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Pulmonary Hypertension: Beyond WHO Group 1Michael Kwan, MD
San Antonio Advanced Lung SymposiumDecember 7, 2019 1
2 0 1 9 S A N A N T O N I O A D V A N C E D L U N G S Y M P O S I U M
Pulmonary Hypertension:Beyond WHO Group 1Michael D. Kwan, MD, FACCProgram Director
Advanced Heart Failure and Cardiac Transplant Program
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Disclosure
No relationships to disclose
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Case Presentation
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66 y/o AAM
• PMH: HTN, HLP, DMII, sleep apnea, BPH• 2010: aflutter, s/p ablation• 2010‐2016: afib, aflutter, VT• 2015: recurrent bronchitis
• Bronchoscopy ‐> sarcoidosis
• Steroids: Feb 2015, Jan 2016
• 2017: PET scan negative• 2018: BAL and bronchial biopsy negative
• MEDS: torsemide 10 bid, dig 0.125 qD, rivaroxiban 20 qD, metformin 500mg bid, atorvastatin 20mg qHS, tamsulosin 0.4 mg qD
• 2019: recurrent pulmonary sarcoidosis by PET• Started on leflunomide• Worsening fatigue, dyspnea
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• Echocardiogram (OSH):• Normal LV size, mild‐mod LVH, EF 50‐55%, normal diastolic function
• RV size was dilated, systolic function reduced
• PA pressure 25
• Bubble study negative
• CPEX:• 5 min 33 sec exercise time
• RER 1.25
• VO2max 12.1 ml/k/m (49% predicted)
• O2 pulse 11.5 ml/beat (62% predicted)
• VE/VCO2 slope 42
• VD/VT decreased from 37% to 20%
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Pulmonary Hypertension: Beyond WHO Group 1Michael Kwan, MD
San Antonio Advanced Lung SymposiumDecember 7, 2019 2
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• Invasive hemodynamics:• RA 13/16, mean 11
• RV 25/9
• PA 25/10, mean 16
• PCW 13/14, mean 11
• PA sat 51%, CO/CI 3.1/1.53
• SVR 1442, PVR 1.61, TPG 5, DPG 4
• RVSWI 101.8, PAPi 1.36
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Pulmonary Hypertension: Beyond WHO Group 1Michael Kwan, MD
San Antonio Advanced Lung SymposiumDecember 7, 2019 3
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Pulmonary Hypertension
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Physiology
• Pulmonary circuit low pressure, low resistance, high distensibility
• RV very sensitive to changes in afterload• Failure may occur w/PA pressures < 50
• In animal models, acute increases in PAs > 60 resulted in hemodynamic collapse
Eur Resp J;2016:47:1526
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Pathophysiology
• Swelling of the pulmonary capillary endothelial cells
• Thickening of the basal lamina
• Proliferation of reticular and elastic fibrils
• Increased PVR• Decreased permeability of the vascular bed• Hence, less likely to have edema
Cont Cardiol Edu; 2018;4(1):4
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Diagnosis: clinical
• Signs and symptoms• Fatigue
• Breathlessness
• Dypnea on exertion
• Lung volumes relatively preserved
• DLCO decreases relatively late
• Physical exam• RV heave
• Prominent P2
• TR murmur
• Crackles rare
• Clubbing
• Raynaud’s
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Eur Resp J 2015;46:912
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Pulmonary Hypertension: Beyond WHO Group 1Michael Kwan, MD
San Antonio Advanced Lung SymposiumDecember 7, 2019 4
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Diagnosis: echocardiography
• Echocardiography• E/A ratio
• E/E’
• Neuman Int J Cardiol 2008;127:174‐178• Normal diastolic function: mPA31.1+6
• Grade 1 (impaired relaxation): 35.6+10.2
• Grade 2 (pseudonormal): 38.9+10.6
• Grade 3 (restrictive): 55.1+11.4• RV failure
Eur Resp J Dec 2018
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PAH – or RV failure?
