1. Malattie cardiovascolari e BPCO
Modena, 6-7/8-9 Settembre CORSO DI FORMAZIONE PER PERSONALE MEDICO Nycomed
Malattie cardiovascolari e BPCO
Pietro Roversi, Alessia Verduri e Fabrizio Luppi
Clinica di Malattie dell’Apparato Respiratorio
Azienda Ospedaliero – Universitaria
Policlinico di Modena

2. ? TNFa IL-6 Cardiovascular Events
Metabolic Syndrome
Type 2 diabetes
Muscle
Weakness / Wasting
TNFa
IL-6 ?
Local
Inflammation
Osteoporosis
La BPCO è primariamente caratterizzata da ostruzione delle vie aeree scarsamente reversibile e solitamente progressiva, associata con un’anomala risposta infiammatoria in risposta ad agenti nocivi, in particolare al fumo di sigaretta; tuttavia nella maggior parte dei pazienti la malattia è associata a diverse manifestazioni sistemiche, pertanto non può più essere considerata una malattia esclusiva del polmone –
Il fumo di sigaretta è il maggior agente causale come lo è per il cancro e per molte malattie croniche, in quanto capace di determinare un’infiammazione sistemica che oltre al danno polmonare si associa alla presenza di stress ossidativo sistemico, a danno endotelio-vascolare , all’aumento di marcatori circolanti di flogosi e pro-coagulanti.
Gli effetti sistemici del fumo inoltre, si associano al altre disfunzioni , in particolare del muscolo scheletrico, cachessia, ipertensione diabete, cardiopatia ischemica, osteoporosi, obesità e\o sindrome metabolica (definita da resistenza all’insulina o iperglicemia, ipercolesterolemia o iperlipidemia aterogenetica, ipertensione, obesità addominale,anemia, reflusso GE, presenza di mediatori circolanti di flogosi (della fase acuta ---CRP) citocine (TNF-alfa, IL-6) chemochine (CXCL8) ad azione chemiotattica ed amplificante la flogosi tessutale, e procoagulativi (fatt. inibitori l’attività del plasminogeno, fibrinogeno).
I due fattori di rischio principali, che agiscono in modo sinergico nel determinare la sindrome da complesse comorbidità croniche (CSIS) sono il fumo e l’obesità
La diagnosi di BPCO impone pertanto un ampliamento degli accertamenti volti a determinare la presenza di comorbidità che influenzano grandemente gli esiti della gestione di questi pazienti.
Se si considera che l’attuale strategia terapeutica della BPCO è sostanzialmente volta al controllo dei sintomi , un approccio più completo alle comorbidità può fornire le opportunità per incidere sul decorso naturale della BPCO e identificare nuovi targets terapeutici.
IL-6 incrementa la secrezione di proteine della fase acuta dell’infiammazione, correla con cachessia muscolare, in modelli animali determina danno cardiaco e si associa ad altre comorbidità
TNF-alfa è correlato con cachessia(depauperamento muscolare) in COPD
CRP secreta in particolare durante la fase acuta dell’infiammazione nel COPD; è un indicatore di rischio cardio-vascolare . Non è nota la sua funzione (nella risposta flogistica è correlata all’attivazione del complemento e partecipa alla risposta difensiva di tipo innato).
CXCL8 (IL-8) reclutamento di neutrofili e monociti
Cardiovascular
Events
Fabbri LM, Luppi F et al, Eur Respir J 2008
Liver
CRP 2

3. This provides a summary of the recommended treatment at each stage of COPD.

4. Prevalence of Comorbid Diagnoses and Symptoms
Among a National Sample of Patients with COPD
OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States but is often undertreated. COPD often overlaps with other conditions such as hypertension and osteoporosis, which are less morbid but may be treated more aggressively. We evaluated the prevalence of these comorbid conditions and compared testing, patient knowledge, and management in a national sample of patients with COPD.
METHODS: A survey was administered by telephone in 2006 to 1003 patients with COPD to evaluate the prevalence of comorbid conditions, diagnostic testing, knowledge, and management using standardized instruments. The completion rate was 87%.
RESULTS: Among 1003 patients with COPD, 61% reported moderate or severe dyspnea and 41% reported a prior hospitalization for COPD. The most prevalent comorbid diagnoses were hypertension (55%), hypercholesterolemia (52%), depression (37%), cataracts (31%), and osteoporosis (28%). Only 10% of respondents knew their forced expiratory volume in 1 second (95% confidence interval [CI], 8-12) compared with 79% who knew their blood pressure (95% CI, 76-83). Seventy-two percent (95% CI, 69-75) reported taking any medication for COPD, usually a short-acting bronchodilator, whereas 87% (95% CI,(84-90) of patients with COPD and hypertension were taking an antihypertensive medication and 72% (95% CI, 68-75) of patients with COPD and hypercholesterolemia were taking a statin.
CONCLUSION: Although most patients with COPD in this national sample were symptomatic and many had been hospitalized for COPD, COPD self-knowledge was low and COPD was undertreated compared with generally asymptomatic, less morbid conditions such as hypertension.
Comorbid Conditions
Table 2 shows the frequencies of comorbid diagnoses and
nonrespiratory symptoms reported by the 1003 patients with
COPD stratified by gender. Hypertension (55%) and hypercholesterolemia
(52%) were the most prevalent comorbidities,
followed in frequency by depression, cataracts, and
osteoporosis. Sleep apnea and diabetes each occurred in
approximately one quarter of patients with COPD. Twentytwo
percent reported angina, 19% reported a history of
myocardial infarction, and 14% reported a history of a
cerebrovascular event (with overlap). Eleven percent reported
chronic kidney disease, and 6% reported congestive
heart failure. Of the 6% with cancer, colon (0.7%), prostate
(0.6%), lung (0.5%), and breast (0.4%) cancers were most
common. The prevalence of comorbid conditions was generally
similar among women and men, except for depression,
osteoporosis, and cardiovascular disease. Symptoms
of joint pain, gastroesophageal reflux disease, and sinus
problems were highly prevalent (Table 2) and more commonly
reported by women than men.
The American Journal of Medicine
(2009) 122,

5. Frequency distribution of comorbid conditions among patients with COPD.
The median number of comorbid conditions among these
patients with COPD was 9 (interquartile range, 6-12). The
frequency distribution of the total number of comorbidities
is shown in Figure 1. The mean MRC Dyspnea Index
increased monotonically with the number of comorbid conditions
from 2.3 among those with 1 to 5 comorbid conditions
to 4 among those with 20 or more comorbid conditions
(Figure 2).
Barr, The American Journal of Medicine, 2009

6. Patients with COPD demonstrated better recall of their blood pressure
The high prevalence of comorbidity in COPD is likely multifactorial and associated with age and multisystem impact of tobacco exposure
COPD was less commonly treated than less symptomatic and less morbid conditions, such as hypertension and hypercholesterolemia, despite the increasing number of proven medications for the treatment of COPD
Patients with COPD demonstrated better recall of their blood pressure
and cholesterol than of their FEV1
This is not surprising in the context of the greater public education regarding hypertension and hypercholesterolemia
CONCLUSIONS
Comorbidities are common in COPD and likely add to the complexity and cost of care. Although patients with COPD
take a large number of medications, relatively few of these medications are for COPD.
This discrepancy may relate to poor physician and patient knowledge about COPD or reflect the more limited evidence base for COPD compared with other leading causes of death.
Although advances in COPD pathophysiology and clinical research are needed to have a full impact, better education and optimal use of existing therapeutic strategies are warranted to improve symptoms and reduce hospitalizations in patients with COPD.
Barr, The American Journal of Medicine, 2009

7. Prevention of exacerbations of chronic obstructive pulmonary diseases with tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trial.
Co-morbilità
Vascolari (compresa l’ipertensione) %
Cardiache %
Gastrointestinali %
Metaboliche o nutrizionali %
Muscolo scheletriche o connettivali %
Genito-urinarie %
Neurologiche %
Niewoehner et al, Ann Intern Med 2005;143:

