stress.

In the current study, CO levels changed

within hours of the stress, could be measured easily
with a venous blood draw (and possibly could be
measured in exhaled breath10), and were affected by
treatment. Other biomarkers, such as tumor necrosis
factor- and C-reactive protein, which are thought to
reflect the damaging effects of apnea, have been
inconsistent in their utility in OSA, as these markers
have multiple influences.11
These data suggest several future directions. For
the scientist, some questions include: what stress
influences CO in OSA patients, and is it repetitive
arousal, hypoxemia, or some other factors? Does CO
level predict long-term cardiovascular morbidity? Is
a low CO level a marker of low cardiovascular risk,
or instead is it a reflection of impaired protective
responses in a patient who is at increased risk of
cardiovascular morbidity? While the HO gene is
thought to be relatively conserved, polymorphisms in
the promoter region have been associated with variable HO-1 expression and associated with higher
risks of cardiopulmonary disease. In the current
study, there was wide unexplained variability in CO
production among patients with OSA. Are these
differences due to promoter polymorphisms or other
factors? How should CO be measured (by exhaled
breath, serum CO level, or hemoglobin-bound CO)?
And when should it be measured (during sleep or on
awakening, or do elevations persist for some time)? For
clinicians, assuming that the CO level has prognostic
value, is it a viable biomarker that should be measured
to assess disease burden? Does it reliably reflect the
response to treatment? And finally, will exogenous CO
one day be a therapy (as has been suggested for other
pulmonary diseases) to prevent cardiovascular disease
in those with OSA, perhaps in patients nonadherent to
CPAP therapy?12 We congratulate Kobayashi et al for
fueling the fire on the CO discussion.
ACKNOWLEDGMENT: The authors thank Drs. Rebecca
Baron, Augustine Choi, and Mark Perrella for their insightful
comments and discussion.

Robert L. Owens, MD
Susie Yim-Yeh, MD
Atul Malhotra, MD, FCCP
Boston, MA
Dr. Owens is a fellow in the Divisions of Pulmonary, Critical
Care, and Sleep Medicine, Brigham and Womens Hospital.
Dr. Yim-Yeh is affiliated with the Sleep Disorders Research
Program, Brigham and Womens Hospital. Dr. Malhotra is
affiliated with the Divisions of Pulmonary, Critical Care, and
Sleep Medicine, Brigham and Womens Hospital, and Harvard
Medical School.
Dr. Malhotra is funded by the National Institute of Health (grants
P50 HL060292, RO1-HL73146, and AG024837) and the Established Investigator Award from the American Heart Association.
Drs. Owens and Yim-Yeh have reported to the ACCP that no
significant conflicts of interest exist with any companies/organi896

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zations whose products or services may be discussed in this

article. Dr. Malhotra has received consulting and/or research
grants from Respironics, Itamar Medical, Restore Medical, NMT
Medical, Inspiration Medical, Apnex Medical, Sepracor, Cephalon, and Pfizer.
Reproduction of this article is prohibited without written permission
from the American College of Chest Physicians (www.chestjournal.
org/misc/reprints.shtml).
Correspondence to: Robert L. Owens, MD, Pulmonary & Critical
Care and Sleep Medicine Fellow, Brigham and Womens Hospital, Sleep Disorders Research Program, 221 Longwood Ave,
Boston, MA 02115; e-mail: rowens@partners.org
DOI: 10.1378/chest.08-1728