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Diagnosis: invasive hemodynamics
• Invasive hemodynamics• Vasodilator challenge
• > 10 mmHg drop in mean
• mPAP < 40
• DPD > 7• Defines pre‐ and post‐capillary PH
• Increase or no change in CO
• Fewer than 10% will be responsive to vasodilators
• Mild: mPA 35‐45
• Moderate: mPA 46‐60
• Severe: mPA > 60
• Predictors of RV dysfunction• RVAD post‐LVAD
• > 14d inotropic therapy post‐LVAD
• RVSWI < 300• [(mPA – RA) x SV]/BMI
• PAPi < 2• (PA systolic – PA diastolic)/RA
• Sensitivity 74%, specificity 67%
Cath and CV Interv 2012;80:593‐600JHLT Jan 2016;35(1):67‐73
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Diagnosis: invasive hemodynamics
Eur Resp J. Jan 2019;53(4):180193 Eur Resp Jour;2018:5
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Acta Physiol Jun 2014;211:315
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Pulmonary Hypertension: Beyond WHO Group 1Michael Kwan, MD
San Antonio Advanced Lung SymposiumDecember 7, 2019 5
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J Card Failure 2010:16(6):465
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6th World Symposium on Pulmonary HTNNice, France Jan 2018• Hemodynamics: changed from mPAP >25 to mPAP > 20
• Systemic sclerosis w/poor prognosis mPAP 21‐24
• and PVR > 3 for all forms PH• Previously just used for WHO Group 1
• “Combined pre‐ and post‐capillary PH (CpcPH)
• Declined to identify useful definition for “exercise PH”• Defined as exercise mPAP > 30 in 2004, but removed in 2008• Still no good way to distinguish physiologic from pathologic
• Added “PAH long‐term responders to CCB” to WHO Group 1• 12.5% acute responders, 6.8% long‐term
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Cont Cardiol Edu; 2018;4(1)6
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WHO Classification (etiologies)
Eur Resp J 53;2019:1801913
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Eur Resp Jour;2018:6
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Treatment: targets of intervention
Acta Physiol Jun 2014;211:318
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Pulmonary Hypertension: Beyond WHO Group 1Michael Kwan, MD
San Antonio Advanced Lung SymposiumDecember 7, 2019 6
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Risk stratification
Chest 2012;141(2):356, 359
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• AMBITION NEJM 2015;373(9):834‐44• 610 pts, 120 centers, 14 countries• Treatment naïve, or < 14 d• 2:1:1 ambrisentan+tadalafil, ambrisentan+placebo, tadalafil+placebo
• Primary: time to clinical failure• Secondary: change in NTproBNP, 6MW, WHO class, Borg dyspnea index
• 54.4 yrs, 78% women, 69% WHO class III, mPA 48.7 mmHg, mean 6MW 352.6m
• Mean f/u 517d
• 18% v. 34% v. 28%, HR 0.50 (p<0.001)
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• GRIPHON NEJM Dec 2018;373(26):2522‐33
• 1152 pts
• Primary: death or complication of PH
• Secondary: 6MW, absence worsening WHO class, death, hospfor PH, death from any cause, change in NTproBNP
• Avg f/u 70.77 wks (active tx)
• 27% v. 41.6%, HR 0.60, p<0.001
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• Coglan. Am J Cardiovasc Drugs 2018;18:37‐47• Post‐hoc analysis• 376/1156 (32.5%) were on background ERA and PDE5i
• 255/376 WHO class III symptoms
• HR 0.63, CI 0.44‐0.90• 81% events due to PAH ADM and disease progression
• Increased difference from WHO class II (HR 0.36) v. WHO class III (HR 0.67, CI 0.45‐1.01)
• 16.8% v 17.3% all‐cause death (HR 1.06, CI 0.65‐1.73)
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WHO Group 2
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WHO Group 2
• Secondary to left heart disease
• Early, secondary to passive congestion from elevated left‐sided filling pressures
• Late• Endothelial damage
• Excessive vasoconstriction
• Structural changes to pulmonary vasculature
• Vasodilatory therapies notrecommended• Unloading of the LV would be required to avoid worsening pulmonary congestion
• Causes:• Systolic dysfunction
• Diastolic dysfunction
• Valvular heart disease
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Pulmonary Hypertension: Beyond WHO Group 1Michael Kwan, MD
San Antonio Advanced Lung SymposiumDecember 7, 2019 7
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• “…there is no specific therapy for the pulmonary component of PH due to LHF, other than optimizing the function of the left heart.” Galie et al 2009
