2014 IAP - Long Course Pulmonary Hypertension Anja C. Roden, M.D. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA Outline • Definition • Classification of PHT • Discussion of phenotypes of PHT Definition & Diagnosis • Mean pulm arterial pressure ≥ 25 mmHg - Right heart catheter (gold standard) - Echocardiogram (screening but suboptimal) • Most patients diagnosed clinically • Surgical bx in patients with atypical presentation Presentation & Treatment • Often non-specific, dyspnea • RV function impairment & overload: Exercise intolerance, fatigue, palpitations, chest pain • RV failure: Edema, ascites 5th World Symposium – 2013 Current Classification 1. Pulmonary arterial hypertension (PAH) 1’ PVOD and/or PCH 1’’ Persistent PHT of the newborn 2. PHT due to left heart disease 3. PHT due to lung diseases and/or hypoxia 4. Chronic thromboembolic PHT 5. PHT with unclear multifactorial mechanisms Simonneau G et al. 2013. J Am Coll Cardiol. 62. D34-41. Group 1 - PAH - Subclassification 1. Idiopathic 2. Heritable (Familial) 3. Drug and Toxin induced 4. Associated with - Connective tissue disease - HIV infection - Portal hypertension - Congenital heart disease - Schistosomiasis Simonneau G et al. 2013. J Am Coll Cardiol. 62. D34-41. Group 1 - PAH – Medial Hypertrophy Normal Elastic Stain PAH Group 1 - PAH - Intimal Remodel Obliteration / Fibrosis Elastic Group 1 - PAH - Intimal Remodel Plexiform Lesion Elastic Group 1 – Heritable PAH • 80% - Mutations in BMPR2 (TGFβ superfamily) • 5% - Mutations in other genes in TGFβ superfamily (ALK1, ENG, Smad 9) • 20% - No detectable mutation • Recently discovered mutations: CAV1, KCNK3 Simonneau G et al. 2013. J Am Coll Cardiol. 62. D34-41. Group 1 – Drug/Toxin-Induced PAH • 1967 – nearly 60% of patients with PAH took Aminorex (W. Germany, Austria, Switzerland) • Usually <1% of patients exposed to drugs • Risk factors - categorized by strength of evidence: Definitely Likely Possible Unlikely Group 1 – Drug/Toxin-Induced PAH Definite Aminorex Fenfluramine Dexfenfluramine Toxic rapeseed oil Benfluorex SSRI Likely Amphetamines L-Tryptophan Methamphetamines Dasatinib Simonneau G et al. 2013. J Am Coll Cardiol. 62. D34-41. Group 1 – Schistosomiasis • Potentially most prevalent cause of PAH worldwide • >200 mio people have schistosomiasis • 10% of patients with schisto develop hepatosplenic schistosomiasis – PAH almost exclusively in this population • Mortality may reach 15% at 3 yrs Group 1’ – Pulmonary Veno-Occlusive Disease (PVOD) • Usually young, mean 30 y.o. (wide range). • Males > females • Incidence: 0.1-0.2 cases/Mio persons/year • Often begins with influenza-like illness. • Survival: Months - few years • Therapy: Lung/heart-lung transplantation Group 1’ - PVOD - Etiology • Idiopathic (usually) • BM transplantation (toxic myeloablative drugs - carmustine, etoposide). • Bleomycin, radiation • Immune-mediated? (Patients with SLE, scleroderma, syst. sclerosis, HIV, RA etc.) • Viral? (some had recent viral illness) • Familial (BMPR2) Group 1 - PVOD Interstitial Thickening Group 1 - PVOD Congested / Proliferating Capillaries Group 1 - PVOD Hemosiderosis Group 1 - PVOD Venous Changes Elastic Group 1 - PVOD Endogenous Pneumoconiosis Iron Group 1 - PVOD Arterial Changes (Elastic Stain) Group 1’- PVOD - Histology • Might be misclassified as idiopathic PAH Hemosiderosis and capillary congestion/ proliferation and/or signs of PAH → Suspect PVOD Differences in treatment! • Maybe reminiscent of PH-LHD → History, clinical findings (PCWP) Group 1’’ – Persistent PH of Newborn • Life threatening • Up to 2/1000 live-born infants • Association with SSRI intake during pregnancy debated (no - 6 fold risk) • Study