Clinical and Research Measurement Techniques of The Pulmonary Circulation: the Present and the Future Robert Naeije, Michele D’Alto, Paul R. Forfia PII: DOI: Reference:

S0033-0620(14)00186-8 doi: 10.1016/j.pcad.2014.12.003 YPCAD 638

To appear in:

Progress in Cardiovascular Diseases

Please cite this article as: Naeije Robert, D’Alto Michele, Forfia Paul R., Clinical and Research Measurement Techniques of The Pulmonary Circulation: the Present and the Future, Progress in Cardiovascular Diseases (2014), doi: 10.1016/j.pcad.2014.12.003

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CLINICAL AND RESEARCH MEASUREMENT TECHNIQUES OF THE

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PULMONARY CIRCULATION: THE PRESENT AND THE FUTURE

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Robert Naeije, MD, PhD, Department of Cardiology, Erasme University Hospitalm, Brussels, Belgium

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Michele D’Alto, MD, PhD, Department of Cardiology, Second University of Naples – Monaldi Hospital, Naples, Italy

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Paul R. Forfia, MD, Temple Heart and Vascular Institute, Temple University

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Hospital, Philadelphia, Pennsylvania.

Correspondence: Dr R Naeije, Department of Physiology Erasme Campus of the Free University of Brussels, CP 604 808, Lennik road, B-1070 Brussels BELGIUM Tel +32 2 5553322 Fax +32 2 5554124 Email [email protected]

ACCEPTED MANUSCRIPT Abbreviations Ca: pulmonary artery compliance

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CTEPH: chronic thromboembolic pulmonary hypertension

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CO: cardiac output DPG: diastolic pressure gradient

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dPAP diastolic pulmonary artery pressure HCT: hematocrit

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HF: heart failure HR: heart rate LAP:left atria pressure

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LVEDP: left ventricular end-diastolic pressure LVOT: left ventricular outflow tract

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mPAP: mean PAP

MRI: magnetic resonance imaging

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PAH: pulmonary arterial hypertension

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PAP: pulmonary artery pressure PH: pulmonary hypertension PP: pulse pressure PVR: pulmonary vascular resistance Q: pulmonary blood flow RAP: right atrial pressure RVOT: right ventricular outflow tract sPAP: systolic pulmonary artery pressure TSV: stroke volume TPG: transpulmonary pressure gradient

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TR: tricuspid regurgitation VTI: velocity time integral

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Abstract

There has been a lot of progress in measurement techniques of the pulmonary

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circulation in recent years, and this has required updating of basic physiological knowledge. Pulmonary artery pressures (PAP) are normally low and dependent on left

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atrial pressure (LAP) and cardiac output (CO). Therefore, defining the functional state of the pulmonary circulation for the detection of pulmonary vascular disease or evaluation of disease progression requires measurements of PAP, Pla and CO.

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Invasive measurements have lately improved by a better definition of zero leveling and of the effects of intrathoracic pressure changes, and understanding of the inherent

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limitations of fluid-filled thermodilution catheters. The effects of LAP and pulmonary flow on PAP in health and disease are now integrated in the hemodynamic diagnosis

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of pulmonary hypertension. Development of alternative noninvasive approaches is

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critically dependent on their potential to quantify pulmonary vascular pressures and CO. Doppler echocardiography and magnetic resonance imaging are coming close. Both approaches are performant for flow measurements, but pressures remain indirectly assessed from flow velocities and/or structural changes. Doppler echocardiography or magnetic resonance imaging have been shown to be accurate, allowing for valid population studies, but with insufficient precision for single number-derived clinical decision making.

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Key-words: pulmonary circulation; pulmonary hypertrension; exercise; pulmonary vascular resistance; viscosity; left atrial pressure; cardiac output; Doppler

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echocardiography

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1. Introduction: pulmonary artery pressures (PAP) and blood flow

A lot of effort has been devoted in recent years to the development of noninvasive

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measurement techniques of the pulmonary circulation. Most have relied on Doppler echocardiography or, more recently, magnetic resonance imaging (MRI). Both have focused either on the imaging of pulmonary vascular flow patterns, with integration of

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pressure gradients calculated maximum velocities of trans-valvular flow-velocities, or, alternatively on changes in right ventricular (RV) structure or function as

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indicators of changes in pulmonary vascular function (1-3). Integration of newly available high quality signals to define pulmonary vascular function has required

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some revisiting of basic physiological concepts, which has also resulted in tightening

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of invasive procedure methodology.

