Overview of Pulmonary Hypertension: Pathophysiology ...
Transcript of Overview of Pulmonary Hypertension: Pathophysiology ...
Overview of Pulmonary Hypertension: Pathophysiology, Classification and DiagnosisPaul Kim, MDAssistant Clinical Professor of MedicineDivision of CardiologyUC San Diego Health
Disclosures
• None
Pulmonary Arterial Hypertension: Key Points• Symptoms often nonspecific; average 14-month
delay from initial presentation to diagnosis
• Poor prognosis without therapy and close follow-up
• Evaluation must be methodical and include right heart catheterization (RHC)
• Prognosis improves with therapy, but PAH remains a progressive fatal disease
• Therapies and management strategies continue to evolve
5th World Symposium on PH: Hemodynamic Definition of PH/PAH
PH
PAHMean PAP ≥25 mm Hg plusPAWP ≤15 mm Hg plusPVR >3 Wood units
Mean PAP ≥25 mm Hg at rest during RHC
Hoeper MM et al. J Am Coll Cardiol. 2013;62:D42-D50.
Adapted from: Sitbon O et al. J Am Coll Cardiol. 2002;40:780-788. D’Alonzo GE et al. Ann Intern Med.1991;115:343-349. McLaughlin VV et al. Chest. 2004;126:78S-91S.
Idiopathic PAH: Survival If Untreated
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 50
20
40
60
80
100
Years of follow-up
Per
cent
age
surv
ivin
g
NIH registrySitbon historical controlACCP estimate
• Incidence: 2-6 cases per million in US
• Poor prognosis in an era lacking therapy
• Therapeutic options and research efforts now offer more hope
3-yr Survival in Treatment Era: CHD, IPAH, or CTD-PAH (French Registry)
From Humbert et al. Eur Respir J. 2010;36:549-555.
0 12 24 36Time (mo)
0.0
0.2
0.4
0.6
0.8
1.0C
umul
ativ
e su
rviv
al (%
)
Subjects, n:35410376
3148673
2717170
2396264
Idiopathic PAHCTD PAHCHD PAH
CHD
IPAHCTD
p<0.05
PAH—WHO Group I: REVEAL Registry Survival Rates
2967 patients enrolled consecutively, Mar 2006 to Sept 2007; 2525 with PCWP ≤15 mm Hg.Benza RL et al. Chest. 2012;142:448-456.
Surv
ival
(%)
868 1169 1263 5751296 1146 894 309
0
70
40
60
80
10090
50
No. at Risk:Full cohort
34.7 ± 1.3%
57.0 ± 1.4%
49.0 ± 1.4%
Time From Diagnosis (years)
67.8 ± 1.4%
0 1 2 3 4 5 6 7
5th World Symposium on PH:Classification1. Pulmonary arterial hypertension
1.1 Idiopathic PAH1.2 Heritable PAH
1.2.1 BMPR21.2.2 ALK1, ENG, Smad 9, CAV1, KCNK31.2.3 Unknown
1.3 Drug- and toxin-induced1.4 Associated with
1.4.1 Connective tissue disease1.4.2 HIV infection1.4.3 Portal hypertension1.4.4 Congenital heart diseases (update)1.4.5 Schistosomiasis
1’. Pulmonary veno-occlusive disease and/orpulmonary capillary hemangiomatosis
1’’. Persistent PH of the newborn
2. PH due to left heart disease
2.1 LV systolic dysfunction2.2 LV diastolic dysfunction2.3 Valvular disease2.4 Congenital/acquired left heart inflow/outflow tract
obstruction and congenital cardiomyopathies
3. PH due to lung diseases and/or hypoxia
3.1 Chronic obstructive pulmonary disease3.2 Interstitial lung disease3.3 Other pulmonary diseases with mixed restrictive
and obstructive pattern3.4 Sleep-disordered breathing3.5 Alveolar hypoventilation disorders3.6 Chronic exposure to high altitude3.7 Developmental lung diseases (update)
4. Chronic thromboembolic PH
5. PH with unclear multifactorial mechanisms
5.1 Hematological disorders: chronic hemolytic anemia, 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: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH
Simonneau G et al. J Am Coll Cardiol. 2013;62:D34-D41.
