SYSTEMIC INFLAMMATION LEADING TO
COMORBIDITIES ASSOCIATED WITH COPD
Leonardo M. Fabbri
Comorbidities and systemic effects of COPD
Cardiovascular diseases in COPD
COPD in Chronic Heart Failure
Cardiovascular drugs in COPD
CHRONIC DISEASE IN THE ELDERLY:
Back to the Future of Internal Medicine
Two or more chronic diseases almost invariably develop together in
the same patient, particularly in the elderly, often making it difficult to
establish a proper diagnosis and assessment of severity
Patient-oriented approach that takes into account the several
coexisting components of chronic disease is required
This “change of concept” implies the need for medical specialists to
extend their expertise to broader diagnostic and treatment
approaches that are traditionally the purview of internal medicine
LM Fabbri and R Ferrari, Breathe, 2006, in press
Leading Causes of
Death in U.S.
#1. MI
#2. CA
#3. CVA
#4. COPD
Cigarette Related Diseases
Leading Causes of
Death Worldwide 2010
What do COPD Patients Die From?
Normal
Restricted
GOLD 2
GOLD 3/4
0%
20%
COPD
40%
ASCVD
60%
80%
Lung Cancer
Mannino D.M., et al. Respiratory Medicine 2006; 100:115
100%
Other
Chronic diseases represent a huge
proportion of human illness
58 million deaths in 2005:
 Cardiovascular disease
30%
 Cancer
13%
 chronic respiratory diseases
7%
 Diabetes
2%
Horton R. Lancet, 2006
COPD AS A SYSTEMIC DISEASE
COPD A COMPONENT OF THE CHRONIC DISEASE
COPD A SYSTEMIC DISEASE
•Systemic inflammation
•Cachexia
•Skeletal muscle wasting
•Osteoporosis
COPD A COMORBIDITY OF
Chronic heart failure
Coronary and peripheral arterial diseases
Lung cancer
Metabolic syndrome

=



?



