1	הגישה ליתר לחץ דם ריאתי ד"ר יששכר בן-דב מכון ריאות מרכז רפואי ע"ש שיבא
2	PHT, classification & approach to diagnosis Venice classification, 2004, J Am Coll Cardiol Pulmonary arterial hypertension 1) primary, sporadic & familial Associated with CVD, congenital Lt-Rt Shunt, Portal HPT, HIV, Drug & toxins, OWR, Gaucher’s Hemoglobinopathies 2) Venous PHT, LV & valvular, & VOD 3) II to lung disease, COPD, IPF, OSA, hypoxia 4) CTEPHT 5) Inflammation and others; schistosomiasis, sarcoidosis, fibrosis mediastinitis splenectomy
3	Diagnostic approach Presentation: symptoms (effort intolerance, fatigability, syncope or Rt CHF) incidental finding by echo-doppler routine screening of populations at risk Definition of PHT, R& Ex, SPAP>40, (but in athletes), mean > 25 R, & >30 Ex. How to prove? R/O parenchymal lung disease or OSA/hypovent R/O Lt heart disease (systolic, valvular, diastolic) R/O CTEPHT Look for risk factors
4	German family study:circulation2000;102:1145-1150
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7	Genes & PHT 50% of familial, BMPR2 (bone morphogenic protein receptor 2), all mutations alter the receptor 20% in sporadic (low penetrance of gene) Belongs to TGFb receptor family (growth factor) BMPR2 also found in 6% of CHD & rarely in VOD 5% ALK1 (Aktivin like kinase), in HHT-OWR But, only 20% of those with mutation develop PHT! Modifying genes: serotonin receptor, ACE?
8	Genetics, modifying genes and environment
9	Role of Echo-doppler Pressure: SPAP=TI jet velocity²x4+RAP DPAP? RV size and function Tei index=isovolemic(contraction+relaxation)time/ejection time, The larger the worse, sensitive but not specific Also, LV function, valve function, diastolic function, shunts and magnitude, anomalies, pericardial effusion
10	Echo parameters in PHT
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14	Echo in PHT
15	Echo/Doppler indices of prognosis
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17	Role of Rt (& Lt) Heart cath Pressures, CO, PVR Pharmacological challenge (who cares?) PCWP or LVEDP The response of PAP and of PCWP to exercise (ultimate test for diastolic function) Shunts and anomalies For FU, when course is complicated and or when not clear if patient is over or under treated
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19	Pathways for therapy When to use ca blockers? Single VS combination therapy Clinical response to therapy Physioplogical response to therapy Effect of therapy on survival Goals of therapy and titration end points
20	ACCP Clinical Guidelines
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22	STEP Hemodynamics at Week 12
23	Inhaled Treprostinil Hemodynamics at Week 12
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26	Treatment goals in common diseases Systemic hypertension Diabetes mellitus Rheumatoid arthritis Pulmonary arterial hypertension
27	PHT, treatment goals & titration To normalize pulmonary vascular & heart function & structure & to restore exercise tolerance, quality of life & survival, or to approach as close as possible to achieving these goals. Cure, increase survival or slow progression & no side effect It is unknown if the dose responses are similar for all these goals PAP is not (a practical) the end-point
28	Can the poor prognostic markers of PHT serve as end-points for titration of therapy? Cardiac index, Rt atrial pressure, PAPm The presence of right heart failure Persistence of NYHA class III-IV, 3 m on therapy! Should goal be to improve class? 6 min walking distance, 6MWD SaO₂ fall during walking Echo indices for RV function (Tei)
29	PHT, treatment goals Dream To normalize pulmonary vascular & heart function & structure & to restore exercise tolerance, quality of life & survival, or to approach as close as possible to these goals. Reality Hemodynamics + Structure + Exercise tolerance + QOL + Survival + (X2)