8. Role of co-morbidities in a cohort of patients with COPD undergoing pulmonary rehabilitation
51% of the patients reported at least one chronic
comorbidity added to COPD.
Metabolic (systemic hypertension, diabetes and/or
dyslipidaemia) and heart diseases (chronic heart
failure and/or coronary heart disease) were the most
frequently reported co-morbid combinations (61% and
24%, respectively)
Crisafulli E, et al.,Thorax 2008;63: 8

9. Screening della comorbilità: alcuni esempi
Patologia
Identificazione
CHF
Rx torace, BNP
Osteoporosi
DEXA, morfometria colonna dorsale
Depressione
Geriatric Depression Scale
Deficit cognitivo
MMSE, Clock Drawing test
Glaucoma
Tonometria oculare
Insufficienza renale
MDRD (stima indiretta GFR)
GOLD Linee guida BPCO 2010 9

10. Cause of death on treatment
Deaths (%)
Placebo
SFC
L’importanza delle patologie associate a BPCO ci viene dallo studio TORCH che rappresenta uno degli studi più accurati e metodologicamente più solidi in quanto sono stati seguiti per tre anni oltre pazienti con diagnosi documentata di BPCO nei vari stadi per valutare la risposta al trattamento sia in termini di sopravvivenza (outcome primario) che riacutizzazioni ; sono state considerate anche le patologie associate e documentate le diverse cause di morte.
La prima causa di morte in soggetti sia trattati che non trattati è risultata la patologia cardiovascolare, a conferma della rilevanza di questa patologia nei soggetti con BPCO
Cause of all deaths up to 3 years was adjudicated by the Clinical Endpoint Committee. The slide shows deaths by treatment as a percentage of total patients in the ITT groups.
In total:
27% of deaths were due to cardiovascular disease
35% of deaths were due to pulmonary causes
21% of deaths were due to cancer
10% of deaths were due to other causes
7% of deaths were unknown
SFC reduced the number of deaths related to cardiovascular, pulmonary and other causes compared with placebo, but not cancer-related deaths.
References
Calverley PMA, Anderson JA, Celli B. for the TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. NEJM 2007; 356(8):
Cardio- vascular
Pulmonary
Cancer
Other
Unknown
Calverley et al. NEJM 2007 10

11. What do COPD Patients Die From?
Mannino et al, ERJ, 2007

12. Systemic Consequences of COPD
Cardiovascular Morbidity 8
P=0.001 7 6 5 4
Cardiac infarction injury score 3 2
The Cardiac Infarction Injury Score (CIIS) is an electrocardiographic classification system that was developed as a diagnostic tool to assess the extent of cardiac injury in acute myocardial infarction.
Moderate airflow obstruction was associated with smaller but still significant increases in these levels.
Moderate and severe airflow obstruction was associated with increased occurrence of ischemic changes on electrocardiograms of participants.
In the presence of both highly elevated CRP and moderate or severe airflow obstruction, the Cardiac Infarction Injury Score was 2.68 and 5.88 U higher, respectively, than in those without airflow obstruction and with low CRP, which suggests an additive effect of CRP and COPD on the risk of cardiac injury. 1
High CRP
Severe
obstruction
High CRP
and severe obstruction
Sin and Man, Circulation. 2003

13. . Soriano , CHEST 2010 450 population participants without CVD
52 population participants with CVD,
119 hospital patients with CAD
The prevalence of airfl ow limitation (AL) in patients with cardiovascular disease (CVD) is unknown, and whether AL is adequately diagnosed and treated in these patients has not been investigated before, to our knowledge.
Methods: We compared clinical and spirometric data in three groups of individuals. Two of them were participants in the follow-up of an ongoing population-based study according to the presence or absence of CVD. The third group included patients with coronary artery disease (CAD) confirmed by coronariography regularly visited at a tertiary referral university hospital.
AL was defined according to the Global Initiative for Obstructive Lung Disease guidelines.
Soriano , CHEST 2010

14. .
Results: We studied 450 population participants without CVD, 52 population participants with CVD, and 119 hospital patients with CAD. The prevalence of AL in these three groups was 17.5% (95% CI, ), 19.2% (95% CI, ), and 33.6% (95% CI, ), respectively ( P , .05). Underdiagnosis of AL ranged from 60% in population participants with CVD up to 87.2% in hospital patients with CAD. Sixty percent of those with spirometrically confi rmed AL (in all three groups) did not receive any respiratory treatment.
First, we found that the prevalence of AL in a population
sample of adults of the Balearic Islands was 18%.
Burden of Lung Disease investigators found in
Salzburg, Austria (26.1%).
Second, we found that the prevalence of AL in
population participants with CVD (19.2%; 95% CI,
) was only slightly higher than that of population
participants without it (17.5%; 95% CI, )
( P . .05). This observation is against our working
hypothesis that predicted a higher prevalence of AL
compatible with COPD in patients with CVD. However,
the small size of this group (n 52) limits the
interpretation of this observation. In fact, when we
studied a larger population of hospital patients with
CAD (n 119), we found that the prevalence of AL
was indeed much higher (33.6%)
Third, and regrettably, we found that 60% to 87%
of patients with CVD and AL identified here were
undiagnosed and, therefore, untreated.
Soriano , CHEST 2010

15. One of every three patients with CAD recruited from the hospital clinic, and one of every five patients with CVD in the general population, suffer AL compatible with COPD
The majority of them are not diagnosed, and, therefore, they remain mostly untreated.
These observations are clinically relevant because COPD is now considered a preventable and treatable disease.
Several previous studies have reported consistently that the burden of CVD is increased in patients with COPD.
For instance, a large (n 5 11,493) retrospective study in health-care databases of Saskatchewan, Canada reported increased risks for arrhythmia, angina, acute myocardial infarction, congestive heart failure, and stroke in patients with COPD. Likewise, the Atherosclerosis Risk in Communities study cohort found that patients with severe COPD had a higher prevalence of hypertension and CVD. Finally, cardiac failure has been found in about 20% of patients with COPD.
To our knowledge, however, our study is the first to investigate the prevalence, severity and treatment of COPD in patients with CVD.
Soriano , CHEST 2010

16. 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 16

17. ARTERIAL STIFFNESS IS INDEPENDENTLY ASSOCIATED WITH EMPHYSEMA SEVERITY IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Emphysema severity is associated with arterial stiffness in patients with COPD
Similar pathophysiological processes may be involved in both lung and arterial tissue
Further studies are now required to identify the mechanism underlying this newly described association
RATIONALE: More patients with chronic obstructive pulmonary disease (COPD) die of cardiovascular causes than of respiratory causes, and patients with COPD have increased morbidity and mortality from stroke and coronary heart disease. Arterial stiffness independently predicts cardiovascular risk, is associated with atheromatous plaque burden, and is increased in patients with COPD compared with control subjects matched for cardiovascular risk factors. Elastin fragmentation and changes in collagen are found in the connective tissue of both emphysematous lungs and stiff arteries, but it is not known whether the severity of arterial stiffness in patients with COPD is associated with the severity of emphysema. OBJECTIVES: To identify whether the extent of arterial stiffness is associated with emphysema severity. METHODS: We performed a cross-sectional study in 157 patients with COPD. MEASUREMENTS AND MAIN RESULTS: We measured pulse wave velocity (a validated measure of arterial stiffness), blood pressure, smoking pack-years, glucose, cholesterol, and C-reactive protein in 157 patients with COPD. We assessed emphysema using quantitative computed tomography scanning in a subgroup of 73 patients. We found that emphysema severity was associated with arterial stiffness (r = 0.471, P < 0.001). The association was independent of smoking, age, sex, FEV(1)% predicted, highly sensitive C-reactive protein and glucose concentrations, cholesterol-high-density lipoprotein ratio, and pulse oximetry oxygen saturations. CONCLUSIONS: Emphysema severity is associated with arterial stiffness in patients with COPD. Similar pathophysiological processes may be involved in both lung and arterial tissue and further studies are now required to identify the mechanism underlying this newly described association.
MacNee W et al, AJRCCM 2007; 176: 17