5th World Symposium on PH:Classification1. Pulmonary arterial hypertension
1.1 Idiopathic PAH1.2 Heritable PAH
1.2.1 BMPR21.2.2 ALK1, ENG, Smad 9, CAV1, KCNK31.2.3 Unknown
1.3 Drug- and toxin-induced1.4 Associated with
1.4.1 Connective tissue disease1.4.2 HIV infection1.4.3 Portal hypertension1.4.4 Congenital heart diseases (update)1.4.5 Schistosomiasis
1’. Pulmonary veno-occlusive disease and/orpulmonary capillary hemangiomatosis
1’’. Persistent PH of the newborn
2. PH due to left heart disease
2.1 LV systolic dysfunction2.2 LV diastolic dysfunction2.3 Valvular disease2.4 Congenital/acquired left heart inflow/outflow tract
obstruction and congenital cardiomyopathies
3. PH due to lung diseases and/or hypoxia
3.1 Chronic obstructive pulmonary disease3.2 Interstitial lung disease3.3 Other pulmonary diseases with mixed restrictive
and obstructive pattern3.4 Sleep-disordered breathing3.5 Alveolar hypoventilation disorders3.6 Chronic exposure to high altitude3.7 Developmental lung diseases (update)
4. Chronic thromboembolic PH
5. PH with unclear multifactorial mechanisms
5.1 Hematological disorders: chronic hemolytic anemia, 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: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH
Simonneau G et al. J Am Coll Cardiol. 2013;62:D34-D41.
PAH Distributions in the US: REVEAL Registry
Based on Venice Clinical Classification (2003); 2967 patients.Adapted from Badesch DB et al. Chest. 2010;137:376-387.
Overall Associated
Associated(50.7%)
Idiopathic(46.2%) Connective tissue/
collagen vascular(49.9%)
Heritable (2.7%)
Pulmonaryveno-occlusive
(0.4%)
Congenitalheart disease(19.5%)
HIV (4.0%)
Other (5.5%)
Drugs/toxins (10.5%)
Portopulmonary (10.6%)
5th World Symposium on PH:Updated Risk Factors for PAHDefinite PossibleAminorex CocaineFenfluramine PhenylpropanolamineDexfenfluramine St. John’s wortToxic rapeseed oil Chemotherapeutic agentsBenfluorex Interferon α and βSSRIs (PPHN only) Amphetamine-like drugs
Likely UnlikelyAmphetamines Oral contraceptivesL-tryptophan EstrogenMethamphetamines Cigarette smokingDasatinib
.Simonneau G et al. JACC. 2013;62:D34-D41.
Methamphetamine and PAH
• Case-control analysis:
– 97 IPAH patients
– 106 PAH with other risk
factors
– 137 CTEPH patients
• Adjusted OR for prior
methamphetamine use:
– IPAH vs PAH with known
risk factors: 7.73
(2.55 – 23.5), p=0.0002
– IPAH vs CTEPH: 11.61
(3.34 – 40.3), p<0.0001
Chin K et al. Chest. 2006;130:1656-1663.
IPAH PAH
with
known
RFs
CTEPH
Pro
po
rtio
n r
ep
ortin
g s
tim
ula
nt
use
0.00
0.05
0.10
0.15
0.20
0.35
0.40
0.30
0.25
PAH Related to ConnectiveTissue Disease• Connective tissue diseases
– limited scleroderma (most common)
– diffuse scleroderma
– mixed connective tissue disease
– systemic lupus erythematosus
– rheumatoid arthritis
– Sjogren’s syndrome
• PH is one of the leading causes of death in scleroderma
• Similar to IPAH pathology
• Medical treatment same as for IPAH, but benefits less than for IPAH
Hachulla E et al. Rheumatology. 2009;48:304-308.
