CPFE - Aimar

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Pierluigi Carratù -Università di BariLucio Casali; Mariano E. Crapa -Università di Perugia-
Clinical Classification of Pulmonary Hypertension (updated at 5th WSPH,
Nice, France 2013)
The World Health Organization (WHO) first defined the classifications of
pulmonary hypertension in 1973 and the classifications have been revised
over the years. The classifications of PH were most recently updated in
Nice, France in 2013.
1. Pulmonary arterial hypertension (PAH)
1.1 Idiopathic (IPAH)
1.2 Heritable (HPAH) (previously known as Familial (FPAH)
1.2.1 BMPR2*
1.2.2 ALK-1*, ENG*, SMAD9*, CAV1*, KCKN3*
1.2.3 Unknown
1.3 Drug- and toxin-induced
1.4 Associated with (APAH) (previously known as Secondary -SPAH)
1.4.1 Connective tissue diseases
1.4.2 HIV* infection
1.4.3 Portal hypertension
1.4.4 Congenital heart diseases
1.4.5 Schistosomiasis
1'. Pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary
hemangiomatosis (PCH)
1''. Persistent pulmonary hypertension of the newborn (PPHN)
2. Pulmonary hypertension owing to left heart disease
2.1 Left ventricular systolic dysfunction
2.2 Left ventricular diastolic dysfunction
2.3 Valvular disease
2.4 Congenital/acquired left heart inflow/outflow tract obstruction and congenital
cardiomyopathies
3. Pulmonary hypertension owing to lung diseases and/or hypoxia
3.1 Chronic obstructive pulmonary disease
3.2 Interstitial lung disease
3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern
3.4 Sleep-disordered breathing
3.5 Alveolar hypoventilation disorders
3.6 Chronic exposure to high altitude
3.7 Developmental lung diseases
4. Chronic thromboembolic pulmonary hypertension (CTEPH)
5. Pulmonary hypertension with unclear multifactorial mechanisms
5.1 Hematologic disorders: chronic hemolytic anemia, myeloproliferative disorders,
splenectomy
5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis
5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders
5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmented
PH
Main modifications to the previous Dana Point 2008 classification are shown in bold.
*ALK1 = activin receptor-like kinase type 1; BMPR2 = bone morphogenetic protein receptor
type 2; HIV = human immunodeficiency virus; ENG = endoglin;
SMAD9 = mothers against decapentaplegic 9; CAV1 = caveolin-1; KCNK3 = a gene encoding
PAPm
41(11)
mm Hg
ASPIRE Registry , Sheffield
Presumed mechanisms for PH associated
with lung disease







Generalised hypoxic vasoconstriction
Hyperinflation
Inflammation
Destruction of the pulmonary vascular bed
Remodelling of the pulmonary vasculature
Polycythaemia
In situ thrombosis
Burden of PH in lung disease
Condition
Prevalence
COPD
20 - 40%
ILD
30 – 40%
IPF
Up to 84% *
Sarcoidosis
6 – 74% *
Pulmonary Langerhans Cell histiocytosis
100%*
Pneumoconiosis
Unknown
Connective tissue related ILD
Unknown; 18-22%
scleroderma ILD
OSAS
17 – 52%
Chronic mountain sickness
45%?
* In advanced disease; data from retrospective case series
Kaplan-Meier survival IPERTENSIONE POLMONARE
DA MAL. POLM. e/o IPOSSIEMIA (gr. 3)
BPCO
Oswald-Mammosser
CHEST 1995
FIBROSI POLM.INTERST.
Lettieri CHEST 2006
ENFISEMA- FIBROSI POLM.
Cottin ERJ 2005
PH Progression
IPERTENSIONE POLMONARE
SECONDARIA A BPCO
Cremona G. Paciocco G.
PH secondary to COPD – impact on
survival
D’Alonzo, Ann Int Med 1991
Chaouat A et al., Am J Respir Crit Care Med, 2005
PH in COPD
CELLULAR PROLIFERATION and REMODELING
è
Small pulmonary arteries (< 500 µm)
è
Hypoxemic Vasoconstriction
è
Proliferation of smooth muscle and endothelial cells
è
In situ thrombosis
è
Inflammation
Medial hypertrophy
Intimal hypertrophy
Plexiform lesion
COPD AND PH: pathogenesis
Barbera JA et al. Drug 2009;69:1153
REVEAL REGISTRY
PCWP between 16-18 mmHg
-
Older
Higher BMI
Higher systemic pressure
Sleep apnea
Renal insufficiency
Diabetes
LV diastolic
dysfunction
Exclude LV dysfunction (systolic or diastolic)!!!
Calculation of Transpulmonary Gradient (mPAP-mPCWP > 12 mmHg)
Evaluate pharmacological tests (fluid load, nitroprusside)
Badesch et al. Chest 2010; 137: 376-387
COPD and PH: prevalence

