Pulmonary Arterial Hypertension: Review and Updates

1. Pulmonary Arterial Hypertension: Review and Updates Veronica Franco, MD, MSPH Section of Pulmonary HypertensionSection of Heart Failure and TransplantationOhio State University

2. Today… Nomenclature review - classification Diagnosis Prognosis Treatment

3. Today… Nomenclature review - classification Diagnosis Prognosis Treatment

4. Is it Primary vs Secondary Pulmonary Hypertension?

5. Pulmonary Hypertension Is a Disease of Triggers

6. Pulmonary hypertension (PH) with left heart disease – WHO Class 2 Trigger: High LA Pressure PH with lung disease/hypoxemia - WHO Class 3 Trigger: Hypoxemia and Parenchyma Distortion PH due to chronic thrombotic and/or embolic disease – WHO Class 4 Trigger: Obstruction The first several points I would like to make are ones regarding the recent changes in nomenclature for pulmonary vascular diseases. I think its vital to remember that all forms of pulmonary hypertension are not the same pathophysiologically and hence their response to treatment is not universally equivalent. This is important particularly in the context of modern pulmonary vasodilator therapy, because these drugs which are potentially life saving for some patients with particular forms of pulmonary hypertension can be uniformly dangerous to use in other forms. With that said, lets take a look at the modern classification scheme for pulmonary hypertension. Its important to note that this constellation of diseases is are no longer classified as primary or secondary, but are grouped according to commonality among underlying aetiologies, genetic patterns and response to pulmonary vasodilators. The first several points I would like to make are ones regarding the recent changes in nomenclature for pulmonary vascular diseases. I think its vital to remember that all forms of pulmonary hypertension are not the same pathophysiologically and hence their response to treatment is not universally equivalent. This is important particularly in the context of modern pulmonary vasodilator therapy, because these drugs which are potentially life saving for some patients with particular forms of pulmonary hypertension can be uniformly dangerous to use in other forms. With that said, lets take a look at the modern classification scheme for pulmonary hypertension. Its important to note that this constellation of diseases is are no longer classified as primary or secondary, but are grouped according to commonality among underlying aetiologies, genetic patterns and response to pulmonary vasodilators.

7. The 2003 Venice Classification of PAH - WHO Class 1 Pulmonary Arterial Hypertension Familial PAH (FPAH) Idiopathic PAH (IPAH) Associated PAH (APAH) Connective tissue disease (CTD) Human immunodeficiency virus (HIV) Portal hypertension Anorexigens Congenital heart disease (CHD) Persistent pulmonary hypertension of the newborn (PPHN) PAH with venule/capillary involvement The first several points I would like to make are ones regarding the recent changes in nomenclature for pulmonary vascular diseases. I think its vital to remember that all forms of pulmonary hypertension are not the same pathophysiologically and hence their response to treatment is not universally equivalent. This is important particularly in the context of modern pulmonary vasodilator therapy, because these drugs which are potentially life saving for some patients with particular forms of pulmonary hypertension can be uniformly dangerous to use in other forms. With that said, lets take a look at the modern classification scheme for pulmonary hypertension. Its important to note that this constellation of diseases is are no longer classified as primary or secondary, but are grouped according to commonality among underlying aetiologies, genetic patterns and response to pulmonary vasodilators. The first several points I would like to make are ones regarding the recent changes in nomenclature for pulmonary vascular diseases. I think its vital to remember that all forms of pulmonary hypertension are not the same pathophysiologically and hence their response to treatment is not universally equivalent. This is important particularly in the context of modern pulmonary vasodilator therapy, because these drugs which are potentially life saving for some patients with particular forms of pulmonary hypertension can be uniformly dangerous to use in other forms. With that said, lets take a look at the modern classification scheme for pulmonary hypertension. Its important to note that this constellation of diseases is are no longer classified as primary or secondary, but are grouped according to commonality among underlying aetiologies, genetic patterns and response to pulmonary vasodilators.

