Pulmonary Hypertension


    Reference: MKSAP16


    • Elevation of the mean pulmonary artery pressure of ≥25mmHg at rest.
    • Normally pulmonary vasculature is low pressure low resistance, doesn't take a lot of force to pump blood.
    • When pulmonary HTN develops, can lead to impaired lung function.



    • 5 distinct causes:
      • Causes of Pulmonary HTN

        Class 1. Pulmonary Arterial Hypertension (artery pathology)

                      (resting mPAP ≥25mmHg and PCWP ≤ 15 mmHg [exclude LV cause])
          (and PVR of >3 Wood Units)


        • Idiopathic PAH
        • Heritable (BMPR2, ALK1, endoglin with/without hereditary hemorrhagic telangiectasia)
        • Drug- and toxin-induced (e.g. weight-loss agents, methamphetamine, rapeseed oil)
        • Connective Tissue Disorders (scleroderma), HIV, portal HTN, congenital heart disease,
          schistosomiasis, chronic hemolytic anemia.

        Treatment: Vasodilators

        1'.  Veno-Occlusive disease and/or pulmonary capillary hemangiomatosis

        Class 2. Secondary to L-sided Heart Disease  (MOST COMMON)
                    (mPAP > 25mmHg w/ elevated PCWP and LV dysfunction)

             (Can be systolic, diastolic or valvular LV dysfunction)

        Treatment: Cause

        Class 3. Hypoxia induced  (Second Most Common)
                     (mPAP > 25mmHg with underlying lung disease)

        • COPD (smoker, cough, obese, "blue")
        • ILD
        • Other pulmonary diseases with mixed restrictive/obstructive pattern.
        • Sleep-disordered breathing (OSA)
        • Alveolar hypoventilation syndrome
        • Chronic high altitude exposure

        Class 4.  Chronic thromboembolism

        (Cancer, travel, hypercoag, prior PE)

        Class 5.  Multifactorial / Unclear (hematologic, systemic, metabolic, etc...)

          (includes mechanical obstruction from tumors, fibrosing mediastinitis, etc...)

        - Hemolytic anemia & Sarcoid are most likely

      • mPAP - mean pulmonary artery pressure
      • PCWP - Pulmonary Capillary Wedge Pressure

    Chronic Thromboembolic Dz

    • Class IV: (Chronic Thromboembolic Disease)
      • Often within a month of treating PE, pulmonary pressures return to normal.
      • Subgroup develop chronic thromboembolic disease. (1-4% of pts surviving PE).
        • White-yellow lesions that are organized and endothelialized (fixed).
        • Look different from red free thrombi.
        • Causes vascular remodeling.
      • 50% have no diagnosed hx of PE, often misdiagnosed.
      • (Those that have acute PE, risk factors for chronic thromboembolism: young age, larger clot, elevated D-dimer 3mo post-diagnosis).
      • VQ scan is test of choice (CT not as good).
        • If both fail, but suspision is high, can do R-heart cath with angiography to see defects (see remodeling).
      • Management:
        • Supportive care
        • Anticoagulation to prevent recurrence if not contraindicated.
        • Can use pulmonary vasodilators to improve RV dysfunction, but unclear if mortality benefit.
        • Surgery: Definitive therapy (thromboendarterectomy - remove organized clots)
          • Results are best if good functional capacity (NYHA III or better) if target lesions are central, and experienced surgeon.
        • Anticoagulate indefinitely, consider IVC filter.


