pulmonary hypertension for cardiologists
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Pulmonary Hypertension For CardiologistsEric Adler MD
Case…• 71 year old female with h/o morbid obesity, pulmonary
hypertension on home O2, HFpEF, hypothyroidism, mild aortic stenosis and Afib.
• Admitted for Volume Overload..• Pulmonary Hypertension
– Unclear Etiology– Treated Previously With Sildenefil/Bosentan at OSH
• Seen in Pulm Clinc B/C fet not to have primary pulmHtn, felt to have HFPEF (WHO 2)
Case Continued• Pt reports worsened SOB for the last 2yrs or so. At
present her activity level is limited to about 50ft, walks from bed to bathroom and that's about it. Limited by SOB. Of late, her home O2 requirements have increased from 2L to 3L
Pulmonary Hypertension
GeneralDefinitionRestingSystolicPAP >35mmHg
RestingDiastolicPAP >15mmHg
RestingMeanPAP >25mmHg
PulmonaryArterialHypertensionPCWP,LAP,LVEDP <15mmHg
PulmonaryArteriolarResistance >3WoodUnits(>240dyn·s/cm5)
Pulmonary Hypertension
PulmonaryArterialHypertensionPre-capillaryHighPVR,HighTPG
PulmonaryVenousHypertensionPost-capillaryNormalTPG
HyperdynamicPulmonaryHypertensionPre-capillaryNormaltranspulmonary resistance
ClassificationGroup1 PulmonaryArterialHypertension
Group2 Left-SidedHeartDisease
Group3 Lungdiseaseand/orHypoxemia
Group4 Chronicthromboticand/orembolicdisease
Group5 Miscellaneous:Sarcoidosis, compressionofpulmonary vessels(adenopathy, tumor, fibrosingmediastinitis)
At-Risk Populations for PAH
Populations PrevalenceIPAH1 6cases/million
ConnectiveTissueDisease2 27%(13%newlyidentified)
CongenitalHeartDisease3 Upto50%ofpatientswithlargeVSDsdevelopEisenmengersyndrome,oftenassociatedwithPAH
HIVinfection4 0.5%
SickleCellDisease5 20%to40%
Drugs/Toxins6Directrelationshipwithanorexigens(amphetamines, cocaine);L-tryptophanmayalsobeassociatedwithPAH
1HumbertMetal. AmJRespirCritCareMed. 2006;173:1023-1020.2WigleyFMetal. ArthritisRheum. 2005;52:2125-2132.3SimonneauGetal. JAmCollCardiol. 2004;43:5S-12S.4Limsukon Aetal.MountSinaiJMed. 2006;73:1037-1044.5LinEEetal. CurrHematolRep. 2005;4:117-125.6RichSetal. Chest. 2000;117:870-874.
Dana Point Clinical Classification of PH (2008)Group 1: PAH1. Pulmonary arterial hypertension (PAH)
1.1 Idiopathic PAH (“primary pulmonary hypertension”)1.2 Heritable
1.2.1 BMPR21.2.2 ALK1, endoglin (with or without hereditary hemorrhagic telangiectasia)1.2.3 Unknown
1.3 Drug- and toxin-induced1.4 Associated with
1.4.1 Connective tissue diseases1.4.2 HIV infection1.4.3 Portal hypertension
1.4.4 Congenital heart disease1.4.5 Schistosomiasis1.4.6 Chronic hemolytic anemia
1.5 Persistent pulmonary hypertension of the newborn
1'. Pulmonary veno-occlusive (PVOD) and /or pulmonary capillary hemangiomatosis (PCH)
Pulmonary Hypertension
Chest. 2004;126:78S–92S.
