PAH Pathophysiology

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PAH disease progression

PAH is a rare and progressive disease1 of the lungs that primarily affects small pulmonary arterioles.2 Normally, pulmonary circulation is a low-pressure, high-flow system, but progressive remodeling and the obliteration of the pulmonary arterioles cause rising pressures in the lungs.3 Although the heart may adapt at first, these rising pulmonary pressures eventually lead to RV dysfunction, heart failure, and death.3-5

RV dysfunction in PAH

Although PAH is a disease of the lungs, it severely affects the heart, ultimately leading to right heart failure.2,6

A closer look at a heart as it goes through rv dysfunction
  • As pulmonary arterioles narrow and pressures in the lungs rise, the RV must work harder to pump blood through the lungs
  • It initially compensates, so symptoms may not depict the severity of PAH
  • As the RV enlarges, it pumps less blood to the lungs, leaving less blood available for the LV to pump to the rest of the body
  • The RV cannot sustain the long-term increased pressures and decompensates
  • Right heart failure is the primary cause of death in patients with PAH

A closer look at pathophysiologic changes as PAH progresses

Normal

Pulmonary arteries*
Illustration of a Normal Pulmonary artery
Right ventricle
Illustration of a Normal Right Ventricle

Normally, pulmonary arteries make up an extensive network in the lungs. The pulmonary arteries have a healthy endothelium, allowing for normal perfusion. Due to the normality of the pulmonary arteries and PVR, the RV remains thin walled and with a normal CO.4

Compensation

Pulmonary arteries*
Illustration of a compensation pulmonary artery
Right ventricle
Illustration of a compensation right ventricle

As PAH progresses, remodeling of the small to medium pulmonary arteries causes them to become narrow and stiff, restricting blood flow. The loss of microvessels leads to a mild increase in PVR and moderate decrease in perfusion. Due to the increasing PVR, and increasing afterload, the RV hypertrophies. CO remains preserved, however, so there are no symptoms at this stage. Hemodynamics are only minimally affected if at all.4

Failure

Pulmonary arteries*
Illustration of a failure in pulmonary arteries
Right ventricle
Illustration of failure in the right ventricle

Cell proliferation and obliterative remodeling in the pulmonary arteries lead to a severe increase in PVR and a severe decrease in perfusion. The RV dilates, and CO is severely depressed, leading to right heart failure.4,5

*Images represent a pulmonary artery cross section and perfusion in a pulmonary artery.4

Echo imaging shows right heart dilation caused by PAH

Apical 4-chamber view

A doppler view of systolic pulmonary artery pressure with right dilation from PAH
  • Paradoxical wall motion septum
  • Severe RV and RA dilation

Doppler: Systolic pulmonary artery pressure

An apical 4-chamber view of an echo showing right dilation from PAH
  • RA pressure estimated to be 15 mm Hg due to noncompressible dilated inferior vena cava
  • Systolic pulmonary artery pressure: 96 mm Hg
Images courtesy of Anjali Vaidya, MD, FACC, FASE, FACP. Pulmonary Hypertension, Right Heart Failure & CTEPH Program, Temple University Hospital.

Patients are at risk for disease progression even when symptoms are absent3,4

PAH disease progression graph of relative changes
Adapted from: Klinger JR. J Respir Dis. 2009;30(1):1-2.

With PAH, increasing pulmonary pressures will ultimately cause right heart failure.3-5

  • As pulmonary arterioles narrow or become blocked, PVR and mPAP rise. Because these increases are compensated for by RV remodeling, CO is maintained, and the patient remains asymptomatic
  • The ability of the RV to adapt to rising PVR, and increasing afterload, is limited. Further increases in PVR will lead to decreases in CO and symptoms upon exertion. However, CO at rest is maintained
  • Eventually the RV fails, leading to a decreased mPAP and increased RAP

Delayed diagnosis: Common and consequential

Symptoms of PAH are often nonspecific7,8

Patients with PAH often present with nonspecific symptoms resulting from the decompensation of the RV. The delay in symptom presentation and the nonspecific symptoms of PAH lead to delay in diagnosis.7-9 This delay can also be compounded by misdiagnoses or other comorbid conditions that include PH-LHD, COPD, asthma, or obesity.10,11

Body illustration showing the location, number labeling and body part affected by the early and late nonspecific symptoms of PAH

Early

  1. Dizzness
  2. SOB (dyspnea)
  3. Palpitations
  4. Fatigue
  5. Edema

Late

  1. Syncope
  2. Jugular venous distension
  3. SOB
  4. Chest pain
  5. Hepatomegaly
  6. Swollen abdomen
  7. Low blood pressure

Most patients diagnosed at FC III or FC IV12

In the USPHSR that enrolled patients from 2015 to 2018, time from symptom onset to diagnosis took an average of 2 years in PAH.13 Because symptoms and symptom worsening occur after significant obstruction in the pulmonary arteries and the resulting RV dysfunction, patients are typically diagnosed after significant disease progression has taken place. Most patients are diagnosed at FC III or FC IV.12 Therefore, even newly diagnosed FC III patients can have substantial disease progression and a decompensating right heart.