    Pulmonary Arterial Hypertension

    • Pulmonary arterial hypertension (mPAP >25) and normal PCWP (≤15 mmHg) due to disease involving pulmonary arteries and not due to elevated wedge pressure or LV failure.
    • Implies elevated pulmonary vascular resistance.
    • Mechanism
      • Not clear... thought to be due to underexpression of vasodilator (such as prostacyclin or nitric oxide) as well as over-expression of vasoconstrictor (endothelin) and overexpression of angiogenic mediators (Vascular endothelial derived growth factor VEGF and platelet derived growth factor PDGF)
        • Heritable forms with low penatrance linked to two members of transforming growth factor-B family (BMPR2, and ALK1).  
        • Histology: intial fibrosis, increased medial thickness, vascular occlusion, plexiform lesions within small pulmonary arteries and arterioles.
    • Lung biopsy is generally avoided (not used in diagnosis, very high bleeding risk in PAH pts).
    • Classified into 3 entities:
      • 1. Idiopathic PAH (formerly primary PH)
      • 2. Heritable PAH
      • **3. PAH associated with conditions (like connective tissue dz).** MOST COMMON.
    • Prognosis:
      • POOR, progressive.
      • Median survival of idiopathic PAH is 2.8 years.
      • Even with current therapy, mortality is 15% within 1 year of diagnosis.
    • Diagnosis:
      • Should undergo R-heart catheterization for confirmation of diagnosis and assess vasodilator response.
        • Required for long-term vasodilator therapy.
    • Treatment
      • Specialist referral recommended. (high mortality + complexity of treatment).
      • Supportive therapy:
        • Oxygen (vasodilator)
        • Diuretics
        • Anticoagulants (prevent in-situ clot formation common in PAH)
        • Cardiac glycosides to augment RV function.
      • Vasodilator therapy
        • Various agents (combination for advanced)
        • 4 classes of drugs available
        • Often requires R-heart cath for assess responsiveness, those that respond do better.  --> can be candidates for calcium-channel blockers.
          • Nitric oxide challenge is made.  If mPASP drops by > 10mmHg, then considered POSITIVE vasodilator challenge
          • If POSITIVE --> Use calcium channel blockers
          • If NEGATIVE --> Use other agents (sildenafil, etc..)
        • Benefits: improved symptoms, QOL, survival.
        • Lung transplant is definitive therapy!  (many will require this despite medical therapy)
          • Often lung (or heart-lung) transplant for those with end-stage disease.
        • Pharmacologic Therapy for Pulmonary Arterial Hypertension



          Calcium channel blockers

          Only for patients with acute vasodilator response at catheterization; acute response does not assure chronic response

          Prostanoids (epoprostenol, treprostinil, iloprost)

          Supplements endogenous levels of prostacyclin (PGI2); a vasodilator with anti–smooth muscle proliferative properties

          Endothelin-1 receptor antagonists (bosentan, ambrisentan)

          Blocks action of endogenous vasoconstrictor and smooth muscle mitogen endothelin; class-wide risk of liver injury and teratogenicity, liver chemistry testing and pregnancy testing for reproductive-aged women are requireda

          Phosphodiesterase-5 inhibitors (sildenafil, tadalafil)

          Prolongs effect of intrinsic vasodilator cyclic GMP by inhibiting hydrolysis by phosphodiesterase 5

          GMP = guanosine monophosphate.

          aAlthough not required for ambrisentan, some experts suggest that it is prudent to perform liver chemistry tests at the outset of treatment for pulmonary arterial hypertension and at periodic intervals thereafter at the discretion of the managing physician.

      • Drawbacks of vasodilator therapy:
        • Hypotension
        • Fluid retention
        • Worsening hypoxemia with V/Q mismatch (esp if given systemically b/c increases flow to hypoxic areas of the lung.  Inhaled (i.e. Flolan(R)) may be better because it (in theory) vasodilates only ventilated areas of the lung.


    • Fatigue and dyspnea with exertion.
    • As disease progresses: RV decompensation
      • Syncope with exertion.
      • R-heart failure (edema, ascites, hepatomegaly).


    Physical Exam

    • RV Dysfunction
      • Increased P2
      • RV heave
      • R-sided S4
      • R-sided systolic murmur (TR), 
      • +/- arrhythmias (atrial fib)
    • RV Failure
      • JVP increase
      • R-sided S3
      • Hepatomegaly/pulsatile liver
      • Peripheral Edema
      • Hypotension (end-stage)
    • Look for causes:
      • Signs of L-sided heart failure (crackles etc..)