Pulmonary blood flow (Q) is determined by mean PAP ( mPpa) minus left atrial pressure (LAP). This is an extrapolation of the Hagen-Poiseuille’s law which governs laminar flows within rigid straight and cylindric capillary tubes of Newtonian fluids. Thus the functional state of the pulmonary circulation can be approximated by a single number, pulmonary vascular resistance (PVR) which depends on the ratio between (mPAP-LAP) and Q:

PVR = ( mPAP - LAP) / Q

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In clinical practice, measurements of pulmonary vascular pressures and Q – assumed

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equal to cardiac output (CO) are usually performed during a catheterization of the

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right heart with a triple-lumen fluid-filled balloon- and thermistance-tipped catheter introduced by Swan, Ganz, Forrester and their colleagues in the early 1970’s (4,5).

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More than 40 years later, a right heart catheterization with a “Swan-Ganz” catheter is still recommended for the diagnosis of pre-capillary pulmonary hypertension (6). The

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procedure allows for the measurement of the components of the PVR equation, with LAP estimated by a balloon occluded, or “wedged” AP (PAWP). Pulmonary hypertension (PH) is defined by a mPAP  25 mmHg (7). Pulmonary arterial

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hypertension (PAH) is defined by a mPAP  25 mmHg, a PAWP < 15 mmHg and a PVR  3 mmHg/L/min (Wood units) (7). Precapillary PH in heart failure (HF) is

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defined by a mPAP  25 mmHg, a transpulmonary pressure gradient (mPAP-PAWP,

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or TPG)  12 mmHg and a diastolic pressure gradient (diastolic PAP, dPAP, minus

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PAWP, or DPG)  7 mmHg (8).

2. Are fluid-filled flow-directed thermodilution catheters reliable?

Because of the exclusive reliance on fluid-filled flow-directed thermodilution catheters for the diagnosis and differential diagnosis of PH and the widespread use of recommended cut-off numbers, it may be appropriate to re-examine how these measurements compare to gold standards. For this purpose, it is important to apply agreed statistics and undisputable gold standards, which are high-fidelity micromanometer-tipped catheters for pressures and the direct Fick method for pulmonary blood flow (9).

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Comparisons between methods of measurements often rely on correlation

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calculations. However, correlations largely reflect the variability of the subjects being

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measured. If one measurement is always twice as big as the other, they are highly correlated but do not agree. Bland and Altman addressed this problem by designing

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difference versus average plots (10). This analysis has since become gold standard to compare methods of measurements (11). Two crucial informations are provided: 1)

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the bias, or the difference between the means and whether it is constant over the range of measurements, and 2) the limits of agreement, or the range of possible errors. Bias

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informs about accuracy, and agreement informs about precision – or reproducibility.

The frequency response of fluid-filled catheters is generally assumed to be adequate

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for measurements of systolic and diastolic PAP (sPAP and dPAP), and derived calculation of mPAP. However, errors may be caused by overdamping or

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underdamping of signals related to the insufficient or excessive flushing or too long

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tubing systems (12).

To answer the question about how accurate and precise optimally calibrated and flushed fluid-filled catheters are, Pagnamenta et al. measured PAP with fluid-filled catheters compared to gold standard high fidelity micromanometer-tipped catheters in 8 dogs with PH induced either by ensnarement of the pulmonary arteries or injection of micro-beads (13). The comparison rested on pulse pressure (sPAP-dPAP, PP), because it is difficult to control the location of the catheter tip micomanometer with respect to the zero level of the external fluid-filled catheter. The results are shown in Figure 1. Measurements of PP were highly correlated, with an analysis according to

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Bland and Altman showing almost no bias, indicating excellent accuracy. However, the limits of agreement reached +/- 8 mmHg, which may be insufficiently precise in

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certain clinical circumstances.

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Fig 1.

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Estimations of LAP by PAWP are generally believed to be accurate based on earlier reports of high levels of correlations (14). This was recently revisited by Halpern and

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Taichman in a large quality-control study which included almost 4000 patients with

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PH who underwent measurements of PAWP during a right heart catheterization and LAP estimated by left ventricular end-diastolic pressure (LVEDP) during a left heart catheterization (15). The results showed a high level of correlation, a bias of - 3 mmHg, corresponding to an expected pressure gradient from small pulmonary veins to the left ventricle at end-diastole, thus indicating excellent accuracy, but limits of agreement ranged from - 15 to + 9 precision. This is illustrated in Figure 2.

mmHg, indicating potentially insufficient

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Fig 2.

