PULMONARY HYPERTENSION

Augustine Lee, MD

Mayo Clinic Florida

Lee.augustine@mayo.edu

Definition

Hemodynamically defined

mPAP >25 mmHg at rest (or >30 with exercise)

PCWP <15 mmHg

(PVR > 3 wood units)

Diagnosis requires hemodynamic

assessment

Echocardiography alone is not sufficient

Right heart or PA catheterization required

LUNGS

RA RV PA PC PV LA LV

PVR CO

PA Pressure PV Pressure

V = I R

WHO Classification

1. PAH Idiopathic

Familial (6%): BMPR2, ALK1, Endoglin (HHT), KCNK3?

Drug and toxin-induced

Fenfluramine

Associated conditions (APAH):

Connective tissue disease: Scleroderma, SLE

HIV

Portal hypertension

CHD: Eisenmenger’s, Systemic-pulmonary shunt

Schistosomiasis

Chronic hemolytic anemia: Sickle cell anemia

1’. PVOD, Pulmonary capillary hemangiomatosis

WHO Classification

2. Left heart disease (“venous”)

Systolic, diastolic, valvular

3. Lung disease and/or hypoxemia

COPD, ILD, Sleep disordered breathing, Hypoventilation syndromes, High altitude

4. Chronic thromboembolic pulmonary hypertension

(CTEPH)

5. Other

Sarcoidosis, PLCH, Neoplastic, Metabolic disorders, Myeloproliferative disorders, Fibrosing mediastinitis

Breakdown (REVEAL)

McGoon, Eur Resp Rev 2012

ALL PH APAH

Idiopathic

No risk factor

No family history or genetic mutation

Leading cause ~40%

Women > men

Mean age 52

Associated conditions

CTD ~15% Systemic sclerosis (~50%) have worst prognosis

HIV ~6% Declining

Schistosomiasis Possibly most prevalent worldwide

Sickle cell ~20% Poor prognosis

COPD, IPF/ILD ~ 40% Worsens prognosis

Venothromboembolism Even after single “normotensive” acute PE ~27%

Might be less if treated with thrombolytics ~11%

Europe: Galie, EHJ 2009

Europe: Galie, EHJ 2009

US: ACCF/AHA 2009

ACCF/AHA 2009

www.Pah-info.com

Right Heart Catheterization

REVEAL Registry

“Registry to Evaluate Early and Long Term

PAH Disease Management”

United States

2006-2009

3515 subjects

Multiple publications

Prognosis (REVEAL) Benza, Chest 2012.

McGoon, Eur Resp Rev 2012

IPF and PAH Nadrous, Chest 2005

COPD and PAH Oswald-Mammosser, Chest 1995

Quick bad prognostic findings

Age > 45

WHO functinal class III or IV

Failure to drop a functional class after therapy

Echocardiography Pericardial effusion

Large right atrial size and RAP >20

Septal shift during diastole

RV dysfunction

Increased BNP

Prolonged QRS

Hypocapnia

Comorbid conditions: COPD, IPF, diabetes, sickle cell, HIV, etc.

Causes of death (IPAH)

73%: RV failure

27% Other

Medication adverse effect

Surgery

Pneumonia

Stroke

D’Alonzo. AIM 1991. (NBHLBI)

McGoon, Eur Resp Rev 2012

Treatment: General Measures

Manage primary disorder E.g. Mitral stenosis, COPD, stop toxins

Manage aggravating conditions E.g. Sleep apnea, renal failure

Oxygen: Goal >90%

Anticoagulation Extrapolated survival data from IPAH

Management of RHF Diuretics, Digoxin

Exercise, rehabilitation

Move quicker & earlier to advanced therapy EARLY Study: Galie, Lancet 2008

Special case: Vasodilator responsive

~ 13% will “Respond”

Absolute mPAP falls <40mmHg

Decrease in mPAP by at least 10mmHg

Vasodilator

Inhaled NO, Epoprostenol, CCB, Adenosine

Therapy (Optional)

CCB (diltiazem, nifedipine, amlodipine)

Sustained response ~54%

Requires regular monitoring

ACCF/AHA 2009

Pathophysiology: “Vasculopathy”

Smooth muscle cell & endothelial cell proliferation (plexiform lesions)

Growth inhibitors, mitogens

Vasoconstriction

Imbalance of vasodilators/constrictors

Thrombosis

Imbalance in local coagulation factors

www.Pah-info.com

Humbert, NEJM 2004

Advanced Therapy

Prostanoid (“Gold standard”)

Epoprostenol (IV)

Treprostinil (IV, SQ, inhaled, [PO])

Iloprost (inhaled)

Endothelin receptor antagonists (ERA)

Bosentan, [macitentan], ambrisentan, sitaxsetan

PDE5 inhibitors

Sildenafil, tadalafil, vardenafil

Guanylate cyclase stimulant (sGC)

[Riociguat]

Adverse effects

Prostanoids

Jaw pain, flushing, headache, nausea, diarrhea,

arthralgias, central line infection, skin reaction

ERA

Edema

Liver toxicity: sitaxsentan > bosentan >

ambrisentan

Teratogenicity

(Pregnancy is contraindicated)

ERA contraindicated. Prostanoid preferred.

Combination therapy (REVEAL) McGoon, Eur Resp Rev 2012

BREATHE-2 TRIUMPH

FREEDOM-C

Benza, Chest 2012

McGoon, Eur Resp Rev 2012

So are patients doing better? (REVEAL)

Super-Advanced

Lung transplantation

Bilateral lung +/- heart

Median survival ~3 years

Pulmonary thromboendarterectomy

Can be curative

Expert centers only

Atrial septostomy

High procedural mortality (15-20%)

Worsening hypoxia from shunt

Palliative measure with goal to improve cardiac output in severe RHF

Summary

PAH is bad news, by itself or when complicating other conditions

Use the WHO classification to guide diagnostic considerations, & specific therapeutics

Diagnose it early, and treat it early.

RHC is necessary for diagnosis.

Lots of therapeutic options now available & more coming

But prostanoids remain gold standard in severe PAH

Consider referral to advanced PH/Transplant center early