Pulmonary Arterial Hypertension: Diagnostic Algorithms and Procedures

Pulmonary Arterial Hypertension Overview

OF HE IN SCIENCES On Lumine Tuo Videbimus Lumen SAINT CAMILLUS Pulmonary Arterial Hypertension Dr. Angelo Coppola angelo.coppola@unicamillus.orgOF HE SCIENCES IN On Lumine Tuo Videbimus Lumen SAINT CAMILLUS

Definition of Pulmonary Hypertension

Definition Increased blood pressure in the pulmonary artery, veins, or capillaries Progressive disease leading to Right ventricular failure and eventual death

Right Heart Catheterization Findings

Right Heart Catheterization Findings Mean Pulmonary Arterial Pressure ≥ 25 Pulmonary Capillary Wedge Pressure ≤ 15 Pulmonary Vascular Resistance > 3 wood units (this part not included in definition)8

Haemodynamic Definitions of Pulmonary Hypertension

Characteristics and Clinical Groups

Haemodynamic definitions of pulmonary hypertension Definition Characteristics* Clinical group(s)b PH PAPm ≥25 mmHg All Pre-capillary PH PAPm ≥25 mmHg PAWP ≤15 mmHg 1. Pulmonary arterial hypertension 3. PH due to lung diseases 4. Chronic thromboembolic PH 5. PH with unclear and/or multifactorial mechanisms Post-capillary PH PAPm ≥25 mmHg PAWP >15 mmHg Isolated post-capillary PH (Ipc-PH) DPG <7 mmHg and/or PVR ≤3 WUc Combined post-capillary and pre-capillary PH (Cpc-PH) DPG ≥7 mmHg and/or PVR >3 WUc 2. PH due to left heart disease 5. PH with unclear and/or multifactorial mechanisms

Abbreviations and Notes

CO = cardiac output; DPG = diastolic pressure gradient (diastolic PAP - mean PAWP); mPAP = mean pulmonary arterial pressure; PAWP = pulmonary arterial wedge pressure; PH = pulmonary hypertension; PVR = pulmonary vascular resistance; WU = Wood units. ªAll values measured at rest; see also section 7. bAccording to Table 4. Wood Units are preferred to dynes.s.cm-5. www.escardio.org European Heart Journal 2016:37;67-119 -doi:10.1093/eurheartj/ehv317 European Respiratory Journal 2015 46: 903-975; ERS EUROPEAN RESPIRATORY SOCIETY EUROPEAN SOCIETY OF CARDIOLOGYSOF HE SCIENCES IN

Pathophysiology of Pulmonary Hypertension

Risk Factors and Associated Conditions

m Lumine Tuo Videbimus Lumen SAT IN' T CAMILL Pathophysiology 1. Risk Factors and Associated Conditions · Collagen vascular disease · Congenital heart disease · Portal hypertension · HIV infection · Drugs and toxins · Pregnancy

Susceptibility and Genetic Factors

Susceptibility · Abnormal BMPR2 gene Other genetic factors

Vascular Injury and Dysfunction

2. Vascular injury . Endothelial dysfunction Nitric oxide synthase - Prostacyclin production - 1 Thromboxane production - 1 Endothelin 1 production · Vascular smooth muscle dysfunction - Impaired voltage-gated potassium channel (Kv1.5) Adventitia Media Intima Early intimal thickening Thrombosis Plexiform lesions IRREVERSIBLE DISEASE NORMAL Smooth muscle hypertrophy Smooth muscle hypertrophy Adventitial, İntimal proliferation REVERSIBLE DISEASE

Disease Progression

3. Disease progression Loss of response to short- acting vasodilator trial MedscapeOF HE SCIENCES IN

Disease Pathways in Pulmonary Hypertension

Prostacyclin Pathway

On Lumine Tuo Videbimus Lumen SAINT CAMILLUS Disease Pathways Prostacyclin pathway Endothelial cells Arachidonic acid + Prostaglandin 12 Pre-piroendothelin -> Proendothelin L-arginine - Endothelin receptor A 1 Prostacyclin (prostaglandin 12) Endothelin-1 Nitric oxide 4 1 CAMP Prostacyclin derivatives Endothelin- receptor antagonists Endothelin receptor # Vasoconstriction and proliferation Phosphodiesterase type S Vasodilatation and antiproliferation Smooth muscle cells Phosphodiesterase type 5 inhibitor Exogenous nitric oxide CGMP Vasodilatation and antiproliferation