Mean survival based on etiology of pulmonary hypertension
Pulmonary Vascular Dysfunction
Risk Factors: Shear stress (HD, CHD), HIV, CTD, toxins
Genetic Predisposition: BMPR2, ALK-1, 5-HTT
Endothelial Cell Dysfunction: NO, PGI2, ET-1
Smooth Muscle Cell Dysfunction: Kv1.5
Pulmonary Vascular Remodeling and Disease
Progression
Inflammation and Remodeling: IL-1, IL-6,
PDGF, Chemokines
Pulmonary Hypertension
NormalPA
SMCproliferation
Fibrosis
Plexiform lesionformation
AdaptedfromCoolCDetal.Chest.2005;128:565S-571S.
Evaluation• History
• Physical Examination• CXR
• ECG• PFTs
• Echo• Overnight Oximetry
• VQ Scan vs. CT Scan
• Blood Tests• Right Heart Catheterization
ANA
RF / Anti-CCP
LFTs/HCV
HIV
Anticentromere
SCL-70
Anti-Jo, Anti U1 RNP, ANCA
BNP (pBNP), RDW, CRP
APLA, LAC
EvaluationECHO:• Mild PH defined by a tricuspid
valve velocity of 2.8-3.0m/sec, which corresponds to a tricuspid insufficiency pressure gradient (TIPG) of 31mmHg or higher
• (Modified Bernoulli equation pressure = 4v2)
• More stringent criteria would be a TIPG of 45mmHg to reduce the number of falls positives.
TAPSE(Tricuspid annularplanesystolicexcursion, <1.8cm)
Other ECHO measures of RV dysfunction
Evaluation
D. Mukerjee, D. St. George, C. Knight, J. Davar, et al. Rheumatology; 43 (4): 461
ECHO:• The greater the degree of pulmonary hypertension by catheterization, the
worse the correlation between echocardiogram measurement of RVSP and catheterization measured values.
PATIENT CONTINUED• Right atrial mean pressure: 12 mmHg • Right ventricular pressure: 104/12 mmHg • Pulmonary artery pressure: 104/32, mean 63 mmHg • Pulmonary capillary wedge pressure, mean: 27 mmHg • Non invasive blood pressure, 115/57 mean 79 mmHg • Fick cardiac output: 5.69 L per minute • Fick cardiac index: 2.68 L per minute/ m2 • Pulmonary vascular resistance (Fick): 6.3 Woods units • Pulmonary artery saturation: 70% • Systemic arterial saturation: 93%
Evaluation: Hemodynamics• Vasoreactivity Testing:
• Fall in mean pulmonary artery pressure of >10mmHg, to a value <40mmHg (older criteria: 20% decrease in mPAP)
• Increased or unchanged CO• No significant decrease in BP
• Agents used for testing:• Epoprostenol: 1-2 ng/kg/min and increased by 2ng/kg/min every
5-10 minutes until significant fall in BP, increase in heart rate or symptoms
• Adenosine: 50 µg/kg/min, increase every 2 minutes until dose of 200-250 µg/kg/min
• iNO: 20ppm for 10 minutes followed by 40ppm for 10 minutes
vasoreactive fixed
Hemodynamics with 1.0 mcg/kg/min Nipride
• Pulmonary artery pressure: 89/26, mean 51 mmHg • Pulmonary capillary wedge pressure, mean: 18 mmHg • Fick cardiac output: 7.05 L per minute • Fick cardiac index: 3.32 L per minute/ m2• Pulmonary artery saturation: 72 % •
IMPRESSION:• 1) Elevated right and left filling pressures• 2) Normal cardiac output / index• 3) Positive response to nipride. PCWP 27 --> 18 mmHg
Right Ventricular Adaptations
• After PAH-targeted therapy, RV function can deteriorate despite a reduction in PVR.
• Loss of RV function is associated with a poor outcome, irrespective of any changes in PVR.
J Am Coll Cardiol 2011;58:2511–9
EvaluationV/Q SCAN:
• Sensitivity 90-100%, Specificity 94-100% for distinction between IPAH and CTEPH
• A Normal V/Q will rule out CTEPH but mismatched perfusion defects can be seen in veno-occlusive disease, pulmonary arterial sarcoma, large-vessel pulmonary arteritis, or extrinsic vascular compression.
