Paolo Fraticelli
Università Politecnica delle Marche
Ospedali Riuniti
ANCONA
Clinica Medica
Ipertensione polmonare e
malattie del tessuto conettivo
•Systemic diseases
•Widespread connective tissue and vascular inflammation
•Autoimmune ethiology
Different (often overlapping) diseases
•Systemic lupus erithematosus
•Rheumatoid arthritis
•Sjogren syndrome
•Polymyositis/dermatomyosisis
•Systemic Sclerosis
•Mixed connective tissue disease
Autoantibodies
Antinuclear antibodies (ANA)
Anti-DNA
Anti-Ro (-SSA)
Anti-La(-SSB)
Anti.Scl-70
Anti-centromere
Anti-U1-RNP
Anti-Jo1
Connective Tissue Diseases
Condizione emodinamica e fisiopatologica comune a molte
malattie e che si associa a sintomi di dispnea, astenia, scarsa
tolleranza allo sforzo, vertigini, sincopi e progressione verso
l’insufficienza cardiaca destra.
Condizione clinica severa caratterizzata da elevata morbilità e
mortalità.
Definizione emodinamica valutata tramite cateterismo cardiaco
in cui si riscontra una Pressione media in arteria polmonare
(PAPm) a riposo 25 mmHg e aumento delle Resistenze
vascolari polmonari (PVR) > 3 unità Wood
Ipertensione polmonare
Definizione emodinamica di Ipertensione Arteriosa
Polmonare al cateterismo destro
Galiè et al., Eur Heart J 2015 (29 Aug)
Ipertensione polmonare pressione arteriosa polmonare (PAP) media rilevata mediante RHC
≥ 25 mmHg a riposo e PVR > 3 Woods units.
PRE-CAPILLARE
• PAP media ≥ 25 mmHg a riposo
• PAWP ≤ 15 mmHg
• CO normale o ridotta
POST-CAPILLARE
• PAP media ≥ 25 mmHg a riposo
• PAWP ≥ 15 mmHg
• CO normale o ridotta
1. IAP
3. IAP sec. a malattia del polmone
4. Malatt. Tromboembolica
5. I meccanismo vario/non chiaro
2. malattia del cuore
5. I meccanismo vario/non chiaro
Fisiopatologia
1. Rimodellamento del letto
vascolare arterioso
polmonare
2. Modificazioni cardiache
secondarie
• Ipertrofia della media
• Ipertrofia/fibrosi intimale
• Ispessimento avventiziale
• Infiltrato infiammatorio perivascolare
• Trombosi in situ
• Lesioni plessiformi
Modificazioni anatomopatologiche della IAP
La classificazione dell’ipertensione polmonare in 5 gruppi
Galiè et al., Eur Heart J 2015 (29 Aug)
La classificazione dell’ipertensione polmonare in 5 gruppi
Epidemiologia
0 20 40 60 80
Gruppo 5
Gruppo 4
Gruppo 3
Gruppo 2
Gruppo 1
6,8
0,6
9,7
78,7
4,2
Gruppi clinici
Gruppo 5
Gruppo 4
Gruppo 3
Gruppo 2
Gruppo 1
Gabbay et al., American Thoracic Society Annual Meeting, 2007 Am J
Resp Crit Care, 2007
Strange et al., Heart 2012; 98(24):1805-1811
Mc Goon Eur Respir Rev 2012; 21: 8-12
PAH
I-PAH 46%
CTD-PAH 25%
Prevalence of PAH in CTDs
Disease Echo prevalence
RHC prevalence/clinically
significant
Systemic sclerosis 20-50% 7.85-12%
SLE 4-43% 0.05-9.3%
MCTD 11-19% 5-16%
PM/DM 11% 0.56%
RA 20% 0.01%
IPAH 1-5/milion
Wigley FM, et al. Arthritis Rheum 2005, 54: 2125-32
Condliffe et al. Am J Respir Crit Care Med. 2009; 179:151-7
Yoshida S. Allergol Int. 2011; 60: 405-409
Clinical and prognostic differences
between IPAH vs CTD-APAH
Chung L, et al. Chest 2010; 138(6):1383–1394
Dada from REVEAL (Registry to Evaluate Early and Long-term Pulmonary
Arterial Hypertension Disease Management)
Patients with SSc-APAH
had a worse survival
compared with different
CTDs
Chung L, et al. Chest 2010; 138(6):1383–1394 Condliffe et al Am J Respir Crit Care Med 2009
PA = pulmonary artery; PASP = pulmonary artery systolic pressure; SSc = systemic sclerosis
Stupi AM, et al. Arthritis Rheum 1986;29:515–24.;
Steen V, et al. Arthritis Rheum 2003;48:516–22.