998 COPD pts
– 27 pts (2.7%) with PAPm > 40 mmHg
– 11 (1.1%) no other causes of PH
•
•
•
•
•
moderate airway obstruction (FEV1 50%)
Severe hypoxemia
Hypocapnia
Lower Dlco
Shorter survival
Chaouat A et al. Am J Respir Crit Care Med 2005; 172:189-94
COPD and PH: progression
Data from three studies (163 patients)
demonstrate that Ppa has a modest progression
over years, with and average increase between
0.5-0.6 mmHg/year
Schrijen F, Am Rev Respir Dis 1978
Weitzenblum E Chest 1979
Weitzenblum E Am Rev Respir Dis 1984
This indicates that in patients with moderatesevere COPD (and normal Ppa), the natural
progression of the disease does not necessarily
lead to PH
Kessler R. AJRCCM 2001
Endothelial dysfunction in PH



Increased Rho
GTPase activity
Reduced
production/activity of
NO, PGI2
Increased production
of ET-1
Endothelin in PH associated with COPD

Increased receptor ET-1 expression in lungs of
patients with cryptogenic fibrosing alveolitis


Plasma levels of ET-1 are increased in patients with
severe COPD


Giaid A, et al. Lancet 341, 1550–1554, 1993.
Channick et al JACC 2004
ETA and ETB receptor expression is increased in the
pulmonary arteries of patients with COPD

Davie et al. AJRCCM 2002
Ward & McMurtry, 2009
evolution of pulmonary hemodynamics in 131 patients with stable COPD by
performing two right heart catheterizations at a mean time interval of 6.8 yr.
The progression of Ppa over time in
COPD is 0.4 mm Hg/yr. Only about
25% of patients with COPD with mild
to moderate hypoxemia and without
resting PH at the onset will develop
PH during a 6-yr follow-up.
PH secondary to COPD – impact on
survival
D’Alonzo, Ann Int Med 1991
Chaouat A et al., Am J Respir Crit Care Med, 2005
PH in COPD
concept of “out of proportion
PAPm
–
–
–
–
–
mPAP > 40 mmHg ?
mPAP > 35 mmHg ?
mPAP > 30 mmHg ?
mPAP > 25 mmHg ?
mPAP > 20 mmHg ?
 PCWP
• < 15 mmHg
• Between 15-18 mmHg
Out of Proportion PH – Second Hit?
Reduced
BMPR-II
activity
Abnormal vascular
development?
Unstable
vasculature
“2nd hit”
Environmental
insult
?
Somatic
mutation?
Modifier genes
“Out of Proportion” PH in CLD

