Martino CheliDottorato di ricerca in biologia e fisiopatologia cardiaca, vascolare, renale e metabolicaDipartimento di Medicina InternaUniversit degli Studi di GenovaIpertensione arteriosa polmonare: percorso diagnostico e stratificazione prognostica

Ipertensione polmonare e malattie del cuore sinistro Fang J et al. J Heart Lung Transplant 2012. Guazzi M, Borlaug B. Circulation. 2012Pu essere riscontrata in ogni patologia del cuore sinistro, principalmente HF (indipendentemente da EF) e valvulopatie

Prevalenza elevata, aumenta con la severit della patologia

Pi sintomi, intolleranza allo sforzo e peggiore QoL

Impatta negativamente sulla sopravvivenza

Bursi F et al. JACC 2012; 59:222N=1049 patients with HF (incident and prevalent) with TR jet60% had EF > 45%

Quando sospettare una ipertensione polmonare dovuta amalattia del cuore sinistroGali et al. Eur Heart J 2009

Clinical featuresEchocardiographyInterim evaluation Age > 65 Elevated systolic BP Elevated pulse pressure Obesity, metabolic syndrome Coronary artery disease Diabetes mellitus Atrial fibrillation Left atrial enlargement Concentric remodelling of the LV Echocardiographic indicators of elevated LV filling pressure Symptomatic response to diuretics Exaggerated increase in BP during exercise Chest X-ray consistent with HF

Ecocardiogramma - Pressioni

Ecocardiogramma Funzione sistolica RV Fractional Area ChangeMeluzin et al. EHJ 2001. Ueti et al. Heart 2002. Dambrauskaite et al. JASE 2005, Huez et al. Am Heart J 2007TAPSETDIS WaveTEI Index

Ecocardiogramma

Essere o non essere PAH???15 mmHg

Classificazione emodinamicaGradiente transpolmonare vs diastolico

DPG predicts survival in patients with increased TPGGerges C et al. CHEST 2012; in pressPatients undergoing RHCN= 3,107 TPG < 12 mmHg N= 604Group 2 PHN= 1,094TPG > 12 mmHg N= 490DPG < 7 mmHg N= 311DPG > 7 mmHg N= 179Cut-off for DPG determined by ROC-curve analysis35% of patients had PH due to LHD, 55% purely passive36% of patients with TPG > 12 also had a DPG > 7 mmHg determined by ROC curve analysis (16% in total)

DPG predicts survival in patients with increased TPGPassive PH: TPG < 12 mmHgOOPH: TPG > 12 mmHgGerges C et al. CHEST 2012; in press

Ipertensione arteriosa polmonareUna patologia raraPrevalenza tra 1525 casi / milioneIncidenza 2 4 casi / milione / anno

A prognosi sfavorevole75% NYHA III/IV al momento della diagnosiSopravvivenza media

Ipertensione arteriosa polmonare: stratificazione prognosticaJ. Hurdman, R. Condliffe, C. A. Elliot,

Prognosi per sottogruppiMcLaughlin VV. Chest. 2004;126:78S92SJ. Hurdman, R. Condliffe, C. A. Elliot, J. Hurdman, R. Condliffe, C. A. Elliot et al. ERS Congress 2010

TimeFunctional ability after 1st interventionDeath is infrequently the 1st event in PAHInterventions are indicated late in the course of the diseaseHospitalizations and clinical deterioration are likely to occur firstTypical time course of PAH in clinical practiceClinical modificationsDeath2nd interventionHospitalizationCourtesy of J.L. Vachiery

Ipertensione arteriosa polmonare In fact, although the pulmonary vascular bed is the primary cause of the disease, right heart failure is the leading cause of deathTorbicki A, Vizza D. 3rd World Symposium on PAH. Venice, June 2003

Gali N, et al. Eur Heart J 2009; 30:2493-537.

