1. FISIOPATOLOGIA DELLA PAH
Carlo Albera
Università di Torino
Facoltà di Medicina San Luigi Gonzaga
Dipartimento di Scienze Cliniche e Biologiche
Ambulatorio Interstiziopatie Polmonari / Malattie Rare
2. Dr Carlo Albera has served as investigator in clinical trials,
consultant, speaker, Steering Committee or Scientific Advisory Board
member for:
– Actelion
– Almirall
– Aptalis
– Bayer
– Centocor
– Eli-Lilly
– GSK
– InterMune, Inc.
2
3. Ipertensione arteriosa
polmonare
• Malattia rara o associata a malattie rare
• Elevata resistenza delle arterie polmonari
• Invalidante, progressiva, prognosi infausta
• Gestione in ambito multidisciplinare
• Disponibili linee guida
• Terapia efficace (alti costi)
4. Anatomy of the pulmonary acinus
Smooth muscle
cells
Contractile
intermediate cells
and pericytes
(intima)
From Olschewski H, Seeger W , 2002 Modif
5. Caratteristiche del circolo polmonare
• Bassa pressione
• Flusso elevato
• Grande possibilità di reclutamento
di vasi normalmente non perfusi
Ø Bassa pressione transmurale
Ø Arterie con parete sottile
6. Ipertensione arteriosa
polmonare
• Malattie delle piccole arterie polmonari
• Ispessimento parete / riduzione lume
• Aumento delle resistenze vascolari
Ø Aumento del post-carico del ventricolo dx
Ø Insufficienza ventricolare dx per incapacità
di tollerare l’aumento del post-carico
9. Rimodellamento della parete
vascolare
• Eterogeneità delle componenti
strutturali della parete vascolare
• Tutte sono coinvolte nel processo
di rimodellamento
10. Rimodellamento della parete
vascolare : concetti di fondo
• Alterazioni funzionali
• Alterazioni strutturali
Ø Vasi di piccolo Ø :
- evento precoce Progressione
anatomica
Ø Vasi di grande Ø :
- evento tardivo
- conseguenza del sovraccarico pressorio
11. Rimodellamento vascolare :
muscolarizzazione delle arterie polmonari non
muscolari
•
Comparsa di uno strato di cellule muscolari
lisce nella parete delle arterie intra-acinari
• Vasi precapillari
– Le cellule intermedie della lamina elastica interna
proliferano ed assumono il fenotipo delle SMC
• elastica)distali (Ø 20-30µm; no lamina
Vasi più
– Periciti e Fibroblasti interstiziali vengono
reclutati ed assumono il fenotipo delle SMC
12. Rimodellamento vascolare :
aumento della muscolarizzazione delle arterie
polmonari muscolari
• Il’incremento pressorio derivante dallaperiferico
L danno / attivazione dell’endotelio porta ad un passaggio
vasocostrizione e dal rimodellamento
di proteine plasmatiche: l’elastasi danneggia la lamine
provoca nellepromuove di modificazioni di media ed ed
elastica e arterie le medio Ø proliferazione
ipertrofia delle cellule muscolari lisce (-> riduzione
avventizia
fissa del Ø)
• Media
– Incremento della componente elastica
– Deposizione di collagene di tipo I
• Avventizia
– Incremento dei fibroblasti
– Deposizione di collagene
13. Rimodellamento vascolare :
formazione della “neointima”
• (IPAH, da cardiopatia)grave PAH
Fenomeno tipico della
Origine dei miofibroblasti:
• Transdifferenziazione delle cellule endoteliali
•
• Migrazione di cellule “smooth muscle-like”
Avviene nelle arterie di ogni Ø
dalla media
• specificadei fibroblasti risposta
Migrazione
• Non costituisce una dell’avventizia
14. Ipertensione arteriosa polmonare
§ Malattie delle piccole arterie polmonari
§ Ispessimento parete / riduzione lume