Definition: resting PAP > 40 mmHg


COPD 1-5%


TPG > 25 mmHg
Chaouat et al. AJRCCM, 2005, Scharf et al
AJRCCM, 2002
ILD: 9%

Shorr et al Eur Resp J, 2007
Therapy






Treat underlying lung disease
Provide long term oxygen therapy when
appropriate
Treat heart failure
Consider anticoagulant therapy
Consider vasodilator therapy
Consider transplantation
IPERTENSIONE POLMONARE
e
FIBROSI POLMONARE IDIOPATICA
Cremona G. Paciocco G.
IPF and PH: increase in PVR
IPF and PH: pathophysiology
 Secondary PH
– Fibrotic ablation of
pulmonary vessels
– Elevetion of PVR
– Exercise hypoxemia
and resting
hypoxemia in late
stages of disease
 Disproportionate PH
– Increased production of
5-LO,TGF-β, TNF-α and
PDGF
– Reduced production of
PGE-2
– Increased ET-1 level
– Angiogenesis and
angiostasis
Prevalence of PH in IPF
o
139 IPF
o 46 untreated – 93 treated
o
55% PAPs > 36 mmHg
o
o
o
o
o
o
Tended to lower Dlco
Lower pO2 at rest
Shorter 6-MWT distance
Lower SpO2 at rest and at end of ex
Higher BNP level
SpO2 < 85% at rest
Papakosta D Lung 2011;189:391-9
PH in IPF: pre- or post-capillar
•
118 pts. IPF with RHC
– 48 with PH (>25 mmHg)
• 19 post-capillar PH
• 29 pre-capillar
Prevalence 26%
– No correlation with PFT’s
Nathan S et al. 2007; 131:657-663
PH in IPF: prognostic value
 Impact
on survival
88 IPF pts with echo-PAPs measurement
mean PAPs = 48  16 mmHg
PAPs correlated with DLco
Worse survival in
PAPs > 50 mmHg pts
– RR 1.34 per 10 mmHg
increase
–
–
–
–
Nadrous HF et al. 2005;128:2393-99
Sildenafil in IPF
180 pts with severe disease
•
(12-week study)
Primary end-point failed
• 20% of in distance walked on 6-MWT
•
Significant improvement in:
DLco%
pO2
SaO2
Shortness of Breath
Questionnaire
– St. George’s Respiratory
Questionnaire
–
–
–
–
The Idiopathic Pulmonary Fibrosis Clinical Research Network N Engl J Med 2010;363:620-8
FIBROSI POLMONARE
ED
ENFISEMA
FERAGALLI B.
CPFE
COMBINED PULMONARY FIBROSIS AND
EMPHYSEMA
Definizione
Sindrome caratterizzata
dall’associazione di
enfisema e fibrosi e da un elevato
rischio di
Ipertensione arteriosa polmonare
Cottin V, Eur Respir J 2010; 35:9-11
In 90% of patients the chest radiograph is abnormal
at the time of diagnosis with:
• enlargement of central arteries
• “pruning” of the peripheral blood vessels
CT shows the same pattern but it is more
accurate in the evaluation of arterial diameter.
Specificity: 90%
PH is present when the
main pulmonary
artery diameter is:
> aorta
> 2.9 cm
36 mm
The specificity of CT is higher (100%) when the segmental
arteries are enlarged and in particular when the
segmental artery-bronchus ratio > 1, in 3 or more lobes.
& Remy-J M. CT angiography of the chest. Lippincott, 2001
Right heart abnormalities
• Dilation of:
 Right ventricle
 Right atrium
 Vena cava
RV
• Leftward ventricular
septal bowing
Severe leftward ventricular septal bowing is often
associated with an unfavourable prognosis !
Sistemic collateral supply with enlargement of
bronchial arteries
CT Angiography (CTA)
& Kauczor HU. JCAT, 1994
CPFE
Quadro interstiziale reticolare con volumi
polmonari conservati
CPFE
Enfisema
lobi superiori
Fibrosi
lobi inferiori
CPFE
CPFE
CPFE
CPFE
 Associazione di enfisema e fibrosi nelle
immagini
HRCT
 Maschi fumatori o ex fumatori
 Volumi polmonari relativamente conservati
 Marcata compromissione della funzionalità
respiratoria
(riduzione DLCO)
 Elevata prevalenza di ipertensione arteriosa
polmonare
Specifica entità o semplicemente un
distinto fenotipo di FPI in maschi fumatori?
CPFE
2009
Elevata prevalenza di IP nella CPFE (rischio di
IP è maggiore nella CPFE rispetto alla FPI senza
enfisema)
Forte correlazione tra eSPAP e l’estensione
delle alterazioni enfisematose in HRCT
La prognosi peggiore dei pz con CPFE è dovuta
CPFE
2010
L’ IP si manifesta rapidamente dalla diagnosi di
CPFE
(tempo medio di 16 mesi tra la dg di CPFE e dg di
IP)
CPFE
2011
Effetto antifibrotico di mediatori
dell’infiammazione cronica legata al fumo e
all’enfisema centrolobulare
(diversa patogenesi dell’enfisema parasettale
che si riscontra sia in fumatori che in non
fumatori)
CPFE
CPFE
Conclusioni
Diagnosi importante per le seguenti ragioni:
1. Il rischio di IP è elevato (50-90%) e si associa
ad una riduzione della sopravvivenza ed aumento
della mortalità
2. La valutazione dei volumi polmonari non è
rilevante nel follow-up (a differenza della FPI)
3. Variazioni della capacità di diffusione,