Definition of patient statusStable and satisfactoryMeets majority of the criteria in the column better prognosis Stable and not satisfactoryHas not reached the goals that were desirableUnstable and deterioratingMeet majority of the criteria in the column worse prognosis

Definition of inadequate responseInitial FC II or IIIStable and not satisfactoryUnstable and deterioratingInitial FC IVNo rapid improvement to FC III or betterStable and not satisfactory

Utilit dei diversi indicatori prognosticiVachiery JL et al. Eur Respir Rev. 2012;21:40-7

VariableBaselineFollow upNYHA FC++++++6MWD++++++BNP/NT-ProBNP+++++Uric Acid+?cTroponin-t+?Pericardial effusion++++TAPSE+++ ?Tei index+++ ?mPAP--RAP++++CI++++++

Inquadramento (mono o) multidimensionale La maggior parte degli strumenti di impiego clinico per valutare laprogressione di malattia influenzata dal VDX

Non esistono mezzi per determinare lo stato di attivit della malattia a livello del letto vascolare polmonareStrumenti & Variabili Nessuna variabile da sola in grado di rilevare la progressione di malattia e di guidare le scelte cliniche

Per quanto auspicabile, linquadramento multidimensionale non stato ancora validato (score prognostico, equazione o formula magica)Stratificazione prognostica - Punti critici

Lipertensione arteriosa polmonare una patologia rara, la cui diagnosi clinica, emodinamica e di esclusione

Una valutazione multiparametrica fondamentaleper linquadramento ed il follow up

Per quanto il danno sia primitivamente vascolare polmonare, il ventricolo destro a determinare la prognosi

Conclusioni

BKU SLIDES

N=11,000 (single center) >90% with right and left cath14.8% diagnosed as PAH 53.8% reclassified if LVEDP usedPCWP underestimated LVEDP by 2.9 mmHg Adapted from Halpern SD and Taichman DB. Chest 2009;136:3743.

Grafico1

12

59

34

2

WHO FUNCTIONAL CLASS AT DIAGNOSIS

WHO FUNCTIONAL CLASS AT DIAGNOSIS (PH)

Foglio1

WHO FUNCTIONAL CLASS AT DIAGNOSIS

I12

II59

III34

IV2

Per ridimensionare l'intervallo di dati del grafico, trascinare l'angolo inferiore destro dell'intervallo.

Caratteristiche dei pazienti con PAH (42)Et alla diagnosi, aa (range) 61 (27-83)Femmine, n (%) 27 (64%)Multifattoriale (1 o pi cause di PH) 16 (38%)PAHCardiopatia sinistraPneumopatia/ipossiaCTEPHMultifattoriale3 (7%)2 (5%)8 (19%)-2 (5%)Decessi11 (26%)

Grafico1

8

22

12

WHO FUNCTIONAL CLASS AT DIAGNOSIS

WHO FUNCTIONAL CLASS AT DIAGNOSIS (PAH)

Foglio1

WHO FUNCTIONAL CLASS AT DIAGNOSIS

I8

II22

III12

Per ridimensionare l'intervallo di dati del grafico, trascinare l'angolo inferiore destro dell'intervallo.

Diagnosi finaleWHO FCIIIIII1.1 Ipertensione arteriosa polmonare idiopatica 1.4.1.1 Associata con m. del tessuto connettivo (sclerodermia)1.4.2 Associata ad infezione HIV1.4.3 Associata ad ipertensione portale1.4.4 Associata a cardiopatia congenita71538911-24*310243*34121*Tot4282211*1Pt. Missing FC

Diagnosi finaleWHO FCIIIIII1.1 Ipertensione arteriosa polmonare idiopatica 1.4.1.1 Associata con m. del tessuto connettivo (sclerodermia)1.4.2 Associata ad infezione HIV1.4.3 Associata ad ipertensione portale1.4.4 Associata a cardiopatia congenita71538911-24*310243*34121*Tot4282211*1Pt. Missing FC

