1. Targeting Pulmonary Hypertension in
Thromboembolic disease, Left heart
disease and Pulmonary disorders
Ashok Kirumaki MD
Director Pulmonary Hypertension Program
Assistant Professor
Pulmonary, Critical Care and Sleep
Department of Internal Medicine
Saint Louis University

2. No Financial Disclosures

3. Learning Objectives
• Classification and Brief overview of PAH
• Pulmonary hypertension in Left heart disease
• Pulmonary hypertension in venous
thromboembolism
• Pulmonary hypertension in common lung
disease – COPD

4. Definition of Pulmonary Hypertension
PH Mean PAP ≥ 25 mm Hg
PAH Mean PAP ≥ 25 mm Hg plus
PCWP/LVEDP ≤ 15 mm Hg
(Absent) AHA -PVR > 3 Wood Units
Badesch D et al. J Am Coll Cardiol. 2009; 54 S55- S66

5. (Dana Point) CLINICAL CLASSIFICATION 2009
ARTERIAL HYPOXIA
THROMBI
VENOUS
Simonneau G et al. J Am Coll Cardiol. 2009 ; 54 ; S 43- S54

6. LOCATION OF OBSTRUCTION
Pre Post
capillary capillary
capillary
TO SYSTEMIC
CIRCULATION
Pulmonary Chronic
Arterial lung Pulmonary
hypertension disease venous
CTEPH

7. PATHOGENESIS OF PULMONARY ARTERIAL HYPERTENSION
Smooth
muscle
hypertrophy
Intimal
proliferation
GOOD FLOW ADVANCED VASULAR
REVERSIBLE PLEXIFORM LESIONS
VASOCONSTRICTION IRREVERSIBLE DISEASE
NORMAL

8. DIAGNOSTIC APPROACH TO PULMONARY HYPERTENSION

9. PAH treatment Goals
Fewer / Less severe symptoms
Improved exercise capacity
Improved hemodynamics
Prevention of clinical worsening
Improved quality of life
Improved survival

10. ACCP Consensus :
Definition of a responder
PAP mean decreased by 10 mm Hg
&
Fall in PA Mean pressure < 40 mm Hg
&
No change or increase in cardiac
output

11. Survival in IPAH – (50% of acute responders
or ≤ 6% of IPAH patients )
p = 0.0007
Sitbon O et al. Circulation 2005;111:3105-3111
Copyright © American Heart Association

12. Calcium Channel Blockers ONLY if “ Vasodilator
Responsive”
Pulmonary Vasodilation Systemic vasodilation Neg Inotropy
↑cardiac output ↓cardiac output
Highly Varibale –Needing larger doses
Influenced by the drug and the disease
Risks of getting it wrong : tachycardia,dyspnea ,syncope and death
Key Point
CCBs should NOT be used empirically

13. FDA approved Medications for PAH with their mechanisms of action
Endothelin 1
Nitric Oxide
Bosentan Sildenafil
Ambrisentan Tadalafil

14. PROSTACYCLIN ANALOGUES
Iloprost
Treprostinil
Treprostinil
Epoprostenol
Treprostinil

15. What is the Optimal Treatment Strategy?

16. Etiology of pulmonary hypertension on
Echocardiogram
KEY POINT --- PAH 2.3% majority in the patients are left
heart disease and pulmonary disease

17. PH due to left heart disease WHO group II
• Due to systolic dysfunction--- heart
failure with reduced ejection fraction
HFREF
• Due to diastolic dysfunction- Heart
failure with Preserved Ejection fraction
HFPEF
• Due to valvular heart disease – Aortic or
Mitral valve disease

18. Pathogenesis of PH in Left heart disease
• Passive process-- backward transmission of
elevated Left atrial pressure (LAP)
• Reactive (Out of Proportion)--Chronically
elevated LAP with lead to pulmonary vascular
remodeling causing functional and or
structural abnormalities of distal pulmonary
arteries
• Fixed- medial hypertrophy and intimal fibrosis

19. PH is present in 2/3rd of patients with heart
failure with reduced ejection fraction
Low pap/nl
RV
Low
pap/low
RVEF
High
PAP/nl
RVEF
High PAP
/low
RVEF
(J Am Coll Cardiol 2001;37:183–8)

20. Pre-transplant pulmonary hypertension, even
when reversible to a PVR of <2.5 WU, is
associated with a higher mortality
J Heart Lung Transplant 2005;24:170 –7

21. Fixed Pulmonary hypertension in a
contraindication to heart transplantation alone
This group of patients will need heart and
lung transplantation