dell’ipossiemia, della pressione arteriosa
polmonare sono indici più attendibili di
progressione di malattia
4. I pz. con CPFE dovrebbero essere esclusi dai
trials clinici sulla FPI
CPFE
Conclusioni
Nel sospetto clinico e radiografico di CPFE è
indicato effettuare una HRCT del torace ed un
esame ecocardiografico
IPERTENSIONE POLMONARE
e
NELLE PID NON IPF
STANZIOLA A.
IPERTENSIONE POLMONARE ED INTERSTIZIOPATIE
POLMONARI NON IPF
◙ IP associata a Collagenopatie vascolari e Interstiziopatia
(PH-SSc-ILD, PH-SLE, RA, DM/PM)
◙ IP nelle PID rare
(sarcoidosi, istiocitosi,lam,pam…)
PH-SSc-ILD
Condliffe, AJRCCM 2009
IP da meccanismi non conosciuti.
Gruppo 5
sarcoidosi
istiocitosi
LAM
Istiocitosi a cellule di Langerhans
•
•
•
•
Lesioni vascolari
♦
Fibrosi intimale / ipertrofia
media vasi arteriosi (+++)
♦
Muscolarizzazione / obliterazione /
fibrosi intimale vasi venosi (+++)
♦
Granulomi a sede vascolare ()
della
3° posto RIPID
variabilità quadri clinico-radiologici
di esordio 1
dispnea non correlata con i
parametri funzionali ventilatori
basali 1
IP severa nei centri IP
riferimento (PAPm > 50 mmHg)
di
Taveira-DaSilva AM, Hathaway OM, Sachdev V, Shizukuda Y, Birdsall CW, Moss J.
Chest. 2007
Fenotipi emodinamici
NL = gruppo normale
ePVH= IP venosa
eoPH= IP out of proportion
ePH = IP exercise induced
SAGGAR et al
IP e PID rare: Sarcoidosi
DERMATO/POLIMIOSITE
Pulmonary hypertension in polymyositis-dermatomyositis: clinical and
hemodynamic characteristics and response to vasoactive therapy.
PH
Minai O, Lupus 2009
ISTIOCITOSI
Microlitiasi
endoalveolare
IPERTENSIONE POLMONARE,
TROMBOEMBOLISMO VENOSO E
BPCO
BECATTINI C.
Pulmonary hypertension &
venous thromboembolism
-Acute pulmonary hypertension
-Chronic thromboembolic pulmonary hypertension
Predictors of adverse short-term outcome
Massive
Non Massive PE
Massive PE
Non Massive PE
Kucher Circulation 2006
Laporte Circulation 2008
ESC Guidelines: Risk stratification for PE
Adam Torbicki
Arnaud Perrier
S Konstantinides
Giancarlo Agnelli
Nazareno Galié
Piotr Pruszczyk
Markers of dysfunction: echocardiography
HR 1.94
95% CI 1.23-3.06
1035 pts BPs >90mmHg
30d. mortality 16,3%
Kucher N, Arch Intern Med. 2005
PE-MAP Study
RV
LV
Burden of emboli at MDCT and clinical course
obstruction index according to the scoring system of Qanadli
∑ (n · d)
n = number of segmental
branches
d = obstruction degree
(1 if partial 2 if complete)
Becattini et al., in press
Treatment for pulmonary embolism
AHA
Circulation 2011
Chronic thromboembolic pulmonary hypertension
pathological lesions are characterized by
organized thrombi tightly attached to the
pulmonary arterial medial layer in the
elastic pulmonary arteries, replacing the
normal intima.
These may completely occlude the lumen
or form different grades of stenosis, webs,
and bands.
In non-occluded areas, a pulmonary
arteriopathy indistinguishable
from that of PAH (including plexiform
lesions) can develop.
CTPH: Pathogenesis
Thromboembolic obstruction of major pulmonary
arteries due to unsolved pulmonary embolism
initial PE
Pulmonary arteries
remodelling
Recurrent PE
CTEPH
Thrombosis of
pulmonary arteries
CTPH: incidence
259 patients with symptomatic objectively
confirmed PE
46-months average follow up
17 patients with new persistent dyspnea:
10 Chronic heart failure
7 COPD
3 normal PAP
2 confirmed CTPH (both patients with idiopathic PE)
Becattini, Chest 2006
Epidemiology of CTPH
About 40% of patients diagnosed with CTEPH have
not had a clinically apparent PE
Recommendations for CTEPH
ESC Task Force 2009
CTPH
TC
CTPH: pulmonary angiography
Chronic thromboembolic pulmonary hypertension
-Definition and epidemiology
-Diagnosis
-Treatment and prognosis
Treatment for CTPH
Anticoagulants: life-long treatment with INR 2.0-3.0
1C
Thromboendarterectomy: in selected patients with central
disease under the care of an experienced team
1C
Vena cava filter: before or at the time of
thromboendarterectomy
Expert center: ≥ 20 PEA
operations per year with a
mortality rate <10%.
2C
ACCP 2008
ESC Task Force 2009
CTPH operability
Thistlethwaite, 2002
CTPH operability
• Location and extension of thrombotic material
(proximal segmental arteries)
• Small arteries arteriopathy
• Severe obstructive or restrictive pulmonary disease
• Advanced age and right ventricle failure increase
risks of surgery but are not contraindications
CTPH medical treatment
Uncontrolled clinical studies:
prostanoids,
ERAs, and