Diagnosi finaleWHO FCIIIIII4. CTEPH1594*2Pts. Missing FC

Ipertensione arteriosa polmonare: Cateterismo cardiaco destro & 6MWTPAPm, media 43,5 +/-15 (25-95) mmHgPVR, media 532 +/-320 (125-1225) dynesCI2,1 +/- 0,7 L/min/m2RA, media 9,6 +/- 4 (2-22) mmHg

6MWT m346 +/- 143Pre Spo2%96 +/- 4,6Post SpO2 %90 +/- 7,9

Ipertensione arteriosa polmonare: Terapia medicaPAH: 15/42 12 AET; 1 IPDE5; 2 (AET + IPDE5);1 (AET + IPDE5 + Prost.Inal)CTEPH: 7/15 4 AET3 AET + IPDE5 [2 + Prost Inal]4 TEAP (-> 1AET; 1 in Trp di combinazione)

Ipertensione arteriosa polmonare: Terapia medicaPH in ILD out of proportion (WHO III) 4/25pts2 AET2 IPDE5

Ipertensione polmonare out of proportionPH in ILD out of proportion (WHO III) 4/25pts2 AT2 IPDE

Mortalit: 52% (13/25)

Ipertensione arteriosa polmonare: Terapia medica - AE

2 (7%) Reazioni allergiche cutanee (1AET; 1 AET e IPDE5)Comune intolleranza [Cefalea, Capogiri, Dispnea], richiesta interruzione in 5 (18%) pts

ConclusioniLipertensione arteriosa polmonare una patologia rara con prognosi severaRichiede una diagnosi tempestiva ed un trattamento mirato, nellottica di prevenire i fenomeni di remodeling vascolare

Una strategia attendista non sempre paga!

Ipertensione arteriosa polmonare: prognosiMcLaughlin VV. Chest. 2004;126:78S92SJ. Hurdman, R. Condliffe, C. A. Elliot, J. Hurdman, R. Condliffe, C. A. Elliot et al. ERS Congress 2010

Caratteristiche dei pazienti con PH (118)Et alla diagnosi, aa (range)64 (22-90)Femmine, n (%)67 (57%)Multifattoriale (1 o pi cause di PH)50 (42%)Decessi34 (29%)

Ipertensione arteriosa polmonare: prognosiSurvival after lung transplantation. A, Overall survival; B, survival after bilateral lung and heartlung transplantation; C, survival according to underlying category of pulmonary arterial hypertension (PAH); and D, survival of patients transplanted in first cohort (cohort 1997-2004) and second cohort (cohort 20052010). CTEPH, Chronic thromboembolic pulmonary hypertension; CTD, connective tissue disease; CHD, congenital heart disease; iPAH, idiopathic PAH.Marc de Perrot, MD, John T. Granton, MD, Karen McRae, MD, et al. J Thorac Cardiovasc Surg 2012;143:910-8

Ipertensione arteriosa polmonare - ECHO La sola pressione polmonare non riflette limpegno emodinamico dellIAP (leco non consente valutazioni di CI e RVP) La severit della malattia pu trasparire, in eco, solo da una valutazione combinata di pressione polmonare e funzione ventricolare destraStima, non misura (misura di 1 di 2 componenti della pressione: gradiente + stima della pressione atriale destra - 0 a 30 mmHg) Non sempre fattibile (70-90 % PAPs e 40-80% PAPd in pz con cardiopatie sx) Non sempre accurata (sotto-stima per allineamento sub-ottimale del Doppler; sovra-stima se lettura erronea delle velocit del getto)

E una definizione emodinamicaMa di esclusioneLa differenza pu apparire sottile ma sostanziale*Dg di esclusione- Vi un percorso piuttosto codificato da seguire, su cui far solo qualche osservazionePer questa ragione il cat dx sta in fondo al percorso diagnostico*Anche nelle patologie del cuore sinistro la PH non un semplice epifenomeno ma un marker di prognosi peggiore