8. Importance of Classification: Why do it? Efficacy: What’s the trigger? Can you change it? Safety: Can it hurt the patient? Cost: How much are we spending for limited efficacy and small changes in QOL? The first several points I would like to make are ones regarding the recent changes in nomenclature for pulmonary vascular diseases. I think its vital to remember that all forms of pulmonary hypertension are not the same pathophysiologically and hence their response to treatment is not universally equivalent. This is important particularly in the context of modern pulmonary vasodilator therapy, because these drugs which are potentially life saving for some patients with particular forms of pulmonary hypertension can be uniformly dangerous to use in other forms. With that said, lets take a look at the modern classification scheme for pulmonary hypertension. Its important to note that this constellation of diseases is are no longer classified as primary or secondary, but are grouped according to commonality among underlying aetiologies, genetic patterns and response to pulmonary vasodilators. The first several points I would like to make are ones regarding the recent changes in nomenclature for pulmonary vascular diseases. I think its vital to remember that all forms of pulmonary hypertension are not the same pathophysiologically and hence their response to treatment is not universally equivalent. This is important particularly in the context of modern pulmonary vasodilator therapy, because these drugs which are potentially life saving for some patients with particular forms of pulmonary hypertension can be uniformly dangerous to use in other forms. With that said, lets take a look at the modern classification scheme for pulmonary hypertension. Its important to note that this constellation of diseases is are no longer classified as primary or secondary, but are grouped according to commonality among underlying aetiologies, genetic patterns and response to pulmonary vasodilators.

9. Efficacy: What’s the trigger? Can you change it? The first several points I would like to make are ones regarding the recent changes in nomenclature for pulmonary vascular diseases. I think its vital to remember that all forms of pulmonary hypertension are not the same pathophysiologically and hence their response to treatment is not universally equivalent. This is important particularly in the context of modern pulmonary vasodilator therapy, because these drugs which are potentially life saving for some patients with particular forms of pulmonary hypertension can be uniformly dangerous to use in other forms. With that said, lets take a look at the modern classification scheme for pulmonary hypertension. Its important to note that this constellation of diseases is are no longer classified as primary or secondary, but are grouped according to commonality among underlying aetiologies, genetic patterns and response to pulmonary vasodilators. The first several points I would like to make are ones regarding the recent changes in nomenclature for pulmonary vascular diseases. I think its vital to remember that all forms of pulmonary hypertension are not the same pathophysiologically and hence their response to treatment is not universally equivalent. This is important particularly in the context of modern pulmonary vasodilator therapy, because these drugs which are potentially life saving for some patients with particular forms of pulmonary hypertension can be uniformly dangerous to use in other forms. With that said, lets take a look at the modern classification scheme for pulmonary hypertension. Its important to note that this constellation of diseases is are no longer classified as primary or secondary, but are grouped according to commonality among underlying aetiologies, genetic patterns and response to pulmonary vasodilators.

10. Safety: Can it hurt the patient? LV dysfunction: Pulmonary edema ILD/COPD: Worsen V/Q mismatch CTEPH: Delay referral for thromboendarterectomy The first several points I would like to make are ones regarding the recent changes in nomenclature for pulmonary vascular diseases. I think its vital to remember that all forms of pulmonary hypertension are not the same pathophysiologically and hence their response to treatment is not universally equivalent. This is important particularly in the context of modern pulmonary vasodilator therapy, because these drugs which are potentially life saving for some patients with particular forms of pulmonary hypertension can be uniformly dangerous to use in other forms. With that said, lets take a look at the modern classification scheme for pulmonary hypertension. Its important to note that this constellation of diseases is are no longer classified as primary or secondary, but are grouped according to commonality among underlying aetiologies, genetic patterns and response to pulmonary vasodilators. The first several points I would like to make are ones regarding the recent changes in nomenclature for pulmonary vascular diseases. I think its vital to remember that all forms of pulmonary hypertension are not the same pathophysiologically and hence their response to treatment is not universally equivalent. This is important particularly in the context of modern pulmonary vasodilator therapy, because these drugs which are potentially life saving for some patients with particular forms of pulmonary hypertension can be uniformly dangerous to use in other forms. With that said, lets take a look at the modern classification scheme for pulmonary hypertension. Its important to note that this constellation of diseases is are no longer classified as primary or secondary, but are grouped according to commonality among underlying aetiologies, genetic patterns and response to pulmonary vasodilators.