phosphodiesterase type-5 inhibitors
may exert haemodynamic and clinical benefits in
patients with CTEPH
Open to discussion
Role of referral centers
Optimal methods for screening
Role of medical therapies
IPERTENSIONE POLMONARE
ED
OSAS
CARRATU’ P.
Definizione di Apnea e Ipopnea
L’apnea durante il sonno è un fenomeno patologico che consiste nella
cessazione del respiro per una durata di almeno 10 secondi, associato ad
alterazioni degli scambi gassosi, della struttura del sonno, e a modificazioni
emodinamiche che perdurano anche nello stato di veglia (1).
L’ipopnea corrisponde invece ad una riduzione del 70% del flusso oronasale
che si accompagna a una desaturazione del sangue arterioso di almeno 4
punti percentuali (2).
Lieu TA, Am J Respir Crit Care Med. 2011 Oct 1;184(7):848-56
Lin CH, Sleep Med. 2011 Aug;12(7):720-9.
Apnee notturne: Classificazione
Le apnee notturne si classificano in:
• OSA (obstructive sleep apnea) con cessazione
del flusso aereo per ostruzione periferica delle
alte vie aeree
• Apnee centrali: cessazione del flusso aereo
con pervietà delle vie aeree superiori
• Apnee miste: iniziano come centrali e
diventano ostruttive
Saturimetria notturna in un paziente con OSAS
Tracciato pulsossimetrico tipico di apnea del sonno: desaturazioni con aspetto a dente di sega,
spesso più gravi in determinati periodi del sonno.
Condizioni favorenti l’insorgenza dell’OSA
 Obesità
 Alterazioni ormonali (ipotiroidismo, acromegalia)
 Alterazioni otorinolaringoiatriche (ipertrofia tonsillare, ostr. nasale)
 Alterazioni maxillo-facciali (micrognazia, flessione del collo)
 Farmaci (tranquillanti e psico-farmaci)
 Fumo
 Alcool
Complicanze cardiovascolari dell’OSAS
OSA may be associated with systemic hypertension and
an increased incidence of stroke, heart failure,
myocardial infarction, and arrhythmias.
An important clinical question is whether sleep-related
hypoxia in patients with OSA and other respiratory
diseases can also cause PH, right ventricular
dysfunction, and right heart failure.
Kato M et al Circulation 2007
OSAS
Chronic Intermittent hypoxia
Sympathetic
excitation
Endothelial
Dysfunction
Inflammation
Recurring arousals
Oxidative
Stress
Cardiovascular Disease
Metabolic
Dysregulation
(Insulin, Leptin)
OSAS e Ipertensione polmonare
Durante l’evento ostruttivo la pressione arteriosa polmonare transmurale si
modifica in maniera inversamente proporzionale al grado di ipossia anche se
l’aggiunta di O2 non modifica la situazione nella maggior parte dei soggetti (1).
L’ipertensione polmonare è stata dimostrata in circa il 17-42% dei pazienti
OSAS (2-3).
Fattori determinanti per l’insorgenza dell’ipertensione polmonare sembrano
essere la PaO2, la PaCO2 e il FEV1 (2).
Studi su linee cellulari animali hanno documentato che l’ipossia intermittente
agisce come stimolo molto più potente dell’ipossia continua sulla attivazione
di molteplici fattori di trascrizione; tra questi troviamo l’Hypoxia-inducible
Factor-1 (HIF-1), con i suoi secondi messaggeri, eritropoietina e fattore di
crescita per l’endotelio vascolare (VEGF), che insieme all’ET-1 sono
responsabili delle modificazioni strutturali e pressorie (4).
1.Marrone, 1989, Chest, 34: 345-351;
2.Laks, 1995, AJRCCM 1896-1902;
3.Chaouat, ERJ 454-460. 1996
4. Belaidi E J Am Coll Cardiol. 2009, 1309-17
Pathophysiology of PH in OSAS
Three main mechanisms have been suggested to be
responsible for the observed obstructive sleep apnearelated increase in PAP as follows:
1. hypoxia, and chronic intermittent hypoxia
2. mechanical factors because of increased
inspiratory effort,
3. reflex mechanisms directly influencing the
vasculature.
Sajkov D, Progress in Cardiovascular Diseases 2010
Pulmonary hypertension in obstructive sleep apnoea: effects of continuous
positive airway pressure: a randomized, controlled cross-over study.
Individual values for the Doppler
echocardiography-derived pulmonary
artery systolic pressure (PASP) after
crossover trial of 3-month sham vs 3-month
effective CPAP treatment in 21 patients
with OSA. Application of CPAP reduces
pulmonary systolic pressure levels.
M.A. Arias, et al. Eur Heart J, 27 (2006), pp. 1106–1113.
RMPI = IVCT+IVRT/ ET
IVCT= T di Contraz Isovol IVRT= T Rilasc Isovol.
Medication adherence and
persistence in severe obstructive
sleep apnea.
Kaplan-Meier curves of the probability of
persistence to antihypertensives, statins,
and antiplatelets during the 2-years