Stupi AM, et al:
Average PA pressure 82/35 (50) mmHg
Average PA resistance 16 Wood units
Average cardiac index 2.1 L/min/m2
Steen V, et al:
Average PASP 76 mmHg
Survival in limited scleroderma
with and without PAH
0
20
40
60
80
100
% C
um
ula
tive
su
rviv
al
1 2 3 4 5
Follow up (Years)
(n=287) (n=106)
(n=106)
(n=20)
SSc without PAH
SSc with PAH
A B C
iPAH
SSc
Kidney Lung Heart
Vasculopathy in scleroderma and idiopathic PAH
However compared to iPAH:
therapeutic responses are less favourable in SSc-PAH
the outcome is worse in SSc-PAH patients
NT-proBNP much higher Mathai et al. Eur Resp J. 2010
Overbeek et al Eur Respir J 2009
Dorfmüller et al Hum Pathol 2007
Pulmonary arterial hypertension
in limited cutaneous scleroderma
with PAH
Presence of intimal fibrosis of both arteries/arterioles
and veins/venules
Presence of PVOD-like pattern in some cases
Absence of plexiform lesions
Arterial and venous remodelling not restricted to
areas of lung fibrosis
Distinctive features compared with idiopathic PAH
• Human pulmonary artery smooth muscle cells acquired a synthetic phenotype
characterized by higher growth rate, migratory activity, gene expression of type I
collagen α1 chain in vitro when stimulated with PDGF and autoantibodies
against PDGF receptor, but not with normal IgG.
• less expression of markers characteristic of the contractile phenotype such as
smooth muscle-myosin heavy chain and smooth muscle-calponin
• Phenotypic change is mediated by increased generation of reactive oxygen
species (ROS) and expression of NOX4 and mTORC1.
• NOX4 silencing reduce SSc-IgG effects
• rapamicine reduce SSc-IgG effects
Svegliati S, et al. Front Immunol. 2017 Feb 8;8:75. 0
10
20
30
40
50
60
70
Sti
mu
lati
on
in
dex
(%
)
IG N
IG SSc
Agonistic anti-PDGF receptor autoantibodies from Patients with
systemic sclerosis impact human Pulmonary artery smooth
Muscle cells Function In Vitro
PAH p=0.05
GI p=0.43
Heart p=0.26
SRC
PAH
GI
PF
Heart
Fre
qu
en
cy (
%)
0
10
20
30
40
50
p<0.001 (SRC)
p<0.001 (PF)
1972-6 1977-81 1982-6 1987-91 1992-6 1997-2001
Causes of death in
scleroderma
Death (years)
Steen VD, Medsger TA, 2007
Launay D et al. Chest 2011;140;1016-1024;
Patients with SSc with PH-ILD have a different phenotype
and a worse prognosis than those with SSc and PAH.
Condliffe et al Am J Respir Crit Care Med 2009
PAH-SSc
PAH-ILD-SSc
Log-rank X2 = 8.83
p < 0.01
0 1 2 3 4 5 6 7 0
25
50
75
Survival in Years
Perc
en
t su
rviv
al
Mathai et al. Arthritis Rheum 2009
SSc-PAH SSc-ILD-PH
Pathophysiology of Pulmonary hypertension
in pulmonary fibrosis Vascular ablation
Chronic hypoxic vasoconscriction
Intermittent nocturnal hypoxia
Inflammatory response within the pulmonary vasculature specific to the
underlying disease and coagulation cascade
Underexpression of angiogenic factors (e.g. vascular endothelial growth
factor and platelet endothelial cell adhesion molecule)
Factors affecting vascular tone (e.g. angiotensin-converting enzyme and
endothelin-1)
Overxpression of inflammatory (e.g. phospholipase A2) and remodelling
genes.
