Update on pulmonary HTN

Transcription

1 Update on pulmonary HTN Feras Bader, MD, MS, FACC Associate Professor of Medicine- Cardiology University of Utah School of Medicine Director, Advanced Heart Failure and Transplant Program Dabbous Cardiac Center- Adan Hospital, Kuwait

2 Definition and Classification. Pathophysiology. Clinical Presentation. Diagnosis. Management.

3 5 th World Symposium on PH: Hemodynamic Definition of PH/PAH PH Mean PAP 25 mm Hg at rest during RHC PAH Mean PAP 25 mm Hg plus PAWP 15 mm Hg plus PVR >3 Wood units Hoeper MM et al. J Am Coll Cardiol. 2013;62:D42-D50.

4 5 th World Symposium on PH: Modified Classification 1. Pulmonary arterial hypertension 1.1 Idiopathic PAH 1.2 Heritable PAH BMPR ALK1, ENG, SMAD9, CAV1, KCNK Unknown 1.3 Drug- and toxin-induced 1.4 Associated with Connective tissue diseases HIV infection Portal hypertension Congenital heart disease (update) Schistosomiasis Chronic hemolytic anemia 1. Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis 1. PPHN 2. PH due to LHD 2.1 LV systolic dysfunction 2.2 LV diastolic dysfunction 2.3 Valvular disease 2.4 Congenital/acquired left heart inflow/outflow obstruction 3. PH due to lung diseases and/or hypoxia 3.1 COPD 3.2 Interstitial lung disease 3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern 3.4 Sleep-disordered breathing 3.5 Alveolar hypoventilation disorders 3.6 Chronic exposure to high altitude 3.7 Developmental lung diseases (update) 4. CTEPH 5. PH with unclear multifactorial mechanisms 5.1 Hematological disorders: chronic hemolytic anemia, myeloproliferative disorders, splenectomy 5.2 Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis 5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders 5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH Simonneau G et al. JACC 2013;62:D34-41.

5 Epidemiology of PH by Echo Single echo lab / Australian community. Etiology of PH noted on echocardiogram PAH, 2.7% Unknown, 15.4% CTEPH, 2.0% Lung disease, Sleep-related hypoventilation, 9.3% Miscellaneous, 2.7% Left heart disease, 67.9% N=936 of 10,314 patients with echo PASP >40 mm Hg. Strange G et al. Heart. 2012;98:

6 Pathogenesis of Pulmonary Arterial Hypertension

7 Pathologic Findings in Pulmonary Arterial Hypertension Pulmonary Arteriopathy Intimal fibrosis Medial hypertrophy Adventitial proliferation Obliteration of small arteries

8 Pathogenesis Proposed Multifactorial Factors Influencing Progression of Pulmonary Hypertension In a suitable genetic background, the interplay of epigenetics and pathobiological injurious events may amplify the severity of the disease, often associated with more pronounced remodeling and worse clinical outcome. J Am Coll Cardiol. 2013;62(25_S). doi: /j.jacc

9 Pathogenesis- The Right Heart Pathophysiology of RV Dysfunction in PAH Increased right ventricular (RV) wall stress, neurohormonal activation, inflammation, and altered bioenergetics contribute to RV remodeling in pulmonary arterial hypertension (PAH). Adaptive remodeling is associated with minimally altered ventriculoarterial coupling. Progressive RV dilation with maladaptive remodeling further contributes to RV stress. J Am Coll Cardiol. 2013;62(25_S). doi: /j.jacc

10 Pathogenesis- Left Heart Disease Mechanism of Pulmonary Hypertension Due to Left Heart Disease J Am Coll Cardiol. 2013;62(25_S). doi: /j.jacc

11 Schematic Progression of PAH Presymptomatic/ Compensated Symptomatic/ Decompensating Declining/ Decompensated Symptom Threshold PAP PVR Right Heart Dysfunction CO = TPG (mpap PAWP) PVR Time TPG = transpulmonary gradient.

12 Patient Presentation: Nonspecific Symptoms Dyspnea Fatigue Near syncope/syncope Chest pain Palpitations Edema Patients (%) Median Time From Symptom Onset to Diagnosis NIH Registry (1981 to 1985) REVEAL Registry (2006 to 2007) 1.3 years 1.1 years Multiple educational efforts Rich A et al. Ann Intern Med. 1987;107: Badesch DB et al. Chest. 2010;137:

13 WHO Functional Class

14 Cardiac Findings in Pulmonary Hypertension Elevated JVP Large A wave from noncompliant RV Large V wave from tricuspid regurgitation RV heave along left sternal border Accentuated P2, early systolic click, midsystolic ejection murmur Right ventricular S3 or S4 Systolic murmur of tricuspid regurgitation Diastolic murmur of pulmonic regurgitation

