1. The Basics of Pulmonary Hypertension
Lana Melendres-Groves
Assistant Professor of Medicine
Director, Adult Pulmonary Hypertension Program
Division Pulmonary & Critical Care Medicine
UNMHSC

2. Objectives Definition of PH/PAH and pathophysiology WHO groups
Natural history of PAH
Clinical presentation/PE/studies
Timing and type of work-up
Who gets therapy
Monitoring of therapy

3. Case #1
27yo woman with PMHx significant for exercise induced asthma and anxiety presenting to the ED after “almost passing out”.
She has a 10mnth old daughter and felt that maybe she just hadn’t gotten into shape after having the baby.
SOB when she tries to jog or walk up her stairs.

4. Case #2
29yo man with HIV presenting to the ED with 2 month h/o of worsening SOB on exertion that has dramatically worsened over the past week to the point that he is now having SOB at rest and feeling dizzy when standing not on any medications.
Recently moved from California and has no information in our system.

5. Case #3
42yo obese woman who doesn’t like doctors that presented after she had worsening fatigue and sob with minimal activity.
She is a hairdresser and overall is upset that she is overweight so never steps on a scale.
She doesn’t take any medications.
Has noticed swelling in her legs.
TTE shows severe RV enlargement and PASP of 95mmHg with rt to left shunt seen.

6. Case #4
65yo woman with little PMHx presenting with SOB and exhaustion. Has no medical problems that she knows of, just retired from teaching for the past 40years in California and relocated to Ruidoso, NM.
Previously playing 18 holes of golf, now only able to walk 15ft before needing to stop and rest.
Massive LEE and decreased mobility of her hands.

7. Case #5
83yo woman has been healthy her whole life now presenting with worsening fatigue with exertion.
Previously able to swim for 30 minutes a day and walk for 30min, now sob with much less. Unable to keep up with her friend.
Experiencing palpitations and chest pressure intermittently.
TTE shows mild RA and RV enlargement with a PASP of 55mmHg

8. Case #6
52yo man with ESRD on HD, htn, DM, CAD, cirrhosis from hep C and prior ETOH abuse and mild COPD, no longer smoking, admitted after missing two HD appointments with profound fluid overload.
Also notes that he has had worsening SOB over the past year and fluid retention.

9. Normal Cardiac Hemodynamics

10. Diagnostic Definition: Pulmonary Hypertension
Rest:
- Mean PAP >25 mmHg
PAH = above + PCWP or LVEDP <15 mmHg
+ PVR >3 WU
Associated with adverse changes
- In the pulmonary vasculature (arteriopathy)
- At the level of the right ventricle (hypertrophy)
No longer part of the definition:
Exercise:
- Mean PAP > 30 mmHg
Genevea convention in 2003 the diagnostic classification was mPAP of >25, included exercise >30 and wedge of <15mmHg with some mention of PVR needing to be >2 or 3 Woods units. At the Dana point conference in 2008 this definition was altered for a variety of reasons. The first was that when reviewing 47 studies on normal patients PAP, at rest the mean was but with exercise there was a wide range especially respective to age (>50 could be as high as 47). Currently, it is felt that mPAP of 8-20 is normal; is a gray zone with insufficient evidence; 25 or greater was PH.
Plexogenic arteriopathy (the parent muscular artery shows medial and intimal thickening) due to inflammatory process from cytokines and chemokines undergoes shear stress which results in damage causing transmural destruction that is repaired by grnaulation tissue= plexiform lesion.
Pleciform lesion= granulation tissue resulting from the parent muscular artery sustaining medial and intimal thickening that combined with shear stress at branch points
Gaine et al. The Lancet, 1998.

11. Aberrant Pathways in PAH

12. Loss of Biological “Balance” in PAH
Vasodilation
Apoptosis
Vasoconstriction
Proliferation
Vasodilation
Apoptosis
Vasoconstriction
Proliferation

13. The Pathobiology Of Pulmonary Hypertension
SMC
Endothelium
elastic
lamina
injury
serum leak
SMC PROLIFERATION
& MIGRATION

