1. PULMONARY HYPERTENSION UPDATE
Dianne L. Zwicke, MD
Clinical Associate Professor of Medicine
University of Wisconsin School of Medicine and Public Health
Milwaukee Clinical Campus
Milwaukee, Wisconsin

2. FINANCIAL DISCLOSURE Dianne L. Zwicke, MD Dianne L. Zwicke, MD
I have been an investigator and received study grants from the following companies:
Glaxo – Welcome *United Therapeutics *Pfizer Medtronic
Myogen Encysive Co Therix Ikaria
PRE-DIX *Gilead Actileon Novartis
Lilly Bayer GENO
* Participated in Advisory Boards

3. PULMONARY HYPERTENSION
Vascular (PAH) Non-Vascular Mixed
Idiopathic COPD Congenital
Collagen Vascular OSA ? COPD
Sickle Cell ILD ? ILD
HIV PE ? PE
Hepatopulmonary Restrictive

4. Clinical Classification: Where Is the Lesion?VC RA RV PA PC PV LA LV Ao
ALK-1, activin receptor-like kinase 1; Ao, aorta; BMPR2, bone morphogenetic receptor type 2; HHT, hereditary hemorrhagic telangiectasia; HIV, human immunodeficiency virus; LA, left atrium; LV, left ventricle; PA, pulmonary artery; PC, pulmonary capillary bed; PV, pulmonary vein; RA, right atrium; RV, right ventricle; VC, vena cava.
Simonneau et al. J Am Coll Cardiol. 2009;54(1 suppl S):S43-S54.
Graphic adapted from

5. PULMONARY ARTERIAL HYPERTENSION
Mean PA pressure > 24 mmHg
PCWP < 15mmHg
PVR > 2.5 / 3.0

7. PATHOLOGIC CHANGES Vascular PH
Smooth muscle hypertrophy
Intimal hyperplasia
In situ thrombosis
Arteritis
Plexogenic lesion

8. PULMONARY HYPERTENSION Severity by Mean PAP
Mild
Moderate
Severe
> Systemic

9. Epidemiology of PAH (WHO Group 1)1
Prevalence of PAH in associated conditions:
CTDa: 8%-12%2,3
CHD: 15%-30%4
PoPH: 2%-6%5,6
HIV: 0.5%7
Distribution of PAH in French Registry8
Appetite suppressant
>1 Risk factor
IPAH
HIV
PoPH
CHD
FPAH
a Systemic sclerosis.
CTD
CHD, congenital heart disease; CTD, connective tissue disease; FPAH, familial pulmonary arterial hypertension; HIV, human immunodeficiency virus; IPAH, idiopathic pulmonary arterial hypertension; PoPH, portopulmonary hypertension.
1. Simonneau et al. J Am Coll Cardiol. 2009;54(1 suppl S):S43-S Hachulla et al. Arthritis Rheum. 2009;60: Mukerjee et al. Ann Rheum Dis. 2003;62: Landzberg. Clin Chest Med. 2007;28: Hadengue et al. Gastroenterology. 1991;100: Krowka et al. Hepatology. 2006;44: Sitbon et al. Am J Respir Crit Care Med. 2008;177: Humbert et al. Am J Respir Crit Care Med. 2006;173:

10. VASCULAR PH EPIDEMIOLOGY
Idiopathic /500,000
Idiopathic (Necropsy) /500,000
Idiopathic (Familial) /1926
Connective Tissue /1000
HIV /100
Hepatopulmonary /100
Anorexic drug /500,000

11. 1-Year Mortality Remains High in FC IV Patients1,2
<30% on prostanoid
1-Year mortality (%)
WHO FC
FC, functional class; QuERI, Quality Enhancement Research Initiative; WHO, World Health Organization.
1. McLaughlin et al. Am J Respir Crit Care Med. 2009;179:A Mathier et al. Am J Respir Crit Care Med. 2009;179:A2658.

12. PULMONARY HYPERTENSION RIGHT HEART FAILURE SYMPTOMS
DOE Years %
CP - RV ischemia %
Syncope / near syncope – 30%
Fatigue %
Raynauds phenomonon – 10%
Ascites - 20%
Peripheral edema - 10%
Early satiety - 50%
Hoarseness - 10%

13. PULMONARY HYPERTENSION Diagnostics - Basics
History & Physical
Labs- CBC, CMP, TSH, ANA, RF, CRP, ESR, HIV, ANTICARDIOLIPIN AB
EKG, CXR
Full PFT’S
Lung scan
Echo with contrast / TEE

14. PULMONARY HYPERTENSION Diagnostics - Advanced
HR Chest CT
Pulmonary Angiography
Sleep study / screen
6 minute walk
Cardiac cath with pharmacologic
challenge -- LAST STUDY!

