Pulmonary Arterial Hypertension. Mark Rumbak, MD Professor of Medicine Morsani College of Medicine University of South Florida

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1 Pulmonary Arterial Hypertension Mark Rumbak, MD Professor of Medicine Morsani College of Medicine University of South Florida

2 PAH Disease State Module Outline Background and definition Clinical classification of PH Epidemiology Pathophysiology/Natural history Signs and symptoms/diagnosis Importance of right heart catheterization Treatment of PAH PAH - pulmonary arterial hypertension; PH - pulmonary hypertension.

3 PAH Background Rare disease of the pulmonary microvasculature affecting 15 to 50 individuals per million 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 : Under diagnosis (e.g., symptoms attributed to other conditions, such as obesity or deconditioning) Misdiagnosis (e.g., asthma, left-heart disease) Increasing prevalence of risk factors (e.g., HIV infection, schistosomiasis HIV - human immunodeficiency virus. 1. Humbert. Eur Respir J. 2007;30: Humbert et al. Chest. 2007;132:

4 Hemodynamic Characteristics of PAH Mean PAP >25 mm Hg PCWP 15 mm Hg mpap, 25 mm Hg 15 mm Hg Increased RVSP mpap- mean PAP; PAP- pulmonary arterial pressure; PCWP- pulmonary capillary wedge pressure; RVSP- right ventricular systolic pressure. McLaughlin et al. Circulation. 2009;119:

5 PAH is a Subset of PH (Dana Point Definitions) PAH PH Mean PAP 25 mm Hg + PCWP/LVEDP 15 mm Hg Mean PAP 25 mm Hg LVEDP- left ventricular end-diastolic pressure; PAP- pulmonary arterial pressure; PCWP- pulmonary capillary wedge pressure. Badesch et al. J Am Coll Cardiol. 2009;54:S55-S66.

6 Clinical Classification of PH: Dana Point 2008 Group 1 PAH Idiopathic PAH Heritable BMPR2 ALK-1, endoglin (with or without HHT) Unknown Drug- and toxin-induced PAH associated with: Connective tissue diseases HIV infection Portal hypertension Congenital systemic to pulmonary shunts Schistosomiasis Chronic hemolytic anemia Persistent pulmonary hypertension of newborn Pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis Group 2 PH owing to left heart disease Systolic dysfunction Diastolic dysfunction Valvular disease Group 3 PH owing to lung diseases or hypoxia Chronic obstructive pulmonary disease Interstitial lung disease Other pulmonary diseases with mixed restrictive and obstructive pattern Sleep-disordered breathing Alveolar hypoventilation disorder Chronic exposure to high altitude Developmental abnormalities Group 4 Chronic thromboembolic PH Group 5 PH with unclear multifactorial mechanisms Hematologic disorders a Systemic disorders b Metabolic disorders c Others d a Myeloproliferative disorders- splenectomy. b Sarcoidosis- pulmonary Langerhans cell histiocytosis. c Glycogen storage disease- Gaucher disease- thyroid disorders. d Tumoral obstruction- fibrosing mediastinitis- chronic renal failure. ALK-1- activin receptor-like kinase 1; BMPR2- bone morphogenetic receptor type 2; HHT- hereditary hemorrhagic telangiectasia; HIV- human immunodeficiency virus. Simonneau et al. J Am Coll Cardiol. 2009;54(1 suppl S):S43-S54.

7 Clinical Classification of PAH (Group 1) Group 1 PAH Idiopathic PAH Heritable BMPR2 ALK-1, endoglin (with or without HHT) Unknown Drug and toxin-induced PAH associated with: Connective tissue diseases HIV infection Portal hypertension Congenital systemic to pulmonary shunts Schistosomiasis Chronic hemolytic anemia Persistent pulmonary hypertension of newborn Pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis ALK-1- activin receptor-like kinase 1; BMPR2- bone morphogenetic receptor type 2; HHT- hereditary hemorrhagic telangiectasia; HIV- human immunodeficiency virus. Simonneau et al. J Am Coll Cardiol. 2009;54(1 suppl S):S43-S54.

8 Epidemiology of PAH (Group 1) 1 Prevalence of PAH in associated conditions: CTD a : 8%-12% 2,3 CHD: 15%-30% 4 HIV Distribution of PAH Subgroups in French Registry 8 Appetite suppressant >1 Risk factor IPAH PoPH: 2%-6% 5,6 PoPH HIV: 0.5% 7 CHD a Systemic sclerosis. CTD FPAH CHD- congenital heart disease; CTD- connective tissue disease; FPAH- familial pulmonary arterial hypertension; HIVhuman immunodeficiency virus; IPAH- idiopathic pulmonary arterial hypertension; PoPH- portopulmonary hypertension. 1. Simonneau et al. J Am Coll Cardiol. 2009;54(1 suppl S):S43-S Hachulla et al. Arthritis Rheum. 2009;60: Mukerjee et al. Ann Rheum Dis. 2003;62: Landzberg. Clin Chest Med. 2007;28: Hadengue et al. Gastroenterology. 1991;100: Krowka et al. Hepatology. 2006;44: Sitbon et al. Am J Respir Crit Care Med. 2008;177: Humbert et al. Am J Respir Crit Care Med. 2006;173:

9 Pathophysiology/Natural History

10 Consequences of PAH PVR RV afterload CO and PBF RV hypertrophy and dilation Death CO- cardiac output; PBF- pulmonary blood flow; PVR- pulmonary vascular resistance; RV- right ventricle. Rich S. In: Braunwald et al, eds. Heart Disease. 2 vols. 6th ed. 2001:

11 Progression of Pulmonary Vascular Disease Progression of Pulmonary Vascular Disease Right Pulmonary Progression Right Arteries Ventricle of Pulmonary Arteries Vascular Disease 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 moderate Loss of PA decrease microvessels Loss of endothelium in perfusion Normal CO, mild increase in PVR, Normal Constricted stiff PAs moderate CO, decrease mild in perfusion PVR, Loss of microvessels Normal moderate CO, mild increase in 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 RV PA 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 Failure Compensation Normal Right Ventricle Pulmonary Arteries Champion H, et al. Comprehensive invasive and noninvasive approach to the RV. Circulation. 2009;120: severe PVR CO- cardiac output; LV- left ventricle; PA- pulmonary artery; PVR- pulmonary vascular resistance; RV - right ventricle. 14 Figure adapted from Champion et al. Circulation. 2009;120: With permission

12 Echocardiographic Characteristics of PAH Parasternal view Apical 4-chamber view Echocardiography provides estimated RV systolic pressure and morphologic cardiac abnormalities LA- left atrium; LV- left ventricle; RA- right atrium; RV- right ventricle.

13 Echocardiographic Characteristics of PAH Parasternal view Apical 4-chamber view Echocardiography provides estimated RV systolic pressure and morphologic cardiac abnormalities LA- left atrium; LV- left ventricle; RA- right atrium; RV- right ventricle.

14 Hemodynamic Progression of PAH Pre-symptomatic/ Compensated Symptomatic/ Decompensating Declining/ Decompensated CO PAP PVR RAP Time CO- cardiac output; PAP- pulmonary arterial pressure; PVR- pulmonary vascular resistance; RAP- right atrial pressure.

15 Signs and Symptoms/Diagnosis

16 Symptoms of PAH Dizziness or syncope Dyspnea Angina Weakness/Fatigue Edema McLaughlin et al. J Am Coll Cardiol. 2009;53:

17 NYHA Functional Classification NYHA Class I Class II Class III Class IV Definition l Patients with cardiac disease but without resulting limitations of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain l Patients with cardiac disease resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain l Patients with cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary physical activity causes fatigue, palpitation, dyspnea, or anginal pain l Patients with cardiac disease resulting in inability to carry on any physical activity without discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased NYHA- New York Heart Association. Kossman et al. Diseases of the Heart and Blood Vessels: Nomenclature and Criteria for Diagnosis. 6th ed

18 WHO Functional Classification 1,2 WHO Class I Class II Class III Class IV Definition l Patients with PH a but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near syncope l Patients with PH resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope l Patients with PH resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue, chest pain, or near syncope l Patients with PH with inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnea and/or fatigue may even be present at rest. Discomfort is increased by any physical activity a Differences from NYHA functional classification are noted in green text. NYHA- New York Heart Association; WHO- World Health Organization. 1. Rubin. Chest. 2004;126(suppl 1):7S-10S. 2. Rich et al. Executive summary from the World Symposium on Primary Pulmonary Hypertension, Evian, France, September 6-10,

19 Evaluation of PAH a Assessment History and physical Chest x-ray Echocardiogram Electrocardiogram Right heart catheterization PFTs with DLCO Purpose l Evaluate signs and symptoms, family history, associated diseases, ANA l Assess for RV enlargement, peripheral hypovascularity (pruning), and prominent pulmonary arteries l Assess for RV and RA enlargement, RV dysfunction, TR velocity to estimate RVSP l Evaluate for right heart enlargement and strain, cardiac rhythm l Measure pressures (RA, RV, PA, and PCWP or LVEDP) to establish the diagnosis; test vasodilator response l Assess obstructive and restrictive lung disease VQ scan l Evaluate for thromboembolic disease a Additional tests may be ordered to rule out possible causes of PAH (pulmonary arteriography, blood tests [HIV, hepatic disease, scleroderma], polysomnography [sleep-disordered breathing]). ANA- antinuclear antibody; DLCO- diffusing capacity of the lung for carbon monoxide; HIV- human immunodeficiency virus; LVEDP- left ventricular end-diastolic pressure; PA- pulmonary artery; PCWP- pulmonary capillary wedge pressure; PFT- pulmonary function test; RA- right atrial; RV- right ventricular; RVSP- right ventricular systolic pressure; TRtricuspid regurgitation; VQ- ventilation-perfusion. McLaughlin and McGoon. Circulation. 2006;114:

20 Diagnostic Tests for PAH Pivotal Tests History Exam CXR ECG Echocardiogram VQ Scan PFTs Overnight Oximetry HIV ANA LFTs Functional Test (6MWT, CPET) Right Heart Cath Contingent Tests TEE Exercise Echo Pulmonary Angiography Chest CT Angiogram Coagulopathy Profile ABGs Polysomnography Other CTD Serologies Vasodilator Test Exercise RH Cath Volume Loading Left Heart Cath Contribute to Assessment of: Index of Suspicion of PH RVE, RAE, RVSP, RV Function Left Heart Disease VHD, CHD Chronic PE Ventilatory Function Gas Exchange Sleep Disorder HIV Infection Scleroderma, SLE, RA Portopulmonary Hypertension Establish Baseline Prognosis Confirmation of PH Hemodynamic Profile Vasodilator Response ABG- arterial blood gas; ANA- antinuclear antibody; CHD- congenital heart disease; CPET- cardiopulmonary exercise test; CT- computed tomography; CTD- connective tissue disease; CXR- chest x-ray; ECG- electrocardiogram; echo- echocardiograph; HIV- human immunodeficiency virus; LFT- liver function test; 6MWT- 6-minute walk test; PE- pulmonary embolism; PFT- pulmonary function test; RArheumatoid arthritis; RAE- right atrial enlargement; RH- right heart; RV- right ventricular; RVE- right ventricular enlargement; RVSP- right ventricular systolic pressure; SLE- systemic lupus erythematosus; TEE- transesophageal echocardiography; VHD- valvular heart disease; VQ- ventilation-perfusion. McLaughlin et al. J Am Coll Cardiol. 2009;53:

21 Importance of Right Heart Catheterization

22 Right Heart Catheterization 1,2 Confirm diagnosis a Gold standard Evaluate severity of PAH Assess congenital heart defects Exclude left-sided heart disease Assess response to vasodilator challenge Assess key hemodynamic parameters Swan-Ganz Catheter a Required for every patient with suspected PAH. 1. McLaughlin et al. Circulation. 2009;119: Tolle et al. Circulation. 2008;118:

23 Clinical Classification of PH: Where Is the Lesion? VC RA RV PA PC PV LA LV Ao ALK-1- activin receptor-like kinase 1; Ao- aorta; BMPR2- bone morphogenetic receptor type 2; HHT- hereditary hemorrhagic telangiectasia; HIV- human immunodeficiency virus; LA- left atrium; LV- left ventricle; PA- pulmonary artery; PC- pulmonary capillary bed; PV- pulmonary vein; RA- right atrium; RV- right ventricle; VC- vena cava. Simonneau et al. J Am Coll Cardiol. 2009;54(1 suppl S):S43-S54. Graphic adapted with permission from Medscape.com, Available at:

24 Importance of Right Heart Catheterization Vast majority of PH cases are non WHO group 1 PAH characterized by PVR TPG Normal left-sided filling pressures PVH characterized by PCWP LVEDP LAP PAH PH PVH LAP- left atrial pressure; LVEDP- left ventricular end diastolic pressure; PCWP- pulmonary capillary wedge pressure; PVH- pulmonary venous hypertension; PVR- pulmonary vascular resistance; TPG- transpulmonary pressure gradient; WHO- World Health Organization.

25 Treatment of Pulmonary Arterial Hypertension

26 PAH Disease Pathways Copyright [2004] Massachusetts Medical Society. All rights reserved. camp- cyclic adenosine monophosphate; cgmp- cyclic guanosine monophosphate. Figure reproduced from Humbert et al. N Engl J Med. 2004;351: With permission.

27 Vasoactive Mediators Involved In PAH ABNORMALITIES Nitric oxide deficiency Prostacyclin deficiency Endothelin overexpression THERAPIES PDE-5 inhibitors Block the activity of PDE-5, restoring vasodilation through an increase in cgmp1 Prostanoids Supplement the deficiency in PGI2, resulting in vasodilation and inhibition of platelet aggregation2 ERAs Block the binding of ET-1 to its receptors, preventing vasoconstrictor effects of ET-13 cgmp- cyclic guanosine monophosphate; ERA- endothelin receptor antagonist; ET-1- endothelin; PDE-5- phosphodiesterase type 5; PGI2- 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:

28 Important Determinants of Prognosis Determinants of risk Clinical evidence of RV failure Lower risk (good prognosis) Higher risk (bad prognosis) Progression Gradual Rapid WHO functional class II, III IV No 6MWD Longer (>400 m) Shorter (<300 m) CPET Peak VO 2 >10.4 ml/kg/min Peak VO 2 <10.4 ml/kg/min Yes Echocardiographic findings Minimal RV dysfunction Pericardial effusion, significant RV enlargement/dysfunction, right atrial enlargement Hemodynamics BNP- B-type natriuretic peptide; CI- cardiac index; CPET- cardiopulmonary exercise test; 6MWD- 6-minute walk distance; RAP- right atrial pressure; RV- right ventricular; VO 2 - volume f oxygen consumption; WHO- World Health Organization. McLaughlin et al. J Am Coll Cardiol. 2009;53: RAP <10 mm Hg CI >2.5 L/min/m 2 RAP >20 mm Hg CI <2.0 L/min/m 2 BNP Minimally elevated Significantly elevated