Pulmonary Arterial Hypertension “The Other High Blood Pressure”

Michael J. Cuttica MD, MSAssistant Professor of Medicine

Director; Northwestern Pulmonary Hypertension ProgramNorthwestern University

What is Pulmonary Hypertension?

• PH is high blood pressure in the blood vessels in the lungs.

• The blood pressure in your lung is normally very low:– about 1/5 your systemic blood pressure

• Many disease processes can cause the pulmonary blood pressure to rise.

What is the Anatomy?Systemic BP:

Systolic 120 mmHg

Diastolic 80 mmHg

Mean 65 mmHG

Pulmonary Artery Pressure:Systolic 20-25 mmHg

Diastolic 5-10 mmHg

PA (mean) 14 mmHG

WHO Clinical Classification of PHNice Guidelines 2013

Group 1―PAH

1.1 Idiopathic PAH

1.2 Heritable

1.2.1 BMPR2

1.2.2 ALK-1, endoglin, SMAD 9, CAV-1, KCNK3

1.2.3 Unknown

1.3 Drug- and toxin-induced

1.4 PAH associated with:

1.4.1 Connective tissue diseases

1.4.2 HIV infection

1.4.3 Portal hypertension

1.4.4 Congenital systemic to pulmonary shunts

1.4.5 Schistosomiasis

1’ Persistent pulmonary hypertension of newborn

1’’ Pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis

Group 2―PH owing to left heart disease

2.1 Systolic dysfunction

2.2 Diastolic dysfunction

2.3 Valvular disease

Group 3―PH owing to lung diseases or hypoxia

3.1 Chronic obstructive pulmonary disease3.2 Interstitial lung disease3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern3.4 Sleep-disordered breathing3.5 Alveolar hypoventilation disorder3.6 Chronic exposure to high altitude3.7 Developmental abnormalities

Group 5―PH with unclear multifactorial mechanisms

5.1 Hematologic disordersa : Chronic hemolytic anemia, MPD, 5.2 Systemic disordersb : sarcoid

5.3 Metabolic disordersc

5.4 Othersd

Group 4―Chronic thromboembolic PH

Simonneau et al. J Am Coll Cardiol. 2013;62(25 supp D):D34-D41.

Group 1― PAH Associated with Connective Tissue Disease1.4.1 Scleroderma

1.4.1 Mixed Connective Tissue Disease

1.4.1 Lupus

1.4.1 Rheumatoid Arthritis

Where is the disease?

Class 1: PAH

Class 2: PVH

Class 3: PH Class 4: CTEPH

Class 5: PH – Multifact.

WHO Clinical Classification of PHNice Guidelines 2013

Class 1: PAH

mPAP at rest > 25mmHg

PCWP < 15mmHg

PVR >3 Wood units

Class 2: PVHmPAP at rest > 25mmHg

PCWP > 15mmHg

Class 3: PH associated with lung disease

mPAP at rest > 20mmHg

Underlying chronic lung disease:COPD, ILD, Alveolar Hypoventilation Syndromes, Sleep disordered breathing

Pulmonary Vascular Resistance (PVR):

Change in pressure/ flow

Right heart Pressure – Left heart Pressure Cardiac Output

Class 1: PAH

mPAP at rest > 25mmHg

PCWP < 15mmHg

Class 2: PVHmPAP at rest > 25mmHg

PCWP > 15mmHg

PVR < 3 Wood units

What Causes PAH?Three Factors are thought to

cause the increased pulmonary vascular

resistance that characterizes the disease:

1. Vasoconstriction• Under expression of vasodilators like NO

and prostacyclin• Over expression of vasoconstrictors

endothelin-1

2. Remodeling of pulmonary vessel wall

3. Thrombosis in situ – blood clots

Clogging UpClampingDown

What is “remodeling” of a pulmonary vessel?

Medial hypertrophy • Abnormal Smooth Muscle Cell growth

• Extension of smooth muscle into small PA’s

• Abnormal Endothelial cell growth– monoclonal origin

• Inflammatory Cell infiltration around plexiform lesions.

• In situ thrombosis– clots.

PAH Normal

What is the Clinical Presentation of PAH?