OBJECTIVES: The purpose of this study was to determine among community patients with heart failure (HF) whether pulmonary artery systolic pressure (PASP) assessed by Doppler echocardiography was associated with death and improved risk prediction over established factors, using the integrated discrimination improvement and net reclassification improvement.BACKGROUND: Although several studies have focused on idiopathic pulmonary arterial hypertension, less is known about pulmonary hypertension among patients with HF, particularly about its prognostic value in the community.METHODS: Between 2003 and 2010, Olmsted County residents with HF prospectively underwent assessment of ejection fraction, diastolic function, and PASP by Doppler echocardiography.RESULTS: PASP was recorded in 1,049 of 1,153 patients (mean age 76 13; 51% women). Median PASP was 48 mm Hg (25th to 75th percentile: 37.0 to 58.0). There were 489 deaths after a follow-up of 2.7 1.9 years. There was a strong positive graded association between PASP and mortality. Increasing PASP was associated with an increased risk of death (hazard ratio [HR]: 1.45, 95% confidence interval [CI]: 1.13 to 1.85 for tertile 2; HR: 2.07, 95% CI: 1.62 to 2.64 for tertile 3 vs. tertile 1), independently of age, sex, comorbidities, ejection fraction, and diastolic function. Adding PASP to models including these clinical characteristics resulted in an increase in the c-statistic from 0.704 to 0.742 (p = 0.007), an integrated discrimination improvement gain of 4.2% (p < 0.001), and a net reclassification improvement of 14.1% (p = 0.002), indicating that PASP improved prediction of death over traditional prognostic factors. All results were similar for cardiovascular death.CONCLUSIONS: Among community patients with HF, PASP strongly predicts death and provides incremental and clinically relevant prognostic information independently of known predictors of outcomes.

*Evidente quindi l importanza di una corretta valutazione ecocardiografica*Scinti VQ permette di inquadrare eventuali CTEPH, unica forma in PH per cui esista un trattamento potenzialmente curativo...*RHC non solo pressioni ma anche portata cardiaca*RHC non solo pressioni ma anche portata cardiaca*Come si fa a stabilire lentit del danno vascolare polmonare? Puramente passivo da reattivo??*Misura precisa delle pressioni, della portata ed eventuale vasoreattivit*BACKGROUND: Left-sided heart disease (LHD) is the most common cause of pulmonary hypertension (PH). In patients with LHD, elevated left atrial pressure causes a passive increase in pulmonary vascular pressure by hydrostatic transmission. In some patients, an active component caused by pulmonary arterial vasoconstriction and/or vascular remodeling superimposed on left-sided pressure elevation is observed. This reactive or out-of-proportion PH, defined as PH due to LHD with a transpulmonary gradient (TPG) > 12 mm Hg, confers a worse prognosis. However, TPG is sensitive to changes in cardiac output and left atrial pressure. Therefore, we tested the prognostic value of diastolic pulmonary vascular pressure gradient (DPG) (ie, the difference between invasive diastolic pulmonary artery pressure and mean pulmonary capillary wedge pressure) to better prognosticate death in out-of-proportion PH.METHODS: A large database of consecutive cases was analyzed. One thousand ninety-four of 2,351 complete data sets were from patients with PH due to LHD. For proof of concept, available lung histologies were reviewed.RESULTS: In patients with postcapillary PH and a TPG > 12 mm Hg, a worse median survival (78 months) was associated with a DPG 7 mm Hg compared with a DPG < 7 mm Hg (101 months, P = .010). Elevated DPG was associated with more advanced pulmonary vascular remodeling.CONCLUSIONS: DPG identifies patients with out-of-proportion PH who have significant pulmonary vascular disease and increased mortality. We propose a diagnostic algorithm, using pulmonary capillary wedge pressure, TPG, and DPG in sequence to diagnose pulmonary vascular disease superimposed on left-sided pressure elevation.

*Comincia da una corretta diagnosi...**Presa da un altro pto di vista, praticoQuali sono dunque le variabili che determinano la prognosi*