11. Cost: How much are we spending for limited efficacy and small changes in QOL? Bosentan: ~35-40k per year Sildenafil: ~12-15k per year Inhaled Iloprost: ~60k per year IV Prostacyclins: ~60-120k per year The first several points I would like to make are ones regarding the recent changes in nomenclature for pulmonary vascular diseases. I think its vital to remember that all forms of pulmonary hypertension are not the same pathophysiologically and hence their response to treatment is not universally equivalent. This is important particularly in the context of modern pulmonary vasodilator therapy, because these drugs which are potentially life saving for some patients with particular forms of pulmonary hypertension can be uniformly dangerous to use in other forms. With that said, lets take a look at the modern classification scheme for pulmonary hypertension. Its important to note that this constellation of diseases is are no longer classified as primary or secondary, but are grouped according to commonality among underlying aetiologies, genetic patterns and response to pulmonary vasodilators. The first several points I would like to make are ones regarding the recent changes in nomenclature for pulmonary vascular diseases. I think its vital to remember that all forms of pulmonary hypertension are not the same pathophysiologically and hence their response to treatment is not universally equivalent. This is important particularly in the context of modern pulmonary vasodilator therapy, because these drugs which are potentially life saving for some patients with particular forms of pulmonary hypertension can be uniformly dangerous to use in other forms. With that said, lets take a look at the modern classification scheme for pulmonary hypertension. Its important to note that this constellation of diseases is are no longer classified as primary or secondary, but are grouped according to commonality among underlying aetiologies, genetic patterns and response to pulmonary vasodilators.

12. Pulmonary Arterial Hypertension Classification Diagnosis Prognosis Treatment

13. Schema for Patient Evaluation 

14. RHC Diagnosis PAH

15. Cardiac Catheterization to Assess Severity and Prognosis of PAH To measure wedge pressure or LVEDP Scrutinize wedge tracings!!!! Wedge sat; End expiration To exclude or evaluate CHD To establish severity and prognosis To test vasodilator therapy

16. Pulmonary Arterial Hypertension Mean Pulmonary artery = 25 mmHg (rest) = 30 mmHg (exercise). Wedge pressure = 15 mmHg PVR > 3 Woods units

17. Pulmonary Venous Hypertension: Valvular heart disease (HD) Hypertensive HD Cardiomyopathies Transmitted pressure results in reactive vasoconstriction

18. Pulmonary Arterial Hypertension Classification Diagnosis Prognosis Treatment

19. Natural History of PAH: NIH Registry1,2

20. Survival by PAH Etiology

21. PAH Determinants of Risk

22. Impact of Functional Class on Survival Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy.

23. Correlation of Six-minute-walk Test and WHO Functional Class *p<0.05 vs control subjects †p<0.05 vs WHO functional class II ‡p<0.05 vs WHO functional class III Correlation of atrial natriuretic peptide (ANP) with baseline hemodynamic parameters. Open circles = patients with PPH; closed circles = patients with NPPH. Atrial natriuretic peptide levels were from pulmonary artery samples. cGMP = pulmonary artery cyclic guanylate monophosphate concentration; CI = cardiac index; mPAP = mean pulmonary arterial pressure; mSAP = mean systemic arterial pressure; PVR = pulmonary vascular resistance; RAP = right atrial pressure; RVEF = right ventricular ejection fraction; SvO2 = central venous oxygen saturation. Correlation of atrial natriuretic peptide (ANP) with baseline hemodynamic parameters. Open circles = patients with PPH; closed circles = patients with NPPH. Atrial natriuretic peptide levels were from pulmonary artery samples. cGMP = pulmonary artery cyclic guanylate monophosphate concentration; CI = cardiac index; mPAP = mean pulmonary arterial pressure; mSAP = mean systemic arterial pressure; PVR = pulmonary vascular resistance; RAP = right atrial pressure; RVEF = right ventricular ejection fraction; SvO2 = central venous oxygen saturation.