15. 5th World Symposium: Classification of Pulmonary Hypertension (Nice, France 2013)
1. Pulmonary Arterial Hypertension 1.1 Idiopathic PAH 1.2 Heritable BMPR ALK1, ENG, SMAD9, CAV1, KCNK Unknown. 1.3 Drug- and toxin-induced 1.4 Associated with Connective tissue disease HIV infection Portal hypertension Congenital heart diseases Schistosomiasis 1’ Pulmonary veno-occlusive disease (PVO) and/or pulmonary capillary hemangiomatosis (PCH) 1’’ Persistent pulm hypertension of the newborn (PPHN) 2. Pulmonary hypertension due to left heart disease 2.1 LV Systolic dysfunction 2.2 LV Diastolic dysfunction 2.3 Valvular disease 2.3 Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies
3. Pulmonary hypertension due to lung diseases and/or hypoxia
Chronic obstructive pulmonary disease
Interstitial lung disease
Other pulmonary diseases with mixed restrictive and obstructive pattern
Sleep-disordered breathing
Alveolar hypoventilation disorders
Chronic exposure to high altitude
Developmental lung disease
4. Chronic thromboembolic pulmonary hypertension (CTEPH)
5. PH with unclear multifactorial mechanisms
Hematologic disorders: chronic hemolytic anemia myeloproliferative disorders splenectomy.
Systemic disorders, sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis
Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders
Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure on dialysis.

16. Back to the Cases What do all the patients presented have in common?
Each patient was found to have pulmonary arterial hypertension after full w/u and diagnosis by right heart catheterization.

17. Pulmonary Arterial Hypertension
Case #1: IPAH
Case #2: PAH associated with HIV

18. PAH Case #3: PAH assoc with drugs/toxins Case #4: PAH assoc with CTD
- The list gets longer and
longer
Case #4: PAH assoc with CTD
- Sometimes the PH presents
before other complications
of the disease

19. Drugs and Toxins Associated PAH
Definite
Possible
Aminorex
Fenfluramine
Dexfenfluramine
Toxic rapeseed oil
Benfluorex
SSRIs
Likely
Amphetamines
L-tryptophan
Methamphetamines
Dasatinib
Cocaine
Phenylpropanolamine
St John’s Wort
Chemotherapeutic agents
Interferon alpha/beta
Amphetamine-like drugs
Unlikely
Oral contraceptives
Estrogen
Cigarette smoking

20. PAH
Case #5: PAH assoc with CHD
Case #6: PAH assoc with portal htn

21. Hemodynamic Classification of PH (mean PAP >25 mm Hg)
Post-capillary PH VC RA RV PA PV LA LV Ao PC
Pulmonary hypertension is defined hemodynamically by a mean pulmonary artery pressure of 25 mmHg or greater at right heart catheterization. Post-capillary pulmonary hypertension is a result of pulmonary venous hypertension due to elevated left sided cardiac filling pressures or pulmonary vein pressures which are passively transmitted to the pulmonary arterial bed raising the pulmonary arterial pressures. In pre-capillary pulmonary hypertension there is excess pulmonary arterial vasoconstriction with or without vascular remodeling resulting in elevated pulmonary arterial pressures and pulmonary vascular resistance. Mixed PH has hemodynamic features of both post-capillary and pre-capillary PH which are explained in further detail in ensuing slides. High-flow states such as can occur with systemic-to-pulmonary shunts, AV fistulas, chronic anemia, thyrotoxicosis and other high cardiac output can lead to pulmonary hypertension.
Mixed PH
High-flow PH
(O2 sat run)
Pre-capillary PH
Diagram courtesy of Teresa De Marco, MD, UCSF

22. Hemodynamic Classification of PH (mean PAP >25 mm Hg)
Post-capillary PH
PCWP>15 mm Hg; PVR normal VC RA RV PA PV
PVP LA
LAP LV Ao PC
With post-capillary PH, the hemodynamic derangements include elevation of the pulmonary arterial wedge pressure above 15 mmHg due to elevation in left sided filling pressures (left ventricular end-diastolic, left atrial, and pulmonary venous pressures). But because the elevation in mean PAP is proportional to the elevation in pulmonary arterial wedge pressure with a normal of PA mean to PAWP gradient when dividing by an adequate cardiac output, the pulmonary vascular resistance will be within a normal range.
LVEDP
Diagram courtesy of Teresa De Marco, MD

