Pulmonary hypertension. Miloslav Špaček, MD

Transcription

1 Pulmonary hypertension Miloslav Špaček, MD

2 Key points Pulmonary hypertension (PH) is a hemodynamic and pathophysiological abnormality found in many clinical conditions, most commonly heart and lung disease Pulmonary arterial hypertension (PAH) is a progressive and debilitating disorder affecting pulmonary vasculature

3 Definition PH is defined as mean pulmonary artery pressure (mpap) of 25mmHg.

4 Definition Diagnosis based on measurement of PH during exercise is no longer accepted. Patients with mpap of present grey zone. Normal resting mpap: Upper limit of normal: mpap at heart rate 100: Maximal exercise mpap: Exercise in normal person >50yrs: 14 +/- 3mmHg 20mmHg 32mmHg 37mmHg 47mmHg

5 Classification 1 Pre-capillary PH Post-capillary PH mpap >/= 25mmHg mpap >/= 25mmHg mpcwp </= 15mmHg mpcwp >/=16mmHg CO normal or reduced CO normal or reduced "Passive" - TPG </=12mmHg "Reactive" - TPG >12mmHg TPG - transpulmonary gradient / CO - cardiac output / PCWP - pulmonary capillary wedge pressure

6 In some patients with postcapillary PH due to left heart disease or in some patients with COPD, mpap is higher than expected (TPG >12mmHg and PVR > 3) -> mixed / reactive / "out-of-proportion" PH

7 Classification 2 Pre-capillary PH Post-capillary PH PAH PH due to lung disease CTEPH PH due to left heart disease PH due to unclear or multifactorial mechanisms

8 Classification 3 Nice, France 2013

9 Classification 3 5th, Nice, France 2013

10 Prognosis of PAH The natural history of PAH is extremely poor and comparable to advanced cancer in NYHA III/IV Without treatment NYHA I-II: NYHA III: NYHA IV: 4.9yrs 2.6yrs 1/2yr With treatment (depends on etiology!!!) >50% 5year survival! 10% annual mortality 18yrs 90% survival in CCB responders!

11 Pathology in PAH Fibrotic and proliferative vascular lesions in the small (<0.5mm) pulmonary arteries are responsible for increased pulmonary pressures Plexiform lesions vary in frequency (no longer considered pathognomonic for IPAH only)

12 Prognosis of PAH Prognosis and symptoms are determined largely by RV function As hypertrophied RV function deteriorates and the RV dilates due to inability to compensate increased RVEDP, annulus is stretched and dilates causing TReg and further deteriorating Increased RA pressure and size is consistent sign of adverse prognosis

13 Pathology in PAH Medial/adventitial hypertrophy and hyperplasia Intimal proliferation ("onion bulb") Fibrotic changes Perivascular infiltrates Intravascular trombosis Plexiform

14 Pathology in PAH Pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis are rare causes of PAH typically affecting venules and septal capillaries (resp.) that become fibrotic and thickened (Occult) pulmonary hemorrhage is common

15 Pathology in left heart PH (Pressure passively transmitted back: LV-LA-PV-PA) Pulmonary veins enlarged and thickened, capillaries dilated, enlarged lymphatics Medial hypertrophy and intimal fibrosis may be present in distal PAs (?reactive?)

16 Pathology in lung diseases Medial hypertrophy and intimal obstructive proliferation of the distal PAs (mild) driven by vasospasm in hypoxemia Loss of capillary cross sectional area in advanced disease -> no role for vasodilators!!!

17 Pathology in CTEPH Organized thrombi attached to the medial layer of PAs are covered by neointima - webs/stenosis/ bands/complete obstruction Arteriopathy indistinguishable from PAH in the nonoccluded arteries (develop secondary)

18 Pathobiology in PAH The cause remains UNCLEAR, several proposed mechanisms include: Impaired vasoreactivity?? Apoptosis of cells? Inflammation?? Thrombosis?? Abnormal function of cell channels??

19 Pathobiology in PAH!! Reduced production of PROSTACYCLIN!! Reduced production of NO (EDRF)!! Overexpression of ENDOTHELIN! -> vasoconstriction, increased platelet aggregation, increased proliferation

20 Genetics in hereditary PAH Female:male ratio 1.7:1! Autosomal dominant with incomplete penetrance In case of familial PAH mutations in bone morphogenetic protein receptor 2 (BMPR2) can be found in >70%. More rarely: activin receptor-like kinase type1 (ALK1) endoglin (ENG)

21 5th, Nice, France 2013

22 PAH associated conditions Connective-tissue disease PAH (->!!! screening in scleroderma!!!) HIV associated PAH Porto-pulmonary PAH Congenital L-R shunt PAH

23 Dg. approach in PAH Progressive thickening and narroving of small PAs lead to increase in PVR and pressure overload on the RV, leading to RV hypertrophy, dilation and ultimately failure and death. When RV fails, prognosis is poor. Other markers of poor prognosis are: Poor functional capacity (NYHA, 6MWD) Rapid progression of symptoms Falling saturations and/or BP on exercise High mrap Progressive increase in NTprBNP RA dilation and LV compression

24 Dg. approach in PAH The average delay between onset of symptoms to dg. is >2yrs. PAH often advanced at the time of dg. with 75% of pts. in NYHA III/IV. Symptoms occur only after there has been EXTENSIVE pulmonary vascular obliteration.

25 Dg. approach in PAH Symptoms of "low output/aortic stenosis" Gradually progressive shortness of breath/weakness Exertional chest pain (mismatch) Exertional lightheadedness/syncope Ultimately symptoms of right heart failure Peripheral edema, abdominal discomfort

26 Dg. approach in PAH In early PAH the examination is often normal Left parasternal lift, loud P2 TR murmur, 3rd heart sound Tachycardia, tachypnoea, cyanosis Signs of associated disease (Heart Failure, Interstitial Lung Disease, Connective Tissue Disease,...)