Prevalence of PAH in Scleroderma
• Prevalence 7.9% in large prospective study (N=599) with confirmatory catheterizations
– excluded severe PFT abnormalities– all underwent Doppler echocardiography – catheterization if VTR >3 m/sec or VTR
2.5–3 m/sec + unexplained dyspnea
• Prevalence of PAH: 47 of 599– 29 had known PAH at study entry – 18 patients were newly diagnosed with PAH
Hachulla E et al. Arthritis Rheum. 2005;52:3792-3800.
PAH Related to CongenitalHeart Disease• Incidence of PAH varies
– higher flow / pressure = higher risk (large VSD)
– ASD as a trigger?: only ~10% develop PAH
– progression may be seen even after surgery
• Common causes: VSD, ASD, AV canal defect, PDA
• Eisenmenger’s complex: reversal of L-R shunt
• Prognosis is significantly better than PAH withouta shunt
Galie N et al. Circulation. 2006;114;48-54. Oya H et al. Am Heart J. 2002;143:739-744.
PAH Related to CongenitalHeart Disease
Galie N et al. Circulation. 2006;114;48-54. Oya H et al. Am Heart J. 2002;143:739-744.
0
20
40
60
80
100
Similar to IPAH, right heart failure (low CO, high [relatively] RA pressure) is a poor prognostic marker
Systemic Cardiac Output RA Pressure
0 5 10 15 20Time (yr)
Surv
ival
rate
(%)
Systemic blood flow ≥2.9 L/min
Systemic blood flow <2.9 L/min
0 5 10 15 20Time (yr)
RAP ≤7 mm Hg
RAP >7 mm Hg
Portopulmonary Hypertension
• Prevalence overall: 2-5% by RHC; liver transplant candidate: 4% to 17%
• Dependent on portal HTN, not hepatocellular dysfunction
• Poor prognosis: higher risk of death than IPAH pts
• Liver transplant
– may improve survival with mild to moderate PAH(28-56%, 5 yr)
– significant PAH (mPAP >35 mm Hg) predicts unacceptably high perioperative mortality
Budhiraja R et al. Chest. 2003. Hadengue A et al. Gastroenterology. 1991. Castro M et al. Mayo Clin Proc. 1996. Kawut SM et al. Liver Transpl. 2005. Ramsay MA et al. Liver Transpl Surg. 1997. Krowka MJ et al. Clin Chest Med. 2005. Krowka MJ et al. Liver Transpl. 2004. Swanson KL et al. Hepatology. 2004.
Portopulmonary Hypertension: RHC to Distinguish Hemodynamic Subsets
• Normal
• Volume overload: normal PVR
– PA mean ≥25 mm Hg, PCW >15, PVR normal
• High output: normal PVR
– PA mean ≥25 mm Hg, CI >4, PVR normal
• Portopulmonary hypertension: PVR >3 WU
– PA mean ≥25 mm Hg, PCW ≤15, PVR >3
PAH Related to HIV • Prevalence
– 0.5% both before and after HAART introduced– higher among IVDU
• Occurs in early and late disease; not related to degree of immunodeficiency
• Pathology identical to IPAH
• PAH-specific therapies and antiretrovirals are most commonly used treatments
• Independent predictor of mortalityLimsukon A et al. Mt Sinai J Med. 2006;73:1037-1044.Sitbon O et al. Am J Respir Crit Care Med. 2008;177:108-113.