follow-up. CPAP refers to those patients
who were compliant with continuous
positive airway pressure (CPAP) use; nonCPAP, those patients who refused
treatment with CPAP or did not use CPAP
for at least 4 hours per day.
“Our findings do not support the
hypothesis that nonuse of CPAP could be a
marker for nonadherent behavior, as well
as, for increasing cardiovascular diseases”
Villar I et al. Sleep 2009 May;32(5):623-8
Daytime pulmonary hypertension in
patients with obstructive sleep apnea: the
effect of continuous positive airway
pressure on pulmonary hemodynamics
Alchanatis M, Tourkohoriti G, Kakouros S, Kosmas E,
Podaras S, Jordanoglou JB
“Severe OSA (AHI>30) alone
constitutes an independent risk factor
for the development of systemic and
pulmonary hypertension”.
Respiration2001;68(6):566-72
Association of chronic
obstructive pulmonary disease
and sleep apnea syndrome.
L’OSAS si può associare a COPD nel 10-11 % dei casi
I pazienti «overlap» sono a più alto rischio di
sviluppare Ipertensione Polmonare e Cuore
Polmonare Cronico rispetto ai BPCO, anche con
deficit ostruttivi meno severi.
Chaouat A., AJRCCM 1995
Pathophysiological aspects of “Overlap Syndrome”
Both COPD and OSAS are
associated with elevated levels of
C-reactive protein (CRP) and IL-6, in
addition to tumor necrosis factor
(TNF)- and IL-8, and are also
associated with oxidative stress.
However, cigarette smoking and
obesity are confounding variables
in these associations. Hypoxia is a
key factor in elevated TNFproduction in OSAS, which is
particularly relevant to the overlap
syndrome. Each inflammatory
pathway has been associated with
atherogenesis and subsequent
cardiovascular disease.
Chaouat A., AJRCCM 1995
Individual values for the Doppler echocardiography-derived pulmonary
artery systolic pressure (PASP) after crossover trial of 3-month sham vs
3-month effective CPAP treatment in 21 patients with OSA 63 M.A.
Arias, F. Garcia-Rio and A. Alonso-Fernandez, et al. Pulmonary
hypertension in obstructive sleep apnoea: effects of continuous
positive airway pressure: a randomized, controlled cross-over study.
Eur Heart J, 27 (2006), pp. 1106–1113. | View Record in Scopus | |
Cited By in Scopus (84)[63].
This question has finally been resolved by studies that have found a significant fall in PAP after 3
to 6 months of nocturnal CPAP treatment of OSA [57] , [63] and [66] including one randomized
controlled trial comparing active vs sham CPAP63 (Fig. 2). Reductions in PAP occurred without any
concomitant change in lung function or awake arterial blood gases66 suggesting that episodic
sleep apnea and intermittent sleep hypoxemia are sufficient to cause PHT. In one study, the
reactivity of the pulmonary circulation to hypoxia also decreased after CPAP therapy.66 D. Sajkov,
T. Wang and N.A. Saunders, et al. Continuous positive airway pressure treatment improves
pulmonary hemodynamics in patients with obstructive sleep apnea. Am J Respir Crit Care
Med, 165 (2002), pp. 152–158. | View Record in Scopus | | Cited By in Scopus (87)66
OSAS
Ipertensione
Insulinoresistenza
Obesità
centrale
Dislipidemia
IPERTENSIONE POLMONARE
ed
ECOCARDIOGRAFIA NELLA PAH
ARGIENTO P.
2009
Diagnostic algorithm.
ESC/ERS Guidelines 2009
Circolo polmonare:
Valutazione ecocardiografica
 Dilatazione delle cavità destre /
volumetria VS ALTERAZIONI
DEI
 Valutazione funzione biventricolare
VENTRICOLI
 Pressione polmonare
 Insufficienza tricuspidale
 Dilatazione dell’ asse epatocavale
Valvulopatie sinistre
 Malformazioni congenite
PRESSIONI
LESIONI
ASSOCIATE O
CAUSA DI PAH
2009
PH possibile:
- segni indiretti di impegno destro,
o
- PAPs 37-50 mmHg (TVR 2.9-3.4
m/s)
PH probabile:
- PAPs >50 (TVR > 3.4 m/s)
Ecocardiogramma
Segni diretti di PAH
- PSP > 36 (50)
mmHg
Segni indiretti di
PAH
- Alta velocità ins. Polmonare
(PAPm)
- Ridotto t. acc. polm. (PAPm)
- VD, AD o AP dilatati
- Setto IV rettilineizzato (IE VS
<0.8)
- Aumento spessore VD
- TAPSE ridotto (<18 mm)
-Vena cava inf. dilatata (>25 mm) con
scarsa escursione respiratoria
2009
Segni indiretti di PAH:
setto IV rettilineizzato, ipertrofia VD
Indice di eccentricità del VS: rapporto tra i due diametri (D2/D1) del VS in short axis
(VN = 1)
VD
D1
VS
D2
EI = 0.65
Valutazione ecocardiografica e
prognosi
VN
LV index
Prognosi 1
0.7
TAPSE
>18 mm
<14 mm
Tei index
<0.4
>0.88
Vers pericardico
no
Area AD
16 cm2
moderato
30 cm2
TAKE HOME MESSAGE

