Greg Calligaro Definition and classification of pulmonary hypertension

Definition andclassification ofpulmonary hypertensionGreg CalligaroDivision of PulmonologyGroote Schuur HospitalUCT Lung Institute

Pulmonaryhypertension

Haemodynamic definition of pulmonaryhypertensionPHMean PAP ≥25 mmHg (rest)• As assessed by right heart catheterisation (RHC)• Value used in registries and RCTs• Normal mPAP 14±3mmHg (ULN 20mmHg)• Definition of mPAP>30mmHg on exercise hasbeen dropped• ACCP/AHA also include a PVR > 3 Wood unitsBadesch et al. JACC, 2009.

Haemodynamic definition of pulmonaryhypertensionPHMean PAP ≥25 mm HgPre-capPHPost-capPHMean PAP ≥25 mm Hg plusPCWP/LVEDP ≤15 mm HgMean PAP ≥25 mm Hg plusPCWP/LVEDP >15 mm HgBadesch D et al. J Am Coll Cardiol. 2009;54:S55-S66.McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.Badesch et al. JACC, 2009.Halpern SD, et. al. Chest, 2009.

PH: importance of PCWP• Identifies patients with PH due to leftheart disease• An accurate PCWP can be difficultto obtain in patients with PH andenlarged pulmonary arteries• Patients with PCWP ≥ 15mmHgshould have their LVEDP directlymeasured by left heartcatheterisation (LHC)• A recent retrospective study ofsubjects undergoing both RHC andLHC showed that 5% of patientswith elevated PCWP had normalLVEDPHalpern SD, et. al. Chest, 2009.

Classification of PH• Evolution of the classification of PH:– Pre-capillary vs. post-capillary- “Primary” vs. “secondary”– WHO classification:groups with similar natural histories,pathologies and treatments

WHO Group 1 PAH1. PAH•Idiopathic PAH•Heritable•Drug- and toxin-induced•Associated with:−CTD−HIV infection−portal hypertension−CHD−schistosomiasis−chronic hemolytic anemia• Persistent PH of newborn• Consists of IPAH, heritablePAH (BMPR2 and ALK1genes)• Drugs and toxin-inducedPAH:– Definite: aminorex,fenfluramine, toxic rapeseedoil– Likely: amphetamines, L-tryptophan, cocaine, St.John’s Wort, SSRI’sSimonneau G et al. J Am Coll Cardiol. 2009;54;S43-S54.

Group 1: PAH associated with CT disease• Connective tissue diseases:– limited scleroderma (most common)– diffuse scleroderma– systemic lupus erythematosus– Sjogren’s syndrome– rheumatoid arthritis– MCTD• PH is an important cause of death in scleroderma (2 nd toILD); recommend yearly screening• Similar to IPAH pathology• Medical treatment same as for IPAH, but benefits lessthan for IPAHHachulla E et al. Rheumatology, 2009.

Group 1: PAH associated with HIV infection• Prevalence of 0.5-0.8%• One study found that 35% of HIV-infected patients hadPASP>30mmHg• No relationship with CD4 count or VL• Pathogenic findings: plexogenic pulmonary arteriopathyHsue et. al., AIDS, 2008Mehta et. al., Chest, 2000

HIV-associated PAH: pathogenesisStimulation ofcytokines andgrowth factors bychronic HIVinfectionTat protein:excessendothelialgrowth viaBMPR2Nef protein:potential role inplexiform lesionsStimulation ofendothelin bygp120?co-infectionwith HHV-8Marecki et. al., ARJCCM, 2006Mandell et. al., Virology, 1999

PAH related to portal hypertension• Prevalence of 2-5% by RHC: up to 17% in livertransplant candidates• Related to degree of porto-systemic shunting, notunderlying hepatocellular dysfunction• Worse mortality than IPAH alone• Liver transplant may improve survival (if mild tomoderate PH) - (28-56% 5 year survival)Budhiraja R et al. Chest. 2003.Kawut SM et al. Liver Transpl. 2005.Krowka MJ et al. Clin Chest Med. 2005.