5th World Symposium on PH:Classification1. Pulmonary arterial hypertension
1.1 Idiopathic PAH1.2 Heritable PAH
1.2.1 BMPR21.2.2 ALK1, ENG, SMAD9, CAV1, KCNK31.2.3 Unknown
1.3 Drug- and toxin-induced1.4 Associated with
1.4.1 Connective tissue disease1.4.2 HIV infection1.4.3 Portal hypertension1.4.4 Congenital heart diseases (update)1.4.5 Schistosomiasis
1’. Pulmonary veno-occlusive disease and/orpulmonary capillary hemangiomatosis
1’’. Persistent PH of the newborn
2. PH due to left heart disease
2.1 LV systolic dysfunction2.2 LV diastolic dysfunction2.3 Valvular disease2.4 Congenital/acquired left heart inflow/outflow tract
obstruction and congenital cardiomyopathies
3. PH due to lung diseases and/or hypoxia
3.1 Chronic obstructive pulmonary disease3.2 Interstitial lung disease3.3 Other pulmonary diseases with mixed restrictive
and obstructive pattern3.4 Sleep-disordered breathing3.5 Alveolar hypoventilation disorders3.6 Chronic exposure to high altitude3.7 Developmental lung diseases (update)
4. Chronic thromboembolic PH
5. PH with unclear multifactorial mechanisms
5.1 Hematological disorders: chronic hemolytic anemia, 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: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH
Simonneau G et al. J Am Coll Cardiol. 2013;62:D34-D41.
Most Common Cause of Elevated PAPs by Echo: Left Heart DiseaseSymptoms
– paroxysmal nocturnal dyspnea
– orthopnea
History– diabetes
– hypertension
– obesity
– coronary artery disease
– metabolic syndrome
ECG– atrial fibrillation
– absence of right axis deviation
Echo– left atrial enlargement
– left ventricular hypertrophy
– normal RA, RV
– abnormal diastolic filling
– mitral or aortic disease
100
75
50
25
0
IPAH Is Not the Most Common Cause: In Older Patients, Consider Diastolic Heart Failure• PH by echo in a community-
based sample: – heart failure with preserved EF:
83% with PH
– HTN but no CHF (control): 8% with PH
• Patients with PH:– older
– higher systolic BP
– larger LA size
– higher E/e’ ratio
Lam CS et al. J Am Coll Cardiol. 2009;53:1119-1126.
Cum
ulat
ive
(%)
10 30 50 70 90 110PASP (mm Hg)
HTNHFpEF
p<0.001
100
75
50
25
0
PH
pre
vale
nce
(%)
HTN
8
HFpEF
83
p<0.001
Pulmonary Venous Hypertension:A Simplified View• Normal, or mildly elevated transpulmonary gradient
with readily apparent cause
– treat underlying cause
• Substantially elevated transpulmonary gradient (PH out of proportion to LHD)
– treat cardiovascular risk factors (including aggressive volume control) as best you can
– improvement in PH may be slow (months)
– No FDA-approved therapies for diastolic dysfunction yet
Percentage of PAH and PVH Patients With All 4 Metabolic Syndrome Factors
*p≤0.005; **p=0.023.Robbins IM et al. Chest. 2009;136:31-36.
0
20
40
60
80
100
Percentof
patients**
*
*
*
PAHPVH
HTN13.7
(1.6-113.0)
Obesity7.1
(1.9-26.8)
DM5.7
(1.6-20.4)
HL4.2
(1.2-15.7)OR
95% CI
Distinguishing Clinical FeaturesCharacteristics HFpEF PAH PH-HFpEFAge Older Younger OlderComorbidities* Frequent Rare More frequent
RAE Absent More frequent Less frequent
LAE Frequent Absent Frequent
ASP Elevated Normal Elevated
mRAP Normal Normal-High High
mPAP Normal Markedly elevated
Moderately elevated
CO Normal Low Normal
PVR Normal Markedly elevated
Moderately elevated
*Includes hypertension, DM, obesity, and CAD.Modified From Thenappan et al. Circ Heart Fail. 2011;4:257-264.