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Thus, measurements of PAP and PAWP during a right heart catheterization are accurate, but lack precision. This is related to the inherent variability of the physiology being assessed (16). Moreover, fluid-filled catheter measurements are critically dependent on adequacy of zero leveling and correction for respiratory

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swings. It has only been recently proposed to standardize the zero leveling of the

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external manometer at the cross-section of three trans-thoracic planes respectively mid-chest frontal, transverse through the fourth intercostal space, and mid-sagittal,

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and the reading of pulmonary vascular pressure curves averaged over several respiratory cycles (17). The latter is particularly important in patients with obstructed

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airways; dynamic hyper-inflation can falsely elevate pulmonary vascular pressures at end-expiration because of increased esophageal pressure (18,19).

Recently, Le Varge et al. reported on pulmonary vascular pressure measurement in a cohort of patients with confirmed pre-capillary PH and found that one-third of subjects would have been wrongly classified as “postcapillary” because of a PAWP higher than 15 mmHg measured at end-expiration (20). This scenario was more common in the obese and in subjects with obstructive airway disease. The question could be asked whether a contrario averaging PAWP across the respiratory cycle might lead to a clinically signficant pressure underestimation, thereby wrongly

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classifying “postcapillary” as “precapillary” PH. However, this would require pleural pressure swings to be predominantly negative, which has not been shown to occur in

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HF.

There has been traditionally a concern about the accuracy of thermodilution for the

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measurement of very low pulmonary blood flow or in the presence of tricuspid regurgitation (TR). This issue was addressed by Hoeper et al, who compared 105

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measurements of CO by thermodilution or by the direct Fick method in 35 patients with PH (21). The results, illustrated in figure 3, show little bias, +/- 0.1 L/min, thus excellent accuracy but limits of agreement of +/- 1 L/min, which is larger than

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generally assumed.

Fig 3.

In summary, fluid-filled thermodilution catheters are accurate for the evaluation of the functional state of the pulmonary circulation, but of limited precision, so that single measurement decision making has to be discouraged. Errors on accurate but unprecise measurements can be limited by repetition and averaging. This is why it is recommended to average 3 to 5 thermodilution CO measurements remaining within

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less than 10 % variation. No repetition of pulmonary vascular pressure measurements is usually recommended, probably wrongly so. However, accurate but unprecise

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measurements are adequate for population studies.

3. Doppler echocardiographic measurements of pulmonary vascular pressures

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and CO

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Doppler echocardiography is the most widely available modality for the noninvasive estimation of the 3 components of the PVR equation.

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Systolic AP can be calculated from the maximum velocity of TR using the simplified form of the Bernouilli equation and a measurement or estimate of right atria pressure

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(RAP) (22)

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sPAP = 4 x TR2 + RAP

A mPAP can be calculated from sPAP using an equation based on the tight correlations between systolic, diastolic and mean PAP found using high fidelity micromanometer-tipped catheters in patients with variable severities and causes of PAH (23)

mPAP = 0.6 x sPAP + 2

LAP can be estimated from the ratio of the E and e’ waves of Doppler transmitral flow and mitral annulus tissue Doppler imaging (24)

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LAP = 1.24 x E/e’ + 2

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CO can be estimated from Doppler left ventricular outflow tract diameter (LVOT) and

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CO = [0,785 x (LVOT)2 x VTI] x HR

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velocity (VTI), and heart rate (HR) (25)

An estimate of RAP at 0, 5, 10, 15 or > 20 mmHg can be obtained from the inferior

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vena cava diameter and inspiratory collapse (26).

Doppler echocardiography also allows for a series of internal controls, including

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estimates of PAP from pulmonary regurgitant jets or the analysis of the morphology of pulmonary flow waves, and PVR from the ratio of TR velocity to pulmonary flow,

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and the impact of increased PAP on RV structure and function (1,27).

Of particular importance is the simple visual inspection of the shape of the Doppler flow velocity envelope of the right ventricular outflow tract (RVOTDoppler), which has normally a rounded shape, but is affected in PH by a shortened acceleration time, a late systolic decelation and eventually, a typical mid-systolic deceleration of flow (“notching) (28). This “notching” is explained by an earlier wave reflection, either on proximal pulmonary arterial obstruction, or on increased wave velocity due to pulmonary arterial stiffening (29). Practically, it has been shown that PH but without RVOTDoppler notching strongly favors pulmonary venous hypertension (odds ratio

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29:1), while PH in the presence of RVOTDoppler notching predicts a PVR > 3

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mmHg/l/min with an odds ratio of over 33:1 (30).