Addressing the pathophysiology of PAH

No matter a patient’s risk status, initial treatment with at least 2 medications is recommended by treatment guidelines for most patients.1,14 For patients diagnosed with substantial disease progression, or determined to be at high-risk status, treatment guidelines recommend combination therapy with an IV prostacyclin-class therapy. Monotherapy has but a residual role in treating PAH, and therefore has become the exception for most patients with PAH.14

When monitoring your patient’s response to treatment, it is important to remember that PAH is a progressive disease even if outward symptoms may not be evident. For example, symptoms may stabilize because patients have adjusted their lifestyle. Detrimental changes to the RV can occur before declines are seen in a patient’s FC or 6MWD.15-17

In a meta-analysis of multiple clinical studies, a 12- to 16-week delay in initiation or escalation of PAH therapy was shown to be detrimental to patient outcomes.18 Patients whose treatment initiation or escalation were delayed were never able to achieve the treatment successes of those who added therapy earlier.19

Regular risk assessments can help you catch disease progression early, even if the outward signs of progression remain hidden. Early intervention and regular monitoring can help minimize or delay functional impairment19,20 (see chart). If intervention is delayed, the opportunity to minimize functional impairment may be lost.18,21 By helping your patients achieve and maintain low-risk status with routine risk assessments and appropriate treatment escalation, you can improve their outcomes.1,14

Indicators of disease progression17:

A graph showing the indicators of PAH disease progression
Image Description

Indicators of disease progression17:

  • Changes in the right heart
  • Changes in biomarkers (BNP/NT-proBNP levels)
  • Changes in FC and 6MWD
  • Hospitalization
Adapted image from Dr. Raymond Benza.

Functional Capacity in PAH Over Time19

A graph showing the functional capacity of PAH over time
Adapted from: Sitbon O, Galiè N. Eur Respir Rev. 2010;19(118):272-278.

Treatment guidelines call for escalating therapy within 3 to 6 months if your patient has not achieved low-risk status14

Review Treatment Guidelines
6MWD=6-minute walk distance; CO=cardiac output; COPD=chronic obstructive pulmonary disease; FC=Functional Class; LV=left ventricle; mPAP=mean pulmonary arterial pressure; PAP=pulmonary arterial pressure; PH-LHD=pulmonary hypertension due to left heart disease; PVR=pulmonary vascular resistance; RA=right atrium; RAP=right atrial pressure; SOB=shortness of breath; USPHS=United States Pulmonary Hypertension Scientific Registry.References: 1. Galiè N, et al. Eur Heart J. 2016;37(1):67-119. 2. Lai YC, et al. Circ Res. 2014;115(1):115-130. 3. Klinger JR. J Respir Dis. 2009;30(1):1-2. 4. Champion HC, et al. Circulation. 2009;120(11):992-1007. 5. Gaine S, et al. Eur Respir Rev. 2017;26(146):170095. 6. Tang H, et al. Circ Res. 2015;116(1):6-8. 7. Bishop BM, et al. Pharmacotherapy. 2012;32(9):838-855. 8. McLaughlin VV, et al. J Am Coll Cardiol. 2009;53(17):1573-1619. 9. Rich S, et al. Ann Intern Med. 1987;107(2):216-223. 10. Hussain N, et al. Pulm Circ. 2016;6(1):3-14. 11. Brown LM, et al. Chest. 2011;140(1):19-26. 12. Badesch DB, et al. Chest. 2010;137(2):376-387. 13. Badlam JB, et al. Chest. 2021;159(1):311-327. 14. Galiè N, et al. Eur Respir J. 2019;53(1):1801889. 15. Besinque GM, et al. Am J Manag Care. 2019;25(3 suppl):S47-S52. 16. van de Veerdonk MC, et al. Chest. 2015;147(4):1063-1071. 17. Milks MW, et al. J Heart Lung Transplant. 2021;40(3):172-182. 18. Vizza CD, et al. Int J Cardiol. 2018;254:299-301. 19. Sitbon O, Galiè N. Eur Respir Rev. 2010;19(118):272-278. 20. Vachiéry JL, et al. Eur Respir Rev. 2012;21(123):40-47. 21. Galiè N, et al. N Engl J Med. 2015;373(9):834-844.