18. RELATIONSHIP BETWEEN COPD AND CARDIOVASCULAR DISEASE
CRP (FIBRINOGEN)
Systemic
Inflammation
Cytokines
Complement
activation
ENDOTELIN-1
IL-6
LDL
uptake
Certain molecules can promote (or amplify) this inflammatory process. The most studied of these molecules is CRP. It is an acute phase protein that responds to infectious or inflammatory stress. When released into the systemic circulation, CRP can upregulate production of other inflammatory cytokines, activate the complement system, promote uptake of lowdensity lipoproteins (LDL) by macrophages, and foster leukocyte adhesion to vascular endothelium, thereby amplifying the inflammatory cascade. CRP can also upregulate the expression of adhesion molecules and monocyte chemotactic protein-1, promote macrophage uptake of LDL and interact with endothelial cells to stimulate the production of IL-6 and endothelin-1 [80–83]. Other acute phase proteins released by the liver, such as plasma fibrinogen, can also be used to predict future cardiovascular events
ICAM VCAM
(adhesion molecules)

19. The risk ratio of developing CHF in COPD patients is 4.5
(compared with age-matched controls without COPD after
adjustments for cardiovascular risk factors ) (1)
The rate-adjusted hospital prevalence of CHF is 3 times greater among patients discharged with a diagnosis of COPD compared with patients discharged without mention of COPD (2)
(1) Curkendall SM, DeLuise C, Jones JK, et al. Cardiovascular disease in patients with chronic obstructive pulmonary disease, Saskatchewan Canada cardiovascular disease in COPD patients. Ann Epidemiol 2006;16:63–70.
(2) Holguin F, Folch E, Redd SC, Mannino DM. Comorbidity and mortality in COPD-related hospitalizations in the United States,
1979 to Chest 2005;128:2005–11.

20. How common is HF in COPD? Prevalence (%) Prevalence (%)
Italian Health Search Database
n=341,329
7.9% prevalence HF in COPD overall
Scottish Continuous Morbidity Record
n=377,439
11.9% prevalence HF in COPD overall
Cazzola M. Respiration 2010; epub; Hawkins NM. Data on file.

21. How common is LVSD in COPD?
high prevalence
selected populations
severe COPD
suspected LVSD
coronary disease
Prevalence (%)
I clinici che si trovano ad affrontare il problema diagnostico della dispnea in soggetti anziani considerano come cause prioritarie lo scompenso cardiaco e la BPCO molto spesso in modo separato con il primo nell’ambito dello specialista cardiologo e il secondo viene considerato nell’ambito dell’interesse pneumologico.
In questo lavoro Frans Rutten compie un accurata revisione bibliografica per documentare quale sia la presenza delle due diverse patologie e come si associano; se sono poche le indagini tese a documentare la presenza di BPCO in popolazioni di cardiopatici, più numerose sono quelle reciproche ossia la ricerca di segni di disfunzione ventricolare sinistra in soggetti con BPCO. La ricerca tramite Medline comprendeva lavori pubblicati in lingua inglese dal 1966 al 2005.
Sei studi (riportati in rapporto all’anno di pubblicazione ) quantificavano il riscontro percentuale di LVSD : il range varia considerevolmente, dal 10 al 46%
La differenza nei lavori considerati si spiega con la differenza delle popolazioni studiate e le maggiori prevalenze si riscontrano in casistiche di soggetti con BPCO riacutizzata. Il dato deve comunque far riflettere perchè si tratta sempre di percentuali molto significative e gli autori concludono che il dato della coesistenza di HF e BPCO è spesso ignorato o sottostimato nella pratica clinica (Rutten è un medico generale di Utrecht, NL) ma se ricercato dimostra una coesitenza molto significativa che deve indurre alle opportune considerazioni in termioni di trattamento, prognosi, follow up.
La presenza di LVSD e più in generale di cardiopatia associata a BPCO deve sempre essee considerata nella pratica clinica-
Rutten FH. Eur J Heart Fail 2006: 8(7): 21

23. Kaplan–Meier event-free survival curves according to chronic obstructive pulmonary disease coexistence
Studio retrospettivo di coorte su 187 pazienti seguiti presso un ambulatorio con riscontro di LVSD e spirometria per classificarli secondo stadio GOLD
Questo studio analizza la sopravivenza in popolazioni di pazienti con HF in funzione della presenza di COPD : si dimostra una sopravvivenza significativamente minore nei soggetti con CFH e COPD rispetto quelli che non hanno COPD. Se si analizzano le curve di sopravvivenza in funzione degli stadi di gravità della COPD, si vede come le sopravvivenze si riducono significativamente negli stadi più gravi mentre la variazione non è apprezzabile per i soggetti fumatori senza COPD e per lo stadio I
Mascarenhas,
Am Heart J 2008

24. Why is heart failure important?
Section 3: Diuretic Therapy in Acute Decompensated Heart Failure
Why is heart failure important? 12 24 36 48 60 72
0.5
0.6
0.7
0.8
0.9
1.0
Time (Months)
Survival
COPD + Heart failure
COPD GOLD + Heart Failure
COPD
COPD GOLD
primary care patients with COPD ≥ 65 years (n=404)
follow up for a mean duration of 4.2 (SD 1.4) years.
HF doubles mortality of patients with COPD: adjusted HR 2.1 (1.2–3.6 C.I.)
Perché è importante diagnsticare la presenza di CHF in pazienti con COPD?
Questo studio analizza l’impatto della presenza di CHF sulla sopravvivenza di soggetti con e si dimostra che i soggetti diagnosticati con criteri GOLD e (verosimilmente con diagnosi più accurata) hanno una mortalità quasi raddoppiata rispetto i soggetti senza CHF.
AIMS: To compare prognosis in patients with chronic obstructive pulmonary disease (COPD) with or without concomitant heart failure. METHODS AND RESULTS: Patients aged 65 years or over with a general practitioner (GP)'s diagnosis of COPD but without a prior diagnosis of heart failure underwent an extensive diagnostic work-up including echocardiography and pulmonary function tests in the period An expert panel then confirmed the presence or absence of COPD according to the GOLD criteria and (previously undiagnosed) heart failure according to the criteria of the ESC heart failure guidelines. This cohort of 405 patients was followed up for a mean duration of 4.2 (SD 1.4) years. The GP's electronic medical files relating to the participants, including any specialist letters, were scrutinized until April 2007 for information about drug use, exacerbations of COPD, pneumonia, hospitalizations, death, and cause of death. The mean age of patients at the start of the study was 73.0 (SD 5.3) years, and 54% were male. The presence of newly detected heart failure significantly increased all-cause mortality independent of gender, age, history of ischaemic heart disease, hypertension, diabetes mellitus, atrial fibrillation, smoking, and cardiovascular drug use at baseline (adjusted hazard ratio, 2.1; 95% confidence interval, ; P = 0.01). CONCLUSION: Heart failure is a strong independent predictor of all-cause mortality in patients with a diagnosis of COP
Boudestein LC. Eur J Heart Fail 2009; 11(12):

25. M. Padeletti- LeJemtel : International Journal of Cardiology, 2008
Mechanisms of Skeletal Muscle
Atrophy in Patients With CHF or COPD
Per quanto la COPD e CHF possano coinvolgere molti organi, questi pazienti sviluppano comunemente simili alterazioni a carico della muscolatura scheletrica (SM).
Il meccanismo che sta alla base è una ridotta sintesi proteica muscolare ed un aumentato catabolismo secondario al disuso (inattività muscolare di questi pazienti), alla presenza di flogosi sistemica di basso grado e di un aumentato stress ossidativo caratteristico in particolare della BPCO.
La ridotta sintesi e l’aumentata degradazione proteica condividono comuni strade patogenetiche.
Si parte da una aumentata resistenza all’insulina (che caratterizza la sindrome metabolica della BPCO) e da una riduzione dell’ormone IGF-1 (insulin growth factor) che determina ridotta fosforilazione (fosfatidil-inositolo) che riduce una protein Kinasi che riduce glucogeno sintetasi –kinasi e mTOR (mammalian target of rapamicina) ossia chinasi che regloano la crescita cellulare, e l’attivazione di fattori di trascrizione nucleare (FOXO) che in ultima analisi incrementano un processo di defosforilazione che produce una accelerata degradazione proteica .
Un’ulteriore segnale e ipotizzato essere l’attivazione di capsasi che induce aumentata apoptosi cellulare muscolare
M. Padeletti- LeJemtel : International Journal of Cardiology, 2008