• Small studies • Sildenafil (LHF, LHF + PH, VAD + PH), but plateau after 3 mos
• ETAs worsened outcomes in LHF w/o PH (REACH‐1)
• Epoprostenol increased mortality in LHF w/o PH (FIRST)
• sGC stimulators improve hemodynamics in LHF w/PH• However, recent Phase III trial of praliciguat terminated early
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• 2 components:• Hydrostatic – directly related to PCW• Less related to systolic than diastolic function
• Vasoreactive – responsible for remodeling• Neurohormonal changes (adrenergic stimulation, endothelin activation, renin‐angiotensin‐aldosterone activation) all contribute
J Card Failure 2010;16(6):462
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Cont Cardiol Edu; 2018;4(1)7 Eur Resp Jour;2018:4
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• PH pts w/higher HR, RAP, PCW• Lower CO and SV
• Worse diastolic dysfunction
• More MR
• More RV dysfunction
• Mixed PH w/highest PA, PVR, TPG• Lower PCW, CO, SV
Miller. JACC HF 2013:1(4):296
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• “Comparative epidemiologic data on the prevalence of the different PH categories are lacking, but realistically LHD represents the most common cause of PH in high‐income countries, including both LHD with a preserved ejection fraction and LHD with a reduced ejection fraction”Pagnamenta. Resp 2018
Gorlin. NEJM 1977;296(4):204
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• Higher incidence of metabolic syndrome
• Associated w/poor prognosis and higher mortatliy• Those w/TR > 2.5 m/s had 40% higher mortality, 50% higher HF admissions than normal
• CRT patients with elevated PA pressures have higher mortality, HF admission, or transplantation• Independent positive prognostic marker was decrease in PA pressures post‐CRT
• 1 of the most important hemodynamic indicators of death in 4.4 yrs of f/u
• 9% increase in mortality for every 5 mmHg increase in RV systolic pressure
Abramson. Ann Intern Med 1992:116:888‐95Shalaby. Am J Cardiol 2008;101:238‐41Cappola. Circ 2002;105:1663‐68Kjaergaard. Am J Cardiol 2007;99:1146‐50
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Pulmonary Hypertension: Beyond WHO Group 1Michael Kwan, MD
San Antonio Advanced Lung SymposiumDecember 7, 2019 8
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• Higher mortality after cardiac transplantation• Responsible for up to 20% of early deaths post‐transplant
• PVR > 2.5 Woods units (present in about 30%)• 2.5 fold increase in 3 mo mortatliy
• Increased in 3, 6, 12 month mortatlity if TPG > 15
• 5.6% 1 yr mortality, v 24.4%
• Relative contraindication to transplantation• PVR > 5 WU, PVRI > 6, TPG > 16‐20, PA > 60 (with another + criteria)
• “The determination of TPG in combination with PVR is a more reliable predictor of posttransplant survival than PVR alone.” Guglin. J Cardiac Failure 2010;16(6):464
• 80% normalize PA pressures 1 year post‐transplant
Erickson. J Heart Transplant 1990;9:526‐37Chen. J Thorac Cardiovasc Surg 1997;114:627Delgado.J Heart Lung Transplant 2001;20:942‐8
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Treatment
• PDE5i• Sildenafil acutely reduces resting and exercise PA pressures, SVR, and PVR
• Increases resting and exercise CI via selective pulmonary vasodilation
• Enhanced and prolonged hemodynamic effects of inhaled NO
• Prostaglandins• PGI2 (epoprostenol): systemic
• PGE1: degraded in pulm vessels
• Flolan International Randomized Survival Trial (epoprostenol in HFrEF) prematurely stopped
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Treatment• ET inhibition
• Use in heart failure trials disappointing • Endothelin A Receptor Antatgoist Trial in Heart Failure (EARTH)
• No improvement in remodeling, symptoms, or outcomes
• Endothelin Anatagonist Bosentan for Lowering Cardiac Events in HF (ENABLE) increased HF hospitalizations
• Value of Endothelin Receptor Inhibition with Tezosentan in AHF (VERITAS) neither improved dyspnea nor reduced death or worsening HF
• Inhaled nitric oxide• Frostell described doses up to 80 ppm did not decrease systemic BPs (1991)
• Most pronounced effect @ 20 ppm
• Inotropes• PDE3i: increase contractility, CO, ensous and pulmonary vasodilataion
• Decrease R and L heart filling pressures
• LVAD
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J Card Failure 2010:16(6):465
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• 120 pts w/post‐capillary PH• Tx’d w/inotropes x 1 wk prior to progression to LVAD• mPAP > 25, PVR > 2.5 WU, TPG > 12
