URGENCES 13 novembre Hypertension Artérielle Pulmonaire SEMINAIRES IRIS. Robert Naeije. Case report

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1 URGENCES 13 novembre 2007 Hypertension Artérielle Pulmonaire Robert Naeije Case report Médecin, sportif, pratique 3 à 4 fois par semaine divers sports, dont la bicyclette et le jogging A l âge de 40 ans: constate qu il est plus essoufflé à l effort qu auparavant, ce qu il attribue à l âge, fatigue professionnelle, un divorce récent et un bébé pleurant la nuit Aggravation lente en quelques mois RX thorax: normale Après un an, arrête le jogging sinon, vie normale

2 Case report - suite Sa femme (anesthésiste), pense à un asthme, et lui conseille de consulter un pneumologue Examen clinique normal Biologie usuelle + tests hépatiques: normal EFR (volumes, test de provocation) normales CT thorax: normale Scintigraphie VA/Q: normale Epreuve d effort: déconditionnement Diagnostic: fatigue professionnelle, dépression? Avis psychiatrique: non contributif Diagnostic de d HTAP après 2 années d évolution et 9 consultations, dont 7 spécialistes Dyspnée d effort deux volées d escaliers Après une nouvelle visité négative chez un autre pneumologue, un collègue interniste l envoie chez un cardiologue ECG: axe vertical, altération non spécifique de la repolarisation Echocardiographie: vitesse max des jets d insuffisance tricuspide 4 m/s Reféré pour cathétérisme cardiaque avec test de réversibilité et instauration d un traitement

3 L Hypertension Arterielle Pulmonaire Pulmonary Arterial Hypertension (PAH) Maladie orpheline, caractérisée par un syndrome de dyspnée-fatigue causé par une défaillance cardiaque droite sur augmentation de la RVP, sans affection causale cardiaque ou pulmonaire La PAH est idiopathique ou, dans 50 % des cas, associée à la prise de fenfluramines, au virus HIV, à la sclérodermie, à une cardiopathies congénitale à shunt, ou à une hypertension portale Survie médiane sans traitement limitée à 3 ans Farber and Loscalzo, NEJM 2004; 351: PAH: une vasculopathie artériolaire Normal PAH Plexiform lesion PAH Medial hypertrophy Adventitial proliferation Intimal proliferation Chen et al. J Appl Physiol 1995;79:2122. Gaine S, Rubin L. Lancet 1998; 352: Wagenvoort & Wagenvoort,, Circulation 1970; 42:

4 WHO classification of pulmonary hypertension Evian 1998, revised Venice 2003 Based on clinical evolution, histopathology, and response to therapy 1. Pulmonary arterial hypertension Idiopathic PAH Familial PAH Related to anorexigens, CTD, HIV, portal hypertension, CHD PPHN PAH with venule/cap inv (PVOD) 2. PH with left heart disease Atrial or ventricular Valvular Level 3. PH with lung diseases/hypoxemia COPD Interstitial lung diseases Sleep-disordered breathing 4. PH due to chronic thrombotic and/or embolic disease TE obstruction of proximal PA TE obstruction of distal PA Pulmonary embolism 5. Miscellaneous JACC 2004; 43:S5-S12, Chest 2004; 126:14S-34S Asymptomatic (I) Pulmonary pressure Progression of PAH Moderate symptoms (II-III) Severe symptoms (IV) Cardiac output at peak exercise two years Cardiac output at rest Time

5 PAH: A devastating disease with poor prognosis Survival (%) Time (years) CHD Portopulmonary CTD HIV IPAH McLaughlin VV, et al. Chest 2004; 126:78S-91S. Clinical presentation Female/male ratio 3/ yr (1 to 85) NYHA III/IV in 75 % of cases 6-min walk 330 ± 109 m Delay to diagnosis ~ 2 yr (weeks to 20 yr) Sources: D Alonzo et al, Ann Intern Med 1991;115:343-9 Abenheim et al, NEJM 1996;335: Humbert et al AJRCCM 2006;173:

6 Symptoms Dyspnoea Fatigue Chest pain Syncope Palpitations Haemoptysis Hoarseness 98% 73% 46% 41% 33% 13% 3% Physical examination Tachypnoea (even during sleep) Weak pulse Cyanosis (central / peripheral) Lung ausculation normal Cardiac auscultation: increased pulmonary component of second heart sound, right ventricular heave and rightsided fourth heart sound Hepatojugular reflex, tender hepatomegaly, ascites, leg oedema No clubbing, except Eisenmenger s

