Primary and Secondary Pulmonary Hypertension
August 21, 2012 W. H. Wilson Tang, MD FACC FAHA
Section of Heart Failure and Cardiac Transplantation Medicine
Definition and Epidemiology of Pulmonary Hypertension
• Raised mean pulmonary artery pressures – > 25 mmHg at rest – > 30 mmHg with exercise
• Raised pulmonary vascular resistance: – > 3 Woods units
• Associated with normal PCWP or LA pressure: – < 15 mmHg
• Associated with biological changes: – In the pulmonary vasculature and – In the right ventricle
Intensive Review of Cardiology
Pulmonary Arterial Hypertension
• Rare: 1-2 cases/million • Estimated 100,000 NYHA Plexiform lesions
III-IV patients in U.S.
• 300 new cases /year in U.S.
• Classic plexiform lesions on biopsy
Examples of Risk factors: Drugs and toxins • Aminorex • Fenfluramine • Dexfenfluramine syndrome • Toxic rapeseed oil • Amphetamines • L-Tryptophan • Cocaine
Diseases • HIV infection • Liver cirrhosis • CREST • Congenital HD • Hypertension
Female gender
Intensive Review of Cardiology
Pathophysiology of Pulmonary Hypertension Risk Factors
Genetic Predisposition
Anorexigens, HIV infection, pulmonary flow, portal hypertension, connective tissue disease
Mutations: BMPR2, ALK-1 Polymorphisms: 5-HTT, ec-NOS, CPS
Altered Serotonergic / TGF Pathways
Pulmonary vascular damage Vasoconstriction
Cell Proliferation
Thrombosis
Thromboxane A2 Prostaglandin I2 Nitric oxide Endothelin-1 Serotonin VIP
VEGF Prostaglandin I2 Nitric oxide Endothelin-1 Serotonin VIP
Thromboxane A2 Prostaglandin I2 Nitric oxide
Serotonin VIP
Farber & Loscalzo, N Engl J Med 2004
Intensive Review of Cardiology
Pathophysiology of Pulmonary Hypertension Risk Factors
Genetic Predisposition
Anorexigens, HIV infection, pulmonary flow, portal hypertension, connective tissue disease
Mutations: BMPR2, ALK-1 Polymorphisms: 5-HTT, ec-NOS, CPS
Altered Serotonergic / TGF Pathways
Pulmonary vascular damage Vasoconstriction
Cell Proliferation
Thrombosis
Matrix changes, platelets, inflammatory cells activation Endothelial dysfunction Smooth muscle cells dysfunction
Pulmonary hypertensive vascular disease • Medial hypertrophy • Cellular intimal proliferation and fibrosis • Plexiform lesions
Intensive Review of Cardiology
Pathophysiology of Right Heart Failure and Cor Pulmonale in Pulmonary Hypertension Pulmonary Hypertension
Compensated Phase Normal CO, RAP
RV Pressure Overload
Declining Phase RAP Inadequate CO
Adaptive concentric RV hypertrophy RV chamber size normal or Decreased wall stress Neurohormonal and other mediator activation RV remodeling
Maladaptive RV hypertrophy, fibrosis RV diastolic dysfunction
RV diastolic & systolic failure RV dilatation Wall stress + heart rate, TR RV dilatation Septal shift
RV Ischemia
Decompensated Phase CO, RAP Hypoxia Acidosis Dysrhythmia
LV compliance LV preload, CO
Intensive Review of Cardiology
Dana Point Clinical Classification Update (2008) • Group 1: Pulmonary Arterial Hypertension – – – –
1.1 1.2 1.3 1.4
– 1.5
Idiopathic Heritable (BMPR2, ALK1, endoglin, unknown) Drug- and Toxin-induced Systemic diseases (Connective tissue disease, HIV, portal, congenital heart, schistosomiasis, hemolytic anemia) Persistent PH of the newborn
• Group 1’: Pulmonary Venous Occlusive Disease and/or Pulmonary Capillary Hemangiomatosis
• Group 2: Pulmonary Hypertension owing to Left Heart Disease – 2.1 Systolic dysfunction – 2.2 Diastolic dysfunction – 2.3 Valvular disease
• Group 3: Pulmonary Hypertension owing to Lung Disease/ Hypoxia
• Group 4: Chronic Thromboembolic Pulmonary Hypertension • Group 5: Pulmonary Hypertension of Unclear Mechanisms (Hematologic, systemic, metabolic, other) Simonneau et al, J Am Coll Cardiol 2009
Intensive Review of Cardiology
