Pulmonary Hypertension: Clinical Features & Recent Advances

Transcription

1 Pulmonary Hypertension: Clinical Features & Recent Advances Lisa J. Rose-Jones, MD Assistant Professor of Medicine, Division of Cardiology Advanced Heart Failure/Cardiac Transplantation & Pulmonary Hypertension Director, Training Program in Cardiovascular Disease

2 Disclosures I have no relevant financial disclosures

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4 Diagnosis is often late Symptoms are non-specific -99% Dyspnea % Chest Pain -30% LE edema % Syncope *Key is that it makes it into the differential diagnosis when we evaluate for dyspnea, exercise intolerance, and even angina

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7 Failure Compensation Normal Progression of Pulmonary Vascular Disease Progression of Pulmonary Vascular Disease Right Pulmonary Progression Right Arteries Ventricle of Pulmonary Arteries Vascular Disease Right Ventricle Pulmonary Arteries Progression of Pulmonary Vascular Disease Thin RV wall Healthy Thin RV PA wall Endothelium Healthy Thin Thin PA walled endothelium RV wall relaxed PAs Right Ventricle Pulmonary Arteries Thin-walled Healthy Large PA capillary relaxed Endothelium network PAs Large Normal Thin capillary walled CO/PVR relaxed network and PAs perfusion Large Thin capillary RV wall network Normal Healthy CO/PVR PA Endothelium and perfusion Normal CO/PVR and perfusion Thin walled relaxed PAs Large capillary Hypertrophied network RV Normal Hypertrophied CO/PVR Abnormal and PA perfusion endothelium RV Hypertrophied Constricted stiff RV PAs Abnormal Abnormal PA Loss PA of microvessels endothelium Normal Constricted Hypertrophied CO, mild stiff RV increase PAs in PVR, Abnormal Loss moderate Loss of of PA decrease microvessels endothelium in perfusion Normal CO, mild increase in PVR, Normal Constricted stiff PAs moderate CO, decrease mild in perfusion PVR, Loss of microvessels moderate in Normal CO, mild increase Dilated perfusion in RV PVR, moderate Cell decrease proliferation in perfusion in the PA wall Dilated RV Cell Obliterative proliferation PA in the remodeling PA wall Severe Dilated decrease RV Obliterative in CO and perfusion Dilated PA RV remodeling Cell Severe proliferation with severe increase PA wall in PVR Cell proliferation decrease in the CO PA and wall perfusion Obliterative with severe PA increase remodeling PVR Champion H, et al. Comprehensive invasive and noninvasive approach to the RV. Circulation. 2009;120: Severe decrease CO and in CO perfusion, and perfusion with Champion H, et al. Comprehensive invasive and noninvasive approach to the RV. Circulation. 2009;120: with severe increase in PVR Champion H, et al. Comprehensive invasive and noninvasive approach to the RV. Circulation. 2009;120: severe PVR 14 CO, cardiac output; LV, left ventricle; PA, pulmonary artery; PVR, pulmonary vascular resistance; 14 RV right ventricle. 14 Figure adapted from Champion et al. Circulation. 2009;120: With permission.

8 PAH Background Rare disease (orphan designation) of the pulmonary microvasculature affecting 15 to 50 people per million inhabitants in the Western world 1 Affects all races Affects all ages; however, most prevalent in 4th and 5th decades of life Higher prevalence in females Global burden of PAH may be underestimated because of: 1,2 Underdiagnosis (eg, nondescript symptoms) Misdiagnosis (eg, asthma, left-heart disease) 1. Humbert. Eur Respir J. 2007;30: Humbert et al. Chest. 2007;132:

9 PAH is a Devastating Disease

10 PAH is a Devastating Disease

11 PAH is a Devastating Disease Seven-year survival from time of diagnostic right-sided heart catheterization for full REVEAL Registry cohort, using left truncation methods. = estimated survival estimate ± SE at each particular time point REVEAL, Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management Benza et al Chest 2012;142 (2):

12 The Expert Consensus document says that if after the history (chief complaints of dyspnea/decreased exertional tolerance/angina), physical examination, the risk factor assessment, ECG, and chest x-ray, you still suspect pulmonary hypertension, the next step is an **echocardiogram**.

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14 Diagnostic Criteria For PAH 3 PVR >3 WU PVR >3 WU 1 mpap 25 mm Hg mpap, 25 mm Hg 15 mm Hg 2 PAWP 15 mm Hg

15 PH-Nice Classification, 2013 Pulmonary Hypertension WHO GROUP 1 PAH Idiopathic (IPAH) Heritable Drug- and toxininduced Associated with other conditions (APAH) Connective tissue disease HIV infection Portal hypertension Congenital heart disease (repaired) Schistosomiasis WHO Group 1 Pulmonary venoocclusive disease Pulmonary capillary hemangiomatosis WHO Group 1 Persistent PH of the newborn WHO GROUP 2 Left-heart related Systolic dysfunction Diastolic dysfunction Valvular disease Congenital/ acquired left heart inflow/outflow tract obstruction and congenital cardiomyopat hies WHO GROUP 3 Lung/hypoxia COPD related ILD Other pulmonary diseases with mixed restrictive and obstructive pattern Sleepdisordered breathing Alveolar hypoventilation disorders Chronic exposure to high altitude Developmental lung diseases WHO GROUP 4 CTEPH Chronic thromboembolic pulmonary hypertension WHO GROUP 5 Other Unclear multifactorial mechanisms Hematologic disorders Systemic disorders Metabolic disorders Others CTEPH, chronic thromboembolic pulmonary hypertension; COPD, chronic obstructive pulmonary disease; ILD, interstitial lung disease; HIV, human immunodeficiency virus; PH, pulmonary hypertension; WHO, World Health Organization. Simonneau G et al. J Am Coll Cardiol. 2013;62:D34-D41.