Panagiotu et al. Eur Respir Rev 2017
Corte T, Wort S, Wells A. Sarcoidosis Vasc Diffus Lung Dis 2009
Sajkov D and McEvoy RD. Prog Cardiovasc Dis 2009
PH due to PVOD
• Probably underrecognized in CTDs, particularly in SSc
• Differentiating PVOD from PAH can be clinically challenging
• The high prevalence of veno-occlusive disease in SSc may
explain, in part, the refractoriness to targeted PAH therapy in
some patients.
• PAH therapy can actually precipitate severe pulmonary edema.
• Preferential involvement of small pulmonary veins together with patchy capillary
proliferation vs predominant involvement of small pulmonary arteries in PAH.
• Chest HRCT is characterized by the triad of mediastinal lymphadenopathy,
smooth interlobular septal thickening, and centrilobular ground glass opacities
• Very low DLCO and severe hypoxemia
• Features suggestive of PVOD have been found in as many as two-thirds of
patients who are classified as “SSc-PAH” based on postmortem histological
examination. Montani et al. Eur Respir J 2009
Gunter et al. Arthrits Rheum 2012
Molecular pathways
Leucocyte
recruitment
and cytokine
release
Inflammatory
pathway
e.g. RANTES,
fractalkine
Vasoconstriction Cell
proliferation
e.g.
IL-13
IL-14
PDE-5
inhibitor
NO
L-arginine
Vasodilation and
antiproliferation
cGMP
Exogenous
NO
NOS
PDE-5
Endothelin-1
Arachidonic acid
Prostaglandin I2
Prostacyclin
derivates
PGI2
cAMP
Vasodilation
and antiproliferation
ETA = endothelin-A receptor; ETB = endothelin-B receptor; ETRA = endothelin receptor antagonist; NOS = nitric oxide synthase;
cGMP = cyclic guanosine monophosphate; cAMP = cyclic adenosine monophosphate; PDE-5 = phosphodiesterase type 5; IL = interleukin
Endothelial
cells
Smooth
muscle
cells
ETB
Preproendothelin
Proendothelin
ETA ETB
Vasodilation
and antiproliferation
ETRAs
• Dispnea
• Edemi declivi
• Turgore giugulare
• Epatomegalia da stasi
• Cianosi
• Ipossiemia/normo-ipocapnia
• Poliglobulia
• Iperuricemia
• BNP o NT-proBNP aumentato
Il sospetto clinico
Pazienti giovani senza patologie
cardio-polmonari note.
Pazienti con patologie cardio-
polmonari note (scompenso
cardiaco, BPCO, fibrosi
polmonare, connettiviti, ecc) che
peggiorano in mainera
ingiustificata o “sproporzionata”
al quadro clinico-strumentale
della malattia sottostante.
ECG
• P polmonare
• Deviazione assiale dx
• BBdx
• Ipertrofia ventricolare dx
Ecocardiografia
Galiè et al., Eur Heart J 2015 (29 Aug)
Ecocardiografia
TAPSE, TDI e Strain VD: indici con
maggiore sensibilità come
screening tool
Bonderman D et al. Eur Respir J 2011
Funzionalità respiratoria
• DLCO ridotta nella totalità dei pazienti
• DLCO < 45% associata a outcome peggiore.
• FVC e FEV 1 e altri indici spirometrici se alterati indicativi di una
patologia polmonare.
