Stress Echocardiography and PH: What Do the Findings Mean?

Definitions
There are five subtypes of pulmonary hypertension (PH) in the most recent classification from the 5th World Symposium on Pulmonary Hypertension in 2013.1 Group 1 is typical pulmonary arterial hypertension (PAH), and group 2 is PH due to left heart disease. Group 2 PH is the most common subtype encountered in clinical practice, including in the stress echocardiography laboratory.

Pre-capillary PH is invasively defined as a mean pulmonary artery pressure (PAP) >25 mmHg at rest, pulmonary capillary wedge pressure (PCWP) <15 mmHg, and a calculated pulmonary vascular resistance <3 Wood units.2 It is distinguished from post-capillary PH in which PCWP is >15 mmHg. Mean PAP of 25 mmHg approximates a right ventricular systolic pressure of 38 mmHg.

Despite this apparently clear subdivision, there may be phenotypic continuum between these groups.3,4 In 2013, Vachiéry et al. proposed subdivision of PH due to left heart disease into 2 categories on the basis of the diastolic pressure difference (DPD).5 DPD = diastolic PAP – mean PCWP. Isolated pre-capillary PH was defined as PCWP >15 mmHg and DPD <7 mmHg. Combined pre- and post-capillary PH was defined as PCWP >15 mmHg and DPD ≥7 mmHg. This sub-classification was incorporated into the most recent European guidelines.2

Invasive criteria for diagnosis of exercise-induced PH have been proposed,6 but there are limited exercise echocardiographic data concerning standards for right atrial pressure (RAP) and PAP7 and their prognostic implication. Consequently, both the 5th World Symposium on Pulmonary Hypertension1 and European Society of Cardiology2 guidelines discourage the use of the term exercise-induced pulmonary hypertension. Therefore, making a diagnosis of PH during stress echocardiography is challenging because specific, validated, consensus diagnostic criteria do not exist.

The preferred test to assess PAP with exercise is supine bike ergometry. This allows for sequential assessment of pulmonary pressures at progressively higher workloads, usually at 2-3 minute intervals. Less optimally, treadmill exercise testing can be performed with pressure assessments, done preferably within 1-2 minutes post-exercise. PAP is then calculated using peak tricuspid regurgitant velocity (TRV) and estimated RAP in the modified Bernoulli equation: 4(TRV)2 + RAP.8 Because the TRV is squared, minimal measurement error leads to disproportionately higher error in the estimated PAP.

Underestimation of Pulmonary Pressure
TRV should be measured in multiple views, parallel to the color Doppler tricuspid regurgitation signal because it is angle dependent. RAP is estimated based on standard criteria using inferior vena cava size and degree of inspiratory collapse.9 However, this assumes constant RAP at rest and exercise. RAP may be significantly increased at high workloads, particularly in patients with heart failure.7 This may cause underestimation of exercise PAP. TRV may not truly reflect right ventricle/right atrium pressure gradient in cases of severe tricuspid regurgitation due to rapid equalization of pressures.

Overestimation of Pulmonary Pressure
Exercise right ventricular systolic pressure may be overestimated by incorrect measurement of tricuspid regurgitation signal. A full modal signal with a clear peak, rather than weak or incomplete signals, must be used. Administration of agitated saline or contrast agents can be quite useful in improving signal intensity and measurement accuracy. TRV may be overestimated by measurement of contrast artifacts.

Physiologic Variations in Pulmonary Pressure
To avoid a false positive diagnosis of PH, the normal physiologic variations in PAP must be understood. Grünig et al. described a bimodal distribution of TRV with exercise or hypoxia; 5-10% of subjects have an exaggerated PAP with exercise.10,11 These outliers may be predisposed to hypoxia-associated pulmonary edema and chronic mountain sickness.

PAP is also higher in athletes, especially at high workloads, compared with normal non- athletic controls. These differences are due to higher levels of cardiac output and left ventricular filling pressures.12,13 A cut-off exercise PAP of 60 mmHg has been suggested for athletes.7 PAP also increases with each decade of life, possibly due to non-flow mediated increases in pulmonary vascular resistance.14,12 In individuals >50 years, resting PAP may be as high as 40 mmHg. PAP is also higher in obese patients. The 2017 recommendations from the European Association of Cardiovascular Imaging and the American Society of Echocardiography suggest a threshold of PAP ≥60 mmHg during exercise stress echocardiography. A threshold of TRV of 3.1 m/sec or PAP >43 mmHg generally applies in young, healthy individuals.13

Pathologic States
PAP may be elevated in high-flow states such as anemia or hyperthyroidism because it is a flow-dependent variable. Elevated PAP both at rest and with exercise may be present in patients with varying degrees of diastolic dysfunction and heart failure with preserved ejection fraction (HFpEF), systolic heart failure, and valvular heart disease. Recent studies have reported that up to 80% of patients with HFpEF have PH.3 A number of mechanisms have been described, including impaired myocardial contractility, afterload mismatch, pulmonary vasculopathy, and various load-dependent and load-independent processes.5,15

Patients at risk for PAH, such as first-degree relatives of PAH patients and patients with connective tissue disease, sickle cell disease, and human immunodeficiency virus, may also have abnormal exercise PAP; screening should be considered in these groups.7,13,16

