Eduardo Bossone, MD, Ph.D, FESC, FACC Società Italiana di Ecografia Cardiovascolare XV Congresso Nazionale Ecocardiografia – Napoli, Aprile 2011 Ecostress ed Ipertensione Arteriosa Polmonare Utilità e Limiti Eduardo Bossone, MD, Ph.D, FESC, FACC Cardiology Division Cava de’ Tirreni and Amalfi Coast University of Salerno, Italy Vietri sul Mare, Amalfi Coast, Italy

Background The pulmonary circulation is characterized by high flow and by low pressure and low resistance, one-tenth of systemic vascular resistance. mPAP = PVR x Q + LAP

Background In old adults: mPAP - Q  2.5 mmHg.min.L-1 Linear regressions relating mPAP to Q: on average, each liter per minute of increase Q is accompanied by 1 mmHg increase in mPAP in young adult men and women. Aging to 60-80 years was found to be 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 Reeves JT, Dempsey JA, Grover RF. Pulmonary circulation during exercise. In: Pulmonary Vascular Physiology and Physiopathology. Edited by Weir EK and Reeves JT. New York, Marcel Dekker, 1989, chap 4, pp 107-133.

Hemodynamic Values for Normal Adult Males at Rest and Moderate Exercise REST EXERCISE 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

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

Reference Ranges for Normal Systolic Pressure Gradients Assessed with Doppler between RV and RA (TIPG) 95% CI for TIPG (mmHg) Age (yrs) n Women (n = 2,065) Men (n = 1,147) <20 865 8.6-24.2 8.2-26.2 20-29 669 9.2-24.4 9.9-26.3 30-39 650 9.3-25.7 8.7-27.5 40-49 494 9.9-27.5 9.1-28.3 50-59 344 10.2-29.4 11.0-30.6 >60 199 10.5-32.1 11.2-33.6 McQuillan BM. et al. Circulation 2001;104:2797-2802

ENDURANCE ATHLETES STRENGTH ATHLETES TRV (m/sec) p<0.0001 r = 0.59; p<0.0001 TRV (m/sec) Also age (p<0,01), duration of training (p<0,01) and resistance training (p<0,01) were independent predictors of TRV at the multivariate analysis. D’Andrea A, Naeije R, D’Alto M, and Bossone E. Chest 2010.

in Highly-Trained Athletes * *p < 0.01: endurance vs. strength and controls *p < 0.01: endurance vs. strength and controls *p < 0.01: endurance vs. strength and controls *p < 0.01: endurance vs. strength and controls Pulmonary Artery Systolic Pressure in Highly-Trained Athletes * Variable Controls (n=230) Strength (n= 245) Endurance (n=370) TRV (m/sec) 1.8  0.7 (1.3-2.4) 1.9 0.5 (1.5-2.6) 2.30.5* (1.9-2.9) PASP (mmHg) 17.6  4.6 (14 – 33) 19.4  8.1 (14 – 36) 26.1  6.6* (19 – 39) Stroke Volume (ml) 63.4  5.9 69.43.3 98.4 6.2* Cardiac Index (ml/min/m2) 2.30.6 2.40.3 2.80.7* Peak E / Ea ratio 4.9  1.4 5.5  1.5 5.3  1.3 TRV/RVOTTVI (m/s/cm) 0.13  0.04 (0.07 – 0.15) 0.12  0.04 (0.07 – 0.16) 0.13  0.05 (0.09 – 0.18) *p < 0.01: endurance vs. strength and controls. D’Andrea A, Naeije R, D’Alto M, and Bossone E. Chest 2010

Pulmonary Artery Systolic Pressure Response to Exercise: The Physiologic Range Physiology: Pulmonary resistance LV filling pressure Cardiac Output Bossone E. et al. J Am Coll Cardiol.1999; 33:1662-6.

Left Ventricular Filling Pressure during Exercise A Cardiological Blind Spot John B West, Chest 1998 Intense exercise Increased cardiac output Decreased pulmonary vascular resistance Increased left ventricular filling pressure Increased pulmonary artery pressure Very high pulmonary artery and During intense exercise may Stress failure of pulmonary capillaries Exercise - induced pulmonary hemorrhage

Pulmonary Artery Systolic Pressure Response to Exercise: The Physiologic Range Bossone E. et al. J Am Coll Cardiol.1999; 33:1662-6.

Pressure-Fow (P-Q) Measurements: at Rest and during Exercise Argiento P. et al. Eur Respir J. 2009; 35:1273-8.

Pressure-Fow (P-Q) Relationship The best adjustment for the individual mPAP-Q relationships was slightly curvilinear with a distensibility alpha of α = 1.7  1.8 %/mmHg This result is in perfect agreement with previous in vitro and invasive in vivo measurements Reeves JT et al. Am J Physiol Lung Cell Mol Physiol. 2005; 288: L419-25. Argiento P. et al. Eur Respir J. 2009; 35:1273-8.