5th World Symposium on PH:Classification1. Pulmonary arterial hypertension
1.1 Idiopathic PAH1.2 Heritable PAH
1.2.1 BMPR21.2.2 ALK1, ENG, SMAD9, CAV1, KCNK31.2.3 Unknown
1.3 Drug- and toxin-induced1.4 Associated with
1.4.1 Connective tissue disease1.4.2 HIV infection1.4.3 Portal hypertension1.4.4 Congenital heart diseases (update)1.4.5 Schistosomiasis
1’. Pulmonary veno-occlusive disease and/orpulmonary capillary hemangiomatosis
1’’. Persistent PH of the newborn
2. PH due to left heart disease
2.1 LV systolic dysfunction2.2 LV diastolic dysfunction2.3 Valvular disease2.4 Congenital/acquired left heart inflow/outflow tract
obstruction and congenital cardiomyopathies
3. PH due to lung diseases and/or hypoxia
3.1 Chronic obstructive pulmonary disease3.2 Interstitial lung disease3.3 Other pulmonary diseases with mixed restrictive
and obstructive pattern3.4 Sleep-disordered breathing3.5 Alveolar hypoventilation disorders3.6 Chronic exposure to high altitude3.7 Developmental lung diseases (update)
4. Chronic thromboembolic PH
5. PH with unclear multifactorial mechanisms
5.1 Hematological disorders: chronic hemolytic anemia, 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: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH
Simonneau G et al. J Am Coll Cardiol. 2013;62:D34-D41.
Pulmonary Hypertension in Lung/Respiratory Disease
• May explain worsening symptoms in patient with stable PFTs
• May contribute to exercise limitation: ventilatory vs cardiovascular limitation
• Disproportionately low DLCO may suggest pulmonary vascular disease
• Correlates better with low oxygen levels than PFTs
Chronic Obstructive Pulmonary Disease (COPD) and PH• Retrospective study of 215 COPD patients• 13.5% had a PA mean >35 mm Hg• Correlated best (inversely) with PaO2
• A small number had only moderate obstruction: treatable sub-group?
Thabut G et al. Chest. 2005;127:1531-1536. FEV1 (% pred.)
mPAP (mm Hg)
10
20
30
40
60
50
0 20 40 60 80
4
12
3
0
Lettieri CJ et al. Chest. 2006;129:746-752.
PH
No PH (mPAP <25 mm Hg)
p<0.001
N=79No difference in lung volumesLower 6MWD
PH as a Predictor of Survival in Patients With IPF
1000500 1500 2000 2500Days to event
Cum
ulat
ive
prob
abili
ty o
f sur
viva
l
0.0
0.2
0.4
0.6
0.8
1.0
Sleep-disordered Breathing and PH
• Nocturnal hypoxemia results in pulmonary arterial constriction
• PH can occur with either obstructive sleep apnea (OSA) or central sleep apnea
• PH can occur with obstructive sleep apnea in the absence of intrinsic heart or lung disease
• Little correlation in severity of OSA and degree of PH
• Sleep-disordered breathing increases the risk of both PAH and PVH
Sajkov D et al. Am J Respir Crit Care Med. 1994;149:416-422.
Impact of PH on Outcomes in Obstructive Sleep Apnea
Minai O et al. Am J Cardiol. 2009;104:1300-1306.