26. PROGRESSION OF CHF AND COPD
La presenza di BPCO è un fattore che contribuisce alla sofferenza ed ipotrofia della muscolatura scheletrica (TNF, infiamm, sistemica) e aumento dello stres ossidativo. Ridotta sintesi proteica
è presente ipotrofia muscolare, ridotta massa con ridotta area sezionale con riduzione delle fibre muscolari di tipo aumento delle fibre tipo II e II con attività glicolitica e riduzione di quella ensimatica-ossidativa, maggior propensione a sviluppare vie metaboliche che comportano una maggior produzione di acidosi durante lo sforzo.
La riduzione dell’uptake di ossigeno procede proporzionalmente con la progressione della gravità della malattia (COPD_HF)
In definitiva:
Si può schematizzare un tempogramma in cui alla perdita di funzione cardiaca e polmonare (A) funzione muscolare (B) corrisponde una riduzione della incapacità funzionale dell’individuo che aumenta in modo più marcato quando all’incremento della disfunzione d’organo (cuore polmone) si associa quella muscolare. I dati sono estrapolati da osservazioni cliniche e di studi della funzione VS
M. Padeletti- LeJemtel : International Journal of Cardiology, 2008 26

27. Weight loss is a prognostic factor in COPD
BMI > 29 Kg/m2
BMI Kg/m2
Tra i fattori prognostici , il danno muscolare (perdita di massa muscolare...) è uno di quelli che determina direttamente (inabilità, ridotta tolleranza allo sforzo) o indirettamente (insufficienza respiratoria) il decorso della patologia e la qualità degli outcomes.
In questa indagine retrospettiva si dimostra che il BMI è un fattore prognostico indipendente di aumentato rischio di mortalità in BPCO.
The combined results of the two survival analyses provide further evidence to support the hypothesis that body weight has an independent effect on survival in COPD
Treatment response, i.e., both weight gain as well as improvement of respiratory muscle strength, however, were significantly related to survival.
Knowledge of the pathogenesis of weight loss and muscle wasting is essential for an optimal implementation and interpretation of nutritional and metabolic therapy. It is clearly established (23) that a substantial proportion of patients with moderate to severe COPD exhibit an elevated resting metabolic rate. Careful analysis of the available nutritional intervention studies in view of our recent data on total daily energy expenditure in COPD, suggests that nonresponse to nutritional therapy may have been partly due to inadequate judgment of energy expenditure or patient’s inability to ingest the required energy intake.
Another possible explanation could be the presence of alterations in intermediary metabolism superposed on the elevated energy metabolism.
The objective of the study was to further unravel the prognostic significance of body weight changes
in patients with COPD. Two survival analyses were performed: (1) a retrospective study, including
400 patients with COPD none of whom had received nutritional therapy; (2) a post hoc analysis of a
prospective study, including 203 patients with COPD who had participated in a randomized placebocontrolled trial. There was no overlap between the patient groups. Baseline characteristics of all patients were collected on admission to a pulmonary rehabilitation center in stable clinical condition. In the prospective randomized placebo-controlled trial, the physiologic effects of nutritional therapy alone (n 5 71) or in combination with anabolic steroid treatment (n 5 67) after 8 wk was studied in patients with COPD prestratified into a depleted group and a nondepleted group. Mortality was assessed as overall mortality. The Cox proportional hazards model was used to quantify the relationship
between the baseline variables age, sex, spirometry, arterial blood gases, body mass index
(BMI), smoking, and subsequent overall mortality. Additionally, the influence of treatment response
on mortality was investigated in the prospective study.
The retrospective study revealed that low BMI (p, 0.001), age (p , ) and low PaO2 (p , 0.05) were significant independent predictors of increased mortality.
After stratification of the group into BMI quintiles a threshold value of 25 kg/m2
was identified below which the mortality risk was clearly increased.
In the prospective study, weight gain (. 2 kg/8 wk) in depleted and nondepleted patients with COPD, as well as increase in maximal inspiratory mouth pressure during the 8-wk treatment, were significant predictors of survival.
On Cox regression analysis weight change entered as a time-dependent covariate remained an independent predictor of mortality in addition to all variables that were entered in the retrospective study.
The combined results of the two survival analyses provide evidence to support the hypothesis that body
weight has an independent effect on survival in COPD. Moreover the negative effect of low body
weight can be reversed by appropriate therapy in some of the patients with COPD.
Schols AMWJ, Slangen J, Volovics L, Wouters EFM. Weight loss is a reversible factor in the prognosis of
chronic obstructive pulmonary disease.
AM J RESPIR CRIT CARE MED 1998;157:1791–1797.
BMI Kg/m2
BMI < 20 Kg/m2
Schols et al. AJRCCM 1998; 157:

28. INSULIN RESISTANCE AND INFLAMMATION - A FURTHER SYSTEMIC COMPLICATION OF COPD
This study demonstrates greater insulin resistance in non-hypoxaemic patients with COPD compared with healthy subjects, which was related to systemic inflammation. This relationship may indicate a contributory factor in the excess risk of cardiovascular disease and type II diabetes in COPD
Chronic obstructive pulmonary disease (COPD) is associated with a continuous systemic inflammatory response. Furthermore, COPD is associated with an excess risk for cardiovascular disease and type II diabetes. Systemic inflammation in other populations is a factor in atherogenesis and has been associated with insulin resistance. We assessed the association between systemic inflammation and insulin resistance in non-hypoxaemic patients with COPD. Fasting plasma glucose, insulin and inflammatory mediators were measured in 56 patients and 29 healthy subjects. Body mass index (BMI) and height squared fat- and fat-free-mass index were similar between subject groups. Using homeostatic modelling techniques, mean (SD) insulin resistance was greater in the patients, 1.68 (2.58) and 1.13 (2.02) in healthy subjects, p= Fasting plasma insulin was increased in patients while glucose was similar to that in healthy subjects. Patients had increased circulating inflammatory mediators. Insulin resistance was related to interleukin-6 (IL-6), r=0.276, p=0.039, and tumour necrosis factor alpha soluble receptor I, r=0.351, p= Both IL-6 and BMI were predictive variables of insulin resistance r(2)=0.288, p<0.05. We demonstrated greater insulin resistance in non-hypoxaemic patients with COPD compared with healthy subjects, which was related to systemic inflammation.
This relationship may indicate a contributory factor in the excess risk of cardiovascular disease and type II diabetes in COPD
Bolton CE et al, COPD Jun ;4(2):121-6 28