22. FIRST TRIAL -EPOPROSTENOL
A randomized controlled trial of epoprostenol
therapy for severe congestive heart failure: The
Flolan International Randomized Survival Trial
(FIRST) 471 PATIENTS WITH
ADVANCED HFREF
CONTINUOUS
EPOPROSTENOL STANDARD OF CARE
INFUSION + STANDARD
OF CARE
American Heart Journal - Volume 134, Issue 1 (July 1997)

23. Increased mortality rates and no evidence of improved quality of life
American Heart Journal - Volume 134, Issue 1 (July 1997)

24. CHRONIC USE OF EPOPROSTENOL IN PATINETS WITH HEART FAILURE IS
CONTRAINDICATED
American Heart Journal - Volume 134, Issue 1 (July 1997)

25. Endothelin Receptor Antagonists
• Endothelin plasma levels are elevated in heart failure
and correlate with severity
• In animal models of HF – ERAs prevented LV
remodeling and improved exercise capacity
• Short-term hemodynamic effects were encouraging
with ERA bosentan and tezosentan which led to RCT

26. Research on Endothelein Antagonists
in Chronic Heart Failure (REACH -1)
NYHA class III /IV
370 patinet
Heart failure
Randomized
BOSENTAN PLACEBO
500MG BID
26
WEEKS
STOPPED PREMATURELY – SAFETY
ELEVATED LIVER FUNCTION TEST
European Journal of Heart Failure 1999;1:197-200

27. Endothelin Antagonist Bosentan for Lowering
Cardiac Events in Heart Failure (ENABLE)
NYHA class III /IV
1613 Patients
Heart failure EF< 35%
BOSENTAN PLACEBO
125 MG BID
1.No improvements in Outcomes
2.Increased risk of early heart failure
exacerbation due to fluid retention with
Bosentan

28. Sildenafil Improves Exercise Capacity and Quality of Life in Patients
with Systolic heart failure with pulmonary Hypertension
Randomized to 12 weeks of treatment
with
Sildenafil (50 mg orally 3 times daily) or
placebo
Improvement in 6-minute walk distance
(29 m versus placebo; P 0.047) and
Minnesota Living With Heart Failure score
(14 versus placebo; P 0.01)
Sildenafil group experienced
fewer hospitalizations for HF Circulation. 2007;116:1555-1562

29. PDE 5 inhibitor in heart failure
• NO RCT has looked into long term use of this
class of drugs in pulmonary Hypertension due
to HFpEF

30. Management of Pulmonary
Hypertension due to left heart disease
• Optimizing traditional therapies for Heart
failure
• Out of proportion Pulmonary hypertension –
look for other causes –V/Q scan, PFT and PSG
• RHC can be done to clarify hemodynamic
details
• NO CLEAR INDICATIONS FOR ADDITIONAL
PAH specific therapies

31. NO evidence that Drugs approved for
PAH are effective or safe in this setting
Medications that lower PVR increase flow and
this increase in venous return to the left
ventricle may increase left ventricular filling
pressure resulting in deterioration rather than
improvement

32. HF with Preserved EF -- HEFPF
Occurs with the Left ventricle is unable to
accommodate an adequate volume of blood
during diastole and maintain an appropriate
stroke volume
Commonly due to Left ventricular diastolic
dysfunction

33. Risk factors
• Post menopausal Women
• Hypertension
• Ischemic Heart Disease
• Diabetes Mellitus
• Obesity
• Atrial fibrillation
• Age --- 50% in HF patient greater than 70 years

34. RHC – in HFPEF
PCWP – may be borderline high at rest
Saline challenge or exercise challenge in this
setting may induce an increase of PCWP
No consensus on protocols for either saline or
exercise testing

35. Pulmonary hypertension with preserved ejection fraction work up
Page 32

36. Even after normalization of the left
atrial pressure
Whether modification of the metabolic
syndrome features
dietary modification, weight reduction and
aggressive blood pressure control
results in improvements in patients symptoms
and PAP with HFPEF with elevated pap is still
unknown?
RELAX trial – ongoing – Sildenafil in HFPEF

37. Summary - WHO class II
• Optimizing traditional therapies for Heart
failure
• NO PAH medication is FDA approved and may
be harmful
• Remember a normal PCWP at rest does not
rule out Diastolic heart failure as the cause of
Pulmonary hypertension

39. Definition of CTEPH WHO class IV
• At least 3 months of effective anticoagulation
• Mean pulmonary artery pressure ≥ 25 mmhg
and PCWP ≤ 15 mmhg
• One of more mismatched segmental or large
perfusion defects detected by V/Q scanning,
pulmonary angiography or multidetector CT
angiography