Endothelin Pathway

Endothelin pathway Vessel lumen

Nitric Oxide Pathway

Nitric oxide pathwayOF HE SCIENCES IN

Classification of Pulmonary Hypertension Causes

Group 1: Pulmonary Arterial Hypertension

On Lumine Tuo Videbimus Lumen SAINT VT CAMILL Classification of Causes Group 1 Idiopathic & Heritable Autoimmune disease/ Connective Tissue disease HIV Drugs and toxins Portal Hypertension Congenital Heart Disease Schistosomiasis

Group 2: Left Heart Disease

Group 2 (Left heart disease)

Group 3: Lung Disease

Group 3 (lung disease) COPD Interstitial Lung disease OSA

Group 4: Chronic Thromboembolic Disease

Group 4 Chronic Thromboembolic Disease (chronic pulmonary emboli)

Group 5: Miscellaneous Causes

Group 5 (Miscellaneous)9

Comprehensive Clinical Classification of Pulmonary Hypertension

Group 1: Pulmonary Arterial Hypertension Subtypes

Comprehensive clinical classification of pulmonary hypertension 1. Pulmonary arterial hypertension 1.1 Idiopathic 1.2 Heritable 1.2.1 BMPR2 mutation 1.2.2 Other mutations 1.3 Drugs and toxins induced 1.4 Associated with: 1.4.1 Connective tissue disease 1.4.2 human immunodeficiency virus (HIV) infection 1.4.3 Portal hypertension 1.4.4 Congenital heart disease (Table 5) 1.4.5 Schistosomiasis 1'. Pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis 1'.1 Idiopathic 1'.2 Heritable 1'.2.1 EIF2AK4 mutation 1'.2.2 Other mutations 1'.3 Drugs, toxins and radiation induced 1'.4 Associated with: 1'.4.1 Connective tissue disease 1'.4.1 HIV infection 1". Persistent pulmonary hypertension of the newborn

Group 2: Left Heart Disease Causes

2. Pulmonary hypertension due to left heart disease 2.1 Left ventricular systolic dysfunction 2.2 Left ventricular diastolic dysfunction 2.3 Valvular disease 2.4 Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies 2.5 Congenital/acquired pulmonary veins stenosis

Group 3: Lung Diseases and Hypoxia Causes

3. Pulmonary hypertension due to lung diseases and/or hypoxia 3.1 Chronic obstructive pulmonary disease 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 (Web Table III)

Group 4: Chronic Thromboembolic Pulmonary Hypertension

4. Chronic thromboembolic pulmonary hypertension and other pulmonary artery obstructions 4.1 Chronic thromboembolic pulmonary hypertension 4.2 Other pulmonary artery obstructions 4.2.1 Angiosarcoma 4.2.2 Other intravascular tumors 4.2.3 Arteritis 4.2.4 Congenital pulmonary arteries stenoses 4.2.5 Parasites (hydatidosis)

Group 5: Unclear and Multifactorial Mechanisms

5. Pulmonary hypertension with unclear and/or multifactorial mechanisms 5.1 Haematological disorders: chronic haemolytic anaemia, myeloproliferative disorders, splenectomy 5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis 5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders 5.4 Others: pulmonary tumoral thrombothic microangiopathy, fibrosing mediastinitis, chronic renal failure (with/without dialysis), segmental pulmonary hypertension ERS EUROPEAN RESPIRATORY SOCIETY www.escardio.org European Heart Journal 2016:37;67-119 -doi:10.1093/eurheartj/ehv317 European Respiratory Journal 2015 46: 903-975; EUROPEAN SOCIETY OF CARDIOLOGYS10

Clinical Classification of Pulmonary Arterial Hypertension Associated with Congenital Heart Disease

Eisenmenger's Syndrome

Clinical classification of pulmonary arterial hypertension associated with congenital heart disease 1. Eisenmenger's syndrome Includes all large intra- and extra-cardiac defects which begin as systemic-to-pulmonary shunts and progress with time to severe elevation of PVR and to reversal (pulmonary-to- systemic) or bidirectional shunting; cyanosis, secondary erythrocytosis, and multiple organ involvement are usually present.

PAH with Prevalent Systemic-to-Pulmonary Shunts

2. PAH associated with prevalent systemic-to-pulmonary shunts · Correctableª · Non-correctable Includes moderate to large defects; PVR is mildly to moderately increased, systemic-to- pulmonary shunting is still prevalent, whereas cyanosis at rest is not a feature.

PAH with Small/Coincidental Defects

3. PAH with small/coincidentalb defects Marked elevation in PVR in the presence of small cardiac defects (usually ventricular septal defects <1 cm and atrial septal defects <2 cm of effective diameter assessed by echo), which themselves do not account for the development of elevated PVR; the clinical picture is very similar to idiopathic PAH. Closing the defects is contra-indicated.

