1. Pulmonary Hypertension
Kazemi.toba,M.D.   Birjand University of Medical Sciences
24th Ordibeheshte 1390
SYLLABUS

2. Outline Introduction, definition Pathophysiology Diagnosis
Laboratory Findings
Idiopathic Pulmonary Arterial Hypertension
Natural History
Treatment

3. Introduction Pulmonary hypertension: Cor pulmonale :
an abnormal elevation in pulmonary artery pressure
result of left heart failure, pulmonary parenchymal or vascular disease, thromboembolism, or a combination of these factors.
Regardless the etiology of pul.htn, it is a feature of advanced disease.
it is essential that the etiology underlying the pulmonary hypertension be clearly determined before treatment.
Cor pulmonale :
RV enlargement secondary to any underlying cardiac or pulmonary disease.
Pulmonary hypertension is the most common cause of cor pulmonale. Advanced cor pulmonale is associated with the development of RV failure.

4. Cor pulmonale

5. DEFINITION 
The definition of pulmonary hypertension (PH) is based upon right heart catheterization measurements.
PH is defined as a mean pulmonary artery pressure greater than 25 mmHg at rest.
A mean pulmonary artery pressure of 8 to 20 mmHg at rest is considered normal,.

6. Pathophysiology Dilated RV- Intact pericardium  RAP 
 Intrapericardial pressure (IPP)
 LV transmural filling pressure=
LVEDP-IPP +
Shift of IV septum toward LV
 LV preload and  LV distensibility
 Systemic Cardiac Output

7. Pathophysiology
The ability of the RV to adapt to increased vascular resistance is influenced by several factors, including age and the rapidity of the development of pulmonary hypertension
Acute:  RV afterload,  EDV,  EF, SV of RV
Chronic: progressive systolic pressure overload of RV that dilates and hypertrophies, gradual RV dysfunction
venous return compromises RV preload and pulm blood flow
Coexisting hypoxemia can impair the ability of the ventricle to compensate

8. Pathogenesis of Pulmonary Arterial
NORMAL
REVERSIBLE DISEASE
IRREVERSIBLE DISEASE
Pathogenesis of Pulmonary Arterial
Hypertension

10. Symptoms of PH Dyspnea 60% Fatigue 19% Near syncope/syncope 13%
Chest pain 7%
Palpitations 5%
Leg edema 3%

11. Physical Exam JVD Loud P2 (increases PAP)
Left parasternal lift (RV heave=R sided overload)
murmur of TR
S3 gallop (advanced RV failure)
CLEAR lungs

12. Signs of Disease Severity
Dyspnea at rest
Low cardiac output with metabolic acidosis
Hypoxemia
Signs of right heart failure (large V wave on jugularis vein, periph edema, hepatomegaly)
Syncope (poor prognosis)
Chest pain (2 to RV ischemia)

13. Diagnosis CXR: Enlarged proximal pulmonary vessels,”
ECG: RAD, RAE, RVH most common
Echo :Estimate PA pressure
Assess for shunts and valvular disease; ventricular function

14. ECG Findings
Often suggestive of RVH and RAE

15. RAE,RVH

16. Chest X-ray Findings
central Pul arterial and/or RV enlargement , distal “pruning”

18. . Note the dilated proximal pulmonary arteries with a relative lack of pulmonary vasculature in the periphery. No cardiomegaly is noted .

19. Chest roentgenogram from a patient with primary pulmonary hypertension showing the marked dilation of the main pulmonary arteries and right ventricular enlargement.

20. Pulmonary hypertension
Pulmonary hypertension. Chest radiograph in a patient with secondary pulmonary hypertension reveals enlarged pulmonary arteries. This patient was found to have an atrial septal defect.

21. Severe right chamber dilation
Estimate PA pressure
Assess for shunts
and valvular disease
ventricular function

22. secondary pulmonary hypertension

23. Severity of Pulmonary Hypertension
Degree of disease
Mild
Moderate
Severe
Mean PAP (mmHg)
>55

24. Right Heart Cath Essential for firm diagnosis:
Helps to not dx people with PAH that do not have it!
Vasoreactivity testing
NO, Adenosine—drop in mPAP by 10 mmHg to value < 40 mmHg
Predicts CCB response
Evaluate for septal defects
Shed light on the issue of diastolic dysfunction
Interpret data in context of patient’s volume status

25. Lab Exam Selected labs ANA, RF, ESR LFTs, hepatitis serologies
HIV antibody
Drugs (cocaine)

26. Algorithm for investigation of suspected PH

28. Complications of PH Right-sided heart failure (cor pulmonale).
Blood clots.
Arrhythmia. Irregular heartbeats from the upper or lower chambers of the heart are complications of pulmonary hypertension. These can lead to palpitations, dizziness or fainting and can be fatal.
Bleeding. Pulmonary hypertension can lead to bleeding into the lungs and hemoptysis.