• PaO2 ridotta
• PaCO2 normale o ridotta
• PaCO2 aumentata nelle COPD
• Elevata prevalenza di IP nelle OSAS
(monitoraggio respiratorio)
Sun XG, et al. J Am Coll Cardiol 2003
Trip T et al. Eur Resp J 2013
Hoeper MM et al. Eur Resp J 2007
Ipertensione polmonare ed indici funzionali
DLCO: ridotta per ▪ alveolite
▪ fibrosi
▪ danno del microcircolo polmonare
▪ alterazione ventilazione/perfusione
FVC: marcatore pattern ventilatorio restrittivo associato a fibrosi
Behr et al.: Rheumatology 2008 RATIO: FVC%/DLCO%
▪ RATIO > 2: suggestiva di ipertensione arteriosa polmonare isolata
▪ RATIO < 1,4: suggestiva di ipertensione arteriosa polmonare
associata ad interstiziopatia polmonare Gupta. Rheumatology 2004
RATIO > 1.8 correla con PAPs > 36-51 mmHg Steen VD. J Clin Rheumatol 2005
van Laar et al. Drugs 2007
popolazione generale
RATIO (FVC%/DLCO%)
PA
sP
(m
mH
g)
p<.0005
r² = 0,118
Fraticelli et al unpublished
Ratio correlate with PAPs
popolazione generale
DLCO%
PA
sP
(m
mH
g)
p<.001
r² = 0,105
All patients
No correlation in Scl70+ patients
RATIO (FVC%/DLCO%)
p<.5
PA
sP
(m
mH
g)
r² = 0,007
pts. anti-Scl-70 +
DLCO%
PA
sP
(m
mH
g)
p<.2
r² = 0,034
Fraticelli et al unpublished
pts. anti-centromere +
DLCO%
p<.1
PA
Ps (
mm
Hg)
r² = 0,086
pz. anti-centromero +
p<.0007
RATIO (FVC%/DLCO%) P
AP
s (
mm
Hg
)
r² = 0,431
Ratio correlate with PAPs
in anti-centromere+ patients
Curva ROC per PAPs ≥ 51 mmHg in pazienti con SSc
sottoposti a RHC
1-specificità
sen
sib
ilit
à
AUC=0,789
1,698
RATIO
DLco
DLco/VA
Sens 75%
Spec 80%
BNP and NT-proBNP in CTDs-PAH
NT-proBNP levels have been shown to correlate with hemodynamics
and prognosis (Mukerjee et al. Respir Med 2003, Williams et al. Eur Hearth J 2006)
Combination of high NT-proBNP level and low Dlco have been
suggested to be useful in the diagnosis and follow up of SSc-PAH
patients (Allanore et al. Arthritis Rheum 2008)
Elevated levels does not help differentiate left from right ventricular
dysfuntion, and is less helpful when there is a known left heart disease
(Mukerjee et al. Respir Med 2003)
Normal levels does not exclude an early PH (Warwick et al. Eur Respir J
2008)
SSc-PH compared with IPAH exibit disproportionate high levels of NT-
proBNP, despite similar hemodynamics (Mathai et al. Eur Respir J 2010)
Surrogate of severity and response to therapy in PH (Dimitroulas et al.
Semin Arthr Rheum 2010).
Imaging
Imaging
HRCT
Imaging
Scintigrafia polmonare Angio-TC
Escludere CTPH
(LES, APL)
Potential benefit of earlier diagnosis:
importance of screening
1. Advantage over IPAH patients (well known disease and potential
developement of PAH)
2. Recommended screening programmes and guidelines offer earlier
diagnosis
1. Novel therapeutic approaces that can influence survival when early
established
Annual transthorcic echocardiogram
Pulmonary function tests every 6-12 months
ECG
Serum BNP or NT-proBNP EPOSS-OMERACT guidelines
1. clinical (progressive dyspnoea over the past 3 months,
unexplained dyspnoea, worsening of WHO dyspnoea functional
class, any finding on physical examination suggestive of elevated
right heart pressures and any sign of right heart failure),
2. echocardiography (systolic pulmonary artery pressure >45 mm
Hg and right ventricle dilation)
3. pulmonary function tests (diffusion lung capacity for carbon
monoxide <50% without pulmonary fibrosis).
three domains:
Expert consensus for performing right heart catheterisation for
suspected pulmonary arterial hypertension in systemic
sclerosis: a Delphi consensus study with cluster analysis.
Avouac J, Huscher D, Furst DE, Opitz CF, Distler O, Allanore Y; for the EPOSS
group.