15. Hemodynamic Progression of PAH
Time
PAP
PVR
RAP CO
Pre-symptomatic/ Compensated
Symptomatic/ Decompensating
Symptom Threshold
Right Heart Dysfunction
Declining/ Decompensated
Symptoms
CO, cardiac output; PAP, pulmonary arterial pressure; PVR, pulmonary vascular resistance; RAP, right atrial pressure. 15

16. Vasoactive Mediators Involved In PAH
ABNORMALITIES
Nitric oxide
deficiency
Prostacyclin
deficiency
Endothelin
overexpression
THERAPIES
PDE-5 inhibitors
Block the activity of PDE-5, restoring vasodilation through an increase in cGMP1
Prostacyclin
Supplement the deficiency in PGI2, resulting in vasodilation and inhibition of platelet aggregation2
ERAs
Block the binding of ET-1 to its receptors, preventing vasoconstrictor effects of ET-13
cGMP, cyclic guanosine monophosphate; ERA, endothelin receptor antagonist; ET-1, endothelin; PDE-5, phosphodiesterase type 5; PGI2, prostacyclin.
1. Humbert et al. J Am Coll Cardiol. 2004;43(suppl S):13S-24S. 2. Humbert et al. N Engl J Med. 2004;351: Galiè et al. Eur Heart J. 2004;25: 16 16

17. Overall PAH Therapy Use in Enrolled Population1,2
Patients (%)
ERA, endothelin receptor antagonist; PDE-5I, phosphodiesterase type 5 inhibitor; QuERI, Quality Enhancement Research Initiative.
1. McLaughlin et al. Am J Respir Crit Care Med. 2009;179:A Mathier et al. Am J Respir Crit Care Med. 2009;179:A2658.

18. Has Survival Meaningfully Improved With Modern Therapies?12 24 36 48 60
n=269
n=260
n=118
Before 1992 (no specific Tx)
(only IV PGI2)
After 2000 (current therapies) NS
P<0.05, log-rank test
Months 25 50
Survival (%) 75
100
IPAH, HPAH, and anorexigen-associated PAH
HPAH, hereditary pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension; IV, intravenous; NS, not significant; PGI2, prostacyclin; Tx, treatment.
Sitbon et al. Slides presented at European Respiratory Society; September 16-18, 2007; Stockholm, Sweden.

19. PULMONARY ARTERIAL HYPERTENSION MEDICAL THERAPIES

20. EPOPROSTINIL (Flolan, Veletri)
Prostacyclin
75% sustained ¯ in PVR
10% are non responders
Double lumen catheter
Requires continuous infusion

21. BOSENTAN (Tracleer) ET – 1 antagonist
Binds ETA – ETB receptors in endothelium and vascular smooth muscle
P450 pathway (2C9, 3A4)
3-5 hour max plasma concentration
t½ is five hours
95% bound to albumin, excreted in bile
62.5 – 125 mg bid orally, 1-2 month Rx

22. TREPROSTINIL (Remodulin)
UT – 15
Prostacyclin analogue
SQ or IV infusion
Modified insulin pump – SQ

23. INHALED NITRIC OXIDE Endothelial derived relaxing factor
Endogenous mediator for smooth muscle relaxation
Selective pulmonary vasodilator through cGMP pathway
Increases oxygenation

24. SILDENAFIL (Revatio) PDE – 5 Inhibitor
Found abundantly in pulmonary vasculature
Inhibits proliferation
Potent pulmonary vasodilation
Increased epistaxis and GI bleed
Can’t prescribe nitrates

25. ILOPROST (Ventavis) Inhaled prostacyclin derivative 6-9 treatments/day
10-15 minutes/treatment
Mini Nebulizer

26. AMBRISENTAN (Letairis)
Endothelin receptor blocker
WHO group 1-3, WHO class 2 or 3 symptoms
5 or 10mg daily, tablet
IPH, CTD, HIV, diet drugs
Caution=pregnancy; liver toxicity (Label removed)