24. Correlation of Six-minute-walk Test With Survival in PPH Correlation of atrial natriuretic peptide (ANP) with baseline hemodynamic parameters. Open circles = patients with PPH; closed circles = patients with NPPH. Atrial natriuretic peptide levels were from pulmonary artery samples. cGMP = pulmonary artery cyclic guanylate monophosphate concentration; CI = cardiac index; mPAP = mean pulmonary arterial pressure; mSAP = mean systemic arterial pressure; PVR = pulmonary vascular resistance; RAP = right atrial pressure; RVEF = right ventricular ejection fraction; SvO2 = central venous oxygen saturation. Correlation of atrial natriuretic peptide (ANP) with baseline hemodynamic parameters. Open circles = patients with PPH; closed circles = patients with NPPH. Atrial natriuretic peptide levels were from pulmonary artery samples. cGMP = pulmonary artery cyclic guanylate monophosphate concentration; CI = cardiac index; mPAP = mean pulmonary arterial pressure; mSAP = mean systemic arterial pressure; PVR = pulmonary vascular resistance; RAP = right atrial pressure; RVEF = right ventricular ejection fraction; SvO2 = central venous oxygen saturation.

25. Plasma BNP as a Prognostic Indicator of Mortality in Patients With PPH

26. Predicting Survival andFollowing Therapy Clinical parameters functional class exercise capacity neurohormones Hemodynamics Imaging right ventricle: function and size pulmonary artery remodeling (future)

27. Schematic Progression of PAH This slide represents a synthesis of human and animal models of PAH that shows a putative model of disease progression. Pulmonary hypertension may be classified into 3 rough categories, pre-symptomatic/compensating, symptomatic/decompensating, and declining/decompensated. In this hypothetical model, as the vascular pathology progresses (proliferation of intima, hyperplasia of the SMC, and adventicial fibrosis), PVR increases and pulmonary artery pressure rises in concert in order to maintain CO. As long as the RV is able to compensate for the resistance, pressure continues to increase as PVR increases. The increased RV work-load causes the RV to hypertrophy and its efficiency falls, right heart failure ensues, and PAP will fall as the patient decompensates. Failure to maintain CO leads to the symptoms of the disease and ultimately right heart dysfunction and death CO- Cardiac Output PAP- Pulmonary arterial pressure PVR- Pulmonary vascular resistanceThis slide represents a synthesis of human and animal models of PAH that shows a putative model of disease progression. Pulmonary hypertension may be classified into 3 rough categories, pre-symptomatic/compensating, symptomatic/decompensating, and declining/decompensated. In this hypothetical model, as the vascular pathology progresses (proliferation of intima, hyperplasia of the SMC, and adventicial fibrosis), PVR increases and pulmonary artery pressure rises in concert in order to maintain CO. As long as the RV is able to compensate for the resistance, pressure continues to increase as PVR increases. The increased RV work-load causes the RV to hypertrophy and its efficiency falls, right heart failure ensues, and PAP will fall as the patient decompensates. Failure to maintain CO leads to the symptoms of the disease and ultimately right heart dysfunction and death CO- Cardiac Output PAP- Pulmonary arterial pressure PVR- Pulmonary vascular resistance