PAH Determinants of Risk
LowerRisk DeterminantsofRisk HigherRisk
No ClinicalevidenceofRVfailure Yes
Gradual Progression Rapid
II,III WHOclass IV
Longer(>400m) 6MWdistance Shorter (<300m)
Minimallyelevated BNP Veryelevated
MinimalRVdysfunction Echocardiographicfindings Pericardialeffusion,significantRVdysfunction
Normal/nearnormalRAPandCI Hemodynamics HighRAP,lowCI
McLaughlin VV, McGoon MD. Circulation. 2006; 114:1417-1431.
6MWD Predicts Survival at Initial Screening
Miyamoto et al Am J Respir Crit Care Med 2000;161:487-492
Short distance group(<332 meters)
Long distance group(332 meters)
Months
0
20
40
60
80
100
0 10 30 4020 50 60
p < 0.001(Logrank test)
Surv
ival
(%
)
MedicalTreatmentofPulmonaryHypertension
N Engl J Med 2004;351:1425-36.
Vasoactive Mediators Involved In PAH
1.HumbertM, Morrell NW, Archer SL, etal. Cellular and molecular pathobiology of pulmonary arterial hypertension. JAmCollCardiol. 2004;43(supplS):13S-24S. 2.GalièN, TorbickiA, BarstR, etal. Guidelines on diagnosis and treatment of pulmonary arterial hypertension: the Task Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension of the European Society of Cardiology. EurHeartJ.2004;25:2243-2278. 3.HumbertM, SitbonO, Simonneau G.Treatment of pulmonary arterial hypertension. Nengl J Med. 2004;351:1425-1436.
Nitric Oxidedeficiency
EndothelinOverexpression
Prostacyclindeficiency
ETRA’sBlock the binding of ET-1 to its receptors, preventing vasoconstrictor effects of ET-12
PDE-5 inhibitors/sGCBlock the activity of PDE-5, restoring vasodilationthrough an increase in cGMP1
ProstacyclinSupplement the deficiency in PGI2, resulting in vasodilation, anti proliferation and inhibition of platelet aggregation4
THERAPIES
ABNORMALITIES
pahdiseasestate_v.124
SitbonOetal.Circulation. 2005;111:3105-3111.
Long-termCCBresponders represent<10%ofiPAHpatients
CCB Therapy is Effective in Only a Small Percent of PAH Patients
A retrospective study of 557 patients who were tested for acute vasoreactivity:
§ 70 (12.6%) patients responded and were put on CCB therapy
§ Of those 70 patients, only 38 improved
§ Therefore only 6.8% of the total number of patients benefited from long-term CCB therapy
§ For the 32 patients who responded positively to acute vasoreactivity testing but who failed to respond to CCB therapy, the 5-year survival rate was 48%
Treatment: Adjunctive Therapy
• Anticoagulants (oral)– Used in ~70% of patients in recent RCTs– Recommended to be used if no
contraindications exist– Caution with potential drug-drug interactions
(DDIs)– There is no difference in efficacy based on FC
severity
• Diuretics:– Usedin~50−70%ofpatientsinrecentRCTs– Notstudiedincontrolledtrials(andwon’tbe)– Recommendedtobeusedincasesoffluidretention– SpirinolactonemaybehelpfulindecreasingRVfibrosis
• Digoxin:– Usedin~25−50%ofpatientsinrecentRCTs– Noevidenceforitsefficacy
• Supplementaloxygen
Why do we decompensate?
