Optimal management of pulmonary arterial hypertension: prognostic indicators to determine treatment course

Figures & data

Table 1 Clinical classification of PH

Group 1: PAH

1.1 Idiopathic PAH

1.2 Heritable PAH (BMPR2, ALK1, endoglin, SMAD9, CAV1, KCNK3, unknown)

1.3 Drug- and toxin-induced

1.4 Associated with: connective tissue diseases; HIV infection; portal hypertension; congenital heart disease; schistosomiasis

Group 1’: Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis

Group 1”: Persistent PH of the newborn

Group 2: PH due to left heart disease

2.1 Left ventricular systolic dysfunction

2.2 Left ventricular diastolic dysfunction

2.3 Valvular disease

2.4 Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies

Group 3: PH due to lung diseases and/or hypoxia

3.1 Chronic obstructive pulmonary disease

3.2 Interstitial lung disease

3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern

3.4 Sleep-disordered breathing

3.5 Alveolar hypoventilation disorders

3.6 Chronic exposure to high altitude

3.7 Developmental lung diseases

Group 4: Chronic thromboembolic PH

Group 5: PH with unclear multifactorial mechanisms

5.1 Hematologic disorders: chronic hemolytic anemia; myeloproliferative disorders; splenectomy

5.2 Systemic disorders: sarcoidosis; pulmonary histiocytosis; lymphangioleiomyomatosis

5.3 Metabolic disorders: glycogen storage disease; gaucher disease; thyroid disorders

5.4 Others: tumoral obstruction; fibrosing mediastinitis; chronic renal failure; segmental PH

Abbreviations: PAH, pulmonary arterial hypertension; PH, pulmonary hypertension; ALK-1, activin receptor-like kinase 1 gene; BMPR2, bone morphogenetic protein receptor, type 2; CAV1, caveolin-1; KCNK3, gene encoding potassium channel super family K member-3; SMAD9, mothers against decapentaplegic 9.

Table 2 Parameters with established importance for assessing disease severity, stability, and prognosis

Better prognosis	Determinants of prognosis	Worse prognosis
No	Clinical evidence of RV failure	Yes
Slow	Rate of progression of symptoms	Rapid
Classes I, II	WHO functional class	Class IV
Longer	6-minute walking distance	Shorter
Peak oxygen consumption >15 mL/minute/kg	Cardiopulmonary exercise testing	Peak oxygen consumption <12 mL/minute/kg
Normal or near normal	BNP/NT-pro-BNP plasma levels	Very elevated
No pericardial effusion	Echocardiographic findings	Pericardial effusion
RAP <8 mmHg and CI ≥2.5 L/minute/m^2	Hemodynamics	RAP >15 mmHg or CI ≤2.0 L/minute/m^2

Abbreviations: RV, right ventricular; WHO, World Health Organization; BNP/NT-pro-BNP, brain natriuretic peptide/N-terminal fragment of pro-BNP; RAP, right atrial pressure; CI, cardiac index.

Table 3 Functional classification of pulmonary hypertension according to the World Health Organization

Class I: Patients with pulmonary hypertension but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near syncope.

Class II: Patients with pulmonary hypertension resulting in a slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope.

Class III: Patients with pulmonary hypertension resulting in marked limitation of physical activity. Less than ordinary activity causes undue dyspnea or fatigue, chest pain, or near syncope.

Class IV: Patients with pulmonary hypertension with an inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnea and/or fatigue may even be present at rest. Discomfort is increased by any physical activity.