15 Is There a Reason to Suspect PAH? ECG Right Axis RVH RV Strain Right Atrial Enlargement

16 Chest X-ray in Pulmonary Arterial Hypertension Peripheral Hypovascularity Prominent Central Pulmonary Artery Right Ventricular Enlargement

17 Is There a Reason to Suspect PAH? Echo RV enlargement RA enlargement Septal straightening Loss of IVC inspiratory collapse Tricuspid regurgitation Pericardial effusion Decreased RV systolic dysfunction TAPSE (tricuspid annular plane systolic excursion) TAPSE 2.3 cm Relatively preserved RV function TAPSE 1.5 cm RV dysfunction McLaughlin VV et al. J Am Coll Cardiol. 2009;53:

18 Severe PAH and RV Failure Systole in short-axis view Apical 4-chamber view Severe PAH29.avi Severe PAH 34.avi Diastole in short-axis view TR jet Severe PAH29.avi

19 Diagnostic Cardiac Catheterization Establish the presence of PH Make the diagnosis of PAH measure wedge pressure and/or LVEDP Determine severity and prognosis of disease Exclude congenital heart disease Perform acute vasodilator test Catheterization is required when pulmonary hypertension is suspected

20 PH: Define the Lesion (mean PAP 25 mm Hg) Post-capillary PH PCWP >15 mm Hg PVR <3 Wood units RA RV PA PV PC LA LV Ao Pre-capillary PH PCWP <15 mm Hg PVR 3 Wood units Mixed PH PCWP >15 mm Hg PVR 3 Wood units Other: High CO PCWP <15 mm Hg PVR <3 Wood units

21 Acute Vasodilator Trial Purpose: identify vasodilator responders who are candidates for CCB therapy Short-acting vasodilators inhaled nitric oxide is preferred Definition of response decrease in mpap by 10 mm Hg down to mpap of 40 mm Hg with improvement or maintenance of cardiac output Rubin LJ. Chest. 2004;126:4S-6S.

22 Agents for Acute Vasodilator Testing Epoprostenol Intravenous infusion 2 ng/kg/min every minutes Dose range: 2-10 ng/kg/min Side effects: headache, nausea, lightheadness Adenosine Nitric Oxide Inhaled No dose titration Dose range: ppm Side effects: increased left heart filling pressures in susceptible patients Nitroprusside* Intravenous infusion 50 mcg/kg/min every 2 minutes Dose range: mcg/kg/min Side effects: dyspnea, chest pain, AV block Intravenous infusion 0.5 mcg/kg/min every 3 minutes Dose range: mcg/kg/min Side effects: hypotension *Not in PH guidelines, used in heart transplant evaluation

23 Screening Guidelines: Patients With Known PAH Risk Substrate Further Assessment Rationale Known BMPR2 mutation Systemic sclerosis* HIV Portal hypertension Congenital heart disease Echo yearly; RHC if echo shows evidence of PAH Echo yearly; RHC if echo shows evidence of PAH Echo if symptomatic; RHC if echo shows evidence of PAH Echo if OLT considered; RHC if echo shows evidence of PAH Echo and RHC at diagnosis; consider repair of L-R shunt defect Early PAH detection; 20% chance of developing PAH 8% prevalence of PAH 0.5% prevalence of PAH 4% prevalence of PAH; predictive of poor outcome High PAH probability if unrepaired (Eisenmenger) *Systemic sclerosis: consider echocardiogram if % FVC >1.6 % DLCO or unexplained declining DLCO. McLaughlin VV et al. J Am Coll Cardiol. 2009;53:

24 Diagnostic Algorithm for PH Identical for local practitioners and PH specialists Requirements: thorough evaluation high quality studies and interpretation Establish a suspicion of PAH Confirm the diagnosis (right heart catheterization) Classify the type of PH (Group I-V) Determine the disease severity Select the appropriate treatment for patients with PAH McLaughlin VV et al. J Am Coll Cardiol. 2009;53:

25 ACCF/AHA Diagnostic Algorithm Pivotal Tests Contingent Tests Contribute to Assessment of: History Exam CXR ECG Echocardiogram VQ Scan TEE Exercise Echo Pulmonary Angiography Chest CT Angiogram Coagulopathy Profile Index of Suspicion of PH RVE, RAE, RVSP, RV Function Left Heart Disease VHD, CHD Chronic PE PFT s ABG s Ventilatory Function Gas Exchange Overnight Oximetry Polysomnography Sleep Disorder HIV ANA LFT s Other CTD Serologies HIV Infection Scleroderma, SLE, RA Portopulmonary Htn Functional Test (6MWT, CPET) RH Cath McLaughlin VV et al. J Am Coll Cardiol. 2009;53: Vasodilator Test Exercise RH Cath Volume Loading Left Heart Cath Establish Baseline Prognosis Confirmation of PH Hemodynamic Profile Vasodilator Response