23. Hemodynamic Classification of PH (mean PAP >25 mm Hg)
Post-capillary PH
PCWP>15 mm Hg; PVR normal MR VC RA RV PA PV
PVP LA
LAP LV Ao PC
With post-capillary PH, the hemodynamic derangements include elevation of the pulmonary arterial wedge pressure above 15 mmHg due to elevation in left sided filling pressures (left ventricular end-diastolic, left atrial, and pulmonary venous pressures). But because the elevation in mean PAP is proportional to the elevation in pulmonary arterial wedge pressure with a normal of PA mean to PAWP gradient when dividing by an adequate cardiac output, the pulmonary vascular resistance will be within a normal range.
LVEDP
Systemic HTN
AoV disease
Myocardial Disease
Dilated CMP-ischemic/non-ischemic
Hypertrophic CMP
Restrictive/infiltrative CMP
Obesity related CMP
Pericardial disease
Diagram courtesy of Teresa De Marco, MD

24. Hemodynamic Classification of PH (mean PAP >25 mm Hg)
Post-capillary PH
PCWP>15 mm Hg; PVR normal VC RA RV PA PV
PVP LA LV Ao PC
With post-capillary PH, the hemodynamic derangements include elevation of the pulmonary arterial wedge pressure above 15 mmHg due to elevation in left sided filling pressures (left ventricular end-diastolic, left atrial, and pulmonary venous pressures). But because the elevation in mean PAP is proportional to the elevation in pulmonary arterial wedge pressure with a normal of PA mean to PAWP gradient when dividing by an adequate cardiac output, the pulmonary vascular resistance will be within a normal range.
PV Compression
Diagram courtesy of Teresa De Marco, MD

25. Hemodynamic Classification of PH (mean PAP >25 mm Hg)
PAH
Lung diseases +/- hypoxemia
CTEPH { VC RA RV PA PV LA LV Ao { PC
With pre-capillary PH, since the filling pressures on the left side of the heart and the pulmonary veins are normal, the pulmonary arterial wedge pressure is 15 mmHg or less. But since the mean PA pressure increase is out of proportion to the PAWP, the PA mean to PAW pressure gradient and the pulmonary vascular resistance is elevated greater than 3 Wood units due to excess vasoconstriction, with or without remodeling of the pulmonary arterial bed. Etiologies of pre-capillary PH include, the Group 1, 3, and 4 diseases exclusive of concomitant left heart disease , and some of the Group 5 diseases exclusive of pulmonary vein compression.
Pre-capillary PH
PCWP <15 mm Hg;
PVR >3 woods units
Diagram courtesy of Teresa De Marco, MD

26. 5th World Symposium: Classification of Pulmonary Hypertension (Nice, France 2013)
1. Pulmonary Arterial Hypertension 1.1 Idiopathic PAH 1.2 Heritable BMPR ALK1, ENG, SMAD9, CAV1, KCNK Unknown. 1.3 Drug- and toxin-induced 1.4 Associated with Connective tissue disease HIV infection Portal hypertension Congenital heart diseases Schistosomiasis 1’ Pulmonary veno-occlusive disease (PVO) and/or pulmonary capillary hemangiomatosis (PCH) 1’’ Persistent pulm hypertension of the newborn (PPHN) 2. Pulmonary hypertension due to left heart disease 2.1 LV Systolic dysfunction 2.2 LV Diastolic dysfunction 2.3 Valvular disease 2.3 Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies
3. Pulmonary hypertension due to lung diseases and/or hypoxia
Chronic obstructive pulmonary disease
Interstitial lung disease
Other pulmonary diseases with mixed restrictive and obstructive pattern
Sleep-disordered breathing
Alveolar hypoventilation disorders
Chronic exposure to high altitude
Developmental lung disease
4. Chronic thromboembolic pulmonary hypertension (CTEPH)
5. PH with unclear multifactorial mechanisms
Hematologic disorders: chronic hemolytic anemia myeloproliferative disorders splenectomy.
Systemic disorders, sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis
Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders
Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure on dialysis.

27. Natural History of PAH: NIH Registry1,2
69%
56%
46%
Percent survival
38%
Predicted survival
Predicted survival*
Years
NIH = National Institutes of Health. Predicted survival according to the NIH equation. Predicted survival rates were 69%, 56%, 46%, and 38% at 1, 2, 3, and 4 years, respectively. The numbers of patients at risk were 231, 149, 82, and 10 at 1, 2, 3, and 4 years, respectively. *Patients with primary pulmonary hypertension, now referred to as idiopathic pulmonary hypertension.
1. Rich et al. Ann Intern Med. 1987;107: D’Alonzo et al. Ann Intern Med. 1991;115:

28. Survival by PAH Etiology
Prognosis in Mixed Treated/Untreated Cohorts
Percent survival
Years
CHD = congenital heart disease; CVD = collagen vascular disease; HIV = human immunodeficiency virus; PAH = pulmonary arterial hypertension; PPH = primary pulmonary hypertension; PoPH = portopulmonary hypertension.
McLaughlin et al. Chest. 2004;126:78S-92S

29. Symptoms Breathlessness Chest pain Dizziness Syncope Loss of energy
Edema
Dry cough
Raynaud’s phenomenon

30. Physical Exam Findings in PAH
Increased jugular venous pressure
Accentuated split S2
Presence S3
TR murmur- heard best LL sternal border
Edema and/or ascites
Hepatojugular reflux
Skin- telangiectasias, Raynaud’s, Sclerodactyly
Height of jugular venous distension (Case 7 2L). PAH results in an elevation in jugular venous pressure, indicating an increase in right atrial pressure. To measure jugular venous distention, identify the top of the oscillating jugular vein waveforms with the patient in a semirecumbent position (usually a 45º angle). The distance from the sternal angle to the top of the waveform is measured in centimeters. By convention, 5 cm is then added to this measurement, as the right atrium is approximately 5 cm below the sternal angle. Four centimeters above the sternal angle is the upper limit of normal for jugular venous distension and this corresponds to a jugular venous pressure of 9 cm H20 (4 cm + 5 cm).
S2 (Case 6 or 7: 3L). The second heart sound is frequently accentuated in patients with pulmonary hypertension. This is because the intensity of P2 is dependent on the velocity of blood coursing back toward the right ventricle after ventricular contraction and the suddenness in which that motion is arrested by the closing valve. In patients with PAH, the diastolic pressure within the pulmonary artery is high and therefore the velocity of blood moving toward the tricuspid valve is increased, resulting in an accentuated P2.
 S3. An S3 occurs in early diastole during the ventricular rapid filling stage, following the opening of the atrioventricular valves. While an S3 heard in children or young adults is often a normal finding, in older individuals, patients with a depressed left ventricular ejection fraction, and patients with PAH an S3 is a sign of increased diastolic ventricular filling pressure and ventricular failure.5 The sound is generated by the tensing of the chordae tendineae. A right-sided S3 (more typical of patients with PAH) is best appreciated with the bell of the stethoscope placed over the tricuspid region with the patient in the supine position and during inspiration.
Tricuspid Regurgitation (Case 7: 2L or 3L). Perhaps the most common and recognizable murmur of PAH is tricuspid regurgitation. A tricuspid regurgitation murmur is best heard along the lower left sternal border. It can radiate to the right of the sternum and is high pitched and blowing in quality. The murmur of tricuspid regurgitation is holosystolic and can be augmented by inspiration, increasing return of venous blood to the right ventricle.
Clubbing (Case 4: Insp Hands). Clubbing is a descriptive term, referring to the bulbous, uniform swelling of the soft tissue of the terminal phalanx of a digit resulting in the loss of the normal angle between the nail and the nail bed. Although clubbing is a common physical finding in many pathologic processes, the pathophysiologic mechanism of this finding remains unclear. The earliest forms of clubbing are characterized by increased glossiness of the distal skin of the finger and the root of the nail. There is then obliteration of the normal angle between the base of the nail and the skin. The soft tissue of the pulp becomes hypertrophied and the nail root floats freely. On examination one may note a spongy sensation as the nail is pressed toward the nail plate. The sponginess results from increased fibrovascular tissue between the nail and the phalanx. The skin at the base of the nail may be smooth and shiny.
Clubbing of the digits is common in congenital heart diseases that cause pulmonary hypertension (atrial septal defects, ventricular septal defects). It is an unusual finding in other forms of pulmonary hypertension.
Edema (Case 6: Insp). Edema of the lower extremities is a common finding in advanced pulmonary hypertension resulting in right heart dysfunction. Firm pressure on the pretibial region for 10 to 15 seconds may be necessary for detection of edema in less severe disease.
Hepatojugular reflux. Firm pressure over the liver (or other areas of the abdomen) can cause an increase in jugular venous distension. This is indicative of right heart failure.
Ascites. Abdominal distension with shifting dullness or a fluid wave is a sign of ascites familiar to most clinicians. The presence of ascites tends to be a late finding in patients with PAH and is indicative of severe right ventricular dysfunction and elevated right atrial pressure. Ascites is a common finding in patients with portal hypertension related to hepatic disease. As portal hypertension is recognized as being associated with pulmonary hypertension, this physical finding may provide a clue toward the etiology of the elevated pulmonary pressures.
Raynaud Phenomenon (? Case 4: Insp Hands). The Raynaud phenomenon is an occasional finding in patients with idiopathic pulmonary arterial hypertension (IPAH) and a common finding in individuals with PAH associated with connective tissue disease, in particular, limited-stage scleroderma or CREST (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia).