Treatment: PDE5 Inhibitors
PDE5Inhibitor Dose Sideeffects
Sildenafil(Revatio) 20mgTIDto40mgTID • Minimalsideeffects• Shorter1/2life
Tadalafil(Adcirca) 40mgdaily • Lesscostly• Longer1/2life• Headaches
SideEffects:headaches,lowerbloodpressure,sinuscongestion,diarrhea,visionchanges,myalgias,flushing
Date of download: 12/4/2014 Copyright © 2014 American Medical Association. All rights reserved.
From: Effect of Phosphodiesterase-5 Inhibition on Exercise Capacity and Clinical Status in Heart Failure With Preserved Ejection Fraction: A Randomized Clinical Trial
JAMA. 2013;309(12):1268-1277. doi:10.1001/jama.2013.2024
proBNP, with or without atrial fibril-lation or treated or not with renin-angiotensin system antagonists,!-blockers, or statins.
Secondary End Pointsand Safety DataThere were no significant differences inthe clinical rank score, change in 6-min-ute walk distance at 24 weeks, orchange in peak oxygen consumption or6-minute walk distance at 12 weeks be-tween treatment groups (Table 3).There were no significant differences inthe components of the clinical rankscore at 24 weeks or in the overall in-cidence of adverse, or serious adverse,events in the treatment groups.
Adverse events occurred in 78 pa-tients (76%) who received placebo and90 patients (80%) who receivedsildenafil. Serious adverse events oc-curred in 16 patients (16%) who re-ceived placebo and 25 patients (22%)who received sildenafil. Adverse eventsoccurring in 5% or more of either studygroup are listed in eTable 4 (available athttp://www.jama.com). Patients treatedwith sildenafil had a higher incidence ofvascular adverse events, which in-cluded (but were not limited to) head-ache, flushing, and hypotension, al-though the change in mean arterialpressure from baseline to 24 weeks wasnot significantly different in patients
treated with sildenafil ("1 [95% CI, "8to 6]) and patients treated with placebo("2 [95% CI, "10 to 7]), (P=.45). Allserious adverse events exclusive of deathor cardiovascular or cardiorenal hospi-talization (Table 3) are listed in eTable5. There were no other notable differ-ences in the incidence of specific seri-ousadverseeventsbetweenstudygroups.
Study Drug and Cyclic GuanosineMonophosphate LevelsMedian sildenafil concentrations mea-sured approximately 2 hours after the lastdose were 78 (IQR, 35-130 ng/mL) at 12weeks and 200 (IQR, 92-330 ng/mL) at24 weeks. At week 24, there was a weakcorrelation between sildenafil dose andsildenafil level (r=0.29, P=.008). Inpaired analysis, plasma cyclic guano-sine monophosphate levels increased sig-nificantly from baseline to 24 weeks inpatients randomized to receive sildena-fil (mean increase, 8.72 pmol/mL, [95%CI, 2.56-14.87], P=.006), but not in pa-tients randomized to placebo (mean in-crease, 1.28 pmol/mL, [95% CI, "6.27to 8.83], P=.74), although the change incyclic guanosine monophosphate wasnot significantlydifferentbetweengroups(P=.11).
Additional End PointsAt CMRI, there was no difference inchange in left ventricular mass or left
ventricular end-diastolic volume indexbetween treatment groups (TABLE 4).There was also no difference in changein Doppler-assessed left ventricular dia-stolic function parameters or pulmo-nary artery systolic pressure betweentreatment groups. By CMRI, arterial elas-tance decreased more and systemic vas-cular resistance tended to decrease morein patients treated with sildenafil(P=.09). However, the change in meanarterial pressure in the entire studypopulation was not significantly differ-ent between groups, as noted above.More patients had missing data for aor-tic distensibility at 24 weeks than at base-line, but there was no difference inchange in distensibility between groups.Patients treated with sildenafil had agreater increase in creatinine, cystatin C,NT-proBNP, uric acid, and endothe-lin-1 than patients treated with pla-cebo, whereas changes in aldosteroneand NT-procollagen III were not signifi-cantly different between groups.