29. 5-yrs mortality
The present study analysed data from 20,296 subjects aged >45 yrs at baseline in
the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular
Health Study (CHS)
In questo studio epidemiologico gli autori calcolano il rischio di morte a 5 anni in funzione della presenza di comorbilità in soggetti con BPCO in nei diversi stadi di gravità, in soggetti normali e con deficit restrittivo : la BPCO infatti è associata alla presenza di malattia cardiovascolare, diabete ed ipertensione
Il rischio di morte era calcolato con metodica di COX (Cox Hazard ratio) aggiustato per altre variabili come sesso, età, BMI , fumo su una popolazione di oltre soggetti di età superiore a 45 anni. Il dato più significativo è ll’aumento del rischio in funzione del numero di comorbilità presenti e della progressione della gravità: esiste infatti una differenza altamente significativa tra gli stadi 3-4 e gli altri e nelle varie classi il rischio aumenta con l’aumentare del numero di patologie associate alla BPCO
The aim of the present study was to determine the relationship between COPD and the common,
chronic comorbid conditions of cardiovascular disease, hypertension and diabetes mellitus, and
to determine how these affect the outcomes of hospitalisations and death. This analysis was
carried out by combining two existing databases, the Atherosclerosis Risk in Communities Study
(ARIC) [12] and the Cardiovascular Health Study (CHS) [13], which are described below.
The original ARIC cohort, initiated in 1986, included 15,792 The original CHS cohort of 5,201 males and females.
Results from Cox proportional hazard models (presented as hazard ratio with 95% confidence interval) that predict death within 5 yrs by modified Global Initiative for Obstructive Lung Disease (GOLD) category and the presence of no (&), one (h), two (&) or three (&) comorbid diseases (diabetes, hypertension or cardiovascular disease). The reference group (normal) was subjects with normal lung function for each comorbid disease. Models were adjusted for age, sex, race, smoking status, education level and body mass index.
Subjects were from the Atherosclerosis Risk in Communities Study during 1986–1989 and the Cardiovascular Health Study during 1989–1990. GOLD 3/4: forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) ,0.70 and FEV1 ,50% predicted; GOLD 2: FEV1/FVC ,0.70 and FEV1 o50 to ,80% pred; GOLD 1: FEV1/FVC ,0.70 and FEV1 o80% pred; restricted (R): FEV1/FVC o0.70 and FVC ,80% pred; GOLD 0: presence of respiratory symptoms in the absence of any lung function abnormality and no lung disease.
SE analizziamo l’entità del rischio (di morte a 5 anni) esso aumenta in modo significativo per i soggetti con COPD 3-4 stadio rispetto gli altri gruppi.
Ogni sottogruppo aumenta in funzione del numero di comorbilità e non della progressione dell’ostruzione (eccetto COPD 3-4 st).
Se analizziamo odds ratio di ogni singolo gruppo rispetto il mormale , vediamo che non vi sono differenze significative
The combination of multiple comorbid
diseases, along with respiratory impairment, also resulted in
a higher risk of death (fig. 2). For example, a subject with GOLD
stage 3 or 4 COPD and all three comorbid diseases had a 20-fold
higher risk of death than a subject with normal lung function
and no comorbid disease (fig. 2). There was no significant
interaction between respiratory impairment, comorbid disease
and death (p.0.10 for all models).
The present study analysed data from 20,296 subjects aged >45 yrs at baseline in the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS).

30. diabetes,
b) hypertension
c) cardiovascular disease
Results from Cox proportional hazard models (presented as hazard ratio with 95% confidence interval) that predict death within 5 yrs by modified Global Initiative for Obstructive Lung Disease (GOLD) category and the presence of a) diabetes, b) hypertension or c) cardiovascular disease
Results from Cox proportional hazard models (presented as hazard ratio with 95% confidence interval) that predict death within 5 yrs by modified Global Initiative for Obstructive Lung Disease (GOLD) category and the presence of a) diabetes, b) hypertension or c) cardiovascular disease. The reference group (normal) was subjects with normal lung function who do not have the comorbid disease of interest.
Models were adjusted for age, sex, race, smoking status, education level and body mass index. Subjects were from the Atherosclerosis Risk in Communities Study during 1986–1989 and the Cardiovascular Health Study during 1989–1990. &: with comorbid disease; h: without comorbid disease. GOLD 3/4: forced expiratory volume in one second
(FEV1)/forced vital capacity (FVC) ,0.70 and FEV1 ,50% predicted; GOLD 2: FEV1/FVC ,0.70 and FEV1 o50 to ,80% pred; GOLD 1: FEV1/FVC ,0.70 and FEV1 o80% pred; restricted (R): FEV1/FVC o0.70 and FVC ,80% pred; GOLD 0: presence of respiratory symptoms in the absence of any lung function abnormality and no lung disease.
Within 5 yrs of baseline evaluation, 1,202 (5.9%) study subjects
died. The presence of respiratory impairment and comorbid
disease predicted higher mortality, with cardiovascular disease
and diabetes mellitus demonstrating a larger effect on mortality
than hypertension

31. diabetes,
b) hypertension
c) cardiovascular disease
Results from Cox proportional hazard models (presented as hazard ratio with 95% confidence interval) that predict time to first hospitalisation within 5 yrs by modified Global Initiative for Obstructive Lung Disease (GOLD) category and the presence of a) diabetes b) hypertension or c) cardiovascular
Results from Cox proportional hazard models (presented as hazard ratio with 95% confidence interval) that predict time to first hospitalisation within 5 yrs by modified Global Initiative for Obstructive Lung Disease (GOLD) category and the presence of a) diabetes, b) hypertension or c) cardiovascular disease.
The reference group (normal) comprised subjects with normal lung function who do not have the comorbid disease of interest. Models were adjusted for age, sex, race, smoking status, education level and body mass index

32. REDUCTION OF MORBIDITY AND MORTALITY BY STATINS, ANGIOTENSIN-CONVERTING ENZYME INHIBITORS, AND ANGIOTENSIN RECEPTOR BLOCKERS IN COPD
The combination of statins and either ACE inhibitors or ARBs is associated with a reduction in COPD hospitalization and total mortality not only in the high CV risk cohort but also in the low CV risk cohort
OBJECTIVES: The purpose of this study was to determine if statins (hydroxymethylglutaryl CoA reductase inhibitors [HMG-CoA]), angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs) reduce cardiovascular (CV) events and pulmonary morbidity in chronic obstructive pulmonary disease (COPD) patients.
BACKGROUND: Few current COPD therapies alter prognosis. Although statins, ACE inhibitors, and ARBs improve outcomes in CV populations, their benefits in COPD patients both with and without concomitant heart disease has not previously been studied.
METHODS: A time-matched nested case-control study of two population-based retrospective cohorts was undertaken: 1) COPD patients having undergone coronary revascularization (high CV risk cohort); and 2) COPD patients without previous myocardial infarction (MI) and newly treated with nonsteroidal anti-inflammatory drugs (low CV risk cohort). Prespecified outcomes were COPD hospitalization, MI, and total mortality.
RESULTS: These drugs reduced both CV and pulmonary outcomes, with the largest benefits occurring with the combination of statins and either ACE inhibitors or ARBs. This combination was associated with a reduction in COPD hospitalization (risk ratio [RR] 0.66, 95% confidence interval [CI] 0.51 to 0.85) and total mortality (RR 0.42, 95% CI 0.33 to 0.52) not only in the high CV risk cohort but also in the low CV risk cohort (RR 0.77, 95% CI 0.67 to 0.87, and RR 0.36, 95% CI 0.28 to 0.45, respectively). The combination also reduced MI in the high CV risk cohort (RR 0.39, 95% CI 0.31 to 0.49). Benefits were similar when steroid users were included.
CONCLUSIONS: These agents may have dual cardiopulmonary protective properties, thereby substantially altering prognosis of patients with COPD. These findings need confirmation in randomized clinical trials.
Am J Physiol Lung Cell Mol Physiol May;294(5):L Epub 2008 Feb 29.
Mancini JB, et al. J Am Coll Cardiol Jun 20;47(12): 32

33. Challenges in patients with coexistent COPD and CHF
COPD is the one that most delays the diagnosis of CHF
COPD is most often advocated for nonadherence to therapeutic guidelines, especially betablockade (BB)
safety and efficacy of BB and bronchodilators in patients with COPD and HF
Pazienti con BPCO nota , quando hanno sitomi (dispnea) da scompenso cardiaco possono essere più facilmente sottovalutati (ricondotti alla BPCO) e non indirizzati ad esami cardiologici (eco) che possono dimostrare una disfunzione ventricolare sin , quindi l’esistenza di un scompenso e di conseguenza non vengono trattati.
La BPCO può essere una causa di mancata diagnosi di scompenso cardiaco.
Vedi Rutten……
M. Padeletti- LeJemtel : International Journal of Cardiology, 2008 33

34. restrizione polmonare
gabbia toracica
congestione
ematica
Lo scompenso cardiaco con interessamento della funzione ventricolare sin si caratterizza per una condizione di stasi polmonare che determina un’alterazione ventilatoria di tipo restrittivo dovuta anche alla presenza di cardiomagalia, di associato versamento pleurico e radiologicamente i segni di incremento della componente fluida con congestione delle strutture vascolari ilari ed interstiziali, comparsa di linee di Kerley B ingrandimento dei diametro cardiaco con aumento del rapporto cardiotoracica e aumento dimensionale del peduncolo vascolare . Questo classicamente in una situazione di scompenso cardiaco non associato al altre patologie
versamento
pleurico
Ridotta compliance
Aumento del lavoro respiratorio
cardiomegalia 34