Determine the “Lesion” in Pulmonary Hypertension “Pre-capillary” PH
“Post-capillary” PH
(Normal PCWP, PVR, TPG)
( PCWP, Normal PVR, TPG)
COPD IPF IPAH Hypoxia
VC
RA
RV
Mitral valve disease Myxoma, TAPVR Hypertension Cor Triatriatum
PV
PA
LA
PC
PE PPS
Pulmonary venoocclusive disease
LV
Ao
Aortic valve disease Myocardial disease
Intensive Review of Cardiology
Pulmonary Hypertension in Adult Congenital Heart Diseases
• Shunt lesions: Left-to-Right shunt Eisenmenger’s (50% of large VSDs)
• Extra-cardiac shunts – PDAs and aorto-pulmonary windows – Ruptured sinus of valsalva aneurysm
• Intracardiac shunts: – ASDs (especially with anomalous veins) – VSDs and double-outlet RV
• Complex congenital defects (especially s/p conduits) • Pulmonic stenosis • Uncorrected coarctation (hypertension) Intensive Review of Cardiology
Pulmonary Hypertension due to Scleroderma
• Epidemiology: – Diffuse systemic sclerosis (c/w pulmonary fibrosis) – 30% – CREST (limited systemic sclerosis) – 50% – Newly identified by screening – 11%
• Risk factors for developing PAH in systemic sclerosis: – Limited scleroderma (CREST Syndrome) – Post-menopausal – Anti-centromere antibodies & anti-nucleolar antibodies (U3-RNP, B23, Th/To, U1-RNP)
• Screening: PFTs with DLCO should be performed every 612 months to detect pulmonary vascular or interstitial disease
Intensive Review of Cardiology
Porto-Pulmonary Hypertension in Cirrhosis
• 2-10% of cirrhotic patients • Median survival ~ 6 months • Characterized by proliferative pulmonary arteriopathy and plexiform lesions, mechanism unknown
• Mild-to-moderate porto-pulmonary is frequently reversible after transplantation
• • • •
Often with high cardiac output and filling pressures Pre-transplant IV epoprostenol is feasible High transplant mortality (36-80% if mPAP >45 mmHg) Screening: echo / right heart catheterization
Intensive Review of Cardiology
Pulmonary Hypertension in Sickle-Cell Diseases
• Prevalence in adults: – 18-25% (ages 18-40 years) – 40-60% (ages >40 years)
• Predominantly SS, not SC – Also seen in thalassemia intermedia – 2-year mortality rate: 16-50%
• Proposed mechanism by reduced NO bioavailability by erythrocyte arginase release
• Need to intensify sickle cell treatments
Intensive Review of Cardiology
Genetic Mutations of Familial Pulmonary Hypertension • Bone morphogenetic protein receptor 2 (BMPR2)
– TGF- family – >100 mutations, autosonomal – – –
dominance, 2q31-32 Detectable in two-thirds of FPAH families, 10-20% lifetime penetrance, up to 25% in sporadic PAH Loss of anti-proliferative effects in vascular cells Genetic testing available
• Activin-receptor–like kinase 1 (ALK-1) – Associated with hereditary hemorrhagic telangiectasia
• Endoglin Trembath et al, N Engl J Med 2001
Intensive Review of Cardiology
Clinical Presentation and Physical Examination Presence of PH
• • • • •
Loud P2 at apex Left parasternal (RV) lift Systolic murmur (TR) Diastolic murmur (PR) RV S4
Presence of RV Failure
• • • •
Clinical Presentation
JVD with V-waves (TR) RV S3 Hepatomegaly (pulsatile)
Dyspnea Fatigue Chest pain Near syncope Syncope Leg edema Palpitations
Initial Sx 60% 19% 7% 5% 8% 3% 5%
Eventual Sx 98% 73% 47% 41% 36% 37% 33%
Other presentations: hemoptysis, cyanosis
Ascites and edema
In 90% of patients, the mean length of time to diagnosis is 2 years Intensive Review of Cardiology
WHO Functional Assessment • Class I: Patients with PH but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near syncope.
• Class II: Patients with PH resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope.
• Class III: Patients with PH resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue, chest pain, or near syncope.