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Yet there is a persisting mistrust of Doppler echocardiography (31-34). This is at least in part explaned by the common confusion between accuracy and precision of

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measurements. D’Alto et al addressed this issue by comparing measurements of pulmonary vascular pressures and CO measured during a right heart catheterization

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and quasi simultaneous, within an hour, Doppler echocardiography in 151 patients referred for PH (35). The results expressed as Bland & Altman plots are illustrated in

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Figure 4.

Fig 4.

Echocardiographic measurements were accurate, as the biases were minimal with tight confidence intervals (shaded areas), around zero for CO and PAP, and expectedly of - 3 mmHg for LAP. However, the limits of agreement were of +/- 1.8 L/min for CO, +/- 18 mmHg for mPAP, – 8 to + 12 mmHg for LAO and +/- 5 Wood units for PVR. These results show that Doppler echocardiography of the pulmonary circulation is accurate, but that insufficient precision may be a problem during a

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diagnostic work-up. The approach is thus useful for pathophysiological or epidemiological studies but derived cut-off values have to be integrated in clinical

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probability assessments and internal controls for an individual diagnosis of PH.

4. Magnetic resonance imaging measurements of pulmonary vascular pressures

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and CO

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Noninvasive estimates of pulmonary vascular function using MRI have been more recently reported. They rely on measurements of flows and prediction equations of pulmonary vascular pressures from atrial dimensions or RV mass and/or dimensions

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(2,3). In a recent study focused on the components of the PVR equation, Swift et al estimated mPpa from RV mass and septal curvature, LAP from left atrial volume and

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CO from phase contrast pulmonary flow in 64 patients who underwent the same day a right heart catheterization for PH of variable severities and etiologies (3). As shown in

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Figure 5, the measurements were accurate as there were no biases, but unprecise as

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limits of agreement were of +/- 15 mmHg for mPAP, -9 to + 6 mmHg for LAP and +/- 2.3 L/min for CO. There was almost no bias for PVR, but with limits of agreement of -4 to + 5 Wood units. It is interesting that these biases and limits of agreement are quite similar to those recently determined for Doppler echocardiography measurements. .

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Fig 5.

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The disadvantage of MRI is in its limited availability and flexibility, while Doppler echocardiography devices have become portable and integrated in daily bedside

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5. Viscosity

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clinical practice.

PH occurs in the context of extreme anemia or polycythemia. In the Poiseuille-Hagen equation, resistance is directly proportional to viscosity. The viscosity of the blood is mainly determined by the hematocrit (HCT).

The most often used reference equation to estimate the impact of blood viscosity on resistance was reported by Whittaker and Winston based on studies on hindlimb vessels (36). The equation relates linearly resistance to HCT, and allows to recalculate resistance at a normal reference value of HCT of 45 %:

ACCEPTED MANUSCRIPT R0 45%  R0 HCT 

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1  1 3 0.234

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where Ro is resistance at a HCT of 45 % and φ the measured HCT.

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Linehan et al integrated an exponential relationship in his distensible model of the pulmonary circulation to fit isolated perfused lung measurements at variable levels of

R0 45%  R0 HCT 

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hemodilution or concentration (37):

1 exp 2  0.45

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Both equations allow for similar adjustments of PVR in patients with abnormally high or low HCT, and thus provide more realistic estimates of the extent of pulmonary

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vascular disease. It was recently shown that corrections for HCT smoothens ethnic

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differences in the pulmonary circulation of high altitude Andean vs Himalayans populations (38). In severely anemic patients, normalizing PVR for HCT increases

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PVR in proportion to baseline values, with trivial changes when the PVR is low, around 1 Wood unit, but more important increases along with increased PVR. For example, a normalizing the HCT from 20 to 40 % increases PVR from 2 to 3.5, from 3 to 5 or from 6 to 10, Wood units.

6. LAP and the TPG

The PVR equation assumes that LAP is transmitted upstream to PAP in a 1/1 ratio at any given level of CO. But a chronic increase in LAP may induce pulmonary vascular remodeling, and therefore lead to an "out of proportion" increase in mPAP, or a > 1/1

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upstream transmission (39). This increases the gradient between mPAP and LAP, or

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TPG.

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The upper limit of normmal of the TPG is generally assumed to be of 12 mmHg, but a higher cut-off value of 15 mmHg is proposed in recent reviews (39). A TPG of 12

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mmHg corresponds to a PVR of 1.5 Wood units at a cardiac output at the upper limit of normal of 8 L/min, and of 3 Wood units at a CO at the lower limit of normal of 4

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L/min. Flow-dependency of the TPG makes it potentially misleading for the diagnosis of pulmonary vascular disease in left-sided HF. The TPG has often been found to be higher than 12 mmHg in patients with left-sided HF in whom a return to below 12

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mmHg occurred after cardiac transplantation (40).

