PULMONARY HYPERTENSION

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PULMONARY HYPERTENSION

• J.TAVARES,MD,FCCP,FAASM

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DEFINITIONS(WORLD SYMPOSIUM OF VENICE,ITALY)

• Primary pulmonary hypertension replaced by
  idiopathic pulmonary arterial hypertension.
• Mean resting PAP gt25mm Hg or mPAPgt30 mm Hg with
  exercise.
• WHOPAS pressure gt40mm Hg

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Classification(WHO)

• 1-PAH
• 2-PH with left heart disease
• 3-PH with lung diseases/hypoxemia
• 4-PH due to chronic thrombotic and/or embolic
  disease
• 5-Miscellaneous.

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PAH

• IPAH
• Familial PAH
• Related to
• CTD
• HIV
• Portal Hypertension
• Anorexigenics
• CHD

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GROUP 2-PULMONARY VENOUS HYPERTENSION

• LEFT SIDED HEART DISEASE,DIASTOLIC OR SISTOLIC.

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PHT ASSOCIATED WITH LUNG DISEASE OR HYPOXIA

• COPD
• ILD
• ALVEOLAR HYPOVENTILATION
• CHRONIC HIGH ALTITUDE EXPOSURE

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GENETICS

• Bone morphogenic receptor(BMPR-2).
• mutations result in a loss of normal inhibition
  of proliferation(uncontrolled cell growth)
• Member of the TGF-b family of receptors
• 80-90 of familial cases
• 25 of IPAH.

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GENETICS(OTHERS)

• ALK1(Activin receptor-like kinase1)
• SERT(Serotonin Transporter)

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PATHOBIOLOGY OF PULMONARY HYPERTENSION

• Three components
• 1-vasoconstriction
• 2-thrombosis
• 3-proliferation

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GOOD GUYS
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PROSTACYCLIN

• Major lipid mediator produced by the endothelium.
• Relaxes smooth muscle by increasing cAMP
• Inhibits platelet aggregation
• Inhibits smooth muscle growth

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PROSTACYCLINS(CONT)

• In patients with PAH,urinary metabolites of
  prostacyclin are decreased and thromboxane A2
  are increased.
• Christman and colleagues(NEJM199232770-75)

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NITRIC OXIDE PATHWAY

• Endogenous vasodilator
• Inhibits platelet aggregation
• Exert its effects via cyclic GMC,leading to
  smooth muscle relaxation.

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OTHER GOOD GUYS

• VIP

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BAD GUYS
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ENDOTHELIN-1

• Potent vasoconstictor
• Synthesized and secreted by endothelial cells.
• Can stimulate cellular proliferation and fibrosis

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OTHER BAD GUYS

• Serotonin
• Thromboxane

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Mediators of Pulmonary Vascular Responses in
Pulmonary Arterial Hypertension
Farber H and Loscalzo J. N Engl J Med
20043511655-1665
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GUDELINES FOR SCREENING AND DIAGNOSIS

• Is there a reason to suspect PAH?
• symptoms(cough,hoarseness,dyspnea).
• risk factors(FH,CTD,CHD,PHT,DVT/PE,
• HIV,Appetite supressants).
• .CXR,ECG

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Screening and Diagnosis

• 1-Echocardiogram(be specificassessment of RV
  PAP)---grade A .
• Left heart disease,congenital heart disease
• 2-Serologies(CTD,HIV)
• 3-VQ scan,CT chest
• 4-PFTs,ABG

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• 5-6 minute walk test.
• 6-Pulmonary hemodynamics
• PAP,PCWP,CO,PVR
• Response to vasodilators.

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Cardiac Imaging in PAH

• DOPPLER ECHOCARDIOGRAPHY
• To estimate PAP,RA and LV enlarge/
• TR jet is used to estimate RVSP(4v2)
• less than satisfactory
• CARDIAC MRI
• One the most reliable techniques for
  assessment of RV dysfunction.

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Cardiac Imaging in PAH(cont)

• PET Scan
• RV standardized uptake value(SUV) decrease
  significantly in responders to epoprostenol.

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RESPONSE TO VASODILATORS

• Adenosine50-100ng/kg/mnincrease by 50ng/kg mn
  q2mn to max of 400ng/kg/mn
• stop titration if N/V,HA,C/P,dizziness
• check hemodynamics q2mn
• .Prostacyclin2ng/kg/mnincrease by 2ng/kg/mn
  q15mn to max 16ng/kg/mn
• Nitric Oxide

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Dose Ranges, Routes of Administration, and
Half-Lives of the Most Frequently Used
Vasodilators in Patients with Primary Pulmonary
Hypertension
Rubin L. N Engl J Med 1997336111-117
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Algorithm for the Management of Primary Pulmonary
Hypertension
Rubin L. N Engl J Med 1997336111-117
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RESPONSE TO VASODILATORS

• At least 20 decrease in PAP and PVR without
  adverse effect in cardiac output.
• OR
• Decreased in MPAP of at least 10mm/Hg with a mean
  fall of MPAP to lt40mm/Hg.
• 6-20 of responders.

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Functional Classification of Pulmonary Arterial
Hypertension
Humbert M et al. N Engl J Med 20043511425-1436
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TREATMENT

• Conventional therapy
• calcium channel blocker
• diltiazem900mg/day
• nifedipine240mg/day
• anticoagulant therapy
• diuretics

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THERAPY

• Advanced therapy
• Prostanoids
• Endothelin receptor antagonists
• Nitric oxide pathway

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Targets for Current or Emerging Therapies in
Pulmonary Arterial Hypertension
Humbert M et al. N Engl J Med 20043511425-1436
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PROSTANOIDS

• IV therapy(functional class III/IV
• Epoprostenol(flolan)short half life(mn)
• 20-40ng/kg/mn
• Teprostinil(half life of 4 hrs)
• Costs100,00 to 200,000/year

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PROSTANOIDS

• Subcutaneous therapy
• Teprostinil
• Inhalation therapy
• Iloprost(short half life)
• 2.5-5mcg NEB q4h

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ENDOTHELIN -1RECEPTOR ANTAGONISTS

• Bosentan(tracleer)
• affects receptor A and B
• 62.5mg po q12h-125mg po q12h
• monitor LFTs every month.
• Sitaxsentan(affects receptor A)
• 50-10mg po daily
• Ambrisentan
• 2.5 to 5 mg po daily

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NITRIC OXIDE ENHANCERS

• Sildenafil(SUPER-1 trial NEJM 200535348-57)
• Viagra(25mg po tid)
• Revatio(20mg po tid)

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Emergent Therapies

• 5-HT/5HTT antagonists(prx08066terguride
• Cicletanine(eNOS)
• NS-304((high affinity for PGI2)
• VIP(vasodilator)
• Soluble guanylate cyclase(sGC)
• TKI(tyrosine kinase inhibitors)Imatinib,