• Class IV: Patients with PH with inability to carry out any physical activity without symptoms. These patients manifest signs of right-heart failure or syncope. Dyspnea and/or fatigue may even be present at rest. Discomfort is increased by any physical activity.
Intensive Review of Cardiology
Electrocardiogram
10% of PAH patients have normal EKGs 2
1. R-axis deviation
1
2. Tall R in V1, R/S >1 3
3. qR in V1
5
4. RA enlargement
6 4
5. S1-S2-S3 7
6. ST-T wave inversion in R precordial leads 7. Tall S in V5, R/S 75
* assumes RAP=5 mmHg
Intensive Review of Cardiology
Hemodynamic Progression of Pulmonary Hypertension
Pre-symptomatic/ Compensated
Symptomatic/ Decompensating
Declining/ Decompensated
CO Symptom Threshold
PAP PVR RAP
ms o t p Sym
Right Heart Dysfunction Right Heart Failure
Time Adapted from Rich S et al, Prog Cardiovasc Dis 1998
Intensive Review of Cardiology
Clinical Evaluation of Patients Suspected with PH Suspected Pulmonary Hypertension
Diagnostic Work-up Electrocardiogram
Chest X-ray
Echocardiography
Etiology Considerations PFTs w/ ABG
V/Q scan
High-res CT
Pulmonary angio
Sleep study
Classification and Risk Stratification Type Echo (TTE + contrast, TEE) Blood test (HIV, immunology) Abdominal ultrasound Genetic testing
Exercise Capacity 6-minute walk test Peak VO2
Hemodynamics Right heart catheterization Vasoreactivity testing
Intensive Review of Cardiology
Case 1
A 45 year-old lady presented to the clinic with 2 week history of persistent dyspnea which started after her ski trip when she had dyspnea of exertion and pedal edema. Echocardiography showed preserved cardiac function and moderate-to-severe pulmonary hypertension that was confirmed by cardiac catheterization (BP = 105/75 mmHg, mean PA = 58 mmHg, PCWP = 12 mmHg, cardiac index = 2.8 L/min/m2). You advise her to:
1. Start coumadin and nifedipine 2. Test for BMPR-2 gene mutation and get a screening echocardiogram for her daughter 3. Prescribe home oxygen 4. Perform acute vasoreactivity testing
Intensive Review of Cardiology
Case 1
A 45 year-old lady presented to the clinic with 2 week history of persistent dyspnea which started after her ski trip when she had dyspnea of exertion and pedal edema. Echocardiography showed preserved cardiac function and moderate-to-severe pulmonary hypertension that was confirmed by cardiac catheterization (BP = 105/75 mmHg, mean PA = 58 mmHg, PCWP = 12 mmHg, cardiac index = 2.8 L/min/m2). You advise her to:
1. Start coumadin and nifedipine 2. Test for BMPR-2 gene mutation and get a screening echocardiogram for her daughter 3. Prescribe home oxygen 4. Perform acute vasoreactivity testing
Intensive Review of Cardiology
Vasoreactivity Testing And Interpretation Vasodilator Agents: Epoprostenol (Flolan®) Intravenous infusion Moderate SVR Dose: 2-10 ng/kg/min
Responders CCB • Fall in mPAP 10 mmHg • + Absolute mPAP 45 years • NYHA Class • Exercise time
• Cardiac index • Changes with Rx: – PVR – mPAP – Cardiac index D’Alonzo et al, Ann Intern Med 1991
area index
and distance (6 minute walk test)
• Eccentricity index • Septal shift
• BNP
Raymond et al, JACC 2002
McLaughlin et al, Circulation 2002
• Uric acid
Kuhn et al, Am J Respir Crit Care Med 2003
Intensive Review of Cardiology
Treating Pulmonary Hypertension: Cardiologists’ Perspectives • Goals of Therapy – – – –
Preserve right ventricular function
Volume management Prevent thromboembolic events Clinical monitoring (echo, cardiac catheterization)
• Clinical Pearls – Avoid calcium channel blocker in right heart failure or low cardiac index; avoid verapamil