30	Prognostic markers, quantitative aspects? 6MWD>332 m, 92% 3 yrs survival <332 m, 20% 3 yrs survival <300 m, RR of mortality X2.4 SaO₂ >10% fall with walking, RR X2.9 RR rises 27% for 1 % fall UA >8.9 (man) 25% 3 yrs survival <8.9 (man) 70% 3 yrs survival
31	Can the poor prognostic markers serve as targets for titration therapy? Titrate to avoid persistence of NYHA class III-IV, in the initial 3 m in therapy; improve functional class Revert right heart failure in 3 months Reduce PAPm to < 60 mmHg & PVR by 30% Improve, 6MWD, preferably to > 332 m Minimize or reverse SaO₂ fall with walking
32	Survival by NYHA class on therapy
33	Survival by 6MWD, magic 332 m
34	Survival by 6MWD, on therapy
35	Survival by NYHA class on therapy
36	Survival by 6MWD, magic 332 m
37	Survival by 6MWD, on therapy
38	Survival by echo index of RV function
39	Survival by BNP before & on treatment
40	Survival by Troponin
41	Summary: treatment goals in PHT The natural course of PHT has markedly improved during the last decade Therapy should be targeted to achieve specific goals of improvement (not only “some” improvement), such as é NYHA class, reverting RV failure, é 6MWD to > 332 m, é hemodynamics at ret & exercise Possible important role for metabolic markers (UA, Troponin, BNP & ET-1) Multi drug therapy may be important
42	Problematic situations to classify, I or II Mild LV dysfunction, mild valvular abn Valvular repair with residual PHT Corrected CHD with PHT despite early correction Mild Lung function or parenchymal abn Mild OSA Could all be IPHT and these abnormalities represent the environmental hit on a genetic ground? Clue from COPD and ACE
43	Cardiac index & PAP, rest & exercise
44	Patient AA, Tri-Athlon 32 yrs old F Professional Tri-Athlonist Poor fitness despite correction of anemia ECHO, SPAP 30+RAP, Exercise =60 mmHg VO2 max = 27ml/kg/min=67% of predicted Heart Cath, PA=13/7, m=11, PCWP=5 Exercise, HR from 82-150 b/min, no change in SPAP Pressure gradient across PV of 15 mm/Hg!!!
45	Patient KA, multiple risks and protracted recovery from crisis 56 yrs old F OWR with ALK1 mutation, anorexiogens used -10 yrs, paradoxical brain emboli from chest AVF and splenic infarction. PHT developed after removal of lung AVF. Response to single, double and triple drugs Now, Sildenafil, Bosentan and Remodulin Course after nose bleeding and after roberry in Paris
46	Patient DK 64 yrs old Male VSD repair at age 19 yrs 40 “asymptomatic” yrs PHT, SPAP 100, PCWP 14 mmHg a year ago. Baseline chest X-Ray is shown Anti-endothelin therapy initiated In few days, dyspnea and orthopnea New chest X ray is shown Repeat cath, PCWP is now 25 mmHg Interpretation of course and later course (+flolan)
47	KD, 64 yrs old, PHT post VSD repair 40 yrs ago, before therapy for PHT
48	KD, hemodynamics
49	KD, 64 yrs old, PHT post VSD repair 40 yrs ago few days on therapy for PHT
50	GG with apparent ASD 74 yrs old male with severe effort intolerane PH: TIA 2yrs, hemoptysis 5 yrs W/U by echo SPAP = 100 mmHg & ASD Eisenmenger? CT angio revealed multiple emboli Diagnosis = CTEPHT with opening of Foramen ovale (past events = PE & paradoxical embolus)
51	MM, age & previous severe LV disease do not exclude “I-PHT” 82 yrs old F IHD sp CABG SP AVR, 1999 Recent severe effort dyspnea Echo, SPAP= 100 mmHg Heart Cath, PAP 100/40,m=PCWP=9mmHg Therapy anti-endothelin+Remodulin & marked improvement. "לא פיללתי לשיפור כזה" After 18 months, sepsis after hip replacement
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53	Maximal oxygen consumption as a determinant of survival in PPH
54	Survival correlates with BNP values in IPAH
55	Suggested signalling mechanisms in PHT-Effect of PDE51
56	Considerations in Choice of Therapy for PAH
57	Suggested signalling mechanisms in PHT-Effect of PDE51
58	Remodelling in pulmonary vessels
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