28. Schematic Progression of PAH This slide represents a synthesis of human and animal models of PAH that shows a putative model of disease progression. Pulmonary hypertension may be classified into 3 rough categories, pre-symptomatic/compensating, symptomatic/decompensating, and declining/decompensated. In this hypothetical model, as the vascular pathology progresses (proliferation of intima, hyperplasia of the SMC, and adventicial fibrosis), PVR increases and pulmonary artery pressure rises in concert in order to maintain CO. As long as the RV is able to compensate for the resistance, pressure continues to increase as PVR increases. The increased RV work-load causes the RV to hypertrophy and its efficiency falls, right heart failure ensues, and PAP will fall as the patient decompensates. Failure to maintain CO leads to the symptoms of the disease and ultimately right heart dysfunction and death CO- Cardiac Output PAP- Pulmonary arterial pressure PVR- Pulmonary vascular resistanceThis slide represents a synthesis of human and animal models of PAH that shows a putative model of disease progression. Pulmonary hypertension may be classified into 3 rough categories, pre-symptomatic/compensating, symptomatic/decompensating, and declining/decompensated. In this hypothetical model, as the vascular pathology progresses (proliferation of intima, hyperplasia of the SMC, and adventicial fibrosis), PVR increases and pulmonary artery pressure rises in concert in order to maintain CO. As long as the RV is able to compensate for the resistance, pressure continues to increase as PVR increases. The increased RV work-load causes the RV to hypertrophy and its efficiency falls, right heart failure ensues, and PAP will fall as the patient decompensates. Failure to maintain CO leads to the symptoms of the disease and ultimately right heart dysfunction and death CO- Cardiac Output PAP- Pulmonary arterial pressure PVR- Pulmonary vascular resistance

29. Goals of Therapy Improve symptoms 6-minute walk (>380 m) functional class (I or II) CPET (VO2 max >10.4) quality of life Improve hemodynamics Improve survival

30. What Drug and When

31. PAH Treatments?a Historical Overview

32. When to use a Calcium Antagonist ? Nifedipine 30mg daily or Diltiazem 120 mg dailyNifedipine 30mg daily or Diltiazem 120 mg daily

33. Figure 2: Kaplan-Meier estimates in the 57/70 acute responder patients who survived after one year onward on calcium-channel blockers (CCB). The number of patients included in the “Long-term CCB failure” subgroup was only 19/32, the 13 remaining patients being dead (n=6), transplanted (n=4) or lost to follow-up (n=3, considered as “dead” in the analysis) within the first year. The difference between the group of long-term CCB responders (yellow line) and that of patients who failed on CCB (blue line) was highly significant (p=0.0007 by the Cox-Mantel log-rank test). Figure 2: Kaplan-Meier estimates in the 57/70 acute responder patients who survived after one year onward on calcium-channel blockers (CCB). The number of patients included in the “Long-term CCB failure” subgroup was only 19/32, the 13 remaining patients being dead (n=6), transplanted (n=4) or lost to follow-up (n=3, considered as “dead” in the analysis) within the first year. The difference between the group of long-term CCB responders (yellow line) and that of patients who failed on CCB (blue line) was highly significant (p=0.0007 by the Cox-Mantel log-rank test).

34. Legend of figure 1 : algorithm for management of PAH    1)     The algorithm is restricted to patient in NYHA functional class III or IV because they represent the largest population. In addition, for class I or II very few data are available. These different treatments have been evaluated mainly in sporadic PAH, and in PAH associated with scleroderma or due to anorexigens. To extrapolate these recommendations to the other PAH subgroups should be made with caution. 2)     A positive acute response to vasodilators is defined by a near normalization of pulmonary artery pressure (mean PAP < 35 mmHg associated with a normal or high cardiac output) during acute challenge with NO, PGI2 or adenosine. 3)     Sustained response to CCB is defined as patients being in NYHA functional class I or II with near normal hemodynamic after several months of treatment on CCB only. 4)     Most experts consider that NYHA functional class IV patients in unstable condition should be treated with IV epoprostenol (survival improvement, worldwide experience and rapidity of action). 5)     In patients in functional class III, first line therapy may include oral endothelin receptor antagonists or prostanoids analogues. However, in such patient, it is also adequate to use IV epoprostenol. Legend of figure 1 : algorithm for management of PAH    1)     The algorithm is restricted to patient in NYHA functional class III or IV because they represent the largest population. In addition, for class I or II very few data are available. These different treatments have been evaluated mainly in sporadic PAH, and in PAH associated with scleroderma or due to anorexigens. To extrapolate these recommendations to the other PAH subgroups should be made with caution. 2)     A positive acute response to vasodilators is defined by a near normalization of pulmonary artery pressure (mean PAP < 35 mmHg associated with a normal or high cardiac output) during acute challenge with NO, PGI2 or adenosine. 3)     Sustained response to CCB is defined as patients being in NYHA functional class I or II with near normal hemodynamic after several months of treatment on CCB only. 4)     Most experts consider that NYHA functional class IV patients in unstable condition should be treated with IV epoprostenol (survival improvement, worldwide experience and rapidity of action). 5)     In patients in functional class III, first line therapy may include oral endothelin receptor antagonists or prostanoids analogues. However, in such patient, it is also adequate to use IV epoprostenol.

