Pulmonary Hypertension

PA mean pressure -25 mmHg at rest or >30 mmHg with exertion

Pathobiology (NEjm 2004:351 16SS)

• Imbalance between vasoconstrictors and vasodilators t vasoconstrictors: thromboxane A2 (TXAj). serotonin (5-HT). endothelin-1 (ET-1) 1 vasodilators: prostacyclin (PGIj), nitric oxide (NO), vasoactive peptide (VIP)

• Smooth muscle & endothelial cell proliferation: t VEGF. ET-1. 5-HT; I PGIj, NO.VIP

mutations in bone morphogenic protein receptor 2 (BMPR2; gene involved in prolif. & apoptosis) seen in 50% familial and 26% sporadic cases of PPH (NEJM 2001:345319)

• In situ thrombosis: t TXAj. 5-HT. PAI-1; i PGIj. NO.VIP. tissue plasminogen activator

Etiologies of Pulmonary Hypertension (Venice Classification) Pulmonary arterial • Idiopathic (IPAH) HTN (PAH) • Familial (FPAH)

• Associated conditions (APAH)

Connective tissue disorders: CREST. SLE. MCTD, RA, PM. Sjogren

Congenital L - R shunts: ASD.VSD. PDA

Portopulmonary HTN (I 2° vasoactive substances not filtered in

ESLD; - hepatopulmonary syndrome) HIV; Drugs & toxins: anorexic agents, rapeseed oil. L-tryptophan

• Pulmonary veno-ocdusive disease:! 2° chemo. BMT; orthopnea, CHF. pi eff. nl PCWP. art vasodil. worsen CHF (A/AOX 2000:1611964)

Left heart disease

• Left ventricular systolic or diastolic dysfunction

• MS/MR

Respiratory system disorders or chronic hypoxia

• COPD • Alveolar hypoventilation (eg. NM disease)

• Sleep apnea • Pneumonia (transient and mild PHT)

Chronic thrombotic or embolic disease

• Acute pulmonary embolism (transient PHT)

• Chronic thromboembolic pulmonary HTN (CTEPH)

• Nonthrombotic emboli (tumor, foreign body, parasites)

Miscellaneous

• Sarcoidosis, histiocytosis X. lymphangiomatosis. schistosomiasis

• Compression of pulmonary vessels (adenopathy, tumor, fibrosis)

(EHJ 2004:25:2243) Clinical manifestations

• Dyspnea, exertional syncope (hypoxia. 1 CO), exertional chest pain (RV ischemia)

• Symptoms of R-sided CHF (eg. peripheral edema. RUQ fullness, abdominal distention)

• IPAH: mean age of onset 36 (men older than women); female:male 1.7-3.5:1

Physical exam

• PHT: prominent P2. R-sided S*, RV heave. PA tap & flow murmur. PR (Graham Steell).TR

• r RV failure: T JVP. hepatomegaly, peripheral edema Diagnostic studies

• CXR: dilatation and pruning of pulmonary arteries, enlargement of RA and RV

• ECG: RAD. RBBB. RAE ("P pulmonale"). RVH (Se 55%. Sp 70%)

• PFTs: i DlCO, mild restrictive pattern

• ABG: I PjO; and S.02 (especially with exertion), 1 PaCOj, t A-a gradient

• Echocardiogram: T RVSP (estimated from TR jet), flattening ("D") of septum.TR. PR

• Cardiac catheterization: * RA. RV. and PA pressures, t PVR. I CO. normal PCWP

Workup (IPAH yearly incidence 1-2 per million, r/o 2C causes)

• Echocardiogram: r/o LV dysfxn, mitral valve disease, and congenital heart disease

• Cardiac catheterization: definitive evaluation of filling pressures, r/o I PCWP. r/o shunt

• CXR and high resolution chest CT: r/o parenchymal lung disease

• PFTs: r/o obstructive and restrictive lung disease, check DlCO

• ABG & polysomnography: r/o hypoventilation. OSA

• CTA (large/med vessel).V/Q scan (small vessel). • pulmonary angiogram: r/o PE

• Vasculitis labs: ANA (commonly © in PPH). RF. anti-Scl-70, anti-centromere, ESR

• LFTs & HIV: r/o portopulmonary and HIV-associated PAH

• 6-min walk test (6MWT) or cardiopulmonary exercise testing to establish fxnl capacity

Treatment (AfdVm 2002:162:1925: N£/M 2004.351:1425.JIM 2005;2S8:199)

• Principles

1) prevent and reverse vasoactive substance imbalance and vascular remodeling

2) prevent RV failure: I wall stress (1 PVR. PAP. RV diam); ensure adeq. systemic DBP

Supportive

Oxygen: maintain S,02 >90-92% (reduces vasoconstriction)

Diuretics: I RV wall stress and relieve RHF sx;gende because RV is preload depend.