35. Limitazione del flusso espiratorio
edema peribronchiale
espirazione
bassi volumi polmonari
bronchi
La presenza di bassi volumi polmonari per riduzione della CV associata ad edema peribronchiale secondario alla stasi polmonare su base emodinamica, può deternimare un fenomeno di occlusione precoce delle piccole vie analogo a quanto si riscontra , per certi versi, nell’enfisema e produrre una limitazione di flusso.
In definitiva va tenuto a mente che in soggetti con cardiopatia cronica la riduzione dei volumi espirati (conseguente alla riduzione ci FVC e IC e conseguentemente del Vol. corrente, assieme al fenomeno di una più precoce occlusione delle piccole vie aeree può determinare pattern con componente ostruttiva
alveoli
occlusione
forze radiali ridotte 35

36. Caution diagnosing COPD in HF
Airway compression
Bronchial
hyperresponsiveness
overestimate
severity
misdiagnosis
La limitazione di flusso è pertanto un dato comune in presenza di scompenso cardiaco (acuto) che contrasta con il deficit di tipo resistivo che è presente . L’edema alveolare ed interstiziale può causare compressione delle vie aeree ed ostruzione (compresa nell’ aumento di responsività bronchiale)
L’ondice di ostruzione (FEV-1) può aumentare fino al 35% dopo terapia diuretica.
Una diagnosi errata di ostruzione bronchiale da BPCO inesistente , come una mancata diagnosi di BPCO sono da evitare. Un’ostruzione in soggetto HF deve far riflettere prima di accettare la diagnosi di BOCO e decidere di sospendere B-bloccanti ed instaurare terapie con B-2_ agonisti.
Si deve pertanto sempre considerare di fare una valutazione spirometrica accurata nel paziente (reso) euvolemico.
always perform
Spirometry…
and always
when euvolaemic
inappropriate
avoidance
of β-blockers
inappropriate
bronchodilators

37. COPD masks or mimics heart failure
pulmonary vascular remodeling masks alveolar shadowing
radiology
hyperinflation reduces cardiothoracic ratio
vascular bed loss causes upper lobe venous diversion
Due diverse condizioni clinico-patogenetiche e due diversi quadri radiologici si trovano a coesistere in varia misura nel soggetto con COPD e HF
Radiology
Traditional features of HF obscured by concurrent changes of COPD.
Destruction of vascular bed often masks alveolar infiltrates - unilateral, asymmetric or regional patterns oedema.
Although we know cardiothoracic ratio is an unreliable marker at the best of times, it’s spuriously reduced in the presence of hyperinflation.
Pulmonary vascular remodeling in COPD may actually cause upper lobe venous diversion and mimic heart failure.
asymmetric and regional patterns
Gehlbach BK. Chest 2004; 125: 37

38. COPD masks or mimics heart failure
Riconoscere lo scompenso cardiaco in presenza di BPCO e vice versa può essere difficile. Complicato dalle similitudine dei sintomi e di segni .
La radiografia del torace è meno sensibile nell’evidenziare i segni di un ingrandimento cardiaco perché il rapporto cardio-toracico è condizionato dalla presenza di iperdistensione da enfisema e la dilatazione del ventricolo sinistro può essere mascherata da un’ipertrofia destra secondaria a BPCO . Per di più in COPD severa può essere presente un certo grado di congestione polmonare e persino di edema polmonare in assenza di manifesta insufficienza cardiaca .
I test di funzione ventilatoria possono essere alterati in senso ostruttivo, anziché restrittivo in corso di scompenso cardiaco

40. Why is diagnosis important?
Section 3: Diuretic Therapy in Acute Decompensated Heart Failure
Why is diagnosis important?
Renin-angiotensin-aldosterone system inhibition
bronchodilators
beta-blockers
heart failure
OUTCOMES
COPD
Perché è importante diagnosticare lo scompenso cardiaco in soggetti COPD (e viceversa) .
Le due patologie hanno trattamenti molto diversi ……in particolare l’uso dei b-bloccanti e-o dei broncodilatatori beta adrenergici possono condizionare in modo significativo gli outcomes
beta-agonists
devices
smoking cessation

41. THE IMPACT OF CARDIOSELECTIVE BETA-BLOCKERS ON MORTALITY IN PATIENTS WITH COPD AND ATHEROSCLEROSIS
b-blockers are often withheld from patients with chronic obstructive pulmonary disease (COPD) because of fear of pulmonary worsening
Beta1-blockers may reduce mortality in COPD patients undergoing vascular surgery (1)
In some patients with COPD selective beta1-blockers are safe and may reduce mortality (2)
BB in Patients With CHF and COPD Long-term BB is underused in CHF patients (3,77). Underuse of BB in CHF is largely due to the entrenched belief that it may precipitate respiratory deterioration when COPD coexists with CHF. Few reports of acute bronchospasm after initiation of BB lead to exclusion of patients with coexistent CHF and COPD from large BB trials (78).
Beta-blockers remain underprescribed to patients with CHF and COPD despite extensive safety data in patients with moderate to severe COPD.
Selective beta-1 adrenergic blockade. Respiratory symptoms
and FEV1 are not significantly worsened by selective beta-1 blockade (B1B) in COPD patients (80–86). Selective B1B with metoprolol succinate or tartrate (anche bisoprololo) was well tolerated for 3 months by 50 patients with coexistent ischemic cardiac disease and mild to severe COPD (87).
Patients remained free of adverse respiratory effects, and FEV1 was unchanged. Selective B1B does not attenuate beta-2 receptor (B2R) agonist-induced bronchodilatation (82). The cumulative evidence from trials and meta-analysis indicates that selective B1B should not be withheld when COPD coexists with cardiovascular diseases, because the benefits of selective B1B in cardiac patients with COPD far outweigh the risks
Nonselective BB combined with alpha-blockade.
The safety profile of carvedilol and labetalol that combine alpha-adrenergic blockade with nonselective BB is not as well-established as that of selective B1B in COPD. Labetalol at maximal dose does not affect FEV1 in COPD (79). Among 89 patients with coexistent COPD and CHF who received carvedilol for at least 3 months, only 13 did not tolerate carvedilol. Data regarding the use of carvedilol in COPD patients with reversible airflow obstruction are not available. In contrast to selective B1B, nonselective blockade attenuates B2R agonist-induced bronchodilatation.
Clinical experience with selective B1B and combined nonselective and alpha-blockade in COPD.
Betablockade with selective and nonselective agents does not affect the rate of hospitalization for COPD exacerbation in patients with recent myocardial infarction, whereas it beneficially impacts mortality (92,93). Although case studies have documented nonselective BB-triggered bronchospasm, BB with selective and nonselective agents does not appear to affect the rate of hospitalization for COPD exacerbation
1) Van Gestel , Am J Respir Crit Care Med
2) Salpeter S Cardioselective beta-blockers for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2005;4:CD 41

42. Short PM et al., 2011
Objective To examine the effect of β blockers in the
management of chronic obstructive pulmonary disease
(COPD), assessing their effect on mortality, hospital
admissions, and exacerbations of COPD when added to
established treatment for COPD.
Patients were divided into subgroups based on their maximal stepwise inhaled therapy and β blocker
Use
Design Retrospective cohort study using a disease
specific database of COPD patients (TARDIS) linked to the
Scottish morbidity records of acute hospital admissions,
the Tayside community pharmacy prescription records,
and the General Register Office for Scotland death
Registry.Setting Tayside, Scotland (2001–2010)
Population 5977 patients aged >50 years with a diagnosis
of COPD.
Main outcome measures Hazard ratios for all cause
mortality, emergency oral corticosteroid use, and
respiratory related hospital admissions calculated
through Cox proportional hazard regression after
correction for influential covariates.
Baseline characteristics of 5977 patients at diagnosis of COPD, grouped according to final treatment.

