Παρουσίαση Περίπτωσης Ασθενούς με Κληρονομούμενη Πνευμονική Αρτηριακή Υπέρταση Ιατρείο Πνευμονικής Υπέρτασης Πνευμονολογική Κλινική Πανεπιστημιακό Νοσοκομείο Ηρακλείου Μητρούσκα Ιωάννα Πατριανάκος Αλέξανδρος Πρινιανακης Γεώργιος
Genetic Tree a Cretan family 1 2 3 4 1=35 y 2 3=35y 4=30y 5=33y 6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 I II III IV 1 2=34 3 4 5 6 7 8 9 2019 Significantly younger at PAH diagnosis Shorter survival
Αρχική Παρουσίαση Ασθενής 24 ετών, κύηση 11 wks Μητέρα παιδιού 2 ετών Σύζυγος ιερέα Από 4μήνου προοδευτικά επιδεινούμενη δύσπνοια και εύκολη κόπωση (ΝΥΗΑ ΙΙΙ-ΙV ;;) Κλινική εξέταση:- ταχύπνοια (22 br/min - διχασμός S2, S4 - λοιπή κλιν/εξέτ : κ.φ. 11/2004 PaO2 στην άσκηση ΗΚΓ: SR 90 bpm, RBBB, (-)T II, III, avf, V1-6 ΔΕ άξονας (δεν προϋπήρχαν) Triplex φλεβών κάτω άκρων : (-) DVT
ECHO: Διάταση RA, RV, λειτουργικότητα Διάταση PA και IVC (χωρίς συμπίεση) PASP 92 mmhg LV : μέτρια επηρεασμένη συσταλτικότητα Παράδοξος κινητικότητα IVS (εικόνα D) Μικρή περικαρδιακή συλλογή (χωρίς στοιχεία επιπωματισμού) Διακοπή κυήσεως
The mechanical and hormonal changes of pregnancy affect each major Worsening of PAH frequently occurs in pregnancy and organ system. These changes are primarily due to the postpartum period (1) mechanical compression of the surrounding structures caused by Bédard E Eur Heart J 2009, Jaïs X, Eur Respir J 2012 the enlarging uterus (2) increases in the levels of sex hormones, and (3) increases in the circulatory volume. 1. a rapid change in estrogen levels Statement on pregnancy in PH Hemnes et al 2015 Statement on pregnancy in PH Hemnes et al 2015
Κλινική Εικόνα 11 ος /2004 Άφθονοι μη-μουσικοί ρόγχοι S1,s2 ρυθμικοί ευκρινείς, έντονος β τόνο Οιδήματα κάτω άκρων: ++ The 3 rd trimester and the first month after delivery represents the period of highest risk Mortality ( first 7 days) is driven by 1. Refractory severe RV failure Αποκορεσμός και στην μικρή άσκηση 2. Pulmonary thrombosis 3. Pulmonary hypertensive crisis Σημαντική υποξυγοναιμία (PO2 = 50mmHg on room air) ph 7.39 7.45 PaCO2, mmhg 25 33 PaO2, mmhg 92 107 Elwing JM Pregnancy and PAH Heart Failure Clin 2018
L Savale, M Humbert: Eur Respir Rev 2017
Irene Lang 2016 Μονοθεραπεία
CHRONIC INFUSIONS OF EPOPROSTENOL (Flolan) (Veletri )
Patients diagnosed in WHO FC-III Γενικός κανόνας
Διαγνωστικός Έλεγχος Ανοσολογικός έλεγχος πλήρης: (-) Έλεγχος Θρομβοφιλίας: (-) Ιολογικός έλεγχος: (-) Spiral CT θώρακος: (-) για ΠΕ, λοιπά κ.φ. Σπιρομέτρηση: φυσιολογική Διοισοφάγειο ECHΟ: (-) για ASD Η ασθενής (αρνείται;;) καθετηριασμό Δεξιών Καρδιακών κοιλοτήτων ;Έναρξη Μονοθεραπείας Βοσεντάνη Ιδιοπαθής Πνευμονική Αρτηριακή Υπέρταση??