– – – –
Can use digoxin, although data is sparse Pregnancy is contraindicated (30-50% maternal mortality, Eisenmenger’s 70%) SBE prophylaxis for congenital heart disease with PH Limited data on utility of ACE inhibitors
• Many new drugs (review ACCP 2007 or ACC/AHA 2009 Guidelines)
Intensive Review of Cardiology
“Empirical” Adjunctive Therapy for PAH Digoxin
Diuretics
• Variable inotropic effect and use
• Most patients require them
• No long-term data; need to balance • Consider preload dependence in unproven benefits with known risks
advanced right heart failure
• Useful with atrial arrhythmia Oxygen
Anticoagulation
• Use to prevent hypoxic
• Recommended in IPAH • Retrospective data only; need to
vasoconstriction
• Consider exercise, sleep, altitude
balance unproven benefits with known risks
• Aim for target saturation 92% • May not correct hypoxia with shunt • INR 1.5 – 2.5
Badesch et al. Chest 2007
Intensive Review of Cardiology
Therapeutic Targets for Pulmonary Arterial Hypertension
Benza et al, J Heart Lung Transplant 2007
Intensive Review of Cardiology
Randomized clinical trials in PAH: Prostacyclins Drug(s)
Major Trial
Epoprostenol (Flolan)
Epoprostenol + Sildenafil
Treprostinil (Remodulin)
Ilprost (Ventavis)
Hinderliter
Badesch
Simonneau
Simonneau
McLaughlin
Olschewski
NEJM 1997
NEJM 2000
AIM 2008
AJRCCM 2002
JACC 2010
NEJM 2002
Acronym
--
--
PACES
--
TRIUMPH
AIRS
Route
IV
IV
IV + PO
SC
Inhaled
Inhaled
IPAH
IPAH, CTD
IPAH
IPAH, CTD, CHD
IPAH on oral Rx
IPAH, CTD, CHD
Sample Size
81
111
265
470
235
203
WHO Class
3-4
2-4
2-4
2-3
2-4
Duration
3 months
3 months
3 months
3 months
3 months
3 months
6MWD
+ 47m
+ 94m
+ 29m
+ 16m
+ 20m
+ 36m
Published
Patients
Events Side Effects
Jaw pain, flushing, rebound, GI, infusion site (IV)
Intensive Review of Cardiology
Randomized clinical trials in PAH: Oral Drugs Drug(s)
Major Trial
Bosentan (Tracleer)
Ambrisentan (Letairis)
Sildenafil (Revatio)
Tadalafil (Adcirca)
Rubin
Galié
Galié
Galié
Galié
NEJM 2002
Lancet 2008
Circ 2005
NEJM 2005
Circ 2009
BREATHE-1
EARLY
AIRES-1/2
SUPER
PHIRST
PO
PO
PO
PO
PO
Dosage
62.5-250mg BID
62.5-125mg BID
2.5-10mg QD
20-80mg TID
2.5-40mg QD
Patients
IPAH, CTD
IPAH, CTD
IPAH, CTD
IPAH, CTD, HIV, CHD
IPAH, CTD, HIV, CHD bosentan
Sample Size
213
185
393
278
405
WHO Class
2-4
2
2-3
2-3
2-3
Duration
4 months
6 months
4 months
3 months
4 months
6MWD
+ 44m
+ 19m
+ 45m
+ 45m
+ 44m
Published
Acronym Route
TTCW Side Effects
Flushing, LFTs, edema
Hypotension, headache, flushing
* Time to clinical worsening (TTCW) = Death, lung transplant, initiation of epoprostenol, hospitalization due to worsening PH, premature withdrawal of study drug (decrease in 6MWD, worsening FC, RV failure, worsening end organ function)
Intensive Review of Cardiology
ACCF/AHA Consensus PAH Treatment Algorithm Anticoagulate ± Diuretics ± Oxygen ± Digoxin
Acute Vasoreactivity Testing Positive
Negative Oral CCB No Sustained Response Yes Continue CCB
LOWER RISK
DETERMINANTS OF RISK
HIGHER RISK
No
Clinical evidence of RV failure
Yes
Gradual
Progression of symptoms
Rapid
II, III
WHO class
IV
Longer (>400 m)
6MWD
Shorter (10.4 mL/kg/min
CPET
Peak VO2 20 mm Hg; CI 400 m • No RH failure • RV size/function normal • RAP normal; CI normal • BNP near normal/stable or • Continue oral therapy
Consider transplantation if persistent: • RAP >15 mmHg / mPAP >50 mmHg • Cardiac index 2.0 L/min/m2 • Remains hypoxic on oxygen, syncopal, or NYHA III-IV 3-12 months after therapy • Low or declining 6MWD