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These problems can be avoided by using the gradient between dPAP and LAP, or DPG instead (41,42). The upper limit of normal of the DPG in young athletic adults is

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approximately 5 mmHg (41). A higher cut-off value may be more reasonable in older

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patients with left-sided HF (7). A DPG of > 7 mmHg is associated with a worse prognosis in patients with PH on left-sided heart conditions and a TPG > 12 mmHg (43)

At the most recent world symposium on PH held in Nice, in 2013, it was agreed to call “out of proportion” PH in left-sided heart condition “precapillary PH” or “PcpPH” and DPG was renamed “diastolic pressure difference” or “DPD” (7). Combined TPG and DPD were also recommended to improve the diagnosis of pulmonary vascular diasease in left-sided cardiac conditions (7).

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While Doppler echocardiograzphy and MRI are less precise than right heart catheterization for the estimation of pulmonary vascular pressure gradients (1,3),

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these imaging procedures offer more insight on systolic left ventricular function, and

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are therefore an integral part of the diagnostic work-up of patients with PH and left-

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sided heart conditions.

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7. Exercise measurements

Exercise stress testing of the pulmonary circulation may uncover early pulmonary vascular disease or diastolic HF (44). Aerobic exercise is normally associated with an

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increase in CO and a decrease in PVR (45). This is explained by the natural distensibility of the pulmonary resistive vessels, shown to be of 2 % of diameter

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change per mmHg of distending pressure over a wide range of vascular segments and animal species (46). Linehan integrated resistive vessel distensibility in a simple

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model allowing for more realistic prediction of pulmonary vascular pressures over a

as:

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wide range of flows and HCT (37). In this model PVR at a normal HCT is calculated

PVR = [ (1 + α.PAP)5 - (1 + α.LAP)5 ] / 5.α.CO

The coefficient α is the distensibility factor expressed in % increase in diameter D0 per mmHg increase in pressure:

D = D0 + α.P

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An interesting application of this approach is that the distensibility coefficient  can

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be recalculated from given sets of PAP, LAP and CO measurements.

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Reeves used reported pulmonary hemodynamic data at rest and during exercise, in healthy volunteers to recalculate , and found it equal to 2  0.2 %/mmHg in

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normoxia, a value strikingly similar to that of previous in vitro measurements on isolated vessel segments (46). Even though the individual data available to him for

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analysis was limited, he was able to show that  tends to decrease with aging, or with chronic but not acute hypoxic exposure.

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Similar values of  have been calculated in a series of noninvasive exercise stress Doppler echocardiographic studies of the normal pulmonary circulation (47-50) and

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recently confirmed by invasive measurements (45). This data has allowed for an

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improved definition of the limits of normal of the pulmonary circulation at exercise (44,45). Furthermore,  was shown to be lower in men compared to pre-menopausal

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women (48). The same noninvasive approach confirmed Reeves’ observation of a decrease of  with aging (48) and with chronic hypoxic exposure (49). There is a suggestion that a decrease in  calculated from noninvasive multiple mPpa-Q coordinates could be sensitive to early pulmonary vascular disease, such as in healthy carriers of the bone morphogenetic protein receptor-2 (BMPR-2) mutation, which predisposes to PAH (51).

The limits of normal of the pulmonary circulation at exercise are shown in Figure 6. It can be seen that mPAP does not normally exceed 30 mmHg at a CO < 10 L/min. Upper limits of normal can also be defined by a slope of mPAP-CO of 3

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mmHg/L/min, or a total PVR (mPAP/CO) at maximum exercise of 3 Wood unit

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Fig 6.

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(44,45).

After exercise, mPAP and CO rapidly return to resting values (47). This decreases the relevance of post-exercise measurements as a reflection of exercise-induced changes. On the other hand, the workload-CO relationship varies considerably from one subject to another (48). It is therefore preferable to express mAPa at exercise as a function of CO rather than of workload to define the functional state of the pulmonary circulation.

It must be underscored that abnormal exercise pulmonary vascular responses may be due to either increased PVR or LAP. Therefore, the identification of a mPAP-CO relationship > 3 mmHg/L/min requires a differential diagnostic work-up (44).

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Studies are underway to explore the feasibility of Doppler echocardiography stress

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testing of the pulmonary circulation with an infusion of low-dose dobutamine (52).

No exercise or dobutamine stress testing of the pulmonary circulation with other

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7. Pulsatile flow pulmonary hemodynamics

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imaging modalities have been yet reported.