Eco fondamentale per Screening e prognosi

Valutazione eco è poliparametrica

Diagnosi certa: CATH dx
EMODINAMICA POLMONARE
ED
ADATTAMENTO DEL VENTRICOLO
DESTRO
VIZZA C.D.
Right heart Cath
Poiseuille’s Law
PVR =
Ppa
(Pap - Pcwp) / Q
Assumptions
1. Linearity
2. Origin from the interception
Pcwp
of the axis
Perfusion
Pressure
(Pap-Pcwp)
PVR
Q
Measuring the Pcwp
But the patient usually breaths…….
Pulmonary Hypertension Unit
La Sapienza University of Rome
Poiseuille’s Law
PVR =Pc +((Pap - Pcwp) / Q)
Model: Starling Resistor
Pap
Pc
Pcwp
Perfusion
Pressure
Pc
PVR
Q
Pulmonary Hypertension Unit
La Sapienza University of Rome
Pressure/Flow relationship in normals and PPH
PPH
Ppa, mmHg
50
40
30
20
N
10
1
2
3
4
5
6
Q, L/min
Pulmonary Hypertension Unit
La Sapienza University of Rome
Mc Gregor and Sniderman, Am J Cardiol 1985; 55: 217-21
Abdel Kafi , Naeije et al, J Am Coll Cardiol; 1998
Other parameters to describe pulmonary
circulation (and RV function..)
Pulmonary Vascular Impedance
Pulsatile hydraulic load
Pulmonary Vascular Compliance
Ventricular-Arterial Coupling
Pulmonary Hypertension Unit
La Sapienza University of Rome
Pulmonary Vascular Impedance
Ppa
Spectral analysis of synchronized PA
pressure (Ppa) and flow waves.
Flow
PVZ spectrum includes a measure of
- Total PVR (Z0),
- Indexes of wave reflection
- Characteristic impedance (Zc)
- Hydraulic load
Very long off-line analysis
Not easy/direct interpretation
Pulmonary Hypertension Unit
La Sapienza University of Rome
Huez S. CHEST 2004; 125:2121–2128
Pulmonary Vascular Compliance
Two-parameter Windkessel Model
The SV/PP index has been validated in vivo in the systemic
and splanchnic circulation with a 99% correlation with the
Windkessel method
Pulmonary Hypertension Unit
La Sapienza University of Rome
Lineham JH. J Appl Physiol 1986;61:1802–24.
Conclusion
• Careful technical set-up is mandatory for Right
•
Cath study
Simple PVR calculation may not be adequate in
order to evaluate the response to vasoactive
drug (particularly with high Pc and increase in CO)
Simple analysis could add useful informations
• Pressure/Flow Plot
• Compliance (SV/PP index)
Pulmonary Hypertension Unit
La Sapienza University of Rome
Considerations I
• Afterload mismatch is the main cause of RV
•
failure in severe PH
The most informative parameter of adequate
RV adaptation might be RV Mass/Volume
ratio, the higher the more “concentric” the
hypertrophy
We need further studies to address:
a) The mechanism(s) of RV hypertrophy and RV
adaptation in face of increasing afterload
b) The impact of loss of myocite mass as co-factor
influencing the evolution of RV remodelling
Pulmonary Hypertension Unit
La Sapienza University of Rome
Rilievo ECO Doppler di
Ipertensione Polmonare
Diast VS
IP Post-Capillare
Normale
Anormale
Studio ECO contrasto
Funzione respiratoria
DIA, DIV
Deficit
Scintigrafia Perfusionale
Normale
Mod-severo
TC Alta Ris.
Lieve
Polisonno
grafia
Difetti segmentali
Normale o
difetti sfumati
TC Spirale o Angio
PNEUMOPATIE
OSAS
Ipert Art Pol
Ricerca:
Auto-anticorpi
Capillaroscopia
HIV
Pulmonary Hypertension Unit
ECO
V Porta
La Sapienza
University of Rome
Normale
Botallo
Tromboembolia
Studio emodinamico
Test Vasoreattività
IL RUOLO DELLA CPET NELL’
IPERTENSIONE POLMONARE
SECONDARIA A MALATTIE
POLMONARI
SCODITTI C.
ROLE OF CPET
Why should we analize exercise intolerance?
1. Prognostic evaluation
2. Functional status and mechanism limiting exercise
tolerance
3. Disease progression and response to interventions
CPET IN ILD
PROGNOSTIC FACTOR:
PaO2 slope < 60 mmHg/l/min
Miki K, Respiratory Medicine 2003, Vol 97:482-490
VO2max = Q x (CaO2 – CvO2) max
The minimal CvO2 is determined by the affinity of the
hemoglobyn for O2
The (CaO2 – CvO2) max is similar in all subject, except
in muscolar disease.
So VO2max is determined by Q x CaO2 max
VENTILATORY EVALUATION
• VENTILATORY CAPACITY
MVV calculated = FEV1x 35-40
• VENTILATORY RESERVE
Maximum exercise VE/MVV= 72% ± 15%
• BREATHING RESERVE
MVV- Maximum exercise VE > 11 L/min
WASSERMANN K, Principles of exercise testing and interpretation.
Lippincott Williams e Wilkins, 4th edition 2005.