27. INHALED EPOPROSTINIL (Flolan)
30-80ng / kg / min
Special delivery system

29. TREPROSTINIL (Tyvaso)
Prostaglandin – inhaled.
2-12 breaths / treatment qid
Same side effects as any Prostaglandin during titration

30. TADALAFIL (Adcirca) PDE-5 inhibitor 20-40mg daily po 36 hour ½ life
Avoid with Rifampin and Antifungals

31. PERCUTANEOUS INTERVENTION IN PULMONARY HYPERTENSION
Coil Closure of PDA
ASD Closure
VSD Closure
Atrial Septostomy

32. SURGICAL PROCEDURES IN PULMONARY HYPERTENSION
ASD / VSD Closure
Mitral Valve Repair / Replacement
Anomolous Pulmonary Venous Return
Pulmonary Thrombo-Endarterectomy
Open Lung Biopsy
Pericardial Window / Drainage

33. CURRENT CLINICAL TRIALS
Oral Remodulin - (United Therapeutics)
Selexipag - (Actileon)
Combo Study vs single drug - Adcirca +/-Letairis (United Therapeutics / Gilead)
Riociguat with LV Failure and PHTN - (Bayer)
Tyvaso Registry - (United Therapeutics)
Implantable pump / continuous infusion Remodulin - (Medtronics)
Inhaled nitric oxide - (GENO)
- Inhaled Nitric Oxide via Ambulatory Device (Ikaria)
Taladafil with LV Failure and PHTN (NIH)
Oral Beraprost (LungRx)
▪ Prostacyclins
▪ Nitric Oxide
▪ PD’s
▪ ERA
▪ Combo

34. CASES

35. 48 y/o female PAH / ICM CREST syndrome x 6 years
Anterior wall MI → LVEF 15-20%
PAH – RA-18, RV-86/22, PA-88/22 (55), W-16, CI-1.8, PA-Sat 48%, Ao-92%, PVR WU
IV Remodulin titrated to 100ng/kg/min
Ambrisentan 5→10mg po daily
Digoxin 0.25mg daily

36. 48 y/o female PAH / ICM – (continued)
Lasix 40mg daily
K/Mg replacement
Lisinopril 20mg daily / DC Coreg
More Aggressive immunosuppression
___________________________________________
* LVAD – Heartmate II for 6-7 months
* Successfully transplanted (heart)
* Weaned off Remodulin

37. 42 y/o male - Hep C ETOH Liver Dz
Massive ascites, LE edema, severe RH failure
Normal LV, no significant valve disease
Right Heart Cath….
Hepatic wedge CI – 1.9
RA – PVR – 9 WU
RV – 19 / 22
PA – 92 / 25 (54)

38. 42 y/o male - Hep C ETOH Liver Dz (continued)
IV Lasix, Dobutamine, Flolan
Digoxin 0.25mg daily, K/Mg replacement
Flolan changed to Veletri for home infusion
Revatio 20mg tid added
________________________________________________
Liver transplant after PVR ↓ to 5 WU, CI >2.8
ECHO = marked improvement of RVEF
* 3 months after transplant – weaned off IV Veletri
* 9 months after transplant – weaned from Revatio
* Stable 1 year after cessation of all PAH drugs

39. 69 y/o old female - HCM NYHA 3, 3+ edema to mid thighs, + ascites
Severe DOE and muscle wasting
ECHO – mild RVH, mod LVH, RVSP 55, LVEF 65%
PHTN work up – negative
Cath – RA-18, RV-58/19, PA-55/22, CI-2.8, W-20, PA-Sat 55%, PVR-3.2 WU,
Treatment – IV Lasix → CVVH
________________________________________________________________
* Home on peritoneal dialysis x 9 months
* Evaluate for transplant – status 7

40. PAH – Pulmonary Emboli Well until 3 years ago, 02 6L NC now
56 year old female with PE after Hysterectomy
Well until 3 years ago, 02 6L NC now
Denied PTE at another institution
Reviewed Pulmonary Angiogram
RHC – RA 8, RV 65/20(35), CI 2.3, Sat-62%
Coronary Angiogram
Sent to San Diego

42. Vague Symptoms

43. Major presenting symptoms are syncope, shortness of breath and fatigue

44. Syncope is prodrome to death

45. Correct diagnosis must be established

46. Empiric vasodilator therapy is not recommended

47. Treatment options are frequently available if not seen at end stage