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

– Actelion – Almirall – Aptalis – Bayer – Centocor – Eli-Lilly – GSK – InterMune, Inc.

2  

Dr Carlo Albera has served as investigator in clinical trials, consultant, speaker, Steering Committee or Scientific Advisory Board member for:

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)

Anatomy of the pulmonary acinus

Smooth muscle cells

Contractile intermediate cells

and pericytes (intima)

From Olschewski H, Seeger W , 2002 Modif

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

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

Progressione temporale della PAH

From Olschewski H, Seeger W , 2002 Modif

Causes of precapillary pulmonary hypertension

Rimodellamento della parete vascolare

• Eterogeneità delle componenti strutturali della parete vascolare

• Tutte sono coinvolte nel processo di rimodellamento

Rimodellamento della parete vascolare : concetti di fondo

• Alterazioni funzionali • Alterazioni strutturali Ø Vasi di piccolo Ø : - evento precoce

Ø Vasi di grande Ø : - evento tardivo

- conseguenza del sovraccarico pressorio

Progressione anatomica

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

• Vasi più distali (Ø 20-30µm; no lamina elastica) –  Periciti e Fibroblasti interstiziali vengono

reclutati ed assumono il fenotipo delle SMC

Rimodellamento vascolare : aumento della muscolarizzazione delle arterie

polmonari muscolari

• L’incremento pressorio derivante dalla vasocostrizione e dal rimodellamento periferico provoca nelle arterie di medio Ø proliferazione ed ipertrofia delle cellule muscolari lisce (-> riduzione fissa del Ø)

• Media –  Incremento della componente elastica –  Deposizione di collagene di tipo I • Avventizia –  Incremento dei fibroblasti –  Deposizione di collagene

Il danno / attivazione dell’endotelio porta ad un passaggio di proteine plasmatiche: l’elastasi danneggia la lamine

elastica e promuove le modificazioni di media ed avventizia

Rimodellamento vascolare : formazione della “neointima”

• Fenomeno tipico della grave PAH (IPAH, da cardiopatia)

• Avviene nelle arterie di ogni Ø

• Non costituisce una risposta specifica

Origine dei miofibroblasti:

• Transdifferenziazione delle cellule endoteliali

• Migrazione di cellule “smooth muscle-like” dalla media

• Migrazione dei fibroblasti dell’avventizia

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

Rimodellamento vascolare : lesioni plessiformi

• Solo nelle forme di grave PAH • 80% IPAH • PAH secondaria grave • Originano da arterie di 200-400 µm Ø • Sono “tubi” endoteliali sostenuti da uno stroma (proteine di matrice e miofibroblasti) • Le cellule endoteliali sono VEGF e VEGFr + • Nella IPAH sono monoclonali • Emodinamicamente irrilevanti • Sono marker della anomala risposta endoteliale

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 •  Flogosi •  Sostanze tossiche •  Fattori genetici

Stimoli diversi evocano risposte in parte

differenti

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

• Trombosi in situ – Lesioni endoteliali mediate dalla trombina – Trasudazione di proteine – Edema interstiziale – Stimolo a proliferazione fibroblasti e sintesi

matrice – Aumento aderenza PMNs all’endotelio

I PRODOTTI DI DEGRADAZIONE DEL FIBRINOGENO SONO DA TEMPO NOTI COME FATTORI DI CRESCITA PER I

FIBROBLASTI

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

Ipertrofia della tonaca media

Arteria pre-acinare Arteria intra-acinare

Isspessimento dell’intima

Laminare concentrico arteria pre-acinare

Laminare concentrico arteria intra-acinare

SMA+ cells

Isspessimento dell’intima

Laminare eccentrico arteria pre -acinare

Non laminare eccentrico arteria pre-acinare

Lesioni plessiformi

Arteria intra-acinare Arteria pre-acinare adiacente a lesione plessiforme

SMA- endothelial cells SMA- endothelial cells

Dilation lesions

Altre lesioni

Lesione “colander-like” Lesione infiammatoria tipo arterite linfomonocitaria

Factors stmulatig cell proliferation and collagen synthesis

Smooth muscle cell growth

•  IGF-1, IGF-2 •  PDGF •  EGF •  bFGF, aFGF •  Insulin •  Heparin •  TX A2 •  ET-1 •  Angiotensin II •  Serotonin •  Tenascin •  Leukotriens •  ROS

Type 1 collagen synthesis •  IGF-1, IGF-2 •  TGF-β •  PDGF •  Angiotensin II •  Tenascin