BreathlessnessWithout overt signs of heart and lung disease

Fatigue

Weakness

Angina/Chest Pain

Edema/Swelling

Syncope/passing out

Clinical Suspicion of

PAH

Why do Patients with PAH get short of breath?

Your lungs are the source of oxygen that your body needs for physical activity

Oxygen from your lungs enters your blood as it flows through microscopic blood vessels called capillaries that surround tiny air sacs called alveoli.

Reduced Blood Flow Means Less Oxygen

If you have PAH, it is harder for blood to reach your lungs and pick up oxygen because the pulmonary arteries become so narrow, the resistance increases, and blood can not flow quickly through them.

Over time, this increased resistance to blood flow puts a strain on the right side of the heart as it has to work extra hard to push blood through the lungs.

Right Heart Strain

As the right heart is strained over time we see it dilate/enlarge and we see the function/squeeze of the right heart decrease.

With less oxygen in the blood stream and the right heart pumping less forcefully patients feel tired more often and get short of breath quickly, especially when exerting themselves.

Why do we screen for PAH in Scleroderma?

How sick were

patients at the time of enrollment

into the registry?

Performed a study of

screeningnew

sclerodermapatients for

PAH

EARLY TRIALS

How Do We Diagnose PAH?

• Typically, you undergo a series of tests to determine if you have PAH or another illness with symptoms similar to PAH.

• Making this determination is very important as treatments for different conditions are very different.

• Primary tests usually done first are:– echocardiogram and pulmonary function testing.

What is an Echocardiogram?

• Uses sound waves to create a picture of your heart and measure blood flow

• Provides useful information about the structure and function of your heart

• Can provide an estimation of the pressures in your pulmonary artery.

Dilated Right ventricle with reduced function

What is Pulmonary Function Testing?

• Determine the flow of air in and out of the lung– ? Obstructive lung disease

• Determine the volume of air in the lung– ? Restrictive lung disease

• How well does oxygen go from your lungs and into your blood?– ? Vascular health of the lung

What is a Right Heart Catheterization (RHC)?

• RHC is the gold standard test for making the diagnosis of PAH.– It is absolutely necessary before initiation of any

PAH specific therapy• This test allows us to measure the blood

pressure in your lungs directly.• It allows us to calculate how much blood your

heart is pumping in every minute.

What is a RHC?• A thin catheter is inserted

through a large IV either in the neck or groin.

• This catheter is then guided through the right heart and into the pulmonary artery

• Typically, a RHC can be performed in less than 1 hour.

• Occasionally, an additional catheter will be inserted into an artery to measure pressures on the left side of the heart.

What is the Anatomy?

Right Atrium:2-8 mmHg

PCWP:6-12mmHg (must be <PA diastolic)

Left Atrium:6-10mmHg

Left Ventricle:Systolic 120 mmHG

Diastolic 6-12mmHg

Pulmonary Artery Pressure:Systolic 20-30 mmHg

Diastolic 5-15 mmHg

PA (mean) <25 mmHG

How do we treat PAH?

• The goal of treatment for PAH is to relieve symptoms and slow the progression of disease.

• Initial treatment decisions are based on how far the disease has progressed and how symptomatic a patient is.

• Treatment options include:– Oral therapies: pills– Inhaled therapies– Continuous IV or subcutaneous infusion– Surgery: lung transplant

Treatment of Group 1 PAH

Humbert M et al. N Engl J Med 2004;351:1425-1436

Ambrisentan(Letairis)

Bosentan(Tracleer)

Macitentan(Opsumit)

Sildenafil(Revatio)

Tadalafil(Adcirca)

Epoprostenol(Flolan)

Treprostinil(Remodulin - IV/SQ)(Tyvaso – Inhaled)(orenitram – oral)

Iloprost(Ventavis – Inhaled)

Riociguat(Adempas) Selexipag

(Uptravi)

Conclusions

• Pulmonary hypertension is high blood pressure in the blood vessels in the lungs

• Patients with scleroderma are at an increased risk for developing this complication

• The diagnosis of this disease is made by excluding other causes of symptoms and by right heart catheterization

• Great advances in treatment have been made in the last 10-15 years