comparable adipokine and inflammatory gene expression was reported in subcutaneous
adipose tissue of clinically stable normal-weight COPD patients and matched controls [40].
Also, adipocyte size, adipose tissue macrophage infiltration and systemic adipokine
concentrations were comparable. However, independent of body composition, COPD
patients with high CRP had significantly greater adipose tissue macrophage infiltration than
did patients with low CRP, indicating a possible role of adipose tissue macrophages in the
pathophysiology of systemic inflammation in COPD. In conclusion, specific alterations in
adipose tissue function in patients with concomitant COPD and obesity remain currently
unknown. The impact of fat mass distribution (i.e. subcutaneous versus visceral fat mass or
abdominal versus lower-extremity fat mass) on systemic inflammation in COPD may be
explored in future studies.
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