30. Classification Group 1 "Pulmonary arterial hypertension".
1. Idiopathic (IPAH)
2. Familial (FPAH)
3. Associated with (APAH):
Collagen vascular disease
Congenital systemic-to-pulmonary shunts
Portal hypertension
HIV infection
Drugs and toxins
Other (thyroid disorders, glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders, splenectomy)
4. Associated with significant venous or capillary involvement
Pulmonary veno-occlusive disease (PVOD)
Pulmonary capillary hemangiomatosis (PCH)
5. Persistent pulmonary hypertension of the newborn

31. Classification Group 2 : "Pulmonary venous hypertension". Examples:
1. Left-sided atrial or ventricular heart disease
2. Left-sided valvular heart disease
Group 3 PH — "Pulmonary hypertension associated with disorders of the respiratory system or hypoxemia".
1. Chronic obstructive pulmonary disease
2. Interstitial lung disease
3. Sleep-disordered breathing
4. Alveolar hypoventilation disorders
5. Chronic exposure to high altitude
6. Development abnormalities

32. Classification
Group 4 PH — "Pulmonary hypertension caused by chronic thrombotic or embolic disease".
Examples:
1. Thromboembolic obstruction of proximal pulmonary arteries
2. Thromboembolic obstruction of distal pulmonary arteries
3. Non-thrombotic pulmonary embolism (tumor, parasites, foreign material)
Group 5 PH — These patients have PH caused by inflammation, mechanical obstruction, or extrinsic compression of the pulmonary vasculature (eg, sarcoidosis, histiocytosis X, lymphangiomatosis, compression of pulmonary vessels by adenopathy, and fibrosing mediastinitis).

33. (PCWP>15 mmHg; PVR nl)
Pulmonary Hypertension: Define Lesion
Post-Capillary PH
(PCWP>15 mmHg; PVR nl)
PAH
Respiratory
Diseases PE
Atrial Myxoma
Cor Triatriatum
MV Disease RA PV LA VC RV PA LV Ao PC
LVEDP
The hemodynamic derangements with LV dysfunction can result from systemic hypertension, AoV disease, MV disease predominantly MR presenting a volume overload to LV and myocardial diseases such as dilated CMP-of the ischemic or non-ischemic variety, hypertrophic cardiomyopathy, and restrictive/infiltrative CMP such amyloidosis, hemochromatosis, or sarcoidosis.
Systemic HTN
AoV Disease PV
compression
PVOD
Pre-capillary PH
PCWP<15 mmHg
PVR > 3 Wu
Myocardial Disease
DCM,HCM,ischemic CM
RCM,Obesity , others

34. Idiopathic PH PPH uncommon, incidence : 2 cases per million.
female predominance
presenting in the 4th and 5th decades
although the age range is from infancy to >60 years.
Familial PAH :20% of cases of IPAH
autosomal dominant inheritance

35. Natural History of PPH The natural history of IPAH is uncertain
the disease is typically diagnosed late
Prior to current therapies, a survival of 2–3 years from the time of diagnosis
Functional class remains a strong predictor of survival,
patients who are in NYHAfunctional class IV having a mean survival of <6 months.
The cause of death is usually RV failure, which is manifest by progressive hypoxemia, tachycardia, hypotension, and edema

37. Mediators of PH Prostacycline Thromboxane A2 Endothelin-1
Nitric Oxide (NO)
Serotonin
Adrenomedullin
Vasoactive Intestinal Peptide (VIP)
Vascular Endothelial Growth Factor (VEGF)

38. Prostacycline & Thromboxane A2
Vasodilator
Inhibits platelet activation
Antiproliferative properties
Thromboxane A2
Vasoconstrictor
Platelet agonist
in PH balance shifted to Thromboxane A2

39. ENDOTHELIN-1 Potent vasoconstrictor
Stimulates proliferation of smooth muscle cells in PA
Plasma levels increased in PHT
Level inversely proportional to pulmonary blood flow & CO - ? Direct effect

40. NO & serotonin NO
Vasodilator & inhibitor of platelet activation & vascular SM proliferation
Serotonin
Vasoconstrictor promoting SM hyperplasia & hypertrophy
Elevated plasma levels/ reduced platelet levels in PHT

41. Goals of Therapy
Alleviate symptoms, improve exercise capacity and quality of life
Improve cardiopulmonary hemodynamics and prevent right heart failure
Delay time to clinical worsening
Reduce morbidity and mortality

42. Classes of therapy Medical Diuretics Coumadin (IPAH, Anorexigen)
Oxygen
PAH specific therapy
Surgical therapy
Atrial septostomy
Lung transplantation

43. PAH Therapy: Life style considerations
Sodium restriction
Abstinence from smoking
Avoid high altitude
<4,000 feet above sea level
Avoid physical exertion in setting of pre- or frank syncope sx
Avoid pregnancy

44. Mainstay of treatment

45. ANTICOAGULANTS Warfarin
Anticoagulant therapy is advocated for all patients with PAH .
warfarin increases survival of patients with PAH.
The dose of warfarin is generally titrated to achieve an INR of 2–3 times control.