Plots of increase in right ventricular systolic pressure from rest to peak exercise on room air in 11 normal control subjects (top graph), 9 pts (COPD) with normal (≤ 30 mmHg) resting values for RVSP (middle graph), and 23 pts with pulmonary hypertension at rest (bottom graph). The extent of increase in RVSP with exercise is similar in group A and B pts and is significantly graeter than control pts. Himelman RB. et al. Circulation 1989;79:863-871.

Pulmonary Pressure Response to Ex-Doppler Echocardiography in Patients with High Risk of PAH

Pulmonary Arterial Pressure Responses to Exercise. Lewis GD. Advances in Pulmonary Hypertension. Summer 2010; Vol 9, N°2.

PAP-Flow Relationships based on serial measurements of mPAP and CO during incremental exercise Lewis GD. Advances in Pulmonary Hypertension. Summer 2010; Vol 9, N°2.

Clinical Assessment - ECG - Chest X- ray Suspect PHtn TTE – Doppler Six month follow-up - - + Exercise TTE- Doppler + RIGHT HEART CATHETIRIZATION ACUTE VASOREACTIVITY TESTING Bossone E. et al. Echocardiography in pulmonary arterial hypertension: An essential tool. Chest 2007;131:339-41.

Who to screen for Ex-PHtn Chronic obstructive pulmonary disease; Heart transplantation; Susceptibility to high altitude pulmonary edema; Congenital heart disease; Trombo-embolic pulmonary hypertension; Scleroderma and relatives of patients with PAH.

Conclusions and Future Directions Exercise stress tests of the pulmonary circulation show promise for the detection of early or latent pulmonary vascular disease, and may help to understand the clinical evolution and effects of treatments in patients with established disease. While the exercise stress test based solely on systolic PAP and workload measurements may show interest in screening programs, the approach is unsatisfactory because PAP is a flow-dependent variable, and the cardiac output achieved at a give workload varies from one subject to another .

Conclusions and Future Directions Furthermore, the maximum velocity of TR is markedly dependent on stroke volume, so that a systolic PAP higher than 40 mmHg is easily achieved by exercising athletes in whom this cut-off value is very close to the upper limit of normal at rest . Systolic PAP increases in the elderly, with an increased in BMI, , and in relation to decreased left ventricular diastolic compliance and associated increase in LAP. Knowledge of the limits of normal and further validation of non invasive approaches in various patient populations are needed.

Amate il Paese ove la Natura Vi ha fatto Nascere e seconderete le Leggi dell’ Universo Socrate agli Ateniesi Atrani, Amalfi Coast, Italy

Arrivederci!!!

Clinical Studies using Ex-Echo in the Setting of PAH Author Population Ex. protocol Baseline PAPs (mmHg) Peak PAPs Himelman et al. COPD (n=36) Supine bicycle 10/25W 46 ± 20 (COPD) ± 4 (CRTL) 83 ± 30 (COPD) 31 ± 7(CRTL) Oelberg et al. ASD (n=10) Upright bicycle 31 ± 8 (ASD) 17 ± 8 (CRTL) 51 ± 10 (ASD) 19 ± 8(CRTL) Grunig et al. HAPE-S (n=9) Supine bicycle 25 W 28 ± 4 (HAPE-S) 27 ± 4 (CRTL) 55 ± 11 (HAPE-S) 36 ± 3 (CRTL) Alkotob et al. Scleroderma (n=65) Treadmill 25 ± 8 39 ± 8 Collins et al. Scleroderma (n=51) 24 ± 8 38 ± 12 Relatives of iPAH (n=52) 24 ± 4 (NR) 23 ± 3 (AR) 37 ± 3 (NR) 56 ± 11 (AR) Modify from Vachiéry JL. and Pavelescu A. Eur Heart J. H28-H53, 2007.

Abnormal Pulmonary Artery Pressure Response in Asymptomatic Carriers of Primary PulmonaryHypertension Gene Grünig E. et al. , Circulation 2000;102:1145-1150.

Società Italiana di Ecografia Cardiovascolare XV Congresso Nazionale Ecocardiografia – Napoli, Aprile 2011‏ Ecostress ed Ipertensione Arteriosa Polmonare Utilità e Limiti e limiti     Pulmonary Arterial Hypertension “ A Call to Arms” Eduardo Bossone, MD, Ph.D, FCCP, FESC, FACC Cardiology Division Cava de’ Tirreni and Amalfi Coast Hospital University of Salerno, Italy

"Luna di Capri" The Caprese Moon rising behind the island Arrivederci!!! "Luna di Capri" The Caprese Moon rising behind the island

Right Heart Dysfunction PAH Progression Pre-symptomatic/ Compensated Symptomatic/ Decompensating Declining/ Decompensated CO Symptom Threshold Right Heart Dysfunction PAP Symptoms PVR TIME Rich et al. In: Harrison’s Principles of Internal Medicine. 15th ed. 2001:1506-1507.

