Πνευμονική Υπέρταση Ι.Ε. ΚΑΝΟΝΙΔΗΣ

PH is defined as PAPm 25 mm Hg at rest The general definition of PH remains unchanged Most of the relevant epidemiological and therapeutic studies have used the 25 mm Hg threshold

Borderline PH The upper level of normal resting PAPm is 20 mm Hg How to classify patients with PAPm between 21 & 24 mm Hg? These patients should be carefully followed, in particular when they are at risk for developing PAH patients with CTD family members of patients with IPAH

Risk of Developing Pulmonary Hypertension in Patients With Systemic Sclerosis and Borderline Mean PAP Valerio CJ et al. ARTHRITIS & RHEUMATISM 2013; 65(4): 1074 84

Exercise - induced PH The Exercise induced PH is defined as PAPm 30 mm Hg during exercise. This criterion for PH should not be reintroduced at the present time, due to lack of suitable definition further evaluation standardization on the level of exercise type of exercise position at exercise normal values for various ages

PH is measured by right heart catheterization

1. Galiè N et al. Eur Heart J 2009 7

PA hypertension diagnosis via right heart catheterization From Mayo Clinic Right Heart Catheterization Training Manual Cardiology Rotation

ESC/ ERS guidelines 2009

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PH by Echo PAH Single echo lab / Australian community of 160,000 ~10% of patients had est. spap>40 mm Hg N=483 of 4579 patients with echo PASP >40 mm Hg. Only 2.3% with PAH after full evaluation. Gabby E. Am J Respir Crit Care Med. 2007;175:A713.

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Simonneau G, et al. J Am Coll Cardiol 2013; 62:D34 41.

PREVALENCE of PAH Lung disease/ Sleep-related hypoventilation, 9.7% CTEPH, 0.6% PAH, 2.3% Unknown, 6.8% Congenital heart disease, 1.9% Left heart disease, 78.7%

Histological features of PAH Obstructive remodelling of the pulmonary artery Thickening of the three cellular layers (the intima, media, and adventitia) This is due to hypertrophy (cell enlargement) hyperplasia (cell proliferation ) of endothelial and smooth muscle cells Fibrosis Inflammation Plexiform lesions Thromboses in situ.. Galiè N, et al. Eur Heart J 2009;30:2493 537.

Plexiform lesion Focal proliferation of endothelial and smooth muscle cells

Medial hypertrophy & Intimal fibrosis

Progression of vascular disease

Right Ventricle and Atrium changes Hypertrophy of RV Dilatation of RA Dilatation of RV

Pulmonary vasoreactivity testing Identification of calcium channel blocker responders Is recommended only for patients with IPAH Inh NO at 10-20 ppm iv epoprostenol (2-12 ng/kg/min) iv adenosine (50-350 mg/min) inh iloprost (5 mg)

Pulmonary vasoreactivity testing POSITIVE CRITERIA A drop in mpap by at least10 mmhg A drop in mpap to value < 40 mmhg Cardiac output unchanged or increased

PAH: A Progressive Disease of Poor Survival 100 PAH Survival 80 Survival (%) 60 40 68% 48% 20 34% 0 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 Years of Followup Adapted from: D Alonzo et al. Ann Internal Med. 1991

History First reported case: 1891 Dr. Romberg in Germany published a description of an autopsy case in which significant thickening of the pulmonary artery was noted in the absence of clearly evident cardiac or lung disease. Formally named: 1951 Dr. Dresdale reported on 39 cases in United States

History 1973 : 1 st World Symposium on PH (Geneva) 1998: 2nd World Symposium on PH (Evian Fr) 2003 : 3d World Symposium on PH (Venice It ) 2008 : 4 th World Symposium on PH (Dana Point Ca USA ) 2013 : 5 th World Symposium on PH (Nice Fr)

Signs and symptoms of Pulmonary Hypertension Symptoms and signs are usually not specific; delay in diagnosis very common. Early dyspnea with activity. Late symptoms: syncope chest pain / chest pressure leg edema (signs of right heart failure) abnormal findings on chest X ray or ECG

ECG RVH and R axis deviation tall R wave in V1 prominent S wave in V5 and V6 inverted T wave and ST depression in V1 and V2 (R heart strain) peaked P waves in II (R atrial enlargement)

Diagnostic studies: Chest radiography Radiographic findings are subtle and often missed

Central Pulmonary arterial dilatation Loss of peripheral blood vessels

CXR in PAH

CXR in Eisenmenger Syndrome

Mitral Stenosis

RV, RA Enlargement on Echocardiogram RV LV RA LA Normal PH

Ventilation Perfusion Lung Scan PAH Perf Vent CTEPH Perf Vent

CTEPH: Pulmonary Angiography Confirms diagnosis of CTEPH in patients with PH Assess thrombus accessibility Distinct angiographic patterns Web narrowing Poststenotic dilatation Proximal occlusion Pouch defects

WHO Classification of Severity Class I: No limitation of usual physical activity; Activity doesn t cause dyspnea, fatigue, chest pain, or presyncope Class II: Mild limitation of physical activity; no discomfort at rest; but activity causes dyspnea, fatigue, chest pain Class III: Marked limitation of activity; no discomfort at rest but less than normal physical activity causes increased dyspnea, fatigue, chest pain, or presyncope Class IV: Unable to perform physical activity at rest; may have signs of RV failure; symptoms increased by almost any physical activity

1.Ross RM, et al. BMC Pulm Med 2010;10:31; 2.Miyamoto S, et al. Am J Respir Crit Care Med 2000;161(2 Pt 1):487 92;

Benza RL, et al. Circulation 2010;122:164 72;