The study of the pulmonary circulation as a steady-flow system is a simplification.

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Pulmonary pulse pressure is in the order of mPpa, as compared less than half of it in the systemic circulation. Instantaneous pulmonary blood flow varies from a maximum

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at mid-systole to around zero in diastole.

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PP, the difference between sPAP and dPAP is dependent on pulmonary arterial

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compliance (Ca) and wave reflection. Pulmonary arterial compliance is calculated by the ratio between stroke volume (SV) and PP

Ca = SV/PP

The product of PVR by Ca, or the time constant (RC-time) of the pulmonary circulation varies little over a wide range of severities, etiologies and treatments of PH (53-56). This remarkable property of the pulmonary circulation implies that the impact of wave reflection on pulmonary vascular pressure-flow relationships is negligible.

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Because the RC-time of the pulmonary circulation is constant, Ca becomes a more

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important determinant of RV afterload than PVR when mPAP and PVR are only

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modestly elevated. (57). Another important consequence of the constancy of the RCtime is that RV oscillatory hydraulic load remains a constant fraction of total load

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irrespective of PAP (58).

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The RC-time may actually slightly decrease in left ventricular failure because the increase in venous pressure causes the pulmonary circulation to be stiffer at any level of PVR (59). Another cause of a slight decrease in the RC-time is proximal

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pulmonary arterial obstruction, either experimentally by pulmonary arterial banding (13) or in patients with purely proximal CTEPH (60). A decreased RC-time is

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associated with an increased hydraulic load, or afterload. However, extremes of

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load (61).

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reported RC-times do not greatly affect the oscillatory component of RV hydraulic

The (near)-constancy of the RC-time explains the reported tight correlation between sPAP, dPAP and mPAP normal subjects and in patients with PH of various etiologies (23), which helps the Doppler echocardiography assessment of pulmonary artery pressures.

Doppler echocardiography can be used for the estimation of Ca from PP (estimated from pulmonary regurgitant jets) and stroke volume from left ventricular outflow tract flow-velocity and dimensions. There have been MRI studies on the proximal pulmonary arterial distensibility (62). However, pulmonary arterial compliance is

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widespread over the entire pulmonary arterial tree, and the proximal part of it has

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been shown to contribute to no more than 20 % of Ca calculated as SV/PP (55).

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Conclusions

There has been a lot of progress in clinical and research measurement techniques of

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the pulmonary circulation in recent years. Limitations and methodology of invasive

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and noninvasive measurements of the pulmonary circulation are now better understood, and available for optimal clinical use.

References

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1. Bossone E, D'Andrea A, D'Alto M et al .Echocardiography in pulmonary arterial hypertension: from diagnosis to prognosis. J Am Soc Echocardiogr. 26:1-14, 2013 2. Garcia-Alvarez A, Fernandez-Friera L, Mirelis JG et al. Non-invasive estimation of pulmonary vascular resistance with cardiac magnetic resonance. Eur Heart J 32: 2438-2445, 2011. 3. Swift AJ, Rajaram S, Hurdman J et al. Noninvasive estimation of PA pressure, flow and resistance with CMR imaging. JACC Cardiovasc Imaging 6: 10361047, 2013 4. Swan HJC, Ganz W, Forrester JS et al Catheterization of the heart in man with use of a flow-directed catheter. N Engl J Med 283: 447-451, 1970. 5. Forrester JS, Ganz W, Diamond G et al. Thermodilution cardiac output determination with a single flow-directed catheter. Am Heart J 83: 306-311, 1972 6. Chatterjee K. The Swan-Ganz catheters: past, present and future. A viewpoint. Circulation 119: 146-152, 2009 7. Hoeper MM, Bogaard HJ, Condliffe R et al. Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol 62(25suppl): D45-50, 2013 8. Vachiery JL, Adir Y, Barbera JA et al. Pulmonary hypertension due to left heart diseases. J Am Coll Cardiol 62(25suppl): D100-108, 2013. 9. Milnor WR. Hemodynamics. 2d Ed. Williams & Wilkins, 1989 10. Bland JM, Altman DG. Statistical methods for assessing agreement between two different methods of clinical measurement. Lancet 1: 307-310, 1986 11. Bland JM, Altman DG. Agreed statistics. Measurement method comparison. Anesthesiology 116: 182-185, 2012. 12. Gibbs NC, Gardner RM. Dynamics of invasive pressure monitoring systems: clinical and laboratory evaluation. Heart Lung 17: 43-51, 1988. 13. Pagnamenta A, Vanderpool RR, Brimioulle S et al. Proximal pulmonary arterial obstruction decreases the time constant of the pulmonary circulation