35. What is the Optimal Treatment Strategy?

36. Vascular Pathology: Balance of Powers

38. Prostacyclins Intravenous (epoprostenol, treprostinil)* Subcutaneous (treprostinil*) Inhaled (iloprost*, treprostinil†) Oral (beraprost‡)

39. Epoprostenol: Indications NYHA Class III or IV PAH Contraindicated in severe LV systolic dysfunction (LVEF <30%) Cost ~ $60,000 to $120,000/year depending on dose

40. Important Points: Epoprostenol Functional capacity, hemodynamics, and survival are improved Baseline NYHA functional class is predictor of survival Response after 12 to 18 months can predict subsequent outcomes Most benefit apparent in first 12 to 18 months Dosing: Outcomes with moderate dosing are the same as with aggressive dosing

41. IV Treprostinil Approved by FDA in January 2005 Has safety (longer half-life) and convenience advantages (no mixing or cold packs, smaller pump) over IV epoprostenol Can be used for de novo patients and transitions from epoprostenol Improvements in hemodynamics and functional status similar to epoprostenol Requires at least double the epoprostenol dose (may be more expensive)

42. SC Treprostinil Requires capable patient Site pain is major impediment Affects 85% Local measures: ice, heat, lidocaine, capsaicin, collagenase ± effective NSAIDs, narcotics, gabapentin ± effective PLOgel new topical; promising, but unconfirmed reports of benefit; not useful at active site Expensive (~$60,000 to $120,000/year)

43. Inhaled Iloprost Approved for class III - IV PAH Duration of hemodynamic effect only 90 minutes Requires frequent administration; at least 6x/day at 10 to 15 minutes Has favorable effects on gas exchange in pulmonary fibrosis Cost of ~ $60,000-$70,000/year

44. Endothelin Antagonists (ERAs) Oral “Nonselective” ERA/ERB Bosentan* “Selective” ERA Ambrisentan* Sitaxsentan†

45. Bosentan (Tracleer) Indication PAH with WHO Class III (or II - IV) symptoms “to improve exercise capacity and decrease the rate of clinical worsening” Dose 62.5 mg BID oral for 4 weeks 125 mg BID oral thereafter if liver functions OK Costs ~$36,000/year Contraindicated with glyburide and cyclosporine

46. EARLY trial: Bosentan in NYHA class II

47. Bosentan Monitoring Liver enzymes: initial and monthly (stop if >5x elevation) reversible with cessation; can try rechallenge with lower dose Watch for leg edema/pulmonary edema/nasal congestion Hemoglobin: initial, 1 and 3 months May interfere with hormonal birth control; barrier method advised Caveat: Response takes time (up to 2 to 3 months), should be used with caution in Class IV patients and not without right heart catheterization to document presence of PAH

48. Ambrisentan (Letairis) Indication PAH with WHO Class II - III symptoms “to improve exercise capacity and decrease the rate of clinical worsening” Dose 5 mg qD Consider increasing to 10 mg qD if tolerated Costs ~$36,000/year Contraindicated with cyclosporine