§ Aumento delle resistenze vascolari
Ø Aumento del post-carico del ventricolo destro
Ø Insufficienza ventricolare destra per incapacità
di tollerare l’aumento del post-carico
15. Rimodellamento vascolare :
lesioni plessiformi
• Solo nelle forme di grave PAH
• 80% IPAH
• PAH secondaria grave
• Originano da arterie di 200-400 µm Ø
• stromatubi endoteliali sostenuti da uno
Sono
(proteine di matrice e miofibroblasti)
• Le cellule endoteliali sono VEGF e VEGFr +
• Nella IPAH sono monoclonali
• Emodinamicamente irrilevanti
• endoteliale della anomala risposta
Sono marker
16. Modificazioni cellulari nel rimodellamento
vascolare : cellule endoteliali
• Caratteristiche fisiologiche:
– Barriera semipermeabile
– Antritrombigena
• Possiede proprietà metaboliche che influenzano:
– Tono vascolare
– Crescita cellulare
– Differenziazione cellulare
– Risposta a stimoli lesivi
• Ipossia
• Aumento del flusso Stimoli diversi evocano
• Flogosi risposte in parte
• Sostanze tossiche
• Fattori genetici differenti
17. Modificazioni fisiopatologiche nel rimodellamento
vascolare : endotelio e coagulazioe
Alterazioni che causano PAH attraverso:
• CTEPH
– Emboli dal circolo venoso sistemico
– Rimodellamento in situ con parziale ricanalizzazione
I PRODOTTI DI DEGRADAZIONE DEL
FIBRINOGENO SONO DA TEMPO NOTI
• Trombosi in FATTORI DI CRESCITA PER I
COME situ
FIBROBLASTI
– Lesioni endoteliali mediate dalla trombina
– Trasudazione di proteine
– Edema interstiziale
– Stimolo a proliferazione fibroblasti e sintesi
matrice
– Aumento aderenza PMNs all endotelio
18. Modificazioni cellulari nel rimodellamento vascolare :
risposta delle cellule endoteliali a differenti stimoli
• Ipossia :
– Proliferazione cellule endoteliali
• Shear stress (15 dyn/cm2):
Produzione/rilascio dall endotelio di mediatori
vasoattivi
– ET-1
– Angiotensina II
– Trombossano
– NO
– Prostaciclina
E di fattori di crescita
– PDGF
– TGF-β
25. Factors inhibiting cell proliferation and collagen
synthesis
Smooth muscle cell
growth
Type 1 collagen synthesis
• TGF-βBMPS
• IL-1
• Prostaglandins
• Prostaglandins
• Interferons
• Interferons
• TNF-α
• Heparin sulfates
• NO
• NO
• CO
• ANP
• Adrenomedullin
• ANP
• Isoproterenol
26. Definizione di Ipertensione Polmonare
Ipertensione Polmonare (PH)
§ Condizione emodinamica e fisiopatologica
caratterizzata da aumento della pressione
polmonare media a riposo ≥ 25 mmHg (RHC)
riscontrabile in molteplici condizioni cliniche
Ipertensione Arteriosa Polmonare (PAH) *
§ Condizione clinica caratterizzata da Ipertensione
Polmonare Precapillare (Wedge Pressure RHC < 15
mmHg) in assenza di cause note
(*) In pratica incluse solo le forme del gruppo 1, anche se nella maggior
parte degli altri gruppi la PH è comunque precapillare
27. Hemodynamic progression of PAH
NYHA I:
No limits to
physical activity NYHA II
Some limitation
NYHA III
Marked limitation
NYHA IV Severe limitation
Symtoms at rest
Pulmonary Artery Pressure
RV function
Survival,QOL
Pulm. pressure
Cardiac output
Therapeutic window
Years Months
Time
29. A DIFFICULT DIAGNOSIS
§ PAH is often asymptomatic in its early stages
§ Symptoms are often nonspecific, leading to an
initial effort to diagnose or exclude more
common conditions. 35% are misdiagnosed at
first presentation.
§ Patients with PAH typically face a lag time from
onset of symptoms to diagnosis of approx 2
years.