Factors inhibiting cell proliferation and collagen synthesis

Smooth muscle cell growth

•  TGF-βBMPS •  IL-1 •  Prostaglandins •  Interferons •  TNF-α •  Heparin sulfates •  NO •  CO •  Adrenomedullin •  ANP •  Isoproterenol

Type 1 collagen synthesis •  Prostaglandins

•  Interferons

•  NO •  ANP

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

Hemodynamic progression of PAH

Pulm. pressure

Cardiac output

Pulm

onar

y A

rter

y Pr

essu

re

Time

Years Months

Therapeutic window

RV function

NYHA I: No limits to

physical activity NYHA II Some limitation

NYHA IV Severe limitation

Symtoms at rest

NYHA III Marked limitation

Survival,QO

L

Manifestazioni cliniche • Dispnea • Ridotta tolleranza allo sforzo • Astenia • Dolore toracico • Edemi • Cardiopalmo • Vertigini • Sincope • Morte improvvisa

§  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

A DIFFICULT DIAGNOSIS

Significant numbers of PAH patients have co-morbidities

N=1226

1. Elliott GC et al. Chest 2007; 631S.

Over half of patients enrolled in the study had two or more

co-morbid conditions

DISTRIBUTION OF THE TYPE OF PAH

Humbert M et al Am J Resp Crit Care Med 2006; 173: 1023–1030

iPAH 39,2%

FPAH 3,9%

Anorex 9,5%

CTD 15,3%

CHD 11,3%

PoHT 10,4%

HIV 6,2%

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

Gibbs J. Eur Respir. Rev. 2007; 16; 8-12

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

Clinical Classification of Pulmonary Hypertension (Dana Point 2008)

3. PH due to lung dis/hypoxiaemia 3.1 COPD 3.2 ILD 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 abnormabilities

4. Chronic thromboembolic PH

2. PH due to left heart disease 2.1 Systolic dysfunction 2.2 Diastolic dysfunction 2.3 Valvular diseases

1’. PVOD and/or Pulm capill Haemang.

1. Pulmonary Arterial Hypertension 1.1 Idiopatic 1.2 Heritable

1.2.1 BMPR2 1.2.2 ALK1, endoglin (with or without hereditary haemorrhaigc teleangectasia)

1.2.3 Unknown 1.3 Drugs and toxins induced 1.4 Associated with (APAH)

1.4.1 Connective Tissue Diseases 1.4.2 HIV infection 1.4.3 Portal hypertension 1.4.4 Congenital heart disease 1.4.5 Schistosomiasis 1.4.6 Chronic haemolityc anaemia

1.5 Persistent PH of the newborn

5. PH with unclear and/or multifact mechs 5.1 Haematological dis: myieloproliferative,

splenectomy 5.2 Systemic dis: sarcoidosis, pulmonary

Langerhans cell histiocytosis, lymphangioleiomyomatosis

5.3 Metabolic dis: glycogen storage disease. Gaucher disease, thyroid disorders

5.4 Others: tumoral obstruction, fibrosing mediastinitis, CRF on dialysis

3

1

2

Echocardiographic evaluation M-mode

-  RV free wall motion -  TAPSE

Two-dimensional

-  RV enlargement/hypertrophy -  RA enlargement -  pericardial effusion -  LV compression

Doppler - PAP - Trans-tricuspid peak velocity

- Trans-tricuspid pressure gradient

Newer approaches

- Myocardial doppler Tissue imaging

-  One-dimensional strain

RV: Right ventricular; RA: Right atrial; LV: left ventricular; PAP: Pulmonary artery pressure; TAPSE: Tricuspid annular plane systolic excursion

Ask specifically for right ventricular assessment!

Lindqvist et al. Eur J Echocardiogr 2008 Mar; 9: 225-234

a Class of recommendation, b Level of evidence

Recommendations for right heart catheterization

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.

European Heart Journal (2010) 31, 2080–2086

European Heart Journal (2010) 31, 2080–2086

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  ?  

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.

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.

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.

Eur Respir Rev 2012; 21: 123, 40–47

Tools and variables for detecting disease progression

Eur Respir Rev 2012; 21: 123, 40–47

Variables with established importance for assessing disease severity, stability and prognosis in pulmonary arterialhypertension

Eur Respir Rev 2012; 21: 123, 40–47

Goal-oriented strategy at the pulmonary hypertension clinic at

Erasme University (Brussels, Belgium)

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.

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.

Key pathological mechanisms underlying vascular changes in pulmonary hypertension

Eur Respir Rev 2012; 21: 123, 19–26

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

International Journal of Cardiology 150 (2011) 59–64

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

International Journal of Cardiology 150 (2011) 59–64