46. Algorithm for Assessment of Vasoreactivity in Patients with PAH
Right Heart Catheterization With Acute Vasoreactivity Testing (iNO, epoprostenol, adenosine)
mPA 10 mmHg
 mPA < 40 mmHg
Non - responder
Responder (<15%) and candidate for CCB (no RHF)
Consider p.o. Bosentan
Consider p.o. Sildenafil
Consider Inhaled Iloprost
Consider s.q. Treprostinil
Consider Continuously-Infused Epoprostenol
Hemodynamically-Monitored Trial of
Calcium Channel Blocker Therapy

47. Calcium Channel Blockers
Patients who have substantial reductions in PAP in response to vasodilators at the time of cardiac catheterization (a fall of 10 mmHg in mean PAP and a final mean pressure <40 mmHg) should be treated with CCB.
dramatic reductions in PAP, PVR,improved symptoms, regression of RV hypertrophy
improved survival documented to exceed 20 years
patients require high doses (e.g., nifedipine, 240 mg/d, or amlodipine, 20 mg/d).
<20% of patients respond to CCB in the long term.
should not be given to patients who are unresponsive, as they can result in hypotension, hypoxemia, tachycardia, and worsening right heart failure

48. Endothelin Receptor Antagonists
Bosentan :nonselective endothelin receptor antagonist
approved treatment of PAH for patients who are NYHA functional classes III and IV.
bosentan improved symptoms and exercise tolerance
Therapy is initiated at 62.5 mg bid for 1 month,then increased to 125 mg bid .
Because of the high frequency of abnormal hepatic function tests associated with drug use, primarily an increase in transaminases, it is recommended that liver function be monitored monthly throughout the duration of use.
Bosentan is also contraindicated in patients who are on cyclosporine or glyburide concurrently.

49. PHOSPHODIESTERASE INHIBITORS
Sildenafil
PDE type5 inhibitor
Reduce metabolism of cGMP
Sildenafil should not be given to patients who are taking nitrate compounds
lowers pulmonary artery pressure and inhibits pulmonary vascular growth
sildenafil improves symptoms and exercise tolerance in PAH
The recommended dose is 20 mg tid. The most common side effect is headache

51. Prostacyclins 1-Iloprost IV or Inhaled
is approved via inhalation for PAH patients who are NYHA functional classes III and IV.
improve symptoms and exercise tolerance
Therapy can be given at either 2.5 or 5 mcg per inhalation treatment.
inhaler must be given by a dedicated nebulizer
The most common side effects are flushing and cough
Because of the very short half-life (<30 min) it is recommended to administer treatments as often as every 2 h.
Treprostinol
IV or s/c injection
No CYP inhibition - ? induction
t½ 2-4 hours

52. Prostacyclins 2-Treprostinol
is approved for the treatment of PAH patients who are NYHA functional class III or IV
improvement in symptoms, exercise tolerance, and survival
drug is administered iv
requires placement of a permanent central venous catheter and infusion through an ambulatory infusion pump system.
Side effects include flushing, jaw pain, and diarrhea,

53. Subcutaneous Treprostinil (Remodulin )
SQ administration
Longer half-life than epoprostenol
Pre-mixed
Stable at room temperature

54. IV epoprostenol (flolan)

55. Prostacyclins 3- Treprostinil an analogue of epoprostenol,
for patients with PAH &NYHA classes II–IV.
Treprostinil has longer half-life than epoprostenol (4 h)
is stable at room temperature,
may be given iv or sc through a small infusion pump that was originally developed for insulin.
improvement in symptoms and exercise capacity.
The major problem has been local pain at the infusion site, which has caused many patients to discontinue therapy.
Side effects are similar to those seen with epoprostenol.

56. Surgical Therapy Transplantation - lung / heart-lung
Lung transplantation is considered for patients who, while on an intravenous prostacyclin, continue to manifest right heart failure.
Acceptable results have been achieved with heart-lung, bilateral lung, and single-lung transplant.
The availability of donor organs often influences the choice of procedure

57. Functional classes

58. Good luck