?
?
Inhaled particles:
pulmonary and heart co-morbidity
SYSTEMIC INFLAMMATION LEADING TO
COMORBIDITIES ASSOCIATED WITH COPD
Leonardo M. Fabbri
Comorbidities and systemic effects of COPD
Cardiovascular diseases in COPD
COPD in Chronic Heart Failure
Cardiovascular drugs in COPD
Cardiovascular mortality in
COPD
For every 10% decrease in FEV1,
cardiovascular mortality increases by
approximately 28% and non-fatal coronary
event increases by approximately 20% in
mild to moderate COPD.
Anthonisen et al, Am J Respir Crit Care Med 2002
COPD
CAUSES OF HOSPITAL ADMISSION
CAUSES OF DEATH
Curkendall et al. Ann Epidemiol 2006;16:63–70.
Prevention of Exacerbations of Chronic Obstructive
Pulmonary Disease with Tiotropium, a Once-Daily
Inhaled Anticholinergic Bronchodilator
COEXISTING ILLNESSES
Vascular (including hypertension) 64%
Cardiac 38%
Gastrointestinal 48%
Musculoskeletal or connective tissue 46%
Metabolic or nutritional 47%
Reproductive or urinary 27%
Neurologic 22%
Niewoehner,et al, Ann Intern Med. 2005;143:317-326
Coronary Artery Calcification in Older Adults
Newman AB et al Circulation 2001
Occurrence and Prognostic Significance of
Ventricular Arrhythmia Is Related to
Pulmonary Function
402 men, 68 yrs old – 14 yrs follow-up
Engstrom G et al Circulation 2001
Percentuale di soggetti (maschi) con una placca
carotidea
Carotid Plaque, Intima Media Thickness,
Cardiovascular Risk Factors, and Prevalent
Cardiovascular Disease in Men and Women
800 soggetti, età media 66 anni
65.4 %
59.2%
50.4%
50%
FEV1 terzilies
Ebrahim S et al Stroke 1999
FEV1 e risk of stroke:
the Copenhagen Stroke Study
Rischio Relativo
4
RR per maschi e femmine
RR per maschi
RR per femmine
2
1.5
1
0.5
≥100%
90-99%
80-89%
70-79%
60-69%
50-59%
<50%
Percentuale FEV1 rispetto al previsto
Truelsen T et al Int J Epidemiol 2001
PULMONARY EMBOLISM IN PATIENTS WITH
UNEXPLAINED EXACERBATION OF CHRONIC
OBSTRUCTIVE PULMONARY DISEASE:
PREVALENCE AND RISK FACTORS
25% pulmonary embolism in patients
with COPD hospitalized for severe
exacerbation of unknown origin
Previous TEP, malignancy, low PaCO2
Tillie-Leblond et al, Ann Intern Med. 2006;144:390-396.
Cardiovascular morbidity in
COPD
Cardiac infarction injury score
8
7
P=0,001
6
5
4
3
2
1
0
High CRP
Severe
obstruction
High CRP
and severe
obstruction
Sin and Man, Circulation 2003
Inflammation, atherosclerosis and coronary artery disease
Hansson GK, N Engl J Med. 2005;352(16):1685-95
Activation of a type 1 immune response in atheroma formation
 Cross-sectional study, patients 65 years of age
 Of 405 participating patients with a diagnosis of chronic
obstructive pulmonary disease, 83 (20.5%, 95% CI 16.7–24.8)
had previously unrecognized heart failure
RECOGNISING HEART FAILURE IN ELDERLY PATIENTS
WITH STABLE CHRONIC OBSTRUCTIVE PULMONARY
DISEASE IN PRIMARY CARE
A limited number of items easily
available from history and physical examination,with
addition of NT-proBNP and electrocardiography, can
help general practitioners to identify concomitant
heart failure in individual patients with stable COPD
F H Rutten et al, BMJ 2005, Dec;331(4):1379-81
Peptidi natriuretici come marker
dello scompenso cardiaco cronico
Peptidi natriuretici
ANP
BNP
Peptide natriuretico atriale
Peptide natriuretico cerebrale
ANP
BNP
Cuore normale
ANP
BNP
Cuore scompensato
Breathing Not Properly Multinational Study
 1586 participants who presented with acute dyspnea
 1538 (97%) had clinical certainty of CHF determined by
the attending physician in the emergency department
 Participants underwent routine care and had BNP
measured in a blinded fashion
 ~ 37 % COPD comorbidity
McCullough et al. Circ 2002
Breathing Not Properly (BNP) Multinational Study
McCullough et al. Circ 2002
Utility of BNP in Differentiating Heart Failure from Lung
Disease in Patients Presenting
with Dyspnea
Morrison et al. JACC 2002
Utility of BNP in Differentiating Heart Failure from Lung
Disease in Patients Presenting
with Dyspnea
Morrison et al. JACC 2002
SYSTEMIC INFLAMMATION LEADING TO
COMORBIDITIES ASSOCIATED WITH COPD
Leonardo M. Fabbri
Comorbidities and systemic effects of COPD
Cardiovascular diseases in COPD
COPD in Chronic Heart Failure
Cardiovascular drugs in COPD
Acute MI (0.5–10 days)—SAVE, AIRE or TRACE eligible
(either clinical/radiologic signs of HF or LV systolic dysfunction)
Major Exclusion Criteria:
— BP < 100 mm Hg
— Serum creatinine > 2.5 mg/dL
— Prior intolerance of an ARB or ACEI
— Nonconsent
double-blind active-controlled
Captopril 50 mg tid
(n = 4909)
Valsartan 160 mg bid
(n = 4909)
median duration: 24.7 months
event-driven
Primary Endpoint:
Secondary Endpoints:
Other Endpoints:
All-Cause Mortality
CV Death, MI, or HF
Safety and Tolerability
Captopril 50 mg tid +
Valsartan 80 mg bid
(n = 4885)
VALIANT Trial:
Prevalence of COPD
• 14703 patients included in the trial
• 1258 clinical diagnosis of COPD (8.6%)
Valsartan Heart Failure Trial
Study Design
HF patients 18 yr; NYHA II–IV
LVIDD> 2.9 cm/m² BSA; EF<40%
Receiving Standard Therapy
including ACE inhibitors , diuretics
digoxin , -blockers
Randomized to
Valsartan
40 mg bid titrated
to160 mg bid
906 deaths (events reported)
J. N. Cohn et. al, J. Card. Fail. 1999; 5: 155-160
Placebo
Val-HeFT Trial:
Prevalence of COPD
• 5010 patients included in the trial
• 628 clinical disgnosis of COPD (12.5%)
Val-HeFT Trial
Clinical events at 2 year follow-up
No COPD
COPD
30
25
20
15
10
5
0
Mortality
Mortalità totale
P value
<0.0001
Ospedal per HF
Hospitalization
<0.0001
Contributors to exercise intolerance in
COPD and CHF
Gosker et al. AJCN 1999
SYSTEMIC INFLAMMATION LEADING TO
COMORBIDITIES ASSOCIATED WITH COPD
Leonardo M. Fabbri
Comorbidities and systemic effects of COPD
Cardiovascular diseases in COPD
COPD in Chronic Heart Failure
Cardiovascular drugs in COPD
METHODS
Case-control study of two population-based retrospective cohorts
1) COPD patients having undergone coronary revascularization
(high CV risk cohort)
2) COPD patients without previous myocardial infarction (MI) and
newly treated with nonsteroidal anti-inflammatory drugs (low CV
risk cohort)
Outcomes: COPD hospitalization, MI, and total mortality
Mancini GB, et al. J Am Coll Cardiol. 2006 Jun 20;47(12):2554-60
REDUCTION OF MORBIDITY AND MORTALITY BY STATINS, ANGIOTENSINCONVERTING ENZYME INHIBITORS, AND ANGIOTENSIN RECEPTOR
BLOCKERS IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY
DISEASE
These drugs reduced both CV and pulmonary outcomes
Largest benefits with statins combined with ACEin or ARBs
This combination reduces COPD hospitalization and mortality in
the high and low CV risk cohort
The combination also reduced MI in the high CV risk cohort
Benefits were similar when steroid users were included
Mancini GB, et al. J Am Coll Cardiol. 2006 Jun 20;47(12):2554-60
REDUCTION OF MORBIDITY AND MORTALITY BY STATINS,
ANGIOTENSIN-CONVERTING ENZYME INHIBITORS, AND
ANGIOTENSIN RECEPTOR BLOCKERS IN PATIENTS WITH
CHRONIC OBSTRUCTIVE PULMONARY DISEASE
These agents may have dual cardiopulmonary
protective properties, thereby substantially
altering prognosis of patients with COPD
These findings need confirmation in randomized
clinical trials
Mancini GB, et al. J Am Coll Cardiol. 2006 Jun 20;47(12):2554-60
SYSTEMIC INFLAMMATION LEADING TO
COMORBIDITIES ASSOCIATED WITH COPD
Leonardo M. Fabbri
Comorbidities and systemic effects of COPD
Cardiovascular diseases in COPD
COPD in Chronic Heart Failure
Cardiovascular drugs in COPD