§ PAH is frequently associated with comorbid
conditions, further complicating diagnosis
§ In patients with suspected PAH, right heart
catheterization (RHC) is required to confirm the
diagnosis
30. Significant numbers of PAH patients
have co-morbidities
N=1226
Over half of patients enrolled
in the study had two or more
co-morbid conditions
1. Elliott GC et al. Chest 2007; 631S.
31. DISTRIBUTION OF THE TYPE OF PAH
HIV 6,2%
iPAH 39,2%
PoHT 10,4%
FPAH 3,9%
CHD 11,3%
Anorex 9,5%
CTD 15,3% Humbert M et al Am J Resp Crit Care Med 2006; 173: 1023–1030
PAH is a rare disease: prevalence is between 15–25 cases/million
PAH is rapidly evolving
ü 75% NYHA FC III at diagnosis
ü Median survival of IPAH is 2.8 years
32. Prognosi della Ipertensione Arteriosa Polmonare
L aspettativa media di vita dal momento della diagnosi ed in assenza di terapia è:
2,8 anni nell adulto
10 mesi nei bambini 32
Gibbs J. Eur Respir. Rev. 2007; 16; 8-12
33.
34. Clinical Classification of Pulmonary Hypertension
(Dana Point 2008)
1. Pulmonary Arterial Hypertension 3. PH due to lung dis/hypoxiaemia
1.1 Idiopatic 3.1 COPD
1.2 Heritable 3 3.2 ILD
1.2.1 BMPR2 3.3 Other pulmonary diseases with mixed
1.2.2 ALK1, endoglin (with or without hereditary restrictive and obstructive pattern
haemorrhaigc teleangectasia)
3.4 Sleep-disordered breathing
2
1.2.3 Unknown
3.5 Alveolar hypoventilation disorders
1.3 Drugs and toxins induced
3.6 Chronic exposure to high altitude
1.4 Associated with (APAH)
3.7 Developmental abnormabilities
1.4.1 Connective Tissue Diseases
1.4.2 HIV infection
1.4.3 Portal hypertension 4. Chronic thromboembolic PH
1.4.4 Congenital heart disease
1.4.5 Schistosomiasis 5. PH with unclear and/or multifact mechs
1.4.6 Chronic haemolityc anaemia 5.1 Haematological dis: myieloproliferative,
1.5 Persistent PH of the newborn splenectomy
5.2 Systemic dis: sarcoidosis, pulmonary
1 . PVOD and/or Pulm capill Haemang. Langerhans cell histiocytosis,
lymphangioleiomyomatosis
2. PH due to left heart disease 5.3 Metabolic dis: glycogen storage disease.
2.1 Systolic dysfunction Gaucher disease, thyroid disorders
2.2 Diastolic dysfunction 1 5.4 Others: tumoral obstruction, fibrosing
2.3 Valvular diseases mediastinitis, CRF on dialysis
35.
36. Echocardiographic evaluation
M-mode Doppler
- RV free wall motion - PAP
- TAPSE - Trans-tricuspid peak
velocity
- Trans-tricuspid pressure
Two-dimensional gradient
- RV enlargement/hypertrophy
- RA enlargement Newer approaches
- Myocardial doppler Tissue
- pericardial effusion imaging
- LV compression - One-dimensional strain
Ask specifically for right ventricular assessment!
RV: Right ventricular; RA: Right atrial; LV: left ventricular; PAP: Pulmonary
artery pressure; TAPSE: Tricuspid annular plane systolic excursion
Lindqvist et al. Eur J Echocardiogr 2008 Mar; 9: 225-234
39. In conclusion, the clear recent progress in the treatment of PAH
supported by the concordant results of recent meta-analyses
need to be further extended because the current treatment
strategy is still not satisfactory
There is no time for sterile discussions about the extent of
current achievements based on others’ published papers.
Let usfight the battle against PAH ‘on the field’ together. Our
patients deserve this commitment.
42. ERS 21st Annual Congress Amsterdam 24-28 September 2011
Session 185 ,Evening Symposium, Sunday September 25
The 2011 PAH debate:
what is the biggest challenge we face to optimize patient
outcome?
• To
diagnose
pa-ents
sooner
?
• To
recognise
deteriora-on
sooner?
• To
treat
more
aggressively
?
43. Pulmonary Hypertension
Sanjiv J. Shah, MD
JAMA. 2012;308(13):1366-1374.