COMMENTTo our knowledge, the RELAX trial isthe first multicenter study to investi-gate the effect of PDE-5 inhibition inHFPEF. Contrary to our hypothesis,long-term PDE-5 inhibition in HFPEFhad no effect on maximal or submaxi-mal exercise capacity, clinical status,quality of life, left ventricular remod-
Table 3. Primary, Secondary, and Safety End PointsPlacebo Sildenafil
PValue
No. ofPatients Variable
No. ofPatients Variable
Primary end pointChange in peak oxygen consumption at 24 wk, median (IQR), mL/kg/min 94 "0.20 ("0.70 to 1.00) 91 "0.2 ("1.70 to 1.11) .90
Secondary end pointsClinical rank score, meana 94 95.8 95 94.2 .85Change in 6-minute walk distance at 24 wk, median (IQR), m 95 15.0 ("26.0 to 45.0) 90 5.0 ("37.0 to 55.0) .92Change in peak oxygen consumption at 12 wk, median (IQR), mL/kg/min 96 0.03 ("1.10 to 0.67) 97 0.01 ("1.35 to 1.25) .98Change in 6-minute walk distance at 12 wk, median (IQR), m 96 18.0 ("14.5 to 48.0) 99 10.0 ("25.0 to 36.0) .13
Components of clinical rank score at 24 wkDeath, No. (%)b 103 0 113 3 (3) .25Hospitalization for cardiovascular or renal cause, No. (%) 103 13 (13) 113 15 (13) .89Change in MLHFQ, median (IQR) 91 "8 ("21 to 5) 91 "8 ("19 to 0) .44
Safety end points, No. (%)Adverse events 103 78 (76) 113 90 (80) .49Serious adverse events 103 16 (16) 113 25 (22) .22
Abbreviations: IQR, interquartile range; MLHFQ, Minnesota Living with Heart Failure Questionnaire.aA mean value of 95 in each group is expected under the null hypothesis of no treatment effect.bSite investigator identified causes of death were sudden death (n=1), progressive cardiorenal failure (n=1), and noncardiovascular (n=1).
PHOSPHODIESTERASE-5 INHIBITION IN HEART FAILURE
©2013 American Medical Association. All rights reserved. JAMA, March 27, 2013—Vol 309, No. 12 1273
Downloaded From: http://jama.jamanetwork.com/ on 12/04/2014
Sildenefil in Secondary Pulmonary Hypertension due to Systolic Dysfunction may have benefit
Lewis G D et al. Circulation. 2007;116:1555-1562
Copyright © American Heart Association, Inc. All rights reserved.
Soluble Guanylate Cyclase (sGC) Inhibitors• Cinaciguat and Riociguat• Next Class of Agents that work distally to PDE5 inhibitors.
– Antiproliferative, Antiplatelet, and Vasoldilatory• Multiple Clinical Trials support Benefit in 6 minute walk
time, NYHA Class.• Benefit In CTEPH (Riociguat)• Cannot be combined with PDE5 inhibitors
*Dataaremean± SEM.Walkdistancewassomewhatgreater with250mgBID,butthepotentialforincreasedliverinjurycausesthisdosenotto berecommended[125mgBID(n=74)changeinwalkdistance(m):27±75,250mgBID(n=70)changeinwalkdistance(m):46±62].RubinLJetalNEnglJMed. 2002;346:896-903.
