Eduardo Bossone, Francesco Ferrara, Eugenio Picano*

1. SE2020, April 10, 2018 Pulmonary pressures during exercise. DOSPAH project Eduardo Bossone, Francesco Ferrara, Eugenio Picano* Cardiology Division Cava de’ Tirreni and Amalfi Coast University Hospital, Salerno, Italy *CNR Institute of Clinical Physiology,Pisa, Italy

2. Acronym: DOSPAH Project 8 : Doppler Stress echo for prediction of Pulmonary Arterial Hypertension

3. Pulmonary Pressures in Stress echo • Pathophysiologicalplausibility • Echocardiographicplausibility • Diagnosticplausibility • Prognosticplausibility

5. Background • Pulmonary artery pressure is determined by the amount of blood flowing through the pulmonary circulation (cardiac output), the intrinsic properties of the vasculature (resistance, compliance, and impedance), and the left atrial pressure downstream of the pulmonary circuit (left ventricular diastolic pressure). mPAP = PVR x Q + LAP • Similar to the systemic circulation, high-output states and vascular stiffening may contribute to increases in systolic pressure in the pulmonary circulation.. BossoneE, Naeije R. Exercise-Induced Pulmonary Hypertension. Heart Failure Clinics 2012;8:485-495.

6. Background On average, each liter per minute of increase Q is accompanied by 1 mmHg increase in mPAPin young adult men and women. Aging to 60-80 years is associated with a more than doubling of the slope of mPAP-Q relationships. In young adults: mPAP - Q  1 mmHg.min.L-1 In old adults: mPAP - Q  2.5 mmHg.min.L-1 • Bossone E, Naeije R. Exercise-Induced Pulmonary Hypertension. Heart Failure Cinics. 2012;8:485-495.

7. Relation between Pulmonary Artery Systolic Pressure and Age and BMI • The upper limit of PASP is dependent on Age and BMI and may include 40 mmHg in some older or obese subjects. McQuillan BM. et al. Circulation 2001;104:2797-2802.

8. Background • The pulmonary circulation is characterized by high flow and by low pressure and low resistance, one-tenth of systemic vascular resistance. In healthy subjects, moderate exercise leads to an increase in stroke volume and heart rate and a fall in PVR secondary to passive distension of compliant small vessels and/or recruitment of additional vessels in the upper portion of normal lungs. As a consequence we observe only a slight increase in PAP despite a more than three-fold increase in cardiac output. • On the other hand, the substantial increase of PAP documented in human elite athletes during intense exercise could be accounted for by the large increase in pulmonary blood flow along with the rise in LV filling pressure. This “physiologic counteract” may lead to the impairment of pulmonary blood-gas barrier integrity (pulmonary capillary “breaking stress”) with development of exercise – induced pulmonary hemorrhage. • Reported upper normal limits of Doppler-derived PAPs during exercise are < 40-45 mmHg in healthy individuals vs < 55-60 mmHg in highly trained athletes.

9. Pulmonary Pressures in Stress echo • Pathophysiologicalplausibility • Echocardiographicplausibility • Diagnosticplausibility • Prognosticplausibility

10. Hemodynamic Values for Normal Adult Malesat Rest and Moderate Exercise RESTEXERCISE Cardiac output (liters/min) 6 16 Heart rate (beats/min) 80 130 Right atrial pressure (mmHg) 4-6 6-8 Pulmonary artery pressure (mmHg) Systolic 20-25 30-35 Diastolic 10-12 11-14 Mean 14-18 20-25 Pulmonary wedge pressure (mmHg) 6-9 10-12 Systemic arterial pressure (mmHg) 20/180 150/95 Mean 90/100 110/120 Pulmonary vascular resistance (units) 0.70-0.95 0.60-0.90

11. Although TR is present in > 75% of the normal adult population, in case of a trivial regurgitant jet the injection of contast agents (such as agitated saline or air-blood-saline mixture) may be required to achieve clear delineation of the jet envelope Because velocity measurements are angle-dependent, TRV should be taken from multiple views and off-axis if necessary Patient 14 TRV (m/s) Rest Peak TRV = 2.3 m/s, SPAP = 26 mmHg TRV = 4.1 m/s, SPAP = 72 mmHg SPAP = 4V2 + Right Atrial Pressure (5 mmHg)