7 IN A ES IS Systemic sclerosis SE M Appetite suppressants and PAH Epidemic of PAH in Switzerland, Germany and Austria from 1967 to 1969, related to release of aminorex in % of PAH patients had a history of aminorex intake Epidemic of PAH in France and in Belgium from 1988 to 1995, related to release of dexfenfluramine in % of PAH patients had a history of dexfenfluramine intake

8 IS SE M IN A ES Time, May 23, 1996, about FDA LeMonde, LeMonde, press release of interim approval of Redux in the USA analysis of the IPPHS, May 1995 Abenhaim et al, N Engl J Med 1996; 335: ( )

9 IS ECG: RV hypertrophy, normal in 6% of cases ES Sensitivity 50%, specificity 70%, inadequate for screening IN A ESC Guidelines - Galiè N, et al. Eur Heart J 2004; 25: SE M Chest X-ray: Cardiomegaly, dilated pulmonary arteries, peripheral pruning, normal in 10% of cases Courtesy of S. Gaine Sensitivity, specificity unknown ESC Guidelines - Galiè N, et al. Eur Heart J 2004; 25:

10 Lung function tests Normal/lower limit of normal volumes Normal airway resistance Normal or moderately decreased Dl co Arterial blood gases: normal or moderately decreased PaO 2, constantly decreased PaCO 2 with respiratory alkalosis Diagnosis and evaluation of PAH I. PH suspicion II. PH detection Symptoms & physical examination Screening procedures Incidental findings ECG Chest radiography TT echocardiography III. PH differentiation IV. PAH evaluation ABG: arterial blood gases RHC: right heart catheterisation Pulmonary function tests & ABG Ventilation / perfusion lung scan High resolution CT Spiral CT Pulmonary angiography Blood tests & immunology HIV test Abdominal ultrasound scan Exercise capacity: 6-minute walk test, peak VO 2 Haemodynamics: RHC + vasoreactivity ESC Guidelines - Galiè N, et al. Eur Heart J 2004; 25:

11 Importance of definition of a clinical probability before the implementation of diagnostic tests The sensitivity of a test is influenced by prior probability that an individual has the disease for which the test is performed (Thomas Bayes, 1763) Example: Exercise test for the diagnosis of ischaemic heart disease IS If the prevalence of the disease decreases from 50% to 3%, the probability that an individual with a positive test has the disease decreases from 82% to 13% IN A ES Clinical probability scores (Geneva, Wells, etc) are applied in diagnostic algorithms for pulmonary embolism, and could probably be developed for PAH SE M Tricuspid regurgitant jets for the diagnosis of pulmonary hypertension P = 4 x v2 Syst Ppa = P + Pra m/s Ppa 21/9 mmhg Ppa 74/20 mmhg Naeije and Torbicki, Eur Respir J 1995; 8:

12 Pulmonary Hypertension: Doppler-Echocardiography Definition Venice 3rd World Symposium PAH 2003 Mild pulmonary hypertension is defined as a tricuspid regurgitant velocity on Doppler echocardiography of m/sec which corresponds (assuming a RAP = 5 mmhg) to a systolic pulmonary artery pressure of mmhg, Transthorasic echocardiography (TTE): PAP estimate from tricuspid regurgitation High correlation between TTE and RHC measurements of spap ( ) 1 Moderate agreement Tricuspid gradient (mmhg) RHC = right heart catheterisation R 2 = mpap (mmhg) at RHC Barst RJ, et al. J Am Coll Cardiol 2004; 43:40S-47S. 2. Mukerjee D, et al. Rheumatology 2004; 43:461-6.