49. Which ERA? FDA approved: both Cost: similar Dosing: BID (bosentan) vs QD (ambrisentan) Sildenafil interaction (bosentan) LFT issue: 11% bosentan vs 2-3% ambrisentan

50. PDE 5 Inhibitors Oral Sildenafil* Tadalafil†

51. Sildenafil FDA approved in June 2005 for PAH (WHO Group 1) “to improve exercise ability” regardless of functional class Must not be used with nitrates, but compatible with other drugs Metabolized by liver (CYP3A4 isoenzyme), slowed in cirrhotics, no effect of renal failure Oral and relatively inexpensive (~ $12,000/year) Side effects: headache, Blue haze periphery of vision in up to 11%

52. Sildenafil in PAH: SUPER-1, 6-Minute Walk Test Change from Baseline to Week 12

53. Exercise Capacity at Week 12 and 1 Year

54. What is the Optimal Treatment Strategy?

56. Early, Risk-based and Combination Therapy:Changing Paradigms for PAH?

58. Goal-Oriented Therapy

59. Traditional therapies; diuretics, oxygen, phlebotomy still used as indicated; anticoagulants recommended Calcium Channel Blockers should be used in Class II or III acute responders but followed closely for safety & efficacy Newer agents are tailored to WHO class – ACCP Guidelines Class IV – Infused prostacyclins Class III – Oral endothelin receptor antagonists (ERAs), phosphodiesterase (PDE) 5 inhibitors, infused or inhaled prostacyclins Class II – PDE 5 inhibitors, or ERAs Consider therapy if evidence of Right Ventricular Dysfunction Combination therapies and an array of investigational therapies hold hope for the future Role of transplantation/septostomy now diminished because of new effective pharmacologic therapies

61. veronica.franco@osumc.edu614-293-4967

67. Other Investigational Therapies Statins (HMG coreductase inhibitors) K+ channel openers NO donors Rho kinase inhibitors Tyrosine kinase inhibitors Angiogenesis factors Gene therapy NOS, K+ channel openers Serotonin receptor antagonists Inhaled vasoactive intestinal peptide

68. Subcutaneous Treprostinil: Potential Advantages Over IV

69. Indications for SC Treprostinil PAH with WHO Class II to IV symptoms Cost ~$60,000 to $120,000/year (exclusive of costs for administration/monitoring; IV more expensive)

70. Treprostinil Sodium Injection Administered via continuous infusion using an ambulatory pump designed for subcutaneous infusions Administered via a self-inserted subcutaneous catheter Patients must have immediate access to backup infusion pump to prevent the risk of worsening of PAH symptoms due to interruption of therapy

71. The Endothelin System Endothelin converting enzyme (ECE) produces ET-1 from its inactive precursor, Big ET-1. Although ET-2 and ET-3 have also been identified, only ET-1 has a proven relevant role in human physiology. ET-1 acts mainly on the ETA receptors on the vascular smooth muscle cells to induce vasoconstriction of the vasculature. ET-1 also mediates vasoconstriction via the ETB receptors present on the smooth muscle cells. ETB receptors are also present on the endothelial cells, and here they contribute to ET-1 mediated nitric oxide-dependent vasodilation.Endothelin converting enzyme (ECE) produces ET-1 from its inactive precursor, Big ET-1. Although ET-2 and ET-3 have also been identified, only ET-1 has a proven relevant role in human physiology. ET-1 acts mainly on the ETA receptors on the vascular smooth muscle cells to induce vasoconstriction of the vasculature. ET-1 also mediates vasoconstriction via the ETB receptors present on the smooth muscle cells. ETB receptors are also present on the endothelial cells, and here they contribute to ET-1 mediated nitric oxide-dependent vasodilation.

72. Summary: Use of Clinical Parameters, Hemodynamics, and Imaging Techniques to Predict Survival and Therapeutic Options High index of suspicion Thorough diagnostic evaluation, need RHC Exclude thromboembolic disease Vasodilator testing to eliminate inappropriate CCB use