    • First test is always echocardiogram
    • Gold Standard: R-heart cath --> reveals PA pressure. (recommended in all pts with pulmonary arterial HTN or uncertain cause)
    • Echocardiogram
      • May underestimate PA pressures, esp if advanced diffuse parenchymal lung disease and scleroderma.
    • Typically start with echo, then assess for lung disease and left heart diseases.
      • If no lung or L-heart diseases --> VQ scan --> refer to PH center --> R-heart cath
    • Workup:
      • Chest CT (parenchymal lung disease)
      • PFTs (+DLCO) - expect low DLCO and normal lung volumes
      • VQ Scan (R/O Class 4 chronic thromboembolic disease)
      • HIV serology, liver assessment, connective tissue diseases, sleep study.
      • Trop, BNP (prognostic information)
      • If arterial pulmonary HTN suspected: R-heart cath (dx and therapy)
      • 6min walk study.
        • Can repeat 6min walk, echo assesses progression of disease and response to therapy.
    • Class II - echo, L-sided disease?
    • Class III - OSA sleep study, CT chest, PFTs (DLCO <50 would explain it, >50 likely not enough)
    • Class IV - VQ Scan


    R-Heart Catheterization

    • Hemodynamics (consistent with PAH Class I)
      • PA pressure >25mmHg
      • Pulmonary vascular resistance >240
      • Wedge Pressure <15?  (if high, then L-sided)
      • Assess for shunt [PA O2 saturation], markers of poor prognosis, L-sided disease. 
    • (if above criteria met, then its "pre-capillary disease".  If ruled out Class III, IV, and V prior to RHC, then likely PAH)
    • Poor Prognostic features?
      • RA pressure >20mmHg = 1mo survival  (w/o treatment)
      • PVR 10 Wood Units (if>12, high mortality)
      • prognostic features.png

    • Typically R-heart cath is required for diagnosis (currently MRI, echo parameters investigated), and government does not cover PH drugs unless R-heart cat was done. 
    • ABSOLUTE Contraindications:
      • Mechanical TV or PV
      • RH masses (thrombus/tumor)
      • R-sided endocarditis
    • Relative Contraindications
      • Coagulopathy, Pacemaker, Bioprostateic TV/PV, LBBB (small risk of poking septum making complete AV block), Arrhythmias, skin site infections.
    • Complications
      • Hematoma at puncture site
      • Pneumothorax
      • Arrhythmias
      • Vasovagal/Hypotensive, Pulmonary hemorrhage (rare)


    • Must define if Class I (PAH) or other Class II-V
    • Refer to PH Clinic:
      • CTD with high suspition of PH (regardless of PAP)
      • PASP > 40....
    • Class II-V - treat underlying condition.
    • Class I:
      • See section on PAH
      • Acutely:
        • Keep MAP >65 (otherwise low perfusion pressure to RV can worsen R-failure.  RV perfused in systole&diastole unlike L-side). 
        • Avoid small lung volumes
        • Ensure O2, CO2, pH are normal
        • Avoid negative inotropes
        • Keep sinus rhythm 
      • Vasodilator therapy.
        • Endothelin Pathway
          • bosentan,
          • ambrisentan
          • macitentan
        • Nitric Oxide Pathway
          • PDE5i (sildenafil, tadalafil)
          • sGC stimulator (riociguat)
        • Prostacyclin Pathway
          • Prostacyclins
            • epoprostenol (IV) [Flolan]
            • iloprost (INH)
            • treprostinil (IV, SQ, INH, oral)
          • IP2 agonist
            • selexipag
        • Adverse effects:
          • Hypotension
          • Fluid retention
          • Worsening hypoxemia with V/Q mismatch
    • Class IV
      • Positive VQ mismatch
      • Keep on anticoagulation
      • Surgery referral? (embolectomy?) 
      • Balloon angioplasty? 


    • Lung transplant often required for patients with end-stage pulmonary or pulmonary vascular disease in whom therapy has been unsuccessful or in whom there are no available therapies.
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