13 Severe PAH 40W Healthy subject 120 SSc-related exercise PAH Severe PAH 100 y = 44.9x y = 9.9x y = 2.3x Systemic sclerosis (SSc)related exercise PAH 60W IS Calculated mean Ppa (mmhg) Stress echocardiography ES Cardiac index (l/min/m²) IN A Healthy subject - 90W SE M Pulmonary flowflow-velocity waves in a normal subject and in patients with pulmonary hypertension AT ET Ppa 21/9 mmhg Ppa 84/18 mmhg Ppa 62/24 mmhg Naeije and Torbicki, Eur Respir J 1995; 8:

14 Pulmonary hypertension: a RVF syndrome Tricuspid regurgitation jet Tricuspid regurgitation jet RV RA LV LA Normal Pulmonary flow velocity RV RA LV LA Pulmonary flow velocity Pulmonary hypertension Right heart catheterization: the gold standard for the diagnosis of PH Pulmonary hypertension is defined by a mean pulmonary artery pressure of > 25 mmhg at rest and > 30 mmhg at exercise (NIH registry) - Limits of normal of resting mean Ppa 8-20 mmhg - Upper limit of normal of exercise mean Ppa ~40 mmhg (systolic ~65 mmhg) Naeije R. Pulmonary vascular function. In: Pulmonary Circulation. AJ Peacock and LJ Rubin eds, 2 nd ed, Arnold, 2004, chap 1, pp 3-13,

15 RHC: Procedure PAH: hemodynamic profile Variable PAH, n=180 Normal, n=32 (NIH registry) (Naeije thesis) Ppa, mmhg Q, L/min/m

16 The pathogenesis of PAH: from vasospasms to remodelling PVR Late Detection limit Early Vasoconstrictor factors Vasospasms Cells Remodelling Matrix and fibrin Wood P. Pulmonary hypertension with special reference to the vasoconstrictive factor. Br Heart J 1958; 21: Endothelin pathway Pulmonary circulation: endothelial maintainance of tone and structure NO pathway Prostacyclin pathway Pre-pro-ET pro-et L-arginine L-citrulline Arachidonic acid PgI 2 Endothelin receptor antagonists ET A - Endothelin-1 ET B vasoconstriction proliferation - PDE5 inhibitors Nitric oxide cgmp vasodilatation - PDE5 anti-proliferation Prostacyclin (PgI 2 ) + Prostacyclin derivatives AMPc vasodilatation anti-proliferation

17 Treatment of PAH: Three classes of drugs, targeting three pathways The prostacyclin-camp pathway Prostacyclin analogues (epoprostenol) 1 FLOLAN The endothelin pathway Endothelin receptor antagonists (bosentan) 2 TRACLEER The NO (ANP)-cGMP pathway PDE5 inhibitors (sildenafil) 3 REVATIO 1.Barst R, et al. N Engl J Med 1996;334; Rubin L, et al. N Engl J Med 2002;346: Galié N, et al. N Engl J Med Current ESC treatment algorithm for PAH Oral anticoagulants (IIa C) Diuretics (I C) Oxygen(IIa C) Digoxin (IIb C) NYHA Class I-IV Vasoreactive Pulmonary arterial hypertension Supportive therapy and general measures (IIa C) Expert referral Acute vasoreactivity test Non-vasoreactive Exercise limitation Birth control Psychological assistance Infections prevention NYHA Class IV Oral CCB (I C) Sustained response (NYHA I-II) Continue CCB Endothelin receptor antagonists Bosentan (I A) or Prostanoid analogues Iloprost inh (I A) Treprostinil (IIa B) Beraprost (IIb B) or PDE-5 inhibitors Sildenafil (IA) or Continuous IV prostacyclin Epoprostenol (I A) Epoprostenol (I A) Bosentan (IIa B) Treprostinil (IIa B) Iloprost iv (IIa C) No improvement or deterioration: combination therapy? (IIa B) Ballon atrioseptostomy (IIa C) and/or Lung transplant (I C) Galiè N, et al. Eur Heart J 2004; 25:

18 Results of modern therapies of PAH Marked functional improvement, but not back to normal, and disappointing in about half of patients after 1-2 years Survival doubled, but still limited to 60 % after 5 years in IPAH, even less in HIV or sclerodermaassociated PAH More research is necessary! Percent Survival PAH remains a devastating disease of poor prognosis Portopulmonary CTD CHD IPAH HIV Years McLaughlin VV, et al. Chest 2004; 126: 78S-91S.