Symptom-free survival according to resting (A) and exercise (B) PHT Exercise Pulmonary Hypertension in Asymptomatic Degenerative Mitral regurgitation Symptom-free survival according to resting (A) and exercise (B) PHT Magne, J. et al. Circulation 2010;122:33-41 Copyright ©2010 American Heart Association

Exercise stress tests of the pulmonary circulation show promise for the detection of early or latent pulmonary vascular disease, and may help to understand the clinical evolution and effects of treatments in patients with established disease. Knowledge of the limits of normal and further validation of non invasive approaches in various patient populations are needed.

Conclusions and Future Directions

Conclusions and Future Directions To choose the optimal exercise protocol. Exercise has to be dynamic no resistive. To define the full physiologic range of pulmonary pressure responses to exercise.

Exercise Induced Pulmonary Hypertension E Bossone, Bodini BD, Mazza A, Allegra L. Pulmonary arterial hypertension: the key role of echocardiography. Chest. 2005 May;127(5):1836-43. E Bossone, Bodini BD, Mazza A, Allegra L. Pulmonary arterial hypertension: the key role of echocardiography. Chest. 2005 May;127(5):1836-43. E Bossone, Bodini BD, Mazza A, Allegra L. Pulmonary arterial hypertension: the key role of echocardiography. Chest. 2005 May;127(5):1836-43. E Bossone, Bodini BD, Mazza A, Allegra L. Pulmonary arterial hypertension: the key role of echocardiography. Chest. 2005 May;127(5):1836-43. Exercise Induced Pulmonary Hypertension Pulmonary arterial hypertension (PAH) [mean pulmonary artery pressure (PAPm) >25mmHg at rest, pulmonary wedge pressure ≤ 15 mmHg and pulmonary vascular resistance > 3 mmHg/l/min (Wood units)] is a heterogeneous condition brought on by a wide range of causes characterized by structural changes in small pulmonary arteries, that produce a progressive increase in.pulmonary artery pressure and pulmonary vascular resistance, ultimately leading to right ventricle failure and death. A number of investigators have described subsets of patients with pathologic pulmonary pressure responses during exercise and normal pulmonary pressure at rest so called Exercise Induced Pulmonary Hypertension. Given the absence of any specific symptoms or signs, ExPHtn is rarely considered, and a high degree of clinical suspicion is necessary in certain subsets of patients, such as in those with a history of pulmonary thromboemboli, mitral valve disease, the scleroderma spectrum of disorders, and familial primary pulmonary hypertension. ESC Guidelines on Diagnosis and Treatment of Pulmonary Arterial Hypertension, 2009 Bossone E. et al. Pulmonary Arterial Hypertension: The Key role of Echocardiography. Chest 2005;127:1836-43. Tolle JJ et al, Circulation 2008; 118: 2183-9. Oudiz RJ and Rubin LJ, Circulation 2008;118:2120-2121..  

Exercise Induced Pulmonary Hypertension E Bossone, Bodini BD, Mazza A, Allegra L. Pulmonary arterial hypertension: the key role of echocardiography. Chest. 2005 May;127(5):1836-43. E Bossone, Bodini BD, Mazza A, Allegra L. Pulmonary arterial hypertension: the key role of echocardiography. Chest. 2005 May;127(5):1836-43. E Bossone, Bodini BD, Mazza A, Allegra L. Pulmonary arterial hypertension: the key role of echocardiography. Chest. 2005 May;127(5):1836-43. E Bossone, Bodini BD, Mazza A, Allegra L. Pulmonary arterial hypertension: the key role of echocardiography. Chest. 2005 May;127(5):1836-43. Exercise Induced Pulmonary Hypertension Recently Tolle et al using invasive maximum incremental cardiopulmonary exercise testing fully phenotyped the patient with exercise induced PAH from a large cohort of patients. In particular they demonstrated at maximum exercise VO2 was lowest in resting PAH, intermediate in exercise-induced PAH, and highest in normals, whereas mean pulmonary artery pressure and pulmonary vascular resistance followed an opposite pattern. These results support the notion that exercise induced PAH (EIPAH) represents a mild, intermediate physiological stage of PAH characterized by less severe degrees of pulmonary vascular disease. Tolle JJ et al, Circulation 2008; 118: 2183-9. Oudiz RJ and Rubin LJ, Circulation 2008;118:2120-2121.

Conclusions and Future Directions Well designed longitudinal studies are warranted to investigate the natural history of PHtn and whether preclinical treatment can prevent the development of more severe forms of pulmonary vascular disease in susceptible persons. Ex-PHtn remains a fascinating clinical condition and Ex-echo a versatile tool “to look behind the scene” of otherwise unexplained effort dyspnea. Bossone E. et al. Latent Pulmonary Hypertension: Looking Beyond the Scene. Chest 2008;134:469-70.

(Sulmona, 20 marzo 43 a.C. – Tomi, 18 d.C.) “Principiis obsta; sero medicina paratur cum mala per longas convaluere moras” Remedia Amoris 91-92 Publius Ovidius Naso (Sulmona, 20 marzo 43 a.C. – Tomi, 18 d.C.) “Stop it at the beginning; a cure is attempted too late when, through long delay, the illness has gained strength”