Pulmonary hypertension (PH), defined as elevated pulmonary artery
pressure, is common in the general population and associated with
increased mortality.
Accordingly, physicians commonly encounter patients with dyspnea,
exercise intolerance, and/or right heart failure who have elevated
pulmonary artery systolic pressure (PASP) on echocardiography.
Although pulmonary arterial vasodilators may often be considered in this
setting, these drugs have been predominantly tested in the subset of PH
patients with pulmonary arterial hypertension (PAH).
Elevated PASP alone is not sufficient for the diagnosis of PAH, and
secondary causes of PASP elevation, most commonly left heart disease,
are far more prevalent than isolated PAH.
44. Pulmonary Hypertension
Sanjiv J. Shah, MD
JAMA. 2012;308(13):1366-1374.
Treatment of this more common group of patients with PH due to left heart
disease is challenging because there are few evidence-based treatment
options, and pulmonary vasodilator therapy may lead to worsening symptoms.
Therefore, improving symptoms and avoiding adverse outcomes in patients
with PH requires the following:
(1) understanding the optimal use of echocardiography for the diagnosis of PH;
(2) recognizing the utility and proper interpretation of invasive hemodynamic
testing prior to starting pulmonary vasodilator therapy;
(3) differentiating PAH from pulmonary venous hypertension due to left heart
disease;
(4) understanding the appropriate treatment strategies for PH and resultant
right heart failure.
45.
46. Pulmonary arterial hypertension (PAH) is a rapidly progressive disease,
ultimately leading to right heart failure and death.
Accumulating evidence indicates that intervention early in disease
progression results in better outcomes than delaying treatment.
There is still an urgent need for prospective collaborative initiatives to
assess novel goals and improve treatment strategies that would allow
physicians to personalise and optimise clinical management for their
patients with PAH.
47. Tools and variables for detecting disease progression
Eur Respir Rev 2012; 21: 123, 40–47
48. Variables with established importance for assessing disease
severity, stability and prognosis in pulmonary arterialhypertension
Eur Respir Rev 2012; 21: 123, 40–47
49. Goal-oriented strategy at the
pulmonary hypertension clinic at
Erasme University (Brussels,
Belgium)
Eur Respir Rev 2012; 21: 123, 40–47
50. Pulmonary hypertension (PH) is a complex, multifactorial disorder divided into five
major subtypes according to pathological, pathophysiological and therapeutic
characteristics.
Although there are distinct differences between the PH categories, a number of
processes are common to the pathology of all subtypes.
Vasoconstriction, as a result of endothelial dysfunction and an imbalance in the levels
of vasoactive mediators, is a well-characterised contributory mechanism.
Excessive cell proliferation and impaired apoptosis in pulmonary vessels leading to
structural remodelling is most evident in pulmonary arterial hypertension (PAH), and
several factors have been implicated, including mitochondrial dysfunction and
mutations in bone morphogenetic protein receptor type 2.
51. Inflammation plays a key role in the development of PH, with increased levels of many
cytokines and chemokines in affected patients.
Exciting insights into the role of angiogenesis and bone marrow-derived endothelial
progenitor cells in disease progression have also recently been revealed.
Furthermore, there is increasing interest in changes in the right ventricle in PH and the
role of metabolic abnormalities.
Despite considerable progress in our understanding of the molecular mechanisms of
PH, further research is required to unravel and integrate the molecular changes into a
better understanding of the pathophysiology of PH, particularly in non-PAH, to put us
in a better position to use this knowledge for improved treatments.
53. Initiatives to develop adult congenital centers dedicated to the care of
GUCH patients are warranted, and should include congenital heart
surgeons operating in a setting mimicking children’s hospitals.
Ann Thorac Surg 2010 ; 90:573–9
54. Results
With the publication of this document the interdisciplinary task force considers its first task as
completed.
Conclusions
The compiled recommendations for the structure of the interdisciplinary medical care of adults
with congenital heart disease (GUCH) should ensure that the structural and medical pre-
conditions for comprehensive GUCH medical care are created.
International Journal of Cardiology 150 (2011) 59–64