on 30,000 women with SSRI during pregnancy: SSRI intake in late pregnancy increased risk of PPH by 2-fold → SSRI - risk factor Kieler H et al. 2012. BMJ. 344.D8012. Group 2 - PH 2nd to LH Disease (PH-LHD) • mPAP ≥ 25 mmHg; • PCWP > 15 mm Hg • Normal or reduced cardiac output • Older, female, systemic HTN, features of metabolic syndrome (↔ PAH) • Prevalence unknown but seems most common cause of PH in US Group 2 - PH-LHD - Etiologies Elevated left-sided cardiac filling pressures due to: • LV systolic or diastolic dysfunction • Left-sided valvular or myocardial diseases • Congenital/acquired LH inflow/outflow tract obstruction, congenital cardiomyopathies Group 2 - PH-LHD - Histology Interstitial Thickening / Lymphatic Dilatation Group 2 - PH-LHD - Histology Capillary Congestion / Hemosiderosis Group 2 - PH-LHD - Histology Venous & Arterial / Arteriolar Changes PVOD vs LHD vs Healthy Morphometric Pilot Study • Mean intimal thickening in small vessels: LHD, PVOD > healthy • Mean intimal thickening in PAs and PVs: PVOD > LHD, healthy. • Mean medial thickening of PAs: PVOD > LHD, healthy. • Mean adventitial thickening of PVs: PVOD > LHD Maleszewski et al. 2014. Arch Pathol Lab Med. 138:S704 Group 4 – Chronic Thromboembolic PH (CTEPH) • Prevalence 2 yrs after acute PE: 0.1-8.0% • 25-63% of CTEPH - no history of acute PE • Thrombotic blood emboli (most common), fat, amniotic fluid, talc, in-situ PA thrombosis • 50–70% of pulmonary vascular bed damage necessary for CTEPH • Med. survival <2 years if mPAP >30 mmHg • RH failure = most common cause of death Group 4 – CTEPH – Risk Factors • Antiphospholipid antibodies • Myeloproliferative disorders • Splenectomy • Inflammatory bowel disease • Chronic osteomyelitis • Iatrogenic: permanent central lines, pacemakers, ventriculoarterial shunts • Non-O blood group Hoeper MM. Lancet Respir Med 2014. 2:573-82. Group 4 – CTEPH – Risk Factors • Malignancy • Thyroid replacement • Genetic susceptibility? (↑ fibrinogen AαThr312Ala polymorphism in CTEPH vs controls. Polymorphism can modify fibrin structure in clots.) Group 4 – CTEPH Infarcts Group 4 – CTEPH Luminal Webs - Diagnostic Elastic PA Br Group 5 - Unclear Multifactorial • Hematologic (chronic hemolytic anemia, MPD, splenectomy) • Sarcoidosis, PLCH, LAM • Metabolic (glycogen storage, Gaucher, thyroid) • Restricted venous outflow from lung (e.g. sclerosing mediastinitis, adenopathy, mediastinal tumors, chronic renal failure) Histologic Findings in PH Idiopathic PVOD PAH PH-LHD CTEPH PAs + +/- +/- + Caps - + + - PVs - + + - Hemosiderosis Webs Recanal. thrombi Add. Finds - Hemosiderosis Phenotypes of PHT • Current classification: 5 groups • More phenotypes exist • Genetic, pathobiologic, hemodynamic, clinical aspects of phenotypes → individualized medical care • If phenotypes can predict outcome - useful to determine prognosis and guide therapy • ↑ Homogeneity of study cohorts for research Dweik RA et al. 2014. Am. J Resp Crit Care Med. 189 (3):345-55 Phenotypes Proposed by ATS • • • • • • • • • • Mixed pre- and postcapillary PH “Severe PH” in respiratory disease Maladaptive RV hypertrophy Connective tissue disease-associated PH Portopulmonary hypertension HIV-associated PAH PH in elderly individuals PAH in children Metabolic syndrome Long term survivors Dweik RA et al. 2014. Am. J Resp Crit Care Med. 189 (3):345-55 Summary • Classification – 5th World Symposium 5 groups share hemodynamic, histologic, management characteristics • Be aware of possible arterial changes in PVOD and PH-LHD – watch for hemosiderosis and venous changes • PH phenotyping – important for individualized medicine
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