Group 1: Congenital heart disease• Pulmonary blood volumeoverload from intracardiacshunting• Left-to-right shunts are mostcommon, especially VSDs• PAH can also occur in patientswith ASDs

PAH related to schistosomiasis• Pathogenesis originallythought to be embolic• Plexiform lesions observedin pathological studies• Portal hypertensionindependent risk factor• Egg impaction may act astrigger for:– oxidative stress– inflammation– endothelial dysfunctionRoss E et al. NEJM, 2002.

Group 1: PAH associated with haemolysis• Sickle cell disease (SCD)most important sub-group• Prevalence of PH in patientswith sickle cell diseasereported on echo studies as±30%• Much lower on RHC: ±5%• Free Hb scavenges NO –induces state of resistanceto NO bioactivity• Also associated withplexiform lesionsGladwin MT, NEJM, 2004.

Group 1’: PVOD and PCH• Ground glass opacities, septal thickening andmediastinal lymphadenopathyResten et. al, AJR, 2004.

Group 1’: PVOD and PCH• Vasodilator-induced pulmonary oedema can occur due toincreased driving pressure and post-capillary obstructionHumbert et. al., AJRCCM, 1998.Resten et. al., Radiology, 2002.

Changes to WHO Group 1 (Dana Point 2008)• “Familial” replaced by “heritable”• Classification of congenital heart disease was updated• Chronic haemolytic anaemias listed as own group under“associated PAH”• PVOD/PCH given its own group, related to group 1 (1’)• Schistosomiasis moved from embolic group (Group 4)• Rarer causes (thyroid disease, Gaucher’s etc.) moved togroup 5

Group 2: Left heart disease1. PAH• Idiopathic PAH• Heritable• Drug- and toxin-induced• Associated with:−CTD−HIV infection−portal hypertension−CHD−schistosomiasis−chronic hemolytic anemia• Persistent PH of newborn• Any cause of left atrialhypertension:– systolic or diastolicdysfunction– valvular heart disease– constrictive pericarditis– restrictive CMO– left atrial myxoma1’. PVOD and/or PCH2. PH due to Left Heart Disease• Systolic dysfunction• Diastolic dysfunction• Valvular disease

Group 2: Left heart diseaseNormalTightmitralstenosisSVCIVCRA RV PAPC MVA=4.0 cm 2PV LA LV AoFLOW6L/min5 5 20/5 20/8 (12) 6 6 6 120/6120/8Without PVDMVA=1.0 cm 25 5 45/5 45/25 (32) 25 25 25 120/5FLOW5L/minTightmitralstenosisWith PVD20 20130/20130/80 (100) 30 30 30 110/5FLOW3L/min

Group 3: Secondary to lung disease/hypoxia• PH is a commoncomplication of COPD, butis usually mild• Also mild PH with OSA;becomes significant ifcombined with OHS orother cause of hypoxaemia• ILD another importantcategory3. PH due to Lung Diseases and/or Hypoxia•COPD•ILD•Other pulmonary diseases with mixedrestrictive and obstructive pattern•Sleep-disordered breathing•Alveolar hypoventilation disorders•Chronic exposure to high altitude•Developmental abnormalitiesSimonneau G et al. J Am Coll Cardiol. 2009;54;S43-S54.

Group 3: Secondary to lung disease/hypoxia• PH is a commoncomplication of COPD, butis usually mild• Also mild PH with OSA;becomes significant ifcombined with OHS orother cause of hypoxaemia• ILD another importantcategory• Mechanism: HPV3. PH due to Lung Diseases and/or Hypoxia•COPD•ILD•Other pulmonary diseases with mixedrestrictive and obstructive pattern•Sleep-disordered breathing•Alveolar hypoventilation disorders•Chronic exposure to high altitude•Developmental abnormalitiesSimonneau G et al. J Am Coll Cardiol. 2009;54;S43-S54.