• 39.2% ischemic, 22.5% prior surgery, 81.7% NYHA III or IV
• 63/120 listed
• 40/63 transplanted• 458+242d
• Mortality higher if not reversible w/inotropes pre‐LVAD (12.5% v. 0%)• PVR and TPG correlated, mPAP did not
• Devices used• Incor (64/120)Berlin Heart (17/120)
• HeartMate II (14/120)
• Novacor (9/120)
• Debackey (9/120)
• DuraHeart (4/120)
• Jarvik 2000 (2/120)
• Ventriassist (1/120)
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Pulmonary Hypertension: Beyond WHO Group 1Michael Kwan, MD
San Antonio Advanced Lung SymposiumDecember 7, 2019 9
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Eur J CT Surg. 2011:39:313
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Acta Physiol Jun 2014;211:318,319
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“Simple” algorhythm for RVAD post‐LVAD
JHLT 2012;31(2):144
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• Invasive hemodynamics:• RA 13/16, mean 11
• RV 25/9
• PA 25/10, mean 16
• PCW 13/14, mean 11
• PA sat 51%, CO/CI 3.1/1.53
• SVR 1442, PVR 1.61, TPG 5, DPG 4
• RVSWI 101.8, PAPi 1.36
• RV failure
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• Kang JHLT Jan 2016;35(1):67‐73• 9/83 pts (11%) b/n 2010‐2013 had RV failure after LVAD • CVP > 18, CI < 2, PCW < 18
• RVAD implantation w/i 30d of LVAD
• > 1 wk NO or inotropic therapy
• Early RVAD w/worse INTERMACS profile, higher BUN, higher mRA, lower PAPi, higher CVP/PCW ratio• No difference in mPA, RV sys, RVEDP, PVR, CO/CI, PCW
• PAPi < 2.0 in 74%, no RVAD if > 3.1
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Pulmonary venoocclusive disease (PVOD)
• 3‐12% of all “PAH”• Incidence of 0.1 – 0.2/million
• Obliteration of small pulmonary veins• Fibrous intimal thickening• Patchy capillary proliferation
• Initially loose and edematous, eventually becomes sclerotic and fibrous
• May be variant of pulmonary capillary hemangiomatosis• Both related to EIF2AK4 gene mutation
• 11.8 mo mean from Dx to death or transplant
https://emedicine.medscape.com/
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Pulmonary Hypertension: Beyond WHO Group 1Michael Kwan, MD
San Antonio Advanced Lung SymposiumDecember 7, 2019 10
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PVOD• Risk factors
• Hematopoetic and stem cell transplant• Likely due to alkylating agents
• Mitomycin‐C, 5‐FU
• Organic solvents (tircholroethylene)• Especially with tobacco exposure
• Up to 2/3 of those w/systemic sclerosis
Eur Resp J 47;2016:1521
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PVOD• Rapidly progressive
• Typically resistant to PAH therapies• Death w/i 2 yrs• Alveolar hemorrhage
• Pulmonary edema
• HRCT findings• Mediastinal LAN• Smooth thickening iof the interlobular septa
• Centrilobular ground‐glass opacities
• BAL may show alveolar hemorrhage, hemosiderin‐laden macrophages• Biopsy contraindicated due to high risk bleeding
Eur Resp J 47;2016:1527
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Eur Resp J 47;2016:1529
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Treatment PVOD
• O2 for hypoxemia
• No recommendation for anticoagulation• In situ thrombosis common• So is alveolar hemorrhage
• Short‐term (5‐10min) vasodilator challenge in 24 pts w/o pulm edema• “Life‐threatening pulmonary oedema is the feared complication of pulmonary vasodilatory therapy in PVOD, and can occur with any calss of PAH drug”
• Pulm edema in 75% tx’d w/CCB, 50% for PAH drugs
• Epoprostenol ?• Low doses (median 13 ng/k/m)• High‐doses diuretics• Listed for lung transplantation• Moderate effects for 3‐4 mos
• Immunosuppression w/o benefit except in SLE/MCTD
• Lung transplantation only definitive therapy• Shunting in single lung transplant would overwhelm transplanted lung
• Early referral• 6 mo delisting 22.6% due to death• 11% for other PAH patients
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Summary
• High index of suspicion• Lower extremity edema: calcium channel blockers? Fluid retention?
• Etiology influences treatment• Right heart cath: w/vasodilator? w/LVEDP?
• Review echo for RV dysfunction: RV size? RV function? Septal positioning?
• PVOD?
• Early multiagent therapy
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Pulmonary Hypertension: Beyond WHO Group 1Michael Kwan, MD
San Antonio Advanced Lung SymposiumDecember 7, 2019 11
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Pathology
Cont Cardiol Edu; 2018;4(1):9
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