40. Natural history of Acute PE
• Total or near total resolution and restoration
of normal pulmonary hemodynamics within
30 days in more than 90 percent of patients.
• Right heart pressures return to near normal
values in most patients within 10 to 21 days.
• A minority of patients who have survived an
acute PE develop CTEPH

41. Acute PE – clot removed from Trendlenberg embolectomy

42. CTEPH – white fibrotic clot

43. Incidence of Symptomatic CTEPH
1.0 % at 6 months
3.1 % at 1 year
3.8 % at 2 years
No cases after 2 years -10 year
follow up
N Engl J Med 2004;350:2257-64.

44. CTEPH is a dual vascular disorder
• Obstruction of the vascular bed by non resolving or
recurrent thromboembolism or in situ pulmonary-artery
thrombosis
• In the non occluded areas pulmonary vascular remodeling
and the development of a hypertensive pulmonary
arteriopathy are seen
• The extent of vascular obstruction is a major determinant
of pulmonary hypertension
• In majority of patients, more than 40 percent of the
pulmonary vascular bed is obstructed.

45. Natural History of CTEPH
• “Honey-moon” period of months to years,
during which the patient has no clinical
symptoms
• For this reason, the early natural history of the
condition is not completely known
• 25-30 % deny previous symptoms or diagnosis
of VTE
• Estimated from PE registries 0.1- 9.1%

46. Presentation
• Nonspecific symptoms including exercise
intolerance and dyspnea, chest pain, fatigue
and syncope
• Most patients with chronic thromboembolic
pulmonary hypertension present late in the
course of the disease with Progressive
dyspnea, hypoxemia and Right ventricular
failure

47. RISK factors for CTEPH
• Traditional plasmatic prothrombotic risk
factors are not risk factors for CTEPH
• A negative CT PE protocol does not rule out
CTEPH however a negative V/Q scan rules out
this disorder

48. Risk factors -Observational case –control analysis
• History of splenectomy
• VA shunts and pacemakers with history of device
infection
• IBD
• Thyroid hormone replacement
• Circulating antiphospholipid antibody
• Survived cancer
• Non-O blood groups
• Elevated plasma coagulation factor VIII
• Carriers of Fibrinogen A alpha THr312a1a
polymorphism

49. CTEPH patients with history of splenectomy, infected VA shunt,
inflammatory bowel disease or osteomyelitis have worse outcome
compared to one without a clinical risk factor
Circulation. 2007;115:2153-2158

50. Predictors of Outcome in Chronic Thromboembolic Pulmonary Hypertension
Diana Bonderman, MD; Nika Skoro-Sajer, MD; Johannes Jakowitsch, PhD;Christopher Adlbrecht, MD; Daniela Dunkler, MSc;
Sharokh Taghavi, MD; Walter Klepetko, MD;Meinhard Kneussl, MD; Irene M. Lang, MD
The presence of associated medical conditions
predicts increased operative risk and worse long-
term outcome in CTEPH.
Circulation. 2007;115:2153-2158

51. Pulmonary Thromboendarterectomy
Pulmonary Endarterectomy
is the treatment of choice
Curative in patients with
CTEPH
Operable mortality rates in
specialized centers is < 5%
but 36 % are non operable
N Engl J Med, Vol. 345, No. 20 November 15, 2001

52. Long-term Outcome after Pulmonary Endarterectomy
1994 and 2006,
157 patients
Long-term survival after PEA is excellent
Am J Respir Crit Care Med Vol 178. pp 419–424, 2008

53. Long-term Outcome after Pulmonary Endarterectomy
75% of patients, the long-term functional outcome
was good and almost a half of the patients
recovered good exercise tolerance.
Am J Respir Crit Care Med Vol 178. pp 419–424, 2008

54. Candidates for Endarterectomy
• Confirmed CTEPH in NYHA class II, Class III and
class IV
• A preoperative PVR > 300 dynes.s.cm-5
• Proximal disease – Thrombi in the main lobar or
segmental pulmonary arteries
• Absence of severe comorbidities
• 40% of all newly diagnosed patients are currently
on PAH vasodilator treatment in clinical trials in
Europe

55. BENEFiT STUDY
Bosentan for Treatment of Inoperable Chronic Thromboembolic Pulmonary
Hypertension: BENEFiT (Bosentan Effects in iNopErable Forms of chronIc
Thromboembolic pulmonary hypertension), a Randomized, Placebo-
Controlled Trial
16 week study
Symptomatic Inoperable
CTEPH with
6MWD<450m
J Am Coll Cardiol. 2008;52(25):2127-2134