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Treatment Currently no cure for PAH Modern advanced PAH therapies can markedly improve a patient s symptoms and slow the rate of clinical deterioration 1,2 Management is complex, involving use of a range of treatment options: general measures conventional or supportive therapy advanced therapy (PAH-specific therapy) surgical intervention www.escardio.org/guidelines

Treatment General measures 1 3 limit effects of external circumstances www.escardio.org/guidelines avoid pregnancy prevention and prompt treatment of chest infections awareness of the potential effects of altitude Conventional or supportive therapy 1 3 provide symptomatic benefit supplemental oxygen oral anticoagulants diuretics CCBs

PAH-specific therapy Endothelin receptor antagonists (ERAs) oral treatments that act by blocking the binding of ET to either one (single antagonist) or both (dual antagonist) of its receptors 1 Synthetic prostacyclins and prostacyclin analogues act by helping to correct the deficiency of endogenous prostacyclin seen in patients with PAH may be administered by intravenous infusion, 2 by subcutaneous infusion, 3,4 or by inhalation 5 Phosphodiesterase-5 (PDE-5) inhibitors oral agents which act on NO pathway www.escardio.org/guidelines

Endothelin 1 (ET 1) Endothelin 1 (ET 1) is produced by endothelial cells elevated levels are seen in PAH patients 1 3 levels correlate with disease severity 4 deleterious effects mediated through ET A and ET B receptors 5 fibrosis hypertrophy and cell proliferationwhich can lead to thickening, narrowing, and occlusion of blood vessels inflammation vasoconstriction endothelin receptor antagonists can block these effects 6 1. Stewart DJ, et al. Ann Inter Med 1991; 114: 464 9; 2. Vancheeswaran R, et al. J Rheum 1994; 21: 1838 44; 3. Yoshibayashi M, et al. Circulation 1991; 84: 2280 85; 4. Galiè N, et al. Eur J Clin Invest 1996; 26: A48; 5. Humbert M, Sitbon O, Simonneau G. N Engl J Med 2004;351:1425 36;

Endothelin binds to two receptors, known as ET A and ET B. Both receptors are implicated in PAH and mediate the deleterious effects of endothelin. Endothelin receptor antagonism can either mitigate the effects of only one (single ET A antagonist) or both (dual ET A and ET B receptor antagonist) receptor types. Therapy with orally administered endothelin receptor antagonists (ERAs) that block the binding of endothelin to one or both receptors aims to mitigate the deleterious effects of the high levels of endothelin seen in PAH Channick RN, et al. Lancet 2001;358:119 23

Prostacyclin Prostacyclin 1,2 potent vasodilator inhibitor of platelet activation low levels in patients with PAH which promotes vasoconstriction in the pulmonary vasculature and a tendency for smooth muscle cell proliferation and platelet activation. 2 therapy with prostacyclin or prostacyclin analogues can help to correct this deficiency 1. McGoon MD, Kane GC. Mayo Clin Proc 2009;84:191 207; 2. Humbert M, et al. N Engl J Med 2004;351:1425 36; 3. Galiè N, et al. Eur Heart J 2009;30:2493 537; 4. Galiè N, et al. Prog Cardiov Dis 2003:45:213 24.

Impact of Epoprostenol Therapy on Survival in PPH 88% 76% 62% 59% 46% 35% Three-year survival observed in the present study and predicted by the NIH equation using baseline hemodynamics McLaughlin, V. V. et al. Circulation 2002;106:1477-1482 McLaughlin, V. V. et al. Circulation 2002;106:1477-1482

Impact of Epoprostenol Therapy on Survival in PPH 81% 70% 47% 27% Long term (7 year) survival based on FC (III versus IV) at the time t of epoprostenol initiation McLaughlin, V. V. et al. Circulation 2002;106:1477-1482

Nitric oxide 1,2 potent vasodilator Nitric oxide possesses anti proliferative properties impaired production in PAH 3 vasodilatory effect is mediated by cgmp rapidly degraded by phosphodiesterases (PDEs) Orally administered PDE 5 inhibitors reduce the degradation of cgmp and so promote the accumulation of intracellular cgmp, enhancing NO mediated vasodilation. 4 1. Galiè N, et al. Prog Cardiov Dis 2003;45:213 24; 2. Humbert M, et al. N Engl J Med 2004;351:1425 36; 3. McLaughlin W, et al. Circulation 2009;119:2250 94; 4. Galiè N, et al. N Engl J Med 2005;353:2148 57.

COMBINED THERAPY Indications Important residual functional disturbances and symptomatology following monotherapy Deterioration following an initially very positive reaction to monotherapy

Surgical intervention balloon atrial septostomy lung or heart and lung transplantation Pulmonary endarterctomy www.escardio.org/guidelines

ASD Austen (1964) Rashkind and Miller (1966) Park (1978) BBAS (Blade balloon atrial septostomy) Hausknecht 1990 BDAS (Grated balloon dilatation)

Pulmonary Endarterectomy (PEA)

Lung Transplantation Reitz (1981) Standford : First HLT for IPAH HLT (Heart Lung Transplantation) SLT (Single Lung Transplantation) BLT (Bilateral sequential single Lung Transplantation)

Follow up Patients should be monitored regularly and response to therapy assessed using a range of parameters Exercise capacity (6MWD) Cardiopulmonary Haemodynamics Symptoms Functional markers (BNP. NT- pro-bnp) SURVIVAL www.escardio.org/guidelines

Follow up Based on set goals, a patient s condition at follow-up may be 1 : stable and satisfactory stable but not satisfactory unstable and deteriorating Stable but not satisfactory or unstable and deteriorating re-evaluation and consideration for escalation of treatment www.escardio.org/guidelines

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