Group 4: Chronic thromboembolic PH• Occurs in 2-4% of patientfollowing acute PE• However, up to two thirdsof patients with CTEPH willhave no history of previousVTE• V/Q scanning is thediagnostic modality ofchoice3. PH due to Lung Diseases and/or Hypoxia•COPD•ILD•Other pulmonary diseases with mixedrestrictive and obstructive pattern•Sleep-disordered breathing•Alveolar hypoventilation disorders•Chronic exposure to high altitude•Developmental abnormalities4. CTEPH5. PH With Unclear Multifactorial Mechanisms•Hematologic disorders•Systemic disorders•Metabolic disorders•OthersKlok FA, et. al. Prospective screening program to detect CTEPH following PE. Haem, 2010.Dentali F, et. al. Incidence of CTEPH after first episode PE. Thromb Res, 2009.

Group 4: CTEPH• Most pulmonary emboli resolve without sequelae• A minority of patients will develop chronicthromboembolic pulmonary hypertension (CTEPH)• CTEPH is defined as a mPAP greater than 25mmHg thatpersists 6 months after an acute PE• Occurs in 2-4% of patient following acute PE• However, up to two thirds of patients with CTEPH willhave no history of previous VTEKlok FA, et. al. Prospective screening program to detect CTEPH following PE. Haem, 2010.Dentali F, et. al. Incidence of CTEPH after first episode PE. Thromb Res, 2009.

PathophysiologyPATENT VESSELS:Remodelled withplexiform lesionsOBSTRUCTEDVESSELS:Normal“downstream”histologyPiazza G et al, Chronic thromboembolic pulmonary hypertension. NEJM, 2011.Hoeper M et al, Chronic Thromboembolic Pulmonary Hypertension, Circulation 2006.

Pathophysiology• “Two compartment pulmonary vascular bed” model:– one compartment obstructed by organising thrombus,but with normal downstream vessel calibre andhistology– one compartment exposed to increased flow,increased shear stresses remodelling of smallarteries predisposition to thrombosisHigh PAP = sum of proximal PEs +distal small vessel arteriopathyHoeper M et al, Chronic Thromboembolic Pulmonary Hypertension, Circulation 2006.

Group 4: CTEPH• Surgery is the only definitive therapy for CTEPH –pulmonary thromboendarterectomy (PEA) is procedure ofchoice• Decision to proceed to PEA is based on:– accessibility of the thrombi– presence of haemodynamic ± ventilatory impairment– willingness of the patient– other comorbidities

Group 4: CTEPH

Treatment: surgery• If successful, PEA improves:- haemodynamics (meanreduction in PVR 65%)- WHO functional classimproves by 2 classes- exercise capacity (6MWD,CPET)BEFOREAFTER• Peri-operative mortality is about10%Corsico AG et al, Long term outcome after PEA. ARJCCM, 2008Matsuda H et al, Long term recovery of exercise capacity after PEA for CTEPH. Circulation, 2009.

Group 5: Unclear or multifactorial mechanisms• Heterogeneous collectionof diseases with uncertainpathogeneticmechanisms3. PH due to Lung Diseases and/or Hypoxia•COPD•ILD•Other pulmonary diseases with mixedrestrictive and obstructive pattern•Sleep-disordered breathing•Alveolar hypoventilation disorders•Chronic exposure to high altitude•Developmental abnormalities4. CTEPH5. PH With Unclear Multifactorial Mechanisms•Hematologic disorders•Systemic disorders•Metabolic disorders•Others

Group 5: Unclear or multifactorial mechanisms• Haematological disorders: myeloproliferative disorders,splenectomy• Systemic disorders: sarcoidosis, PLCH, LAM,neurofibromatosis, vasculitis• Metabolic disorders: glycogen storage disease, Gaucher’sdisease, thyroid disease• Others: tumor obstruction, fibrosing mediastinitis, CRF ondialysisSimonneau G et al. J Am Coll Cardiol. 2009.

Summary• Pulmonary hypertension is defined by a mPAP >25mmHg at rest• WHO classifies PH into 5 groups, based on aetiology,natural history, prognosis and treatment• “Pulmonary arterial hypertension” (PAH) describesgroup 1: this includes heritable, drug-induced and“associated with” aetiologies• CTEPH is important to identify; treatment could besurgical

Acknowledgements• Pulmonary Hypertension Association:www.phassociation.org