References
1 Horvath I, Donnelly LE, Kiss A, et al. Raised levels of exhaled
carbon monoxide are associated with an increased expression
of heme oxygenase-1 in airway macrophages in asthma: a new
marker of oxidative stress. Thorax 1998; 53:668 672
2 Yasuda H, Yamaya M, Nakayama K, et al. Increased arterial
carboxyhemoglobin concentrations in chronic obstructive
pulmonary disease. Am J Respir Crit Care Med 2005; 171:
1246 1251
3 Fredenburgh LE, Perrella MA, Mitsialis SA. The role of
heme oxygenase-1 in pulmonary disease. Am J Respir Cell
Mol Biol 2007; 136:158 165
4 Kobayashi M, Miyazawa N, Murakami S, et al. Circulating
carbon monoxide level is elevated after sleep in patients with
obstructive sleep apnea. Chest 2008; 134:904 910
5 Morse D, Choi AM. Heme oxygenase-1: from bench to
bedside. Am J Respir Crit Care Med 2005; 172:660 670
6 Meyer J, Prien T, Van Aken H, et al. Arterio-venous carboxyhemoglobin difference suggests carbon monoxide production
by human lungs. Biochem Biophys Res Commun 1998;
244:230 232
7 Minamino T, Christou H, Hsieh CM, et al. Targeted expression of heme oxygenase-1 prevents the pulmonary inflammatory and vascular responses to hypoxia. Proc Natl Acad Sci
U S A 2001; 78:8798 8803
8 Yet SF, Perrella MA, Layne MD, et al. Hypoxia induces
severe right ventricular dilatation and infarction in heme
oxygenase-1 null mice. J Clin Invest 1999; 103:R23R29
9 Chin K, Ohi M, Shimizu K, et al. Increase in bilirubin levels
of patients with obstructive sleep apnea in the morning: a
possible explanation of induced heme oxygenase-1. Sleep
2001; 24:218 223
10 Petrosyan M, Perraki E, Simoes D, et al. Exhaled breath
markers in patients with obstructive sleep apnoea. Sleep
Breath 2008; 12:207215
11 Romero-Corral A, Sierra-Johnson J, Lopez-Jimenez F, et al.
Relationships between leptin and C-reactive protein with
cardiovascular disease in the adult general population. Nat
Clin Pract Cardiovasc Med 2008; 5:418 425
12 Ryter SW, Morse D, Choi AM. Carbon monoxide and
bilirubin: potehtial therapies for pulmonary/vascular injury
and disease. Am J Respir Cell Mol Biol 2007; 36:175182

The Obesity Paradox

Is Smoking/Lung Disease the
Explanation?
studies indicate that overweight and obeM any
sity are extremely prevalent in Westernized

societies, and during recent decades, the preva-

Editorials

lence has been markedly increasing, especially in

the United States.1 If current trends continue,
obesity will soon overtake cigarette smoking as the
leading cause of preventable death in the United
States.1 Substantial evidence documents the
heavy cardiovascular (CV) burden of obesity.
Overweight/obesity is a strong risk factor for the
development and progression of hypertension,
dyslipidemia (especially elevated triglycerides and
low levels of high-density lipoprotein cholesterol),
metabolic syndrome, and type 2 diabetes mellitus,
and increases systemic inflammation (eg, high
levels of C-reactive protein).13 Although hypertension is a strong risk factor for left ventricular
hypertrophy, obesity contributes to left ventricular
hypertrophy and other ventricular structural abnormalities independent of arterial pressure.1,2
Although all of these factors contribute to atherosclerosis and coronary heart disease (CHD), obesity is probably an independent risk factor.13
Additionally, obesity has adverse affects on both
systolic and diastolic ventricular function, and is
associated with an increased risk of heart failure
(HF).1,4 Therefore, the prevention and treatment
of overweight/obesity are major societal concerns.
Despite the association of obesity with CV risk
factors and increased CV risk, numerous studies1 6
have now documented a strong obesity paradox, in
which obese patients with CV disease, including
hypertension, CHD, and, especially, HF have a
better prognosis than do their lean counterparts. In a
large study2 of patients who had been referred for
echocardiography with normal systolic function, we
have also demonstrated a strong obesity paradox.
The reasons for this surprising paradox have been
difficult to elucidate. Potential contributors have
included nonpurposeful weight loss prior to study
entry (due to unrecognized non-CV diseases), obese
patients presenting earlier due to increased dyspnea
due to non-CV causes, such as deconditioning and
restrictive lung disease, and reduced expression of
atrial natriuretic peptides, which has been documented in cases of obesity.1 6 Although some have
also suggested7 that part of the explanation of the
obesity paradox may be the limitations of the body
mass index (BMI) to define at-risk obesity, suggesting
that other measures such as waist circumference, waist/
hip ratio, or percentage of body fat determinations
would be more accurate, we have demonstrated that a
higher percentage of body fat predicted better prognosis in patients with HF8; preliminary data from our
institution have suggested the same regarding CHD
and mortality.
In the current issue of CHEST (see page 925),
Galal and colleagues9 assessed 4.4-year mortality in
2,392 patients with peripheral arterial disease (PAD)
www.chestjournal.org