43. Short PM et al., 2011
The addition of a β blocker had no deleterious
impact when added to a regimen that included a long
acting bronchodilator or inhaled corticosteroid (such
as inhaled corticosteroids and long acting β agonists
or inhaled corticosteroids, long acting β agonists, and
tiotropium)
Moreover, when FEV1 values at the start of the study period were compared
with those at the end (in media 4 anni), there was no clinically significant
deterioration in any treatment group that included a β
blocker (a clinically significant difference regarded as a
30 mL/year reduction in FEV1.
Effect of different treatment regimens* on FEV1 of patients with COPD during study period

44. Short PM et al., 2011
Cox proportional hazard regression analysis was
then used to calculate crude and adjusted hazard ratios
for all cause mortality, hospital admissions due to
respiratory disease, and emergency oral corticosteroid
use dependent on treatment groups in reference to the
control group
Adjusted hazard ratios for all cause mortality among patients with COPD in reference to the control group (who received only inhaled therapy with short acting β agonists or antimuscarinics)

45. Kaplan-Meier estimate of probability of survival among patients
Short PM et al., 2011
Kaplan-Meier estimate of probability of survival among patients
with COPD by use of β blockers
The Kaplan-Meier analysis and log rank testing to evaluate
the impact of β blockers on survival showed a significant
improvement in overall survival for the 819
patients who received β blockers compared with
those who did not (χ2 test 18.97, P<0.001) (fig 1).
After matched propensity scoring analysis, to balance
associated covariates between groups, we found that β
blocker use was associated with a 22% reduction in
mortality (hazard ratio 0.78 (95% confidence interval
0.67 to 0.92)).
Β-blocker use was associated with a 22% reduction in mortality: hazard ratio 0.78 (95% confidence interval 0.67 to 0.92)

46. Short PM et al., 2011
Conclusions
β blockers may reduce mortality and COPD exacerbations when added to established inhaled stepwise therapy for COPD, independently of overt cardiovascular disease and cardiac drugs, and without adverse effects on pulmonary function.

47. In-hospital mortality was 5.2%
Use of beta blockers and the risk of death in hospitalised patients with acute exacerbations of COPD
In-hospital mortality was 5.2%
Those receiving beta blockers (n = 142) were older and more frequently had cardiovascular disease than those who did not
Beta blocker use was associated with reduced mortality (OR = 0.39; 95% CI 0.14 to 0.99)
The use of beta blockers by inpatients with exacerbations of COPD is well tolerated and may be associated with reduced mortality
BACKGROUND: Cardiovascular disease is a major cause of death in patients with chronic obstructive pulmonary disease (COPD) and predicts hospitalisation for acute exacerbation, in-hospital death and post-discharge mortality. Although beta blockers improve cardiovascular outcomes, patients with COPD often do not receive them owing to concerns about possible adverse pulmonary effects. There are no published data about beta blocker use among inpatients with COPD exacerbations. A study was undertaken to identify factors associated with beta blocker use in this setting and to determine whether their use is associated with decreased in-hospital mortality. METHODS: Administrative data from the University of Alabama Hospital were reviewed and patients admitted between October 1999 and September 2006 with an acute exacerbation of COPD as a primary diagnosis or as a secondary diagnosis with a primary diagnosis of acute respiratory failure were identified. Demographic data, co-morbidities and medication use were recorded and subjects receiving beta blockers were compared with those who did not. Multivariate regression analysis was performed to determine predictors of in-hospital death after controlling for known covariates and the propensity to receive beta blockers. RESULTS: 825 patients met the inclusion criteria. In-hospital mortality was 5.2%. Those receiving beta blockers (n = 142) were older and more frequently had cardiovascular disease than those who did not. In multivariate analysis adjusting for potential confounders including the propensity score, beta blocker use was associated with reduced mortality (OR = 0.39; 95% CI 0.14 to 0.99). Age, length of stay, number of prior exacerbations, the presence of respiratory failure, congestive heart failure, cerebrovascular disease or liver disease also predicted in-hospital mortality (p<0.05).
CONCLUSIONS: The use of beta blockers by inpatients with exacerbations of COPD is well tolerated and may be associated with reduced mortality. The potential protective effect of beta blockers in this population warrants further study.
Dransfield MT, Thorax Apr;63(4):301-5. 47

48. CHARM trial: patients with HF receiving bronchodilators
(n=674 of 7599)
0.7
0.8
0.9
1.0
Survival Rate
0.5
1.5
2.0
2.5
3.0
3.5
Time (years)
No bronchodilator
and beta-blocker
and no beta-blocker
Bronchodilator and beta-blocker
Bronchodilator
Un incremento significativo della sopravvivenza si aveva in coloro che venivano trattati con beta-bloccanti sia che facessero o no terapia con broncodilatatori e l’HR per mortalità di pazienti con o senza b-blocc era significativo (0.76%-p<0.0001)
In precedenti studi si dimostra un’associazione significativa tra broncodil e eventi cardiaci avversi ma non si può escludere che l’uso dei broncodil fosse una conseguenza ( o u n’associazione) e non la causa dell’outcome.
In questo studio la correlazione esiste indipendentemente da altri predittori in quanto sono calcolati ed esclusi sia una maggior gravità di classe che altri fattori confondenti.
L’ipotesi di un danno da beta-2 viene ipotizzata come come maggior vulnerabilità miocardica per una maggior risposta inotropica all’azione stimolante delle catecolamine con maladdatativo remodelling e depressione della funzione miocardica per eccessiva stimolazione da adrenalina e catecolamine endogene. Questo pittosto che un incremento per morti improvvise (da aritmie, ipocaliemia, aumento del QTc etc) che non viene documentato.
Questo studio ha molte limitazioni : la prima è che non viene specificato se la prescrizione era per asma o BPCO.(ossia I cardiologi non danno assicurazioni sulla corretta esclusione di pazienti asmatici che vengono confusi con BPCO) Non viene valutata la classe di gravità
Hawkins NM. Eur J Heart Fail 2010

49. Celli B. et al., Chest 2010; 137:
Kaplan-Meier estimates of the probability of major and fatal CV events in the placebo and tiotropium groups from the 30-trial pooled analysis.
Cumulative frequency of cardiovascular endpoint event
0,01
0,02
0,03
0,04
0,05
0,06
0,07
0,08
0,09
0,1 6 12 18 24 30 36 42 48
Placebo
Tiotropium
Rate ratio = 0.83; 95% CI = ( )
Time to first event (months)
Patients at risk
10846
8699
6889
5506
4698
3599
2420
2240
2274
2068
2133
1917
2022
1787
1911
1681
1785
1571

50. Celli B. et al., Chest 2010; 137:
Kaplan-Meier estimates of the probability of major and fatal CV events in the placebo and tiotropium groups from the 30-trial pooled analysis.
Cumulative frequency of cardiovascular death
0,01
0,02
0,03
0,04
0,05
0,06
0,07
0,08
0,09
0,1 6 12 18 24 30 36 42 48
Placebo
Tiotropium
Rate ratio = 0.77; 95% CI = ( )
Time to first event (months)
Patients at risk
10846
8699
6933
5538
4737
3637
2456
2286
2322
2120
2193
1980
2087
1861
1986
1756
1863
1638

51. Primary analysis: all-cause mortality at 3 years
HR 0.825, p=0.052
17.5% risk reduction
Probability of death (%) 18 16
Placebo 15.2% 14
FSC % 12 10
2.6%
absolute reduction 8 6 4
One subject in the SALM/FP arm with survival status unknown at 3 years was treated as censored at 2 years (the last time point at which survival status was known).
The difference in all-cause mortality between SALM/FP and placebo was analysed by the log-rank test (stratified by smoking status) and presented as a Kaplan-Meier plot. The HR was also calculated.
There was a 17.5% reduction in the risk of mortality at any time during the 3 years for SALM/FP vs placebo (p=0.041 to be compared to a significance level of 0.040; p=0.052 adjusting for a significance level of 0.05)
Two supportive analyses for the primary endpoint were performed (and are presented in following slides:
1) Log-rank stratified by smoking status and country
2) Cox’s proportional hazards model, using time to death as the outcome variable, treatment as the explanatory variable, and covariates of smoking status, age, gender, baseline FEV1, BMI and region. Interactions between treatment and covariates were tested using this model.
P-values of ≤ were considered statistically significant. However, this is an arbitrary cut off and eminent statisticians agree that it is not sensible to interpret the results of a study differently according to whether the p-value obtained was or ,2
P-values were adjusted to account for the previous interim analyses.
The primary endpoint in TORCH was the reduction in all-cause mortality between SALM/FP and placebo. It is important to note that the placebo patients at the start of the TORCH trial may not necessarily have been ‘true placebo’ patients at the end of the study as they could have dropped out and started treatment with products like SALM/FP. However, in line with the protocol of the study, all patients randomised to the placebo arm were counted as placebo for the all-cause mortality endpoint.
References
Altman DG. Practical statistics for medical research, Chapman and Hall, London, 1991, p168.
Pocock SJ. Clinical trials, John Wiley and Sons, London, 1984, p205. 2 12 24 36 48 60 72 84 96
108
120
132
144
156
Time to death (weeks)
Number
alive
1524
1533
1464
1487
1399
1426
Plc
1339 SFC
Vertical bars are standard errors
Calverley et al, NEJM, 2007 51