Treatment: Endothelin Antagonists
Placebo (n=69)
Bosentan 125/250 mg bid(n=144)
0 4 8 16Weeks
62.5 mg bid 125 or 250 mg bid
Treatment Effect: 44 m (P<0.001)
Δin
6M
WD
(m)
12
0
20
30
40
10
-10
Treatment: ProstacyclinProstanoid RoutesofAdministration Half-life
Epoprostenol(Flolan) Intravenous 6min
Treprostinil(Remodulin) SubcutaneousIntravenousInhaledOral
240min
Iloprost(Ventavis) InhaledIntravenous
20-30min
Beraprost Oral 60min
SideEffects:jawpain,diarrhea,legpain,flushing,plateletinhibition
Treatment: Epoprostenol
N Engl J Med 1996; 334:296-304• 12-week prospective, randomized, multicenter open trial
comparing epoprostenol to conventional therapy • 81 patients with severe primary pulmonary hypertension
(New York Heart Association functional class III or IV).• Exercise capacity improved (Net 6MWT difference:
113m)• PAPmean decrease of 8%, PVR decrease by 21%.• Eight deaths, all in conventional arm (p = 0.003).
How Effective is Monotherapy?
In Clinical Trials:
• 1/2 to 3/4 of patients did not improve > 1 functional class• 1/3 to 1/2 of patients did not achieve a 6MWD > 380
meters
Long Term Response in PH:
• Is incomplete• Is not universal
ACCF/AHA Consensus PAH Treatment Algorithm
Interventional and Surgical Therapy
Lung Transplantation• ISHLT 2006 registry survival: 78% at 1 yr, 49% at 5 yr and
25% at 10 yr.
• IPAH: 1990 accounted for 10% of all transplants, 2004 accounted for 3.9% of all lung transplants.
• Options include: single lung, double lung and heart-lung.
• ISHLT registry suggests no survival benefit of double lung over single lung.
• Heart Lung reserved for congenital heart disease / Eisenmenger
Surgical Therapy for PH: Pulmonary Thromboemblectomy
• Cumulative incidence after PE is up to 3.8%.1• PH therapy may have minimal effect on hemodynamics although
may allow for some symptomatic improval.2• UCSD Remains Highest Volume PTE Referral Center Worldwide,
Performing Roughy 150-200 PTE yearly.
1 NEnglJMed350:22572Circulation.2009;120(13):1248-54
• Pulmonary thromboendarterectomy is the only definitive treatment.
• Operative mortality with surgery can be 4.4% at experienced centers and up to 24%. (Refer to UCSD)
• Persistent pulmonary hypertension (PVR > 6 WU) after surgery is marker for poor outcomes.
Patient Follow Up…• Discharged on:
Hydralazine 100mg tid, – Carvedilol 6.25mg bid.
She was then restarted Sildenafil 20mg tid
• Now only 2L NC. • Ambulating farther, still
using her walker.• She is able to sleep
better and her husband feels she is a new woman.
CardioMEMS™ HF System
40
PA Sensor is permanently implanted in the distal pulmonary
artery via a right-heart catheterization procedure.
Patient-initiated sensor readings are wirelessly
transmitted to anexternal electronics unit
Directly monitoring PA pressure not only enables early detection ofworsening heart failure, but also allows the titration of medications for
proactive and personalized patient management.
The CardioMEMS™ HF System provides ambulatory pulmonary artery (PA) pressure monitoring
Data stored in a secure website for cliniciansto access and review.
Findings:1. HemodynamicsRA 6 mean mm HgRV 100/11 mm HgPA 100/38 mean 61 mm HgPAW Mean 21 mm HgTD CO/CI 6.87 L/min / 3.2 L/min/m2 FICK CO/CI 9.5 L/min / 4.56 L/min/m2 SVO2 74 % , SPO2 94%PVR (Wood units): 5.96
Conclusions• Pulmonary Hypertension can be divided into 5 categories.
Patients with Group I PH (PAH) are potential candidates for PH-specific treatments.
• Catheterization is mandatory to work-up PH. Vasodilator testing should be performed during catheterization.
• Non-invasive testing can provide additional information.
• Specific treatment for PAH includes ERAs (bosentan, ambrisentan), PDE5 inhibitors (sildenafil, tadalafil) and prostacyclins (epoprostenol, treprostinil, iloprost)
• Patients who do not respond to therapy should be referred for lung transplantation/heart lung.
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