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29. Naeije R, Torbicki A. More on the noninvasive diagnosis of pulmonary hypertension. Doppler echocardiography revisited. Eur Respir J 8:1445-1449, 1995 30. Arkles JS, Opotowsky AR, Ojeda et al. Size of the right ventricular Doppler envelope predicts hemodynamics and right ventricular function in pulmonary hypertension. Am J Respir Crit Care Med 183: 268-267, 2011 31. Fisher MR, Forfia PR, Chamera E et al. Accuracy of Doppler echocardiography in the hemodynamic assessment of pulmonary hypertension. Am J Respir Crit Care Med 179:615-621, 2009. 32. Rich JD, Shah SJ, Swamy RS et al. Inaccuracy of Doppler echocardiographic estimates of pulmonary artery presures in patients with pulmonary hypertension. Chest 139: 988-993, 2011. 33. Rich JD. Counterpoint: can Doppler echocardiography estimates of pulmonary artery systolic pressures be relied upon to accurately make the diagnosis of pulmonary hypertension? No. Chest 143: 1536-1539, 2013. 34. Rudski LG. Point: can Doppler echocardiography estimates of pulmonary artery systolic pressures be relied upon to accurately make the diagnosis of pulmonary hypertension? Yes. Chest 143: 1533-1536, 2013. 35. D'Alto M, Romeo E, Argiento P et al. Accuracy and precision of echocardiography versus right heart catheterization for the assessment of pulmonary hypertension. Int J Cardiol 168: 4058-4062, 2013.. 36. Whittaker SRF, Winton FR The apparent viscosity of blood flowing in the isolated hindlimb of the dog, and its variation with corpuscular concentration. J Physiol 78:339-369, 1933. 37. Linehan JH, Haworth ST, Nelin LD et al. A simple distensible model for interpreting pulmonary vascular pressure-flow curves. J Appl Physiol 73: 987994, 1992. 38. Faoro V, Huez S, Vanderpool R et al. Pulmonary circulation and gas exchange at exercise in Sherpas at high altitude. J Appl Physiol 116: 919-926, 2014. 39. Guazzi M, Borlaug BA. Pulmonary hypertension due to left heart disease. Circulation. 126: 975-990, 2012. 40. Naeije R, Lipski A, Abramowicz M et al. Nature of pulmonary hypertension in congestive heart failure. Effects of cardiac transplantation. Am J Respir Crit Care Med 147: 881-997, 1994. 41. Harvey RM, Enson Y, Ferrer MI. A reconsideration of the origins of pulmonary hypertension Chest 59: 82-94, 1971. 42. Naeije R, Vachiery J, Yerly P et al. The transpulmonary pressure gradient for the diagnosis of pulmonary vascular disease. Eur Respir J 241 217-223, 2013. 43. Gerges C, Gerges M, Lang MB et al. Diastolic pulmonary vascular pressure gradient: a predictor of prognosis in “out-of-proportion” pulmonary hypertension. Chest 143: 758-766, 2013. 44. Lewis GD, Bossone E, Naeije R et al. Pulmonary vascular hemodynamic response to exercise in cardiopulmonary diseases. Circulation 128:1470-1479, 2013. 45. Naeije R, Vanderpool R, Dhakal B et al. Exercise-induced pulmonary hypertension: physiological basis and methodological concerns. Am J Respir Crit Care Med 187: :576-583, 2013. 46. Reeves JT, Linehan JH, Stenmark KR. Distensibility of the normal human lung circulation during exercise. Am J Physiol Lung Cell Mol Physiol 288: L419-425, 2005.