31. CXR

32. CT Chest
2.6cm on the right pulm artery

33. Pulmonary Arterial Hypertension: Detection and Diagnosis
Is there a reason to suspect PAH
Clinical history (symptoms, risk factors, family Hs.),
Exam, CXR, ECG
yes no
Is PAH likely?
Echo
Rationale
TRV to measure RVSP; RVE; RAE; RV Dysfunction:
No further
evaluation
for PAH no
yes
Is PAH due to LH disease?
Echo
yes
Dx LV systolic, diastolic dysfunction; valvular disease:
Appropriate treatment and further evaluation
if necessary, including R&LHC no
Dx abnormal morphology; shunt:
Surgery. Medical treatment of PAH or evaluation for
further definition or other contributing causes,
including R&LHC if necessary
Is PAH due to CHD?
Echo with contrast
yes no
This detection and diagnosis algorithm was published in a recent Chest supplement focused on diagnosis and treatment of pulmonary hypertension. It provides a rigorous strategy to diagnose PH, and determine it’s cause which is key to determining the appropriate treatment approach. In some cases, medical history and/or the presence of risk factors will afford a re-order of this approach to initially hone in on and either confirm or eliminate the suspected cause.
Dx Scleroderma, SLE, other CTD, HIV: Medical
treatment of PAH and further evaluation for
other contributing causes, including RHC
Is PAH due to CTD, HIV?
Serologies
yes no
Is chronic PE suspected?
VQ scan
McGoon et al. Chest 2004;126:14S-34S

34. Pulmonary Arterial Hypertension: Detection and Diagnosis
Is chronic PE suspected?
VQ scan
yes
Is chronic PE confirmed and operable?
Pulmonary angiogram
yes no
VQ normal
Anatomic definition (CT, MRI may provide additional useful
but not definitive information):
Thromboendarterectomy if appropriate or medical
treatment; clotting evaluation; a/c
Is PAH due to lung disease
or hypoxemia?
PFTs, arterial saturation no
yes
Dx parenchymal lung disease, hypoxemia, or sleep disorder:
Medical treatment, oxygen, positive pressure breathing
as appropriate, and further evaluation for other
contributing causes, including RHC if necessary no
Document exercise capacity regardless of cause of PH:
Establish baseline, prognosis and document progression/
response to treatment with serial reassessments
What limitations are caused by
the PAH?
Functional class; 6-minute walk
test
..... The final step in diagnosing PAH is right heart catheterization
Document PA and RA pressures, PCWP (LV or LA pressure
if PCWP unobtainable or uncertain), transpulmonary gradient
CO, PVR, SvO2, response to vasodilators:
Confirm PAH, or IPAH if no other cause identified
Discuss genetic testing and counseling of IPAH
What are the precise pulmonary
hemodynamics?
RHC
McGoon et al. Chest 2004;126:14S-34S

35. NYHA Classification

36. Right Heart Catheterization is the Diagnostic Gold Standard
Saturations
Rule Out Shunts
Intra-cardiac
Intra-Pulmonary
Hemodynamics
RAP
mPAP
PCWP
Rule out left sided heart disease
CO/CI
PVR
Angiography
Vessel properties
CTEPH
Vasodilator Response
Right heart catheterization is the diagnostic gold standard. This evaluation is necessary to sufficiently rule out secondary causes of disease and left sided heart disease. This evaluation is also necessary to obtain the critical measures of cardiac index and calculated PVR which have significant value prognostically.
RHC can also Prognosticate!
Rich et al. WHO Symposium on PPH. Evian, France,1998.

39. Therapeutic Pathways

40. Therapies
The only groups that have been approved for the specialized medications for pulmonary hypertension are Group 1 (pulmonary arterial hypertension/PAH) and Group 4 (CTEPH)
The other groups require treatment of the underlying condition causing the elevated pressures.