56. Bosentan for Treatment of Inoperable Chronic Thromboembolic Pulmonary
Hypertension
TREATMENT effect
1.Statistically significant decrease in
PVR and hemodynamic
improvement
BNP
NO CHANGE IN 6MWD
J Am Coll Cardiol. 2008;52(25):2127-2134

57. Ongoing multicenter trials in CTEPH
• CTREPH--- subcutaneous Treprostinil
• CHEST– Riociguat
• Ongoing Vasodilator trials in patients with
nonoperable CTEPH will clarify whether
medical therapy for CTEPH is effective

59. Pulmonary hypertension associated with
lung disease or Hypoxemia WHO Group III
• COPD
• ILD
• Alveolar hypoventilation disorder
• Sleep apnea

60. Pathogenesis of Pulmonary
hypertension in COPD

61. Pulmonary Hypertension and COPD
• PH when present in patients with severe COPD is
mild to moderate - extremely prevalent
Mild (PAP 26–35 mmHg)
Moderate (36–45 mmHg)
Severe (45 mmHg)
• In patients listed for LVRS or lung transplantation
the prevalence of PH would lie between 70–90%.

62. Natural History of PH in COPD
• PH may first appear during exercise and during
sleep
• PH occurs in COPD - cardiac output is usually
normal and PVR increases mildly
• The main feature of PH in COPD is it mild to
moderate degree 20-35 mmHg

63. Suspect PH In COPD if
• Distinctive PFT pattern with less severe airflow
obstruction but more severe hypoxemia,
hypocapnia and markedly reduced DLCO
• PH even if mild at baseline may worsen in
sleep , during exercise and during acute
exacerbation of the disease

64. The progression of pH in COPD is generally slow
and PAP usually remains stable over 2-5 years
The level of PAP is a good
indicator of prognosis
Thorax 1981 ;36:752-758
Weitzenblum, Hirth, Ducolone,
Mirhom, Rasaholinjanahary, Ehrhart

65. Survival of patinets with pulmonary hypertension with
no other cause and COPD in 3 groups PAP > 40 mmHg ,
Between 40 and 20 ,and < 20 mmHg
Ari Chaouat, et al Am J Respir Crit Care Med Vol 172. pp 189–194, 2005

66. Sleep and COPD
• Some patients experience transient arterial
hypoxemia during REM sleep
• Not related to apneas but alveolar
hypoventilation or V/Q mismatch
• The more profound the dips of hypoxemia the
more severe the peaks of PH
• Home oxygen protocol reduced mean PAP in 8
weeks of therapy

67. Treatment of PH in COPD is
based on oxygen therapy
LTOT –Long term Oxygen therapy for
greater than 18 hours per day
significantly decreased resting and
exercise PAP after 6 months of use
NOTT –Nocturnal Oxygen therapy trial
MRC – Medical research council study

68. The oral administration of the endothelin
receptor antagonist bosentan not only failed to
improve exercise capacity but also deteriorated
hypoxemia and functional status in severe
chronic obstructive pulmonary disease patients
Eur Respir J 2008; 32: 619–628

69. Key points of PH in COPD
• A pap pressure of >40 mmhg is unusual in a
stable state of COPD with PH
• PH even if mild at baseline may worsen in
sleep , during exercise and during acute
exacerbation of the disease

70. Summary
• PAH – pulmonary arterial hypertension is
present in 2.3 % and is relatively uncommon
and most patinet (90%) with PH are not
appropriate for therapies with PAH specific
medication .
• No PAH medication is approved in patients
with left heart disease, COPD or CTEPH and in
fact is likely to cause harm in these settings.

71. Summary
• A normal PCWP on RHC at rest does not rule out
Diastolic dysfunction as the cause of PH
• CTEPH is a dual vascular disease with risk factors
very different from acute PE
• A negative V/Q scan (and not CT PE protocol) is
needed to rule out CTEPH
• Pulmonary endarterectomy is the treatment of
choice in CTEPH and is curative

72. Summary
• In COPD patinets PH is usually seen in
advanced disease and is usually mild with PAP
less than 40 mmHg but worsens in REM sleep,
periods of acute exacerbation and with
exertion and has poor prognosis
• No Role for PAH specific therapies in patinets
with PH due to left heart disease,COPD or
CTEPH except in an approved clinical trial

73. Thank you
Thank You