Table 4 REVEAL registry PAH risk score calculator

Group 1, subgroup	Associated with CTD: +1	Associated with portal hypertension: +2	Heritable: +2
Demographics and comorbidities	Renal insufficiency: +1	Males, age >60 years: +2
WHO functional class	Class 1: -2	Class III: +1	Class IV: +2
Vital signs	Systolic BP <110 mmHg: +1	Heart rate <92 bpm: +1
6-minute walking distance	≥440 m: -1	<165 m: +1
BNP	<50 pg/mL: -2	>180 pg/mL: +1
Echocardiogram	Pericardial effusion: +1
Pulmonary function test	DLCO ≥80% pred: -1	DLCO ≤32% pred: +1
RHC	mRAP >20 mmHg within 1 year: +1	PVR >32 Wood units: +2
		Sum of above +6 = total risk score

Note: Calculated risk scores range from 0 (lowest risk) to 22 (highest risk).

Abbreviations: REVEAL, Registry to Evaluate Early and Long-Term PAH Disease Management; PAH, pulmonary arterial hypertension; CTD, connective tissue diseases; WHO, World Health Organization; BP, blood pressure; BNP, brain natriuretic peptide; DLCO, pulmonary diffusing capacity for carbon monoxide; pred, predicted; RHC, right heart catheterization; mRAP, mean right atrial pressure; PVR, pulmonary vascular resistance.

Table 5 Variables used in clinical practice to determine response to therapy and prognosis in patients with PAH

Variables	Good response to therapy and better prognosis
WHO functional class	Class I or II
Echocardiography/CMR	Normal/near normal RV size and function
Hemodynamics	Normalization of RV function (RAP <8 mmHg and CI >2.5–3.0 L/minute/m^2)
6-minute walking distance	>380–440 m; may not be aggressive enough in young individuals
Cardiopulmonary exercise testing	Peak VO2 >15 mL/minute/kg and EqCO2 <45 L/minute/L/minute
B-type natriuretic peptide level	Normal

Abbreviations: PAH, pulmonary arterial hypertension; WHO, World Health Organization; CMR, cardiac magnetic resonance; RV, right ventricular; RAP, right atrial pressure; CI, cardiac index; VO₂, oxygen consumption; EqCO₂, ventilatory equivalent for carbon dioxide.

Figure 1 Mechanisms that trigger pulmonary arterial hypertension as targets for pharmacological treatments.

Note: Copyright © 2004, Massachusetts Medical Society. Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med. 2004;351(14): 1425–1436.¹ Adapted with permission from The New England Journal of Medicine.
Abbreviations: ET, endothelin; PgI₂, prostaglandin I₂; ET_A, endothelin receptor A; ET_B, endothelin receptor B; cGMP, cyclic guanosine monophosphate; cAMP, cyclic adenosine monophosphate; PDE5, phosphodiesterase type-5.

Figure 2 Goal-oriented treatment algorithm for patients with pulmonary arterial hypertension.

Note: Reproduced with permission of the European Respiratory Society ©. Eur Respir J November 2005;26:858–863; doi:10.1183/09031936.05.00075305.⁷⁹
Abbreviation: 6MWD, 6-minute walking distance.

Figure 3 Therapeutic approach for pulmonary arterial hypertension based on the WHO-FC.

Note: Adapted from J Am Coll Cardiol, 62(25 Suppl), Galiè N, Corris PA, Frost A, et al, Updated treatment algorithm of pulmonary arterial hypertension, D60–D72,¹¹² Copyright © 2013, with permission from Elsevier.
Abbreviations: CCB, calcium channel blocker; WHO-FC, World Health Organization functional class; IV, intravenous; SC, subcutaneous; inhal, inhaled.

HumbertMSitbonOSimonneauGTreatment of pulmonary arterial hypertensionN Engl J Med2004351141425143615459304

 PubMed Web of Science ®Google Scholar

HoeperMMMarkevychISpiekerkoetterEWelteTNiedermeyerJGoal-oriented treatment and combination therapy for pulmonary arterial hypertensionEur Respir J200526585886316264047

 PubMed Web of Science ®Google Scholar

GalièNCorrisPAFrostAUpdated treatment algorithm of pulmonary arterial hypertensionJ Am Coll Cardiol20136225 SupplD60D7224355643

 PubMed Web of Science ®Google Scholar