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18 Vasoactive Mediators Involved In PAH ABNORMALITIES Nitric oxide deficiency Prostacyclin deficiency Endothelin overexpression PDE-5 inhibitors Block the activity of PDE-5, restoring vasodilation through an increase in cgmp 1 THERAPIES Prostacyclin Supplement the deficiency in PGI 2, resulting in vasodilation and inhibition of platelet aggregation 2 ERAs Block the binding of ET-1 to its receptors, preventing vasoconstrictor effects of ET-1 3 cgmp, cyclic guanosine monophosphate; ERA, endothelin receptor antagonist; ET-1, endothelin; PDE-5, phosphodiesterase type 5; PGI 2, prostacyclin. 1. Humbert et al. J Am Coll Cardiol. 2004;43(suppl S):13S-24S. 2. Humbert et al. N Engl J Med. 2004;351: Galiè et al. Eur Heart J. 2004;25:

19 PAH specific FDA-approved Therapies (in U.S.) 8 oral therapies» Bosentan improvements in 6MW, time to clinical worsening, functional class, hemodynamics» Ambrisentan improvements in 6MW, time to clinical worsening, functional class» Macitentan improvement in morbidity and mortality» Sildenafil improvements in 6MW, functional class, hemodynamics» Tadalafil improvements in 6MW, functional class, time to clinical worsening» Riociguat improvement in 6MW, functional class» Oral treprostinil (Orenitram)» Selexipag--improvement in morbidity and mortality 2 parenteral therapies» Epoprostenol improvements in survival, 6MW, hemodynamics» Treprostinil (subcutaneous also) improvement in 6MW, hemodynamics 2 inhaled therapies» Iloprost improvement in 6MW, hemodynamics» Treprostinil improvement in 6 MW, hemodynamics

20 2015 ERS/ESC PAH Treatment Guidelines

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23 Is it This Simple? Occasionally 28 y/o female presents with progressive dyspnea, LE edema, and near syncope No past medical history Exam normal, CXR normal, Echo suggestive of PH with negative bubble study, V/Q negative, PFTs nl except DLCO 40 % predicted RHC: RA 16 mmhg, mpap 58 mmhg, PAWP 6, CI 1.6 L/min/m 2, PVR 19 WU. ANA neg, HIV neg Dx = IPAH Plan = start parenteral prostacyclin therapy

24 What we deal with more often 59 y/o white male with obesity, DM, A fib, COPD, HTN, and OSA (non-compliant) presents with progressive dyspnea. Obese but o/w normal exam. Echo w/ LVEF 55%, estm PA sys ~ 70 mmhg with mildly dilated RV, dilated LA, and negative bubble. V/Q neg. PFTs with evidence of moderate restriction and DLCO mod reduced. RHC: RA 12 mmhg, mpap 49 mmhg, PAWP 21 mmhg, CI 2.9 L/min/m 2, PVR 6 WU PFTs: FEV1 56% pred, TLC 68% pred, DLCO 25% pred Dx =?? Plan = diurese, ACE-I and/or BB, wear CPAP,?? Trial of PAH therapy

25 Mixed Pre- and Postcapillary PH Refers to combined passive retrograde transmission of LV filling pressure + intrinsic pulmonary arterial disease Most of these patients have features of the metabolic syndrome (HTN, obesity, older age)

26 Pulmonary Venous Hypertension The vast majority of PH falls in this category and it represents a clinical challenge Pulmonary vasodilators could be detrimental b/c if used in setting of elevated LV filling pressures, could result in pulmonary edema Treatment should 1 st and foremost focus on the underlying reason for PA elevation: usually HTN and volume overload

27 In true pulmonary arterial hypertension (ipah, APAH, FPAH), the pulmonary vascular remodeling affects largely the pre-capillary arteries; on the other hand, in venous PH, including pulmonary veno-occlusive disease (PVOD), venous remodeling predominates but is often accompanied by pulmonary arterial changes. In fact, these can be pronounced, to an extent exceeding that seen in pre-capillary PH. 9/22/

28 PVOD 9/22/

29 Looked at patients with HF (n=108; 53 HFpEF and 55 HFrEF) with PH ( [PASP] 40 mm Hg) & compared to normals (n=12) and & PVOD (n=17) on. 2018;137: In lung specimens from autopsy (control, HF-PH, and 7 PVOD) or surgery (10 PVOD) 9/22/

30 9/22/

31 Why increased PA pressures in COPD? Proposed classical mechanisms for secondary PH in COPD:» hypoxia leading to vasoconstriction and vascular remodeling» compression of alveolar vessels from hyperinflation» physical obliteration of pulmonary vasculature» other possible influences include transmission of end-expiratory intrathoracic pressure elevated due to dynamic or static hyperinflation or use of expiratory muscles» other molecular/genetic influences (IL-6, Serotonin transporter)

32 What is Proportionate PH in COPD National Emphysema Treatment Trial (NETT): Evaluation of Lung Volume Reduction Surgery for Emphysema

33 Hemodynamics of COPD patients referred for lung transplant/lvrs ~215 pts with COPD referred for tx Thabut et al. Chest 2005;127:

34 Disproportionate Mixed If after aggressive treatment of underlying comorbidities (the left-sided heart disease, the COPD/ILD) and the Transplumonary (mpap PCWP) gradient >15-20 mmhg then there is likely a superimposed pulmonary vascular disease is present And, referral to a tertiary care center with expertise in PH and chronic lung disease/heart failure should be considered

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