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Pulmonary Hypertension: Beyond WHO Group 1 Michael Kwan, MD San Antonio Advanced Lung Symposium December 7, 2019 1 2019 SAN ANTONIO ADVANCED LUNG SYMPOSIUM Pulmonary Hypertension: Beyond WHO Group 1 Michael D. Kwan, MD, FACC Program Director Advanced Heart Failure and Cardiac Transplant Program 2019 SAN ANTONIO ADVANCED LUNG SYMPOSIUM Disclosure No relationships to disclose 2019 SAN ANTONIO ADVANCED LUNG SYMPOSIUM Case Presentation 2019 SAN ANTONIO ADVANCED LUNG SYMPOSIUM 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 2019 SAN ANTONIO ADVANCED LUNG SYMPOSIUM 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 VO 2max 12.1 ml/k/m (49% predicted) O 2 pulse 11.5 ml/beat (62% predicted) VE/VCO2 slope 42 V D /V T decreased from 37% to 20% 2019 SAN ANTONIO ADVANCED LUNG SYMPOSIUM 1 2 3 4 5 6
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Page 1: Pulmonary Hypertension: Beyond WHO Group 1€¦ · Pulmonary Hypertension: Beyond WHO Group 1 Michael Kwan, MD San Antonio Advanced Lung Symposium December 7, 2019 7 2019SAN ANTONIO

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

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

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

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 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

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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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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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• 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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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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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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[email protected]

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Pathology

Cont Cardiol Edu; 2018;4(1):9

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