Patient Follow-up 10 years : - WHO II/III - RCH: mpasp= 68 mmhg (CO = 3.8 l/min, (CI =2.1 l/min/m2) PVR = 1178.9 dyn/cm3) 14.7 WU / SvO2 = 65%) μικρή περικαρδιακή συλλογή - 6MWD= 400 m 3 συγκοπτικά επεισόδια NT-pro BNP=1898ng/L Sildenafil 60 mg x 3 macitentan 10 mg x 1 remodulin sc : προοδευτική αύξηση της δόσης
Patient Follow-up 13 years : - WHO I - ECHO : PASP= 60 mmhg βελτίωση περικαρδιακής συλλογής - 6MWD= 610 m NT-pro BNP=1388ng/L συγκοπτικά επεισόδια Sildenafil 60 mg x 3 macitentan 10 mg x 1 remodulin sc : προοδευτική αύξηση της δόσης (28n/Kgr/min)
1½ year: RH Catheterization Patient Follow-up 6-9-2017 (13.5 years from diagnosis) Pw=12 PASP mmhg = 95 mmhg CO (MPAP = 4.1 l/min = 68 mmhg) CO = 3.5 l/min PVR = 1133 /cm3 10 year: RH Catheterization CVP = 2 mmhg RAP=4mmHg PASP = 98/37 mmhg (MPAP = 56 mmhg) (CI =2.6 l/min/m2) SvO2=>65% PVR= 858.5 dyn=10.7 WU PASP = 94 mmhg (MPAP = 68 mmhg) Pw=12mmHg CO = 3.8 l/min (CI =2.1 l/min/m2 PVR = 1178.9 dyn/cm3) 14.7 WU
Parameters with established importance for assessing disease severity, stability 12/2017 and prognosis in PAH Ασθενής με απόλυτη ένδειξη παρεντερικής χορήγησης προστανοειδών Υπό sc τρεπροστινίλη: αδύνατη η αύξηση της δόσης λόγω παρενεργειών Σοβαρός ενδοιασμός iv αγωγής Προοδευτική ελάττωση τρεπροστινιλης = αύξηση της NT-proBNP Δοκιμασία χορήγησης selexipag με προοδευτική αύξηση της δόσης. ESC/ERS Guidelines 2015
Patient Follow-up 3/2018 : - WHO I/II (άριστη κλινική εικόνα) - ECHO : PASP= 70 mmhg (TAPSE=1.5) ίδια ευρήματα με προ-6μήνου - 6MWD= 605 m NT-pro BNP=1388ng/L συγκοπτικά επεισόδια Riociguat 2.5 mg x 3 Macitentan 10 mg x 1 Selexipag 1600mg x2
Σ. ΑΛΕΞΑΝΔΡΑ 1/2020 16 ος χρόνος Από διάγνωση
Parameters with established importance for assessing disease severity, stability and prognosis in PAH ESC/ERS Guidelines 2015
ΣΗΦΑΚΗ ΑΛΕΞΑΝΔΡΑ
ΣΗΦΑΚΗ ΑΛΕΞΑΝΔΡΑ
Genetic Tree a Cretan family 1 2 3 4 1=35 y 2 3=35y 4=30y 5=33y 6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 I II III IV 1 2=34 3 4 5 6 7 8 9 Η ασθενής μας 2004 years 2008 Διάγνωση Πατέρα με ΠΑΗ (57 y) Έλεγχος όλων των συγγενών 1 ου Βαθμού Έζησε 11 χρόνια
New Classification PH Dec 2018 ERJ
Genetic Tree a Cretan family 1 2 3 4 1=35 y 2 3=35y 4=30y 5=33y 6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 I II III 1 2=34 3 4 5 6 7 8 9 Η ασθενής μας 15 years 2008 Διάγνωση Πατέρα με ΠΑΗ IV 2019 Διάγνωση αδελφή Πατέρα με ΠΑΗ 63 y
2008 Έλεγχος Ασυμπτωματικών Συγγενών 1 ου βαθμού
Περιοδικός έλεγχος Συγγενών 1 ου βαθμού
Περιοδικός έλεγχος Συγγενών 1 ου βαθμού
ΒΙΝΤΕΟ US ΚΑΡΔΙΑΣ 2018
Περιοδικός έλεγχος Συγγενών 1 ου βαθμού (Διακλινικό Ιατρείο Πνευμονικής Υπέρτασης ΠΑΓΝΗ)
Χωρίς σκιαγραφικό λόγω Αλλεργιών Scan αιμάτωσης πνευμόνων: (-)
Parameters with established importance for assessing disease severity, stability and prognosis in PAH ESC/ERS Guidelines 2015/Nice 2018
Parameters with established importance for assessing disease severity, stability and prognosis in PAH After 4 months on up-frond Combination therapy ESC/ERS Guidelines 2015/ Nice 2018
Historical timeline Heritable pulmonary arterial hypertension 1954 : DRESDALE et al. first described familial pulmonary arterial hypertension (PAH), suggesting the potential role of genetic defects in the development of the disease The study of genetics in pulmonary hypertension began 1984: Heritable PAH segregates as an autosomal dominant trait with incomplete penetrance 1997: NICHOLS et al. and MORSE et al. (linkage analysis in affected families) Independently localise the locus implicated in PAH development on chromosome 2. Candidate genes in this region were then identified and mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene were found in PAH patients Additional genetic analyses revealed that 3.5 40% of sporadic PAH patients and 9 22.5% of anorexigen-associated PAH patients carried a mutation in this main gene
4 principal genetic causes of HPAH (without HHT) Mutations in the BMPR2 gene, and More rarely in: ACVRL Endoglin Caveolin-1 KCNK3 and TBX4 Genes predispose to heritable pulmonary arterial hypertension, an autosomal dominant disease with incomplete penetrance Bi-allelic mutations in the EIF2AK4 gene predispose to: heritable pulmonary veno-occlusive disease pulmonary capillary haemangiomatosis, an autosomal recessive disease with an unknown penetrance.