PAH After Defect Correction

4. PAH after defect correction Congenital heart disease is repaired, but PAH either persists immediately after correction or recurs/develops months or years after correction in the absence of significant postoperative haemodynamic lesions. PAH = pulmonary arterial hypertension; PVR = pulmonary vascular resistance. ªWith surgery or intravascular percutaneous procedure. "The size applies to adult patients. However, also in adults the simple diameter may be not sufficient for defining the haemodynamic relevance of the defect, and also the pressure gradient, the shunt size and direction, & the pulmonary to systemic flows ratio should be considered (Web Table II on the web at; www.escardio.org/guidelines). www.escardio.org European Heart Journal 2016:37;67-119 -doi:10.1093/eurheartj/ehv317 European Respiratory Journal 2015 46: 903-975; ERS EUROPEAN RESPIRATORY SOCIETY EUROPEAN SOCIETY OF CARDIOLOGYSOF HE IN

Pulmonary Hypertension Groups and Mechanisms

Group 1: Pulmonary Arterial Hypertension (PAH)

On Lumine Tuo Videbimus Lumen SAINT CAMILLUS GROUP 1: Pulmonary Arterial Hypertension (PAH) · Idiopathic PAH · Heritable PAH: BMPR2, ALK-1, ENG, SMAD9, CAV1, KCNK3, Unknown . Drug- and toxin-induced · Associated with: CTD, HIV infection, Portal HTN, CHD, Schistosomiasis · 1. Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis . 1". Persistent PH of the newborn (PPHN)

Group 5: PH With Unclear or Multifactorial Mechanisms

GROUP 5: PH With Unclear or Multifactorial Mechanisms · Hematologic disorders · Systemic disorders · Metabolic disorders · Other disorders

Pulmonary Hypertension Overview

Pulmonary Hypertension

Group 4: Chronic Thromboembolic PH (CTEPH)

GROUP 4: Chronic Thromboembolic PH (CTEPH) · Thromboembolic obstruction of the pulmonary arteries

Group 2: PH Due to Left Heart Disease

GROUP 2: PH Due to Left Heart Disease . LV Systolic dysfunction · LV Diastolic dysfunction · Valvular disease · Congenital/acquired left heart inflow/outflow tract obstruction · Congenital cardiomyopathies

Group 3: PH Due to Lung Diseases and/or Hypoxia

GROUP 3: PH Due to Lung Diseases and/or Hypoxia · Chronic obstructive pulmonary disease . Interstitial lung disease . Other pulmonary diseases with mixed restrictive and obstructive pattern · Sleep-disordered breathing . Alveolar hypoventilation disorders · Chronic exposure to high altitude . Developmental lung abnormalities SCIENCES40

Examples of Key Factors Suggestive of Group 2 Pulmonary Hypertension

Clinical Presentation

Examples of key factors suggestive of Group 2 pulmonary hypertension Clinical presentation Echocardiography Other features Age >65 years

Echocardiography Findings

Structural left heart abnormality · Disease of left heart valves · LA enlargement (>4.2 cm) · Bowing of the IAS to the right LV dysfunction · Concentric LV hypertrophy and/or increased LV mass

ECG Findings

ECG . LVH and/or LAH · AF/Afib · LBBB · Presence of Q waves

Symptoms and Doppler Indices

Symptoms of left heart failure Doppler indices of increased filling pressures · Increased E/e' · >Type 2-3 mitral flow abnormality

Other Imaging and Metabolic Features

Other imaging · Kerley B lines · Pleural effusion · Pulmonary oedema · LA enlargement Features of metabolic syndrome

Absence of Specific Findings

Absence of: · RV dysfunction · Mid systolic notching of the PA flow · Pericardial effusion

History of Heart Disease

History of heart disease (past or current) Persistent atrial fibrillation AF = atrial flutter; Afib = atrial fibrillation; ECG = electrocardiogram; IAS = inter-atrial septum; LA = left atrium; LAH = left anterior hemiblock; LBBB= left bundle branch block; LV = left ventricle; LVH = left ventricular hypertrophy; PA = pulmonary artery; RV = right ventricle. www.escardio.org European Heart Journal 2016:37;67-119 -doi:10.1093/eurheartj/ehv317 European Respiratory Journal 2015 46: 903-975; ERS EUROPEAN RESPIRATORY SOCIETY EUROPEAN SOCIETY OF CARDIOLOGYS