52. Background: Randomized clinical trials have not yet demonstrated the mortality benefit of smoking cessation.
Objective: To assess the long-term effect on mortality of a randomly applied smoking cessation program.
Design: The Lung Health Study was a randomized clinical trial of smoking cessation. Special intervention participants received the smoking intervention program and were compared with usual care participants. Vital status was followed up to 14.5 years.
Setting: 10 clinical centers in the United States and Canada.
Patients: 5887 middle-aged volunteers with asymptomatic airway obstruction.
Measurements: All-cause mortality and mortality due to cardiovascular disease, lung cancer, and other respiratory disease.
Intervention: The intervention was a 10-week smoking cessation program that included a strong physician message and 12 group sessions using behavior modification and nicotine gum, plus either ipratropium or a placebo inhaler.
Results: At 5 years, 21.7% of special intervention participants had stopped smoking since study entry compared with 5.4% of usual care participants. After up to 14.5 years of follow-up, 731 patients died: 33% of lung cancer, 22% of cardiovascular disease, 7.8% of respiratory disease other than cancer, and 2.3% of unknown causes.
All-cause mortality was significantly lower in the special intervention group than in the usual care group (8.83 per 1000 person-years vs per 1000 person-years; P 0.03).
The hazard ratio for mortality in the usual care group compared with the special intervention group was 1.18 (95% CI, 1.02 to 1.37). Differences in death rates for both lung cancer and cardiovascular disease were greater when death rates were analyzed by smoking habit.
Limitations: Results apply only to individuals with airway obstruction.
Conclusion: Smoking cessation intervention programs can have a substantial effect on subsequent mortality, even when successful in a minority of participants. 52

53. 53

54. Caratteristiche della TEP in BPCO
Nearly 30% of all exacerbations of COPD do not have a clear etiology
COPD patients are at a high risk for PE due to a variety of factors including limited mobility, inflammation, and comorbidities
Overall, the prevalence of PE was 19.9% (95% confidence interval [CI], 6.7 to 33.0%; p ).
In hospitalized patients, the prevalence was higher at 24.7% (95% CI, 17.9 to 31.4%; p ) than those who were evaluated in the emergency department (3.3%)

55. One of four COPD patients who require hospitalization for an acute exacerbation may have PE.
A diagnosis of PE should be considered in patients with exacerbation severe enough to warrant hospitalization, especially in those with an intermediate-to-high pretest probability of PE.

56. Endothelial-coagulative activation during COPD exacerbations
IL-6: surrogate marker of inflammation
vWF:Ag (von Willebrand Factor antigen): endothelium
activation
F1+2 (prothrombin fragment 1+2 ): clotting stimulation
D-Dimer : fibrinolytic
Polosa et al:
Haematologica , 2008

57. TEP in BPCO: FATTORI DI RISCHIO
precedente storia di neoplasia maligna (rischio relativo, RR 1.82, 95% CI, )
storia di TVP o EP (RR 2.43, 95% CI, )
riduzione della PaCO2 > 5 mm Hg
COPATOLOGIE
cancro
scompenso cardiaco congestizio
I pazienti con EP e BPCO sono inoltre spesso più anziani e fumatori rispetto ai pazienti con BPCO senza EP (4). Il fumo infatti è in grado di aumentare in modo indipendente il rischio trombo-embolico. Uomini che fumano 15 o più sigarette al giorno presentano un rischio relativo di TEV di 2.82 (95% CI, ; p=0.009) rispetto ai non fumatori (16). Durante le riacutizzazioni della BPCO è spesso presente un aumento del fibrinogeno correlato con la presenza di catarro purulento, frequenza ed intensità della tosse e l’età dei pazienti (17). Nella BPCO riacutizzata si determina un aumento dell’interleukina-6, che è correlata in modo stretto con l’aumento del fibrinogeno. L’inteleukina-6 possiede un importante effetto pro-coagulante e pertanto il suo aumento può costituire uno degli elementi causali dello sviluppo di eventi tromboembolici nei pazienti con BPCO(17).
Il fumo è il fattore ambientale più importante nel condizionare le concentrazioni di fibrinogeno e può stimolare il release di catecolamine (18). L’epinefrina a sua volta può aumentare la sintesi di fibrinogeno dal fegato sia direttamente che attraverso la sintesi di mRNA (19). I livelli di tissue factor (TF) sono influenzati dal fumo di sigaretta ed è nota l’importanza del TF nell’innescare la cascata emocoagulativa attraverso l’attivazione del fattore VII. E’ dimostrato che 2 ore dopo il fumo di due sigarette il TF aumenta (217 ± 72 versus 283 ± 106 pmol/L; P=0.003) suggerendo pertanto un altro importante link tra il fumo ed il tromboembolismo venoso (20).Il fumo inoltre può influenzare anche la fibrinolisi. Una fibrinolisi efficace richiede un rapido release di attivatore tissutale del plasminogeno (tPA) da parte dell’endotelio. Il fumo è in grado di inibire acutamente il release di tPA indotto dall’endotelio attraverso un’inibizione della nitrossido-sintetasi (21).
I fumatori di sigarette inoltre presentano anche un’aumentato livello di omocisteina (oddsratio 2.10 CI, ; p < 0.001) che costituisce un fattore di rischio per la patologia trombotica venosa ed arteriosa (22).
Tillie-Leblond I : Ann Intern med 2006

58. Riztkallah, CHEST 2009

59. Riztkallah, CHEST 2009

60. Riztkallah, CHEST 2009

61. Riztkallah, CHEST 2009

62. Riztkallah, CHEST 2009

63. Riztkallah, CHEST 2009

64. Kenneth E Wood International Journal of COPD 2008:3(2) 277–284
AE-COPD
atypical
typical
Pre test probability for PE
TREATMENT
LOW
INTERMEDIATE
HIGH
no improvement
creatinine
D-dimer
>1.5
<1.5
POS
improvement
NEG
Doppler US
V/Q scan
SPIRAL CT
POS
PE excluded
PE confirmed
Kenneth E Wood International Journal of COPD 2008:3(2) 277–284

65. TEP in BPCO: messaggi chiave I
La BPCO è uno dei fattori di rischio per tromboembolia polmonare
La TEP deve essere considerata tra le cause di riacutizzazione di BPCO e la sua frequenza varia in funzione della casistica studiata e del setting clinico, potendo arrivare fino al 25% dei casi
La diagnosi è resa difficile dall’aspecificità dei sintomi e dalla possibile sovrapposizione con quelli di una riacutizzazione e la formulazione di uno score clinico di probabilità è utile sia per porre il sospetto sia per l’accuratezza diagnostica.
La performance clinica delle indagini diagnostiche, con eccezione per la scintigrafia polmonare perfusionale\ventilatoria, non è influenzata in modo significativo dalla presenza di BPCO.

66. TEP in BPCO: messaggi chiave II
Lo studio del circolo polmonare arterioso con tomografia computerizzata (angioTC polmonare) è l’indagine di riferimento
un eccessivo impiego di esami TC con mezzo di contrasto può essere evitato escludendo i soggetti con score di probabilità medio-basso associato a D-dimero negativo.
La valutazione del rischio di morte (stratificazione del rischio con ricerca dei segni di disfunzione ventricolare destra ) è utile a fini prognostici e terapeutici

74. DISSEZIONE AORTICA