VENTILATORY ABNORMALITIES
CPET CHARACTERISTICS in VENTILATORY
LIMITED PATIENTS
• low peak VO2
• low breathing reserve < 11 L/min
• RER<1.0
• high P(a-ET)CO2 during exercise
For ILDs also:
• hign Vt/IC
• respiratory rate >50
• high VE/VCO2 at anaerobic threshold (AT)
• reduced ∆VO2/∆WR
• high P(A-a)O2 during exercise
WASSERMANN K, Principles of exercise testing and
interpretation.
th
Lippincott Williams e Wilkins, 4 edition 2005.
CARDIAC EVALUATION
1. Maximum heart rate= 220-age
2. Heart rate reserve= predicted peak HR-observed
peak HR
3. Oxygen pulse
O2pulse = VO2/HR = SV x C (a-v) O2
5. Blood pressure
6. VE/VCO2 @AT and VE/VCO2 slope
WASSERMANN K, Principles of exercise testing and
interpretation.
th
Lippincott Williams e Wilkins, 4 edition 2005.
1. PULMONARY HYPERTENSION
2. DYNAMIC HYPERINFLATION
3. LEFT-HEART DISEASE
REDUCED CARDIAC OUTPUT
REDUCED O2 TRANSPORT
REDUCED EXERCISE CAPACITY
PULMONARY HYPERTENSION IN COPD
VO2 peak and 6MWD as a function of mean PAP in
COPD patients
VO²- mPAP
Distance - mPAP
600
20
Distance (m)
VO² peak (ml/kg)
25
15
10
5
0
0
20
40
PAP (mmHg)
60
400
200
0
0
20
40
60
PAP (mmHg)
PYNNAERT C. et al, Aerobic exercise capacity in COPD patients with and
without pulmonary hypertension, Respiratory medicine 2009
PULMONARY HYPERTENSION IN COPD
REDUCED VENTILATORY
EFFICIENCY
HOLVERDA S, Cardiopulmonary Exercise Test Characteristics in
Patients with Chronic Obstructive Pulmonary Disease and Associated Pulmonary Hypertension
Respiration 2008
CONCLUSIONS
• The exercise limitation for COPD+PH is cardiac,
for COPD nnPH is ventilatory. Nobody has
deconditioning.
• In both groups is present an increased Vd/Vt as
shown by a positive P(a-ET)CO2@AT. In
COPD+PH it’s based on increased V/Q mismatch
confirmed by decreased PaCO2.
• Also if increased P(A-a)O2, VE/VCO2 and
VE/VO2 slope in COPD+PH is not statistically
significant between 2 groups, it could suggest a
reduced ventilatory efficacy in COPD+PH
patients.
IL TEST DA SFORZO CARDIOPOLMONARE, NELL’ IP
SECONDARIA A MALATTIE
POLMONARI
FORTE S.
Il Test da Sforzo Cardiopolmonare
 Compiere un esercizio fisico comporta l’attivazione
di una serie di meccanismi fisiologici di
adattamento la cui efficienza condiziona lo
svolgimento dell’esercizio stesso in termini di
intensita’ e di durata.
 L’efficienza dei meccanismi di adattamento
all’esercizio definiscono la “tolleranza allo sforzo”.
Il Test da sforzo cardiopolmonare
• Il Test da Sforzo Cardiopolmonare (CPET) e’ una
metodica che consente in maniera non invasiva di
studiare l’adattamento cardiovascolare, respiratorio
e metabolico all’esercizio e di identificare il/i
meccanismo/i
alla
base
della
limitazione
all’esercizio.
• Il Test da Sforzo Cardiopolmonare infatti,
mediante
una
attrezzatura
computerizzata,
consente, durante l’esecuzione dell’esercizio al
treadmill o al cicloergometro, la misurazione di una
serie di parametri che sono quindi espressione della
tolleranza allo sforzo.
TEST DA SFORZO CARDIOPOLMONARE: MISURE
Wasserman K. Priciples Exercise Testing and Interpretation.
Third Edition Lippincott Williams & Wilkins
Impact of pulmonary hypertension pathophysiology on
ventilatory expired gas exchange.
VE = VCO2 x 863
PaCO2
VD/VT
Consumo di Ossigeno (VO2)
Fattori che determinano il VO2:





Scambio di O2 a livello
polmonare
Gittata cardiaca
Trasporto di ossigeno
(Hb %, SatO2)
Distribuzione del sangue
a tutti i tessuti, in
particolare al muscolo
Capacità di estrazione
(densità dei capillari,
densità e funzionalità
dei mitocondri,
perfusione e diffusione)
Relationship between pathophysiology and
clinical interpretation of key
cardiopulmonary exercise testing variables.
RISPOSTA VENTILATORIA
BPCO
NORMALE
MIP
CARDIOPATIA
Lo slope della relazione
VE/VCO2 indica che 23-25
L di VE sono richiesti per
eliminare 1 L di CO2.
Misurata alla AT, una
alterazione è espressione
di aumentata richiesta
ventilatoria (vn <34) o di
alterazioni del VD/VT
MVP
Differences in ventilatory efficiency between
pulmonary arterial hypertension and chronic
thromboembolic pulmonary hypertension
Zhenguo Zhai et al. Chest April 28, 2011

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