26 Mechanisms of Action of Approved Therapies for PAH Pre-proendothelin Endothelin Pathway Proendothelin Endothelial cells Nitric Oxide Pathway Endothelial cells Prostacyclin Pathway Arachidonic acid Prostaglandin I 2 Endothelin receptor A Endothelinreceptor antagonists Endothelin-1 Smooth muscle cells Endothelin receptor B Vasoconstriction and proliferation L-arginine Phosphodiesterase type 5 Nitric Oxide cgmp L-citrulline Vasodilation and antiproliferation Phosphodiesterase type 5 inhibitor Exogenou s nitric oxide SGC stimulator Prostacyclin (prostaglandin I 2 ) camp Vasodilation and antiproliferation Smooth muscle cells Prostacyclin derivatives Adapted from Humbert M et al. N Engl J Med. 2004;351:

27 PAH Treatment Goals Improve survival Improve quality of life Improve exercise capacity 6MWD WHO functional classification Improve hemodynamics Fewer/less severe symptoms Prevent clinical worsening escalation of therapy hospitalization lung transplantation death

28 PAH Determinants of Risk LOWER RISK DETERMINANTS OF RISK HIGHER RISK No Clinical evidence of RV failure Yes Gradual Progression of symptoms Rapid II, III WHO class IV Longer (>400 m) 6MWD Shorter (<300 m) Peak VO 2 >10.4 ml/kg/min CPET Peak VO 2 <10.4 ml/kg/min Minimal RV dysfunction RAP <10 mm Hg; CI >2.5 L/min/m 2 Echocardiography Hemodynamics Pericardial effusion, significant RV enlargement/dysfunction; RA enlargement RAP >20 mm Hg; CI <2.0 L/min/m 2 Minimally elevated BNP Significantly elevated McLaughlin VV et al. J Am Coll Cardiol. 2009;53:

29 Recommendation 5 th World Symposium on PH: 2013 PAH Treatment Algorithm INITIAL THERAPY WITH PAH-APPROVED DRUGS YELLOW: Morbidity and mortality as primary end point in randomized controlled study or reduction in all-cause mortality (prospectively defined) Level of evidence based on WHO-FC of majority of patients of studies I Evidence WHO FC II WHO FC III WHO FC IV A or B Ambrisentan, Bosentan Macitentan Riociguat Sildenafil Tadalafil Ambrisentan, Bosentan, Epoprostenol IV Iloprost inh Macitentan Riociguat Sildenafil Tadalafil Treprostinil SC, inh Epoprostenol IV IIa C Iloprost IV*, Treprostinil IV Ambrisentan, Bosentan, Iloprost inh and IV* Macitentan Riociguat Sildenafil, Tadalafil Treprostinil SC, IV, Inh* B Beraprost* IIb C Initial Combination Therapy Initial Combination Therapy Galiè N et al. J Am Coll Cardiol. 2013;62:D60-D72. *Not approved in US.

30 5 th World Symposium on PH: 2013 Treatment Algorithm Caveat Since 5 th World Symposium, oral treprostinil has been approved by FDA for treatment of PAH (WHO Group 1) to improve exercise capacity 1 Study that established effectiveness included predominantly patients with WHO FC II-III symptoms and etiologies of IPAH or heritable PAH (75%) or CTD-associated PAH (19%) As sole vasodilator, effect on exercise is small Oral treprostinil has not been shown to add to other vasodilator therapy At time of 5 th World Symposium, treatment working group had examined clinical evidence published at that time and noted 2 : oral treprostinil had been evaluated in 2 RCTs in PAH patients on background therapy with bosentan and/or sildenafil and, in both, primary endpoint of 6MWD did not reach statistical significance 3,4 additional RCT in PAH-naive patients showed improvement in 6MWD by 26 m at peak dose 5 1 Orenitram (treprostinil) Prescribing Information, December Galiè N et al. J Am Coll Cardiol. 2013;62:D60-D72. 3 Tapson VF et al Chest. 2012;142: Tapson VF et al Chest. 2013;142: Jing ZC et al. Circulation. 2013;127:

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32 Invasive Therapies for Pulmonary Arterial Hypertension Atrial Septostomy Creates a right to left shunt Decreases right heart filling pressures Increased left heart filling pressures Increased cardiac output Recommend for severe PAH and intractable failure despite maximal medical therapy High mortality from procedure (15%, range 5% -50%) Lung and Combined Heart and Lung Transplantation

33 Summary 1. PH is common, but most often due to LHD or chronic lung disease: selective pulmonary vasodilators are not proven in these patients 1. PAH is rare but deadly: outcomes have improved but not as much as we would like; diagnosis must be made earlier 1. Definitive diagnosis of PH requires right heart cath 2. Identify underlying cause of PH: etiology important = prognostic and Rx implications 3. Treatment of PH is based on correct diagnosis and functional status 4. Lack of response to acute vasodilator challenge in PAH does not mean the patient is untreatable.