41. Therapeutic Options for PAH
Traditional therapies
FDA approved for PAH
Supplemental O2
Diuretics
Oral vasodilators
(CCB)
Anticoagulants
warfarin
Inotropic agents
Digitalis
Prostanoids
Epoprostenol (flolan/veletri)
Treprostinil (IV/SQ/Inhaled)
Inhaled Iloprost
Oral treprostinil (Orenitram)
ERA’s
Bosentan
Ambrisentan
Macitentan
PDE-5 Inhibitors
Sildenafil
Tadalafil
Guanylate Cyclase Stimulator
Riociguat

42. PAH Treatments ― a Historical Overview
IV treprostinil
CCB, anticoagulation, digitalis, diuretics
Riociguat
Macitentan
Orenitram
sildenafil
SC treprostinil
ambrisentan
epoprostenol
veletri
Iloprost
bosentan
<1995
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
tadalafil
Inhaled treprostinil

43. Prostanoids
Prostacyclin (PGI2)- member of the eicosanoids family, inhibits platelet activation and effective vasodilator.
Prostacyclin released by healthy endothelial cells.
Deficiency in PAH patients
Several routes of administration:
IV/parenteral, SQ, Inhaled, oral

44. IV Prostanoids Epoprostenol- Flolan and Veletri
Half-life approximately 2-5min
Treprostinil- Remodulin
Half-life several hours
Both administered in ng/kg/min
Dosing never changes even if weight does, start weight remains the same throughout duration of therapy.

45. Single Lumen Hickman Catheter
Never stop infusion
Never draw labs from line
Never flush

46. CADD Legacy Pump

47. SQ Prostanoids Treprostinil (Remodulin) SQ
Small catheter placed in SQ tissue of the abdomen
Site changed every 3-5 weeks

48. Inhaled Prostanoids Iloprost (Ventavis) Treprostinil (Tyvaso)
6-9 treatments per day
Fewer systemic effects than IV
Treprostinil (Tyvaso)
QID and dosed as breaths
e.g. 3 breaths each inhalation that is increased by increments of 3 up to 9.
Single person nebulizer
Pt must bring in machine from home if hospitalized

49. Inhaled Prostanoids
Tyvaso
Ventavis

50. Oral Prostacyclin Treprostinil (Orinetram)
Antiplatelet and vasodilatory actions, including pulmonary vasodilation
FREEDOM-M trial (only study of 3 that met endpoint)
Available as 0.125mg, 0.25mg, 1mg, 2.5mg ER BID
Starting dose 0.25mg bid and titrated Q3d as tolerated
Only showed improved 6MWD as monotherapy

51. Endothelin Receptor Antagonist
Endothelian-1 (ET-1) levels are increased in PAH and found in the precapillary pulmonary microvasculature which is the site of the increased vascular resistance in PAH.
Two G protein-coupled receptors for ET-1 have been described: “ETA” and “ETB”
Bosentan- dual antagonist
62.5 to 125mg BID
Ambrisentan- Selective ETA receptor
5-10mg daily
Macitentan- Dual but with increased selectivity for ETA
10mg daily
Activation of the ETA receptor on smooth muscle cells, pericytes, and fibroblasts results in vasoconstriction and proliferation in vitro. ETB receptor activation on these cells are inconsistent, and vary with the cell type,

52. Phosphodiestrase-5 Inhibitors
PDE5 Inhibitor- blocks the degradative action of phosphodiesterdase type 5 on cyclic GMP in smooth muscle cells resulting in vasodilation of the vessels.
Sildenafil mg TID
Tadalafil mg daily

53. Guanylate Cyclase Stimulator
Riociguat has a dual mode of action
Synergist with endogenous nitric oxide
Directly stimulating guanylate cyclase independent of NO availability
Phase 3 trial in the NEJM: 12 wk double-blind randomized placebo-controlled trial at 124 centers in 30 countries for PAH patients showed improved walk distance and improvement in secondary end-points.

54. Cost per Year Ambrisentan (Letairis)- $76,047.60
Bosentan (Tracleer)- $76,543.20
Tadalafil (Adcirca)- $18,316.80
Epoprostenol (Flolan)- $34,170
Oral Treprostinil (Orinetram)- $500,000
Triple therapy can be over $130, 000/yr just for specialty medications.

55. Ongoing Management
Standard of care is for PAH patients to be established with a PH center for ongoing care.
Multidisciplinary approach to care
Patients on advance therapies to be seen every 3 months if not more frequently
Ongoing escalation of care, more evidence coming out showing the importance of combination therapies.

56. Questions?