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from the Netherlands who had undergone major

vascular surgery and had a high risk of mortality
during follow-up. That study demonstrated a powerful obesity paradox in patients with PAD, with
progressive reductions in mortality in normalBMI, overweight, and obese groups of patients
compared with an underweight group of patients.
Although lower BMI was an independent predictor of
higher mortality in the entire population, the increased
risk in the underweight patients was almost completely
explained statistically by a high prevalence of moderate-to-severe COPD. Nevertheless, adjusting for the
severity of COPD did not abolish the relationship
between BMI and mortality in the overweight and
obese groups.
The contributions of the study by Galal et al9 are
noteworthy, particularly regarding extending the obesity paradox to patients with PAD as well as documenting the contribution of COPD to this paradox, especially in underweight PAD patients. Nevertheless, the
fact that the underweight patients had higher mortality and more COPD is of no major surprise, and
many studies1,2,4 6 have documented higher mortality rates among underweight persons. Importantly,
this population may be different than other populations, such as cohorts of hypertensive, CHD, and HF
patients, in that smoking, as the authors state, appears to be an especially potent contributor to
PAD.1,9 Nevertheless, other studies5 have also attempted to correct for smoking as a risk factor, and
still lower BMI is an independent predictor of higher
risk. Likewise, even in the present study,9 which
corrects for smoking status as well as COPD, lung
disease did not completely explain this paradox in the
subgroups of overweight and obese patients, who
had the best prognosis.
Considering this surprising paradox, how should
clinicians proceed at present? In fact, some experts9,10 have even questioned the safety and efficacy
of purposeful weight loss in patients with CV diseases. However, we and others have reported1,3 6,11
that purposeful weight loss improves left ventricular
systolic and diastolic function, reduces CHD risk
factors, and is associated with the most favorable CV
prognosis. Certainly, efforts to increase physical activity and overall physical fitness in our society are
desperately needed, as many studies12 have clearly
demonstrated that a reduced level of fitness is a
powerful predictor of mortality and increased fitness
is protective in patients with obesity and other CV
risk factors. As we continue to investigate the mechanisms for this puzzling obesity paradox, the weight of
evidence clearly supports purposeful weight loss, particularly with therapies that do not reduce lean body
CHEST / 134 / 5 / NOVEMBER, 2008

897

mass, such as exercise training in addition to caloric

restriction, for the primary and secondary prevention of
CV diseases.
Carl J. Lavie, MD, FCCP
Hector O. Ventura, MD
Richard V. Milani, MD
New Orleans, LA
Dr. Lavie is Medical Director, Cardiac Rehabilitation and Prevention, Director, Exercise Laboratories, Ochsner Medical Center. Dr. Ventura is Chairman of Graduate Medical Education,
and Director of Advanced Heart Failure and Transplantation,
Ochsner Medical Center. Dr. Milani is Vice Chairman, Department of Cardiovascular Diseases, Ochsner Medical Center.
The authors have reported to the ACCP that no significant
conflicts of interest exist with any companies/organizations whose
products or services may be discussed in this article.
Reproduction of this article is prohibited without written permission
from the American College of Chest Physicians (www.chestjournal.
org/misc/reprints.shtml).
Correspondence to: Carl J. Lavie, MD, FCCP, Medical Director,
Cardiac Rehabilitation and Prevention, Director, Exercise Laboratories, Ochsner Medical Center, 1514 Jefferson Hwy, New
Orleans, LA 70121-2483; e-mail: clavie@ochsner.org
DOI: 10.1378/chest.08-1673

