Pulmonary Hypertension

Question 1

Definition of PH

Answer 1

• Pulmonary hypertension is defined as a resting mean pulmonary arterial pressure of >25 mm Hg, measured by right heart catheterization.
• The subgroup of PH known as pulmonary arterial hypertension (PAH) adds the criterion that the pulmonary venous (or pulmonary capillary wedge) pressure must be <15 mm Hg.

Question 2

Pulmonary arterial hypertension (PAH)

Answer 2

• Idiopathic PAH
• Inherited
• Drug or toxin induced
• Associated with connective tissue diseases, HIV infection, portal hypertension, congenital heart diseases, schistosomiasis
• Group 1

Question 3

Pulmonary hypertension due to left heart disease

Answer 3

• Systolic dysfunction
• Diastolic dysfunction
• Valvular disease
• Group 2

Question 4

3. Pulmonary hypertension due to lung diseases and/or hypoxia

Answer 4

3. 1 COPD
4. 2 Interstitial lung disease
5. 3 Sleep disordered breathing and alveolar hypoventilation disorders
6. 4 Chronic exposure to high altitude
   - Group 3

Question 5

Chronic thromboembolic pulmonary hypertension (CTEPH)

Answer 5

• Group 4

Question 6

Pulmonary hypertension due to unclear multifactorial mechanisms

Answer 6

5. 1 Hematologic disorders (e.g., myeloproliferative diseases)
6. 2 Systemic disorders (e.g., sarcoidosis)
7. 3 Metabolic disorders (e.g., glycogen storage disease)
8. 4 Other (e.g., tumor obstruction)

Question 7

PA mean = (CO x PVR) + PCWP

Answer 7

From this equation, it is apparent that mean PA pressure is determined by: Right-sided cardiac output, AND Pulmonary vascular resistance, AND Mean pulmonary venous pressure/left atrial pressure (measured as PCWP)

Question 8

3 Variables that Can Change and Cause PH

Answer 8

1. Pulmonary Venous Pressure
2. Pulmonary Vascular Resistance
3. Right Sided Cardiac Output

Question 9

Pulmonary Venous Pressure

Answer 9

Left ventricular systolic or diastolic dysfunction and mitral valve disease can increase pulmonary venous pressure.

Question 10

Pulmonary Vascular Resistance

Answer 10

Conditions that decrease the area of the pulmonary vascular bed (e.g., pulmonary emboli, connective tissue diseases, interstitial lung disease, COPD) or induce hypoxic vasoconstriction (any lung disease producing hypoxia) increase pulmonary vascular resistance.

Question 11

Right Sided Cardiac Output

Answer 11

Left-to-right atrial septal defects (ASD), left-to-right ventricular septal defects (VSD), and other systemic-to-pulmonary shunts increase rightsided cardiac output by increasing the right ventricular volume

Question 12

PH Sequence of Events

Answer 12

Regardless of the cause, a predictable sequence of events occurs. The initial injury causes mild pulmonary hypertension. The elevated pressure induces additional damage to the pulmonary vasculature, which narrows the pulmonary vascular bed. The right ventricle hypertrophies in order to overcome the increased resistance. Vascular injury accelerates in the presence of elevated pulmonary artery pressure, which increases right ventricular afterload further. Eventually, the right ventricle dilates and fails. By this time, patients may have severe symptoms, including symptoms at rest.

Question 13

Clinical Presentation of PH - Symptoms

Answer 13

• Symptoms

–Dyspnea on exertion

–Fatigue

–Chest pain/angina

–Syncope

–Ankle swelling

Question 14

Clinical Presentation of PH - Physical Findings

Answer 14

• Physical Findings

–Pulmonic component of S2

• Increased intensity
• Increased splitting

–Tricuspid regurgitation murmur

–Right ventricular S4 or S3

–Increased JVP

–Peripheral edema

–Ascites

Question 15

Answer 15

Right ventricular hypertrophy: marked right axis deviation, tall R wave in V1.

Question 16

Pathogenesis Idiopathic / Inherited PAH

Answer 16

• PAH is related to genetic mutations in the bone morphogenetic protein receptor type 2 gene (BMPR2) and several other genes.

– Mutations in the BMPR2 gene occur in approximately 70% of families with a history of familial PAH and in nearly 25% of patients believed to have sporadic idiopathic PAH.

• BMPR2 is a member of the transforming growth factor beta family.

– The BMPR2 pathway induces apoptosis; hypothesis is that abnormal pathway activity in patients with mutations permits excess endothelial cell growth and proliferation in response to injury.

• Idiopathic PAH is a proliferative vasculopathy, characterized by vasoconstriction, cell proliferation, fibrosis, and thrombosis.

– Pathologic findings include intimal hyperplasia and fibrosis, medial hypertrophy, and in situ thrombi of the small pulmonary arteries and arterioles.

Question 17

Vasoactive Therapy

Answer 17

Patients with PAH – Group I

• Calcium channel blockers

– Nifedipine, diltiazem, amlodipine

• Prostaglandins

– Prostacyclin analogues

– Epoprostenol

– Treprostinil – longer half-life, subQ administration/inhaled

– Iloprost - inhaled

• Phosphodiesterase 5 inhibitors

– Sildenafil

– Tadalafil

– longer half-life

• Endothelin receptor antagonists

– Bosentan

– Ambrisentan

• Soluble guanylate cyclase stimulant

– Riociguat

Question 18

Calcium Channel Blockers

Answer 18

Calcium channel blockers reduce the influx of calcium ions into pulmonary arterial smooth muscle cells, thereby reducing calcium-mediated activity of the contractile mechanism.

Question 19

Prostacyclin Analogues

Answer 19

Prostacyclin analogues (epoprostenol, treprostinil, and Iloprost) supplement deficient levels of prostacyclin caused by underexpression of endothelial prostacyclin synthase.

Question 20

Endothelin Receptor Antagonists

Answer 20

Endothelin receptor antagonists (bosentan, ambrisentan) block the effect of endothelin at smooth muscle cell receptors

Question 21

Phosphodiesterase 5 (PDE5) inhibitors

Answer 21

Phosphodiesterase 5 (PDE5) inhibitors (sildenafil, tadalafil) promote the activity of the nitric oxide pathway by reducing conversion of cyclic guanylate monophosphate (cGMP, a second messenger) to 5ʹ-guanylate monophosphate (an inactive product).

Question 22

Guanylate Cyclase Stimulators

Answer 22

A recently introduced class of drugs activates the conversion of cyclic guanylate monophosphate (cGMP, a second messenger) to 5ʹ-guanylate monophosphate (an inactive product) pathway in the absence of nitric oxide by directly stimulating the activity of soluble guanylate cyclase. The only available drug in this category of guanylate cyclase stimulators is riociguat.