Ann Rheum Dis 2013.
right heart catheterisation
Galiè et al. Eur Respir J 2015; 46: 903-75
Stress doppler echocardiography in systemic sclerosis: evidence for a role in
the prediction of pulmonary hypertension Codullo V et al. Arthritis Rheum 2013
Clinical and echocardiographic correlations of exercise-induced pulmonary
hypertension in systemic sclerosis: a multicenter study Gargani l. et al Am Heart J. 2013;165(2):200-7
• May represent an early, clinically relevant phase of PAH.
• A hemodynamic evaluation of SSc-associated PH patients during
exercise may allow for earlier diagnosis
• No current consensus on the hemodinamic definition of exercise PH.
Exercise-induced pulmonary hypertension
Pulmonary arterial hypertension therapy may be safe and effective in patients
with SSc and borderline pulmonary artery pressure Kovacs G et al. Arthritis Rheum 2012, 64:1257-62
“Borderline PH”
and
risk to develop overt PH
mPAP 21<24 (HR 3.7 p< 0.001)
+
Transpulmonary gradient (mPAP–PAWP) > 11 mmHg (HR 7.9 p< 0.001)
Mortality within 3 years 18%
Patients with mPAP 21<24 mmHg require close monitoring
Valerio CJ, Schreiber BE, Handler CE, et al. Borderline mean pulmonary artery
pressure in patients with systemic sclerosis: transpulmonary gradient predicts risk of
developing pulmonary hypertension. Arthritis Rheum 2013;65:1074-84.
0 10 20 30 40 50 60
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
mPAP < 32 mm Hg
mPAP > 45 mm Hg
Time (months)
mPAP 32-44 mm Hg
Survival curves for 148 SSc patients
with PAH devided into tertiles
Mukerjee et al 2003
mPAP values at presentation and survival
0.0
0.2
0.4
0.6
0.8
1.0
0.00 1.00 2.00 3.00 4.00 5.00 6.00
Years from diagnosis
41
176
42
38
122
19
20
64
10
14
35
4
6
19
2
1 WHO I/II
4 WHO III
1 WHO IV
Patients at risk
IV
III
I-II
p < 0.001
Survival from diagnosis of patients with isolated
SSc-PAH grouped by WHO functional class
Condliffe et al Am J Resp Crit Care Med 2009
Launay D et al. Chest 2011;140;1016-1024;
•Age
•Pericardial effusion
•Left ventricular disfunction
•Low 6MWT
•High mPAP
•High PVR
•NYHA III-IV
predictive of a poor outcome in
PH-ILD
Survival and prognostic factors in systemic sclerosis-associated
pulmonary hypertension: a systematic review and meta-analysis
Lefevre G et al. Arthritis & Rheum 2013.
DOI 10.1002/art.38029
The hazard ratio for death was
3.02 (95% CI 1.91, 4.78) for
systolic pulmonary artery
pressure > 36mmHg in SSc
patients
The hazard ratio for death was
4.94 (95% CI 2.66, 9.17) for DLCO
<64% of predicted in SSc
patients
La valutazione del paziente
Follow-up ogni 3-6 mesi Galiè et al., Eur Heart J 2015 (29 Aug)
Conclusioni
• L’ipertensione arteriosa polmonare è una complicanza non
rara nei pazienti affetti da CTDs
• La sopravvivenza è strettamente correlata alla diagnosi
precoce ad all’inizio di una terapia specifica
• È necessario uno stretto monitoraggio dei pazienti
• Necessaria una valutazione integrata e polispecialistica per
una corretta gestione del paziente
• Necessità di estendere le conoscenze nel campo della
fisiopatologia dei fenomeni vascolari e fibrotici della malattia
Risk factors for pulmonary arterial
hypertension in systemic sclerosis
Limited variant (92%)
Usually considered a late complication (disease duration > 10 years)
Late age of onset of SSc
Severe Raynaud’s phenomenon and digital ulceration and
teleangectases
Low DLco
Anti-centromere and U3-RNP (anti-Scl-70 apparently protecive)
Early onset (within 5 years worse prognosis and no difference
between limited and diffuse SSc)