References
1 Lavie CJ, Milani RV. Obesity and cardiovascular disease:
the Hippocrates paradox? J Am Coll Cardiol 2003; 42:677
679
2 Lavie CJ, Milani RV, Ventura HO, et al. Disparate effects of
left ventricular geometry and obesity on mortality in patients
with preserved left ventricular ejection fraction. Am J Cardiol
2007; 100:1460 1464
3 Lavie CJ, Morshedi-Meibodi A, Milani RV. Impact of cardiac
rehabilitation on coronary risk factors, inflammation, and the
metabolic syndrome in obese coronary patients. J Cardiometab Syndr 2008; 3:136 140
4 Lavie CJ, Mehra MR, Milani RV. Obesity and heart failure
prognosis: paradox of reverse epidemiology? Eur Heart J
2005; 26:57
5 Lavie CJ, Artham SM, Milani RV, et al. The obesity paradox:
impact of obesity on the prevalence and prognosis of cardiovascular diseases. Postgrad Med 2008; 120:34 41
6 Lavie CJ, Milani RV, Ventura HO. Obesity, heart disease, and
favorable prognosis: truth or paradox? Am J Med 2007;
120:825 826
7 Romero Corral A, Lopez-Jimenez F, Sierra-Johnson J, et al.
Differentiating between body fat and lean mass: how should
we measure obesity? Nat Clin Pract Endocrinol Metab 2008;
4:322333
8 Lavie CJ, Osman AF, Milani RV, et al. Body composition and
prognosis in chronic systolic heart failure: the obesity paradox.
Am J Cardiol 2003; 91:891 894
9 Galal W, van Gestel Y, Hoeks SE, et al. The obesity paradox
in patients with peripheral arterial disease. Chest 2008; 134:
925930
10 Allison DB, Zannolli R, Faith MS, et al. Weight loss increases
and fat loss decreases all-cause mortality rates: results from
two independent cohort studies. Int J Obes Relat Metab
Disord 1999; 23:603 611
11 Eilat-Adar S, Eldar M, Goldbourt U. Association of intentional changes in body weight with coronary heart disease
event rates in overweight subjects who have an additional
coronary risk factor. Am J Epidemiol 2005; 161:352358
898

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12 Blair SN, Church TS. The fitness, obesity, and health equation: is physical activity the common denominator? JAMA
2004; 292:12321234

Prophylaxis of VentilatorAssociated Pneumonia

Changing Culture and Strategies to
Trump Disease
Failure is success if you learn from it.
Malcolm Forbes

lacement of an endotracheal tube (ETT) inP creases

a patients risk of pneumonia 6-fold to

20-fold by providing bacteria colonizing the oropharynx a convenient, one-way path around the ETT cuff
into the lower respiratory tract.1 4 Crude mortality
rates for ventilator-associated pneumonia (VAP) range
from 20 to 60% with an estimated cost of $40,000 per
episode.1,2 Many of these poor outcomes result from
system failures that are preventable with changes in
hospital culture.2,3,5
A crucial target for VAP prophylaxis is reducing
the number of pathogenic bacteria colonizing the
oropharynx and entering the lower respiratory tract.3
One strategy is the use of oropharyngeal decontamination with disinfectants, such as chlorhexidine or
combinations of topically applied antibiotics, with
and without systemic antibiotics.2 4 The use of this
approach has been limited due to concerns over
inducing bacterial resistance.2 4 A second strategy,
which is shown in Figure 1, is to prevent the entry of
oropharyngeal bacteria into the trachea by use of a
specially designed ETT having a suction port above
the cuff for continuous aspiration of subglottic secretions (CASS).3,6,7
In this issue of CHEST (see page 938), Bouza and
coworkers6 present data from a large, well-executed
clinical trial of 690 patients undergoing major cardiac
surgery who were randomized to use an ETT capable of CASS or a conventional ETT. VAP was
diagnosed by clinical and radiologic criteria, and was
confirmed by endotracheal aspirates with 104
organisms per milliliter. This is the largest study to
evaluate CASS, and the focus was on a high-risk
population that was more homogeneous than most
ICU patients. The greatest benefit of CASS was
observed in the 95 patients who received ventilation
for 48 h. In these patients, the use of CASS
significantly reduced the rates of VAP (27% vs 48%,
respectively; p 0.04), especially VAP due to Haemophilus influenzae; decreased the duration of ventilation (median duration, 3 vs 7 days, respectively;
p 0.02); shortened the length of ICU stay (median
Editorials