0
No PHPH
100.0
21 4 8Time (years)
Ove
rall
surv
ival
(%)
0
20
40
60
80
100 9690
7693
86
75
43
5th World Symposium on PH:Classification1. Pulmonary arterial hypertension
1.1 Idiopathic PAH1.2 Heritable PAH
1.2.1 BMPR21.2.2 ALK1, ENG, SMAD9, CAV1, KCNK31.2.3 Unknown
1.3 Drug- and toxin-induced1.4 Associated with
1.4.1 Connective tissue disease1.4.2 HIV infection1.4.3 Portal hypertension1.4.4 Congenital heart diseases (update)1.4.5 Schistosomiasis
1’. Pulmonary veno-occlusive disease and/orpulmonary capillary hemangiomatosis
1’’. Persistent PH of the newborn
2. PH due to left heart disease
2.1 LV systolic dysfunction2.2 LV diastolic dysfunction2.3 Valvular disease2.4 Congenital/acquired left heart inflow/outflow tract
obstruction and congenital cardiomyopathies
3. PH due to lung diseases and/or hypoxia
3.1 COPD3.2 Interstitial lung disease3.3 Other pulmonary diseases with mixed restrictive
and obstructive pattern3.4 Sleep-disordered breathing3.5 Alveolar hypoventilation disorders3.6 Chronic exposure to high altitude3.7 Developmental lung diseases (update)
4. Chronic thromboembolic PH
5. PH with unclear multifactorial mechanisms
5.1 Hematological disorders: chronic hemolytic anemia, 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: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH
Simonneau G et al. J Am Coll Cardiol. 2013;62:D34-D41.
Incidence of CTEPH
• Approximately 3% to 4% 1-2 yr after acute PE
• USA: 600,000 cases of acute PE each year
• Only 40% to 50% of CTEPH patients have a history of previous episodes of acute PE
• VQ scan identifies old PE better than CTA
McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.Pengo V et al. N Engl J Med. 2004;350:2257-2264.Tapson VF, Humbert M. Proc Am Thorac Soc. 2006;3:564-567.
Years
Cu
mu
lativ
e in
cid
en
ce o
f C
TE
PH
0 1 2 3 4 7 8 9 10 115 60.00
0.01
0.02
0.03
0.04
PAH: Hemodynamic and Clinical Course
NORMAL
Time
PAP
PVR
CO
INYHA
Adventitia
Media
Intima
Adapted from Gaine S. JAMA. 2000;284:3160-3168.
NORMAL
Adventitia
Media
Intima
REVERSIBLE DISEASE
Time
PAP
PVR
CO
I II III
BNP
NYHA
Smooth Muscle Hypertrophy
Early Intimal Thickening
Adapted from Gaine S. JAMA. 2000;284:3160-3168.
PAH: Hemodynamic and Clinical Course
NORMAL
Adventitia
Media
Intima
Smooth Muscle Hypertrophy
Early Intimal Thickening
REVERSIBLE DISEASE
IRREVERSIBLE DISEASE
Plexiform Lesions
Thrombosis
Adventitial, Intimal Proliferation
Smooth Muscle Hypertrophy
Time
PAP
PVR
CO
I II III IV
BNP
NYHA
PAH: Hemodynamic and Clinical Course
Adapted from Gaine S. JAMA. 2000;284:3160-3168.
Mechanisms of Action of Approved Therapies for PH
Adapted from Humbert M et al. N Engl J Med. 2004;351:1425-1436.
cGMP
cAMP
Vasoconstriction and proliferation
Endothelinreceptor A
Endothelin-receptor
antagonists
Endothelinreceptor B
Phosphodiesterase type 5 inhibitor
Vasodilationand antiproliferation
Phosphodiesterase type 5
Vasodilationand antiproliferation
Prostacyclin derivatives
Nitric Oxide
Endothelin-1
Pre-proendothelin
L-arginine
Prostaglandin I2
L-citrulline
Nitric OxidePathway
EndothelinPathway
ProstacyclinPathway
Endothelial cells
ProendothelinEndothelial cells
Arachidonic acid
Smooth muscle cells
Prostacyclin (prostaglandin I2)
Smooth muscle cells
-Exogenous nitric oxide -sGCstimulator
Yuan JXJ, Rubin LJ. Circulation. 2005;111:534-538.
Other Potential Targets
Summary
• Classification: five major groups
• Idiopathic PAH: uncommon, but serious and progressive
• Multiple treatment options
• Prognosis is improving
• New therapies are still needed