19 Long-term effect of bosentan on WHO functional class Open-label bosentan: n = % IV 41.4% Improvement IV NYHA IV* Number of patients III III III II I Time (months) NYHA III NYHA II NYHA I * Patient initiated on epoprostenol Sitbon O, et al. Chest 2003; 124: Cumulative survival and event-free status Survival and event-free status in PAH patients treated with first-line bosentan % 61 % 87 % 44 % Months II I Overall survival Event-free status Subjects at risk, n Of mortality Of event Provencher S, et al. Eur Heart J 2006; 27:

20 The importance of Research on PAH IS Improved pathobiological understanding is essential to discovery of new treatments Animal models: - Hypoxic rodents - MCT-treated rodents - Left-to-right shunt induced PAH IN A ES Patients! SE M Expédition Belge en Bolivie, janvier 2006

21 Case report Man 50 yr, from Brussels to La Paz «alto» (4000 m), in January 2006 HAPE on the Ruwenzori in 1988 Several uneventful climbs above 5000 m, up to 6800 m Mild headache and fatigue on the Bolivian altiplano Uneventful travel to lake Titicaca (day 3) (4000 m) and hike to Sajama mountain base camp (day 5) (5200 m) Echocardiography, sea level and days 3-5, at m TRICUSPID REGURGITATION Sea level 3600 m 4300 m Vmax=2.4m/s Pgradient=22mmHg Vmax=3.9m/s Pgradient=62mmHg = mppa 44 mmhg Vmax=4.2m/s Pgradient=69mmHg = mppa 49 mmhg mppa = 0.61 sppa + 2 mmhg (Chemla et al, Chest 2005;126:1313)

22 PULMONARY ARTERY FLOW Sea level 3600 m 4300 m Acc Time=165 msec INFERIOR VENA CAVA 2.1 cm Sea level Acc Time=91 msec = mppa 34 mmhg PULMONARY DOPPLER Mid-systolic deceleration Acc Time=74 msec = Ppa 44 mmhg TRICUSPID REGURGITANT JET 4000 m, 3 days 2.7 cm 4000 m, 5 days

23 4 CHAMBER VIEW END-DIASTOLIC SHORT AXIS END-SYSTOLIC SHORT AXIS Sea level Altitude ANNULUS Sea levell Altitude BASE APEX postsystolic shortening Altitude

24 High altitude-induced heart failure Huez S, Faoro V, Vachiery JL, Martinot JB, Naeije R, Circulation 2007;115: HAHF should be added to high altitude pulmonary edema (HAPE) and high altitude cerebral edema (HACE) as severe complications of high altitude exposure Hackett PH, High-altitude illness. N Engl J Med 2004; 141: It is possible that RHF contributes to the limitation of aerobic exercise capacity at high altitude PAH is an orphan disease = prevalence < 1/10000 The prevalence of IPAH is estimated to be approximately 10 per million (incidence 2 par million per year) Until now, IPAH continues to make of for about 50 % of PAH in RCT, monocentric registries (Beclere) and postmarketing surveillance studies of bosentan (TRAX) A recent, French observatory identified PAH 1100 patients in France, with regional disparities, and a maximum revalence of 25 per million Belgium: ~ 60 new cases per year, total of

25 Screening for PAH (echocardiography) HIV infection: 0.1 % - only if symptoms Portal hypertension: 1 à 2 % - only if symptoms, and at work-up for transplantation Systemic sclerosis: % - once a year Congenital heart disease: % - once a year Anorexigens: 0.01 %? if symptoms ESC Guidelines - Galiè N, et al. Eur Heart J 2004; 25: Required staff for a patients PAH clinic (= 1 new patient / month) 1 full time experienced specialist 2 full time nurses for outpatient care 1 full time nurse in the ward 1 half time social worker 1 half time physiotherapist 1 half time psychologist 1 half time administrative assistant COMMITMENT at each level Round-the-clock availability Easy access in case of emergency

26 Cost of initial assesment in Belgium 21% 10% 69% per patient Staff Material Space Delcroix VCP-BHL 2002 Annual cost of treatment in Belgium 5% 15% Staff Material Space 80% / patient Delcroix VCP-BHL 2002

27 The Pulmonary Hypertension Clinic at the Erasme University Hospital (150 patients) Staff physicians IS Nurses : Physiotherapists: Psychologist: Social worker Administrative staff: S Huez, (JL Vachiery) R Naeije, A Pavelescu MT Gautier, I Lanckriet M Lamotte, D Deboeck T Tsiamata S Tossens S Mabtoul, F Elshocht SE M IN A ES shuez@ulb.ac.be - rnaeije@ulb.ac.be - mgautier@ulb.ac.be