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47. Argiento P, Chesler N, Mulè M et al. Exercise stress echocardiography for the study of the pulmonary circulation. Eur Respir J 35: 1273-1278, 2010. 48. Argiento P, Vanderpool RR, Mule M et al. Exercise stress echocardiography of the pulmonary circulation: limits of normal and sex differences. Chest 142: 1158-1165, 2012. 49. Lalande S, Yerly P, Faoro V et al. Pulmonary vascular distensibility predicts aerobic capacity in healthy individuals. J Physiol 590: 4279-4288, 2012. 50. Groepenhoff H, Overbeek MJ, Mulè M et al. Exercise pathophysiology in patients with chronic mountain sickness. Chest 142: 877-884, 2012. 51. Pavelescu A, Vanderpool R, Vachiéry JL et al. Echocardiography of pulmonary vascular function in asymptomatic carriers of BMPR2 mutations. Eur Respir J 40: 1287-1289, 2012. 52. Lau EM, Vanderpool RR, Choudhary P. Dobutamine stress echocardiography for the assessment of pressure-flow relationships of the pulmonary circulation. Chest 146: 959-966. 53. Lankhaar JW, Westerhof N, Faes TJ et al. Quantification of right ventricular afterload in patients with and without pulmonary hypertension. Am J Physiol Heart Circ Physiol 291: H1731-1737, 2006. 54. Lankhaar JW, Westerhof N, Faes TJ et al. Pulmonary vascular resistance and compliance stay inversely related during treatment of pulmonary hypertension. Eur Heart J 29: 1688-1695, 2008. 55. Saouti N, Westerhof N, Helderman F et al RC time constant of single lung equals that of both lungs together: a study in chronic thromboembolic pulmonary hypertension. Am J Physiol Heart Circ Physiol 297: H2154-2160, 2009. 56. Reuben SR. Compliance of the pulmonary arterial system in disease. Circ Res 29:40-50, 1971. 57. Bonderman D, Martischnig AM, Vonbank K et al. Right ventricular load at exercise is a cause of persistent exercise limitation in patients with normal resting pulmonary vascular resistance after pulmonary endarterectomy. Chest 139:122-127, 2011 58. Saouti N, Westerhof N, Helderman F et al. Right ventricular oscillatory power is a constant fraction of total power irrespective of pulmonary artery pressure. Am J Respir Crit Care Med 182: 1315-1320, 2010. 59. Tedford RJ, Hassoun PM, Mathai SC et al. Pulmonary capillary wedge pressure augments right ventricular pulsatile loading. Circulation 125: 289297, 2012. 60. MacKenzie Ross RV, Toshner MR et al. Decreased time constant of the pulmonary circulation in chronic thromboembolic pulmonary hypertension. Am J Physiol Heart Circ Physiol 305: H259-264, 2013. 61. Naeije R, Delcroix M. Is the time constant of the pulmonary circulation truly constant ? (letter). Eur Respir J 43: 1541-2, 2014. 62. Sanz J, Kariisa M, Dellegrottagle S et al. Evaluation of pulmonary artery stiffness in pulmonary hypertension with cardiac magnetic resonance. JACC Cardiovasc Imaging 2: 286-295, 2009

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Legends of the figures

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Figure 1. Pulmonary arteriual pulse pressure (PP) measured using fluid filled Swan

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Ganz (SG) versus high fidelity micromanometer tipped Millar catheters (left panel) and same measurements presented as Bland and Altman plots (right panel). There was

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mmHg (From reference 13, with permission)

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significant correlation and negligible bias, but the limits of agreement were of +/- 8

Figure 2. Left ventricular end-diastolic pressure (LVEDP) versus pulmonary arteruy wedge pressure (PCWP) measurements in 3,926 patients showing significant

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correlation and a bias of - 3 mmHg but limits of agreement - 15 to + 9 mmHg (From

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reference 15, with permission)

Figure 3. Thermodilution versus direct Fick measurements of cardiac output, showing

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significant correlation and almost no bias, but limits of agreement of +/- 1 L/min

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(From reference 21, with permission).

Figure 4. Bland & Altman plots of invasive versus Doppler echocardiographic estimates of mean pulmonary artery pressure (mPAP), left atrial pressure (LAP), cardiac output (Q) and pulmonary vascular resistance (PVR). Shaded areas indicate confidence intervals. Biases were minimal but limits of agreement were of +/- 1.8 L/min Q, +/- 18 mmHg for mPAP, – 8 to + 12 mmHg for LAP and +/- 5 Wood unitsfor PVR (From reference 32, with permission)

Figure 5. Bland & Altman plots of invasive versus magnetic resonance imaging

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estimates of mean pulmonary artery pressure (mPAP), pulmonary capillary wedge pressure (PCWP), cardiac output (CO) and pulmonary vascular resistance (PVR).

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Biases were minimal but limits of agreement were of +/- 15 mmHg for mPAP, -9 to +

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6 mmHg for PCWP and +/- 2.3 L/min for CO and - 4 to + 5 Wood units for PVR

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(From reference 3, with permission).

Figure 6. Limits of normal of mean pulmonary artery pressure (mPAP) as a function of

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cardiac output increased at exercise in healthy young adults, constructed from noninvasive and invasive data reported in reference 42. Stippled lines indicate upper limits of mPAP increasing from 25 mmHg at a cardiac output of 5 L/min to 45 mmHg

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at cardiac output of 20 L/min (From reference 41, with permission)