27 Dg. approach in PAH To establish whether PH is present (mpap >\= 25mmHg) To exclude non-pah causes of PH To determine if PAH is idiopathic or associated with other relevant conditions Where present to determine operability of CTEPH

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29 Low sensitivity ECG

30 ECG

31 ECG Low sensitivity Tachycardia Large P waves RBBB, right axis deviation, RV hypertrophy (R/S > 1 in V1) A-fib (in RA dilation) (Ventricular arrhythmia rather rare) Signs of associated left heart disease

32 CXR Normal CXR does not exclude PAH

33 CXR right descending PA > 16mm Pruning or loss of peripheral vessels Pleural effusions Signs of associated disease

34 Lung function tests To exclude associated lung disease In PAH the LFTs changes are very modest when compared to symptomatic limitation!!! In mild or moderate PAH the PaO2 is normal or slightly reduced A low PaO2 is found in severe lung disease, severe PAH or significant congenital cardiac shunts.

35 Blood tests Routine test include: Immunological tests for CTDs, LFTs, HIV, renal function, haematological, thyroid NTproBNP TnI Genetic testing???

36 V/Q scan To exclude CTEPH Bilateral multiple segmental V/Q defects

37 HRCT To exclude ILD Lymphadenopathy (PVOD, PCH) Effusions RVH, PA>Ao

38 ???

39 Pulmonary angio Usually at the time of right heart cath To assess suitability to endarterectomy! Experience required!

40 Pulmonary angio Abrupt terminations

41 MRI Useful in congenital heart disease Gross anatomy (RVH...) Associated conditions

42 Echo Structural assessment (RV, LV, TR, ASD, effusion, hypertrophy ) RV systolic pressure + TAPSE (TR velocity,!36mmhg/2.8m/s) mpap = 0.61 x PASP + 2 mmhg (Cave! PASP >40mmHg common in obese/elderly) (Cave! Poor correlation between PASP and symptoms/ prognosis - does not reflect RV function!)

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44 CPET/6MWT Exercise capacity reduced (limited CO) and VO2 commonly reduced to 40% of normal in most patients with PAH. May be used for treatment monitoring 6MWT correlates with CPET and is easier to perform. QoL measurement. Many limitations!!

45 RHC Essential for PAH dg. (commonly with SKG/LHC) To confirm dg. To characterize type (pre/post) To test for vasoreactivity To perform pulmonary angiography (PEA suitability) Should be performed at expert center

46 Swan-Ganz

47 Vasoreactivity test Vasodilator testing should be done at the time of the first RHC to identify long-term CCB responders Most likely positive in anorexigen PAH (13%) and IPAH, very rare (<1%) in others Positive response defined as: a decrease in mpap of 10mmHg to reach an absolute value of <40mmHg with no change or an increase in CO (negative if CO decreases!) Long-term vasodilator response defined as marked hemodynamic improvement after 3-4 months of CCB th. (redo RHC necessary!) and in NYHA I or II, at least after 1yr of CCB th. Inhaled NO/iloprost/epoprostenol (CCB risk of severe fall in CO)

48 Management of PAH General approach Specific PAH therapy Supportive Vasodilators Surgical interventions

49 General approach PAH is incurable and irreversibly progresses to preterm death Holistic approach Pregnancy issues Lifestyle issues (incl. traveling) Elective surgery planning End-of life issues

50 Supportive Anticoagulation ( warfarin for most -INR EU, 2-3 in US/UK) Diuretics Oxygen (?) Antidepressants Digoxin

51 Advanced th. CCBs + 3 pathways targeted : The endothelin pathway with endothelia receptor antagonists (ERA - bosentan, ambrisentan ) The NO pathway using PDE-5Is (sildenafil, tadalafil) The prostacyclin pathway using prostanoids (epoprostenol, iloprost, )

52 Advanced th. Specialized centres Aggressiveness of treatment (incl. combination th.) based on severity of symptoms Side effects of th., drug interactions

53 Atrial septostomy Palliative procedure for end-stage PAH with intractable low output HF and syncope Baseline oxygen saturation should be >90% on room air, hematocrit > 35% and LV function normal (risk of edema)

54 Tx For end-stage PAH not curable by any medical th. or conservative approach Criteria: mrap>12mmhg, mpap >60mmHg, CI<2.2L/min/m2 Performed rarely because of shortage of donor lungs Heart-lung in congenital heart disease

55 Non-PAH PH specifics

56 Left-heart disease PH Post-capillary LH disease markers make dg. of PAH unlikely Studies from th. of mitral stenosis and heart devices suggest reversibility of "disproportionate" PH Th. of the underlying cause is a goal Vasodilator th. in disproportionate PH questionable

57 Lung-disease PH mpap typically ranges 25-35mmHg there is no evidence from placebo-controlled RCT that standard PAH th. (anticoagulation, vasodilators) is by any means beneficial O2, immunosuppression LTx

58 CTEPH 4% of PE patients develop CTEPH within 2yrs 2/3 with no recognizable history of acute PE 1/3 with proven trombophilia CTEPH cannot be diagnosed until 3 months of anticoagulation has failed to resolve the obstructions Anticoagulation is the cornerstone of th. (INR 2,5-3,5) Pulmonary embolectomy (5-10% mortality, the higher drop the better effect, though reaching normal levels uncommon) Vasodilators in registers seem beneficial in inoperable/failed pts.

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