Key Points

  1. There are no validated diagnostic criteria for PH during exercise.
  2. The term exercise-induced pulmonary hypertension should generally be avoided.
  3. Careful attention to study quality, including signal acquisition and measurement, is needed to prevent overestimation or underestimation of PAP.
  4. TRV is higher in 5-10% of normal outliers, patients over 50 years of age, obese individuals, and elite athletes.
  5. Except in the above-stated conditions, TRV >3.1 m/sec and estimated PAP >43 mmHg may be abnormal and prompt further evaluation.
  6. PH during stress echocardiography may be seen in pathologic conditions such as high-flow states, HFpEF, and valvular heart disease.
  7. PH seen during stress echocardiography is most commonly due to left heart disease.
  8. PH during stress echocardiography may be seen in patients at risk of or with subclinical PAH.
  9. Routine addition of diastolic function and PAP assessment to standard stress echocardiography testing can provide incremental clinical particularly in patients with exercise-limiting or unexplained dyspnea and reduced exercise capacity.
  10. Further research and validation studies are needed for the development of specific guidelines for the diagnosis of PH during stress echocardiography.

References

  1. Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2013;62:D34-41.
  2. Galiè N, Humbert M, Vachiéry JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J 2016;37:67-119.
  3. Naeije R, Gerges M, Vachiery JL, Caravita S, Gerges C, Lang IM. Hemodynamic Phenotyping of Pulmonary Hypertension in Left Heart Failure. Circ Heart Fail 2017;10:e004082.
  4. Opitz CF, Hoeper MM, Gibbs JS, et al. Pre-Capillary, Combined, and Post-Capillary Pulmonary Hypertension: A Pathophysiological Continuum. J Am Coll Cardiol 2016;68:368-78.
  5. Vachiéry JL, Adir Y, Barberà JA, et al. Pulmonary hypertension due to left heart diseases. J Am Coll Cardiol 2013;62:D100-8.
  6. Herve P, Lau EM, Sitbon O, et al. Criteria for diagnosis of exercise pulmonary hypertension. Eur Respir J 2015;46:728-37.
  7. Rudski LG, Gargani L, Armstrong WF, et al. Stressing the Cardiopulmonary Vascular System: The Role of Echocardiography. J Am Soc Echocardiogr 2018;31:527-50.e11.
  8. D'Alto M, Bossone E, Opotowsky AR, Ghio S, Rudski LG, Naeije R. Strengths and weaknesses of echocardiography for the diagnosis of pulmonary hypertension. Int J Cardiol 2018;263:177-83.
  9. Beigel R, Cercek B, Luo H, Siegel RJ. Noninvasive evaluation of right atrial pressure. J Am Soc Echocardiogr 2013;26:1033-42.
  10. Grünig E, Weissmann S, Ehlken N, et al. Stress Doppler echocardiography in relatives of patients with idiopathic and familial pulmonary arterial hypertension: results of a multicenter European analysis of pulmonary artery pressure response to exercise and hypoxia. Circulation 2009;119:1747-57.
  11. Lancellotti P, Pellikka PA, Budts W, et al. The clinical use of stress echocardiography in non-ischaemic heart disease: recommendations from the European Association of Cardiovascular Imaging and the American Society of Echocardiography. Eur Heart J Cardiovasc Imaging 2016;17:1191-229.
  12. Bossone E, D'Andrea A, D'Alto M, et al. Echocardiography in pulmonary arterial hypertension: from diagnosis to prognosis. J Am Soc Echocardiogr 2013;26:1-14.
  13. Lancellotti P, Pellikka PA, Budts W, et al. The Clinical Use of Stress Echocardiography in Non-Ischaemic Heart Disease: Recommendations from the European Association of Cardiovascular Imaging and the American Society of Echocardiography. J Am Soc Echocardiogr 2017;30:101-38.
  14. Kane GC, Sachdev A, Villarraga HR, et al. Impact of age on pulmonary artery systolic pressures at rest and with exercise. Echo Res Pract 2016;3:53-61.
  15. Gorter TM, van Veldhuisen DJ, Bauersachs J, et al. Right heart dysfunction and failure in heart failure with preserved ejection fraction: mechanisms and management. Position statement on behalf of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2018;20:16-37.
  16. Baptista R, Serra S, Martins R, et al. Exercise echocardiography for the assessment of pulmonary hypertension in systemic sclerosis: a systematic review. Arthritis Res Ther 2016;18:153.

Clinical Topics: Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Noninvasive Imaging, Pulmonary Hypertension and Venous Thromboembolism, Acute Heart Failure, Chronic Heart Failure, Pulmonary Hypertension, Echocardiography/Ultrasound

Keywords: Diagnostic Imaging, Echocardiography, Stress, Pulmonary Wedge Pressure, Blood Pressure, Heart Ventricles, Pulmonary Edema, Tricuspid Valve Insufficiency, Heart Failure, Systolic, Altitude Sickness, Vena Cava, Inferior, Pulmonary Artery, Atrial Pressure, Stroke Volume, Hypertension, Pulmonary, Echocardiography, Vascular Resistance, Anemia, Sickle Cell, Heart Atria, Ergometry, Obesity, Connective Tissue Diseases, Hyperthyroidism


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