12. The resting physiological range of SPAP is dependent on age and body mass index and can be as high as 40 mmHg in older (>50 yrs) or obese (body mass index > 30 Kg/m2) subjects Patient 15 TRV (m/s) SPAP is a flow dependent variable,and a TVR >3.0 is easily achieved at rest in high-flow states such as anemia or hyperthyroidism. Rest Peak TRV = 3.1 m/s, SPAP = 43 mmHg TRV = 4.5 m/s, SPAP = 86 mmHg SPAP = 4V2 + Right Atrial Pressure (5 mmHg)

13. Exercise Echocardiography Data Represented as Multipoint Pressure–Flow Relationship of the Pulmonary Circulation. Modified from Argiento P. et al. Eur Respir J. 2009; 35:1273-8.

14. Pulmonary Pressures in Stress echo • Pathophysiologicalplausibility • Echocardiographicplausibility • Diagnosticplausibility • Prognosticplausibility

15. Pulmonary Hypertension 2009

16. Subjects at Very High Risk of Pulmonary Arterial Hypertension Pts. with known genetic mutations predisposing PHtn First-degree relatives in a familial PAH family Pts. with scleroderma Pts. with congenital systemic to pulmonary shunts Pts. with portal hypertension prior to liver transplantation Bossone E, Citro R, Armstrong WF, Rubenfire M. Chest 2008.

18. Pulmonary Pressures in Stress echo • Pathophysiologicalplausibility • Echocardiographicplausibility • Diagnosticplausibility • Prognosticplausibility

19. Survivaldepends on SPAP response Increase of SPAP >30mmHg 1.0 0.8 Overall survival 0.6 Survival ≤30mmHg >30mmHg: 1,3,4 –Year-SR:92%, 92% and 89% 0.4 ≤ 30mmHg: 1,3,4-Year-SR:92%, 69% and 48% p=0.002 0.2 (Grunig E , Bossone E, Circulation 2013) 0 2 0 1 3 4 Years Numbers at risk [n] Time [years] >30mmHg ≤30mmHg

20. Exercise-induced PASP rise (>18 mmHg) in 170 systemic sclerosis patients predict future overt resting pulmonary hypertension after 41 months of follow-up (Codullo V, Ghio S et al, Arthritis Rheum 2013) Exercise-induced PASP (and, better, pressure-flow slope) in 170 connective tissue disease patients predict future overt resting pulmonary hypertension in 16 after 32 months of follow-up (Kusunose K et al, JACC 2015) Figure 2. Changes in PASP values from rest to peak exercise for each individual patient. Luna Gargani, Alberto Pignone, Gergely Agoston, Antonella Moreo, Eugenia Capati, Luigi P. Badano, Marica Doveri, Laura Bazzichi, Marco Fabio Costantino, Andrea Pavellini, Francesco Pieri, Francesco Musca, Denisa Muraru, Oscar Epis, Eleonora Bruschi, Benedetta De Chiara, Federico Perfetto, Fabio Mori, Oberdan Parodi, Rosa Sicari, Stefano Bombardieri, Albert Varga, Marco Matucci Cerinic, Eduardo Bossone, Eugenio Picano American Heart Journal, Volume 165, Issue 2, 2013, 200–207 http://dx.doi.org/10.1016/j.ahj.2012.10.020

21. The rationale of subclinical detection of PAH Lau EMT, Humbert M, Celermejer D Nat Rev Cardiol 2015

22. Flow Chart Protocol #8, DOSPAH Resting TTE: SPAP eithernormal in Group A (<35 mmHg) Or borderline-mildlyabnormal (< 50 mmHg) in Group B GROUP A : Subjects at risk of PAH: systemic sclerosis, first-degree relatives of familiar PAH, etc GROUP B : Patients with PAH group 1 ESC2015 , NYHA class 1 or 2; Or borderline mean PAP 21-24 mmHg , no contraindication to exercise EXERCISE Yearly clinical TTE follow-up Studyhypothesis Will-be PAH (Group A),more events (Group B) No PAH (Group A), less events (Group B) Peak exercise SPAP Higher Lower Mean PAP/CO slope Higher Lower Higher Mean PAP/ min exercise Lower RV contractile reserve Lower Higher