Distribution of mutations in patients and asymptomatic relatives in the French PAH network Sporadic Familial PAH PVOD/PCH Girerd B. Genetic counselling in a national referral centre for pulmonary hypertension. Eur Respir J 2016; 47: 541 552
Phenotype genotype correlation Heritable pulmonary hypertension: from bench to bedside B Girerd and Marc Humbert: Eur Respir Rev 2017; 26
Characteristics of patients with a BMPR2 mutation PAH patients carrying a BMPR2 mutation develop the disease 7 10 years earlier than non-carriers, have more severe haemodynamic variables at the time of diagnosis and are less likely to respond to acute vasodilator testing The presence of a BMPR2 mutation (idiopathic, familial and anorexigen-associated PAH), is associated with an increased risk of death or lung transplantation AUSTIN et al. demonstrated the implication of particular BMPR2 mutation types (missense, truncating, large rearrangement or splice defect) in the phenotypic expression of the disease. A result that was not confirmed in the French cohort Finally, since PAH mostly occurs in females irrespective of BMPR2 mutation status, it has been suggested that oestrogens and oestrogen metabolism might play a role in the pathogenesis of PAH B Girerd : Eur Respir Rev 2017; 26
Characteristics of patients with an ACVRL1 mutation PAH patients with an ACVRL1 mutation: Significantly younger at PAH diagnosis compared to patients with PAH who had a BMPR2 mutation and PAH patients without an identified mutation. Have less severe haemodynamics at diagnosis compared to BMPR2 mutation carriers Shorter survival when compared with other patients despite similar treatment, suggesting a more rapid progression of disease in ACVRL1 mutation carriers. Although ACVRL1 mutations predispose to HHT as well, PAH may develop in ACVRL1 mutation carriers without any features of HHT PAH may be the first or the only manifestation of HHT PAH accompanying hereditary hemorrhagic telangiectasia (HHT), PCH, or PVOD represent rare phenotypes of HPAH B Girerd : Eur Respir Rev 2017; 26
Characteristics of patients carrying bi-allelic EIF2AK4 mutations PVOD/PCH occurring in patients carrying bi-allelic EIF2AK4 mutations is characterised by a younger age at diagnosis compared to noncarriers PVOD/PCH patients presented with: Severe clinical, functional Haemodynamic impairment Radiological abnormalities on high-resolution computed tomography (septal lines,ground-glass opacities and lymph node enlargement) Low diffusing capacity of the lung for carbon monoxide and hypoxaemia Drug-induced pulmonary oedema occurred in five (23%) of the treated EIF2AK4 mutation carriers and 13 (21%) of treated noncarriers
Historical timeline Dates of genetic discovery In Heritable Pulmonary Hypertension In 1984, Loyd et al. described 14 families affected by PAH
Genetic counselling French PAH referral centre: Hôpital Bicêtre, Le Kremlin-Bicêtre and Hôpital Necker Enfants Malades, Paris French guidelines for genetic counselling: key points of decree 2008-321 of April 4, 2008
French guidelines for genetic counselling: key points of decree 2008-321 of April 4, 2008 Girerd B. Genetic counselling in a national referral centre for pulmonary hypertension. Eur Respir J 2016; 47: 541 552
HHS, USA CANADA
Thousands US $ Hundreds US $
Genetic counselling Genetic counseling is often performed by a genetic counsellor and should precede genetic testing and review the inheritance of PAH, HHT with PAH, or PCH/PVOD and the possible psychosocial effects of genetic test results Patients may have concerns about possible discrimination based on genetic test results. In the United States, the Genetic Information Nondiscrimination Act (GINA) protects asymptomatic HPAH mutation carriers from having their health insurance access or rates changed based on genetic test results. However, GINA does not provide protection against discrimination in life, disability, or long-term care insurance.
Pre-implantation genetic diagnosis The identification of a BMPR2 mutation may lead the carrier to consider prenatal diagnosis or preimplantation genetic diagnosis. These two techniques are used in other diseases to avoid the birth of a child carrying a mutation associated with a serious and life-threatening medical condition: Huntington s disease or Cystic fibrosis ΠΑΝΕΠΙΣΤΗΜΙΟ ΑΘΗΝΩΝ ΕΡΓΑΣΤΗΡΙΟ ΓΕΝΕΤΙΚΗΣ ΙΑΤΙΚΗΣ ΧΩΡΕΜΕΙΟ ΕΡΕΥΝΗΤΙΚΟ ΚΕΝΤΡΟ Ε ΚΑΚΑΒΑΚΗΣ They remain controversial in PAH because of the low penetrance of BMPR2 mutations. B Girerd : Eur Respir Rev 2017; 26
Conclusion The practice of medicine is constantly evolving in response to new technology, epidemiology, and social phenomena, we will always be chasing a moving target N Eng J Med 2017 Prediction in medicine Thus To predict prognosis accurately we must use all the tools available to us Benza RL ERJ 2017