Digoxin: control AF. ? counteract neg. inotopic effects CCB

Dobutamine and inhaled NO for decompensated PHT

Anticoagulation: IVTE risk of RHP. ? prevention of in srtu microthrombi; ? morL benefit (Ore 1984:70580, Chwt 2006:130:545) Vasodilators ocute vasoreaOMty test use inhaled NO. adenosine, or prostacyclin to identify Pts likely to have a long-term response to oral CCB (© vasoreactive response defined as i PAP >10 mmHg to a level - 40 mmHg with T or stable CO): 10% Pts are acute responders; no response still candidates for other vasodilators (nejm 2004:351:1425)

Vasodilators Oral CCB

(nifedipine, diltiazem) (nejm 1991327:76) IV Prostacyclin (epoprostenol; Flolan) (nejm 1996:334 296)

Prostacyclin analogues

Inhaled (lloprost)

(nejm 2002.347:322) SC (Treprostinil)

(ajrccm 2002:165:800) Oral (Beraprost) Endothelin-1 antag (bosentan) (nejm 2002:346.896) PDE-5 Inhibitor (sildenafil) (nejm 2005:353:2148)

Comments

Given if + acute vasoreactive response. Only 1/2 will be long-term responder ( NYHA I or II & near-normal hemodynamics), but they have J mortality. Side effects: hypoTN. lower limb edema Vasodilation, i pit agg, 1 smooth muscle proliferation: benefits t with time (? vascular remodeling) (nejm 1998:338273) t 6MWT 45 m. ¿ PVR 50%. 1 PAP 5 mmHg. 1 mortality H/A, flushing, jaw/leg pain, abd cramps, nausea, diarrhea, central venous catheter dysfxn and infection Same mechanism as prostacyclin IV. but easier to take and w/o central venous catheter system side effects i sx. f 6MWT 36 m. 1 PVR 25%; i PAP 5 mmHg; trend to i clinical events; requires 6-12 inhalations daily I sx. t 6MWT 16 m. i PVR 10%; I PAP 3 mmHg. no A in clinical events; given via SC microcatheter, infusion site rxn common No sustained A in 6MWT. PAP or PVR, or clinical events (n/a in US) i smooth muscle remodeling, t vasodilation, i fibrosis I sx.' 6MWT 44 m. 1 PVR 25%. 1 PAP 2 mmHg. i clinical events Side effects: t LFTs, headache, anemia, edema T cGMP -»' NO - vasodilation. I smooth, muscle proliferation i sx. t 6MWT 51 m. i PVR 28%. 1 PAP 5 mmHg, no A clinical Low side effect profile: H/A. vision A's. sinus congestion

• Treat underlying causes of 2° PHT; can use vasodilators, although litde evidence to support

• Refractory PHT

balloon atrial septostomy: R L shunt causes T CO. I S,Oj. net T tissue Oj delivery lung transplant (single or bilateral); heart-lung needed if Eisenmenger physiology

Figure 2-6 Treatment of PAH

I acute vasoreactivity testing (e.g., iNO) |

NYHA Class

Observe Sildenafil? Bosentan Epoprostenol

Trepostinil? Epoprostenol Bosentan

Sildenafil Treprostinil, lloprost lloprost.Treprostiml |

no improvement or deterioration

sustained response? i yes i continue CCB

Combination Therapy

Prostanoid and/or ET antag. and/or PDE-5 inhib

Interventional Procedure

Atrial septostomy or Lung Tx

Prognosis

• Median survival after diagnosis 2.8 y

PAH (all etiologies): 2-y 66%. 5-y 48% (Oeu 2004;12678-S)

• T NT-ProBNP is associated with RV dysfunction and T mortality in PHT (Own 2006:129:1313)

• Lung transplant: 1-y survival 66-75%; 5-y survival 45-55% (Omt 2004;126:63-S)

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