haemodynamic evaluation of pulmonary hypertensionthe haemodynamic proﬁle is the major determinant...

SERIES 0ADVANCES IN PATHOBIOLOGY, DIAGNOSIS, AND TREATMENT OFPULMONARY HYPERTENSION0

Edited by A.T. Dinh-Xuan, M. Humbert and R. NaeijeNumber 3 in this Series

Haemodynamic evaluation of pulmonary hypertension

D. Chemla*, V. Castelain*, P. Herve#, Y. Lecarpentier*, S. Brimioulle}

Haemodynamic evaluation of pulmonary hypertension. D. Chemla, V. Castelain,P. Herve, Y. Lecarpentier, S. Brimioulle. #ERS Journals Ltd 2002.ABSTRACT: Pulmonary hypertension is characterised by the chronic elevation ofpulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) leading toright ventricular enlargement and hypertrophy. Pulmonary hypertension may resultfrom respiratory and cardiac diseases, the most severe forms occurring in thrombo-embolic and primary pulmonary hypertension.

Pulmonary hypertension is most often defined as a mean PAP w25 mmHg at restorw30 mmHg during exercise, the pressure being measured invasively with a pulmonaryartery catheter. Doppler echocardiography allows serial, noninvasive follow-up of PAPsand right heart function. When the adaptive mechanisms of right ventricular dilatationand hypertrophy cannot compensate for the haemodynamic burden, right heart failureoccurs and is associated with poor prognosis.

The haemodynamic profile is the major determinant of prognosis. In both primaryand secondary pulmonary hypertension, special attention must be paid to the assessmentof pulmonary vascular resistance index (PVRI), right heart function and pulmonaryvasodilatory reserve.

Recent studies have stressed the prognostic values of exercise capacity (6-min walktest), right atrial pressure, stroke index and vasodilator challenge responses, as well asan interest in new imaging techniques and natriuretic peptide determinations. Overall,careful haemodynamic evaluation may optimise new diagnostic and therapeuticstrategies in pulmonary hypertension.Eur Respir J 2002; 20: 1314–1331.

*Dept of Cardiac and RespiratoryPhysiology, Bicetre Hospital, Facultyof Medicine, University of Paris XI,Le Kremlin-Bicetre and, #Dept ofThoracic and Vascular Surgery, MarieLannelongue Hospital, le Plessis-Robinson, France. }Intensive care unit,Erasme Hospital, Brussels, Belgium.

Correspondence: D. Chemla, ServiceEFCR, Broca 7, Hopital de Bicetre, 78rue du General Leclerc, 94 275 LeKremlin Bicetre, Paris, France.Fax: 33 145213778E-mail: [email protected]

Keywords: Cor pulmonalepulmonary hypertensionpulmonary vasodilatory reserveright atrial pressureright ventriclewalk test

Received: July 29 2002Accepted after revision: August 5 2002

The normal adult pulmonary vascular bed is alow-pressure, low-resistance, highly distensible system,and is capable of accommodating large increases inblood flow with minimal elevations of PAP. Pulmo-nary hypertension (PH) is characterised by the chronicelevation of PAP and PVR leading to right ventricularenlargement and hypertrophy [1–8]. At first, PAP isnormal at rest but rises abnormally high with exercise.In more evolved stages, PH occurs at rest (fig. 1).When the adaptive mechanisms of right ventriculardilatation and hypertrophy cannot compensate for thehaemodynamic burden, right heart failure occurs andis associated with poor prognosis. PH may result fromrespiratory and cardiac diseases, the most severeforms occurring in thromboembolic PH and primaryPH. The World Health Organization (WHO) hasrecently proposed a revised diagnostic classification(table 1) [1].

PH is most often defined as a mean PAPw25 mmHgat rest or w30 mmHg during exercise, the PAP being

measured invasively with a pulmonary artery(PA) catheter. However, there is no clear consensusas to what level of PAP constitutes PH [1–8]. Pro-posed upper normal values for mean PAP range18–25 mmHg at rest. Other definitions of PHhave been used, which either include a systolic PAPw30 mmHg, or rely on the level of PVR. Duringexercise, a mean PAP threshold w30 mmHg mayapply in healthy older subjects. Doppler echocardio-graphy allows the noninvasive assessment of PAP,and systolic PAP is most commonly used. Proposedupper normal values range 40–50 mmHg at rest,which correspond to a tricuspid regurgitant velocityof 3.0–3.5 m?s-1 [1]. However, Doppler-derived PAPcritically depends upon age, body mass index (BMI)and right atrial pressure (RAP).

PH may be identified during testing of symptomaticpatients, during screening of patients at risk (table 1),or it may be discovered incidentally [1–8]. PH is a rarecondition and its symptoms are nonspecific, which

Previous articles in this Series: No. 1: Humbert M, Trembath RC. Genetics of pulmonary hypertension: from bench to bedside. Eur Respir J2002; 20: 741–749. No. 2: Galie N, Manes A, Branzi A. The new clinical trials on pharmacological treatment in pulmonary arterialhypertension. Eur Respir J 2002; 20: 1037–1049.

Eur Respir J 2002; 20: 1314–1331DOI: 10.1183/09031936.02.00068002Printed in UK – all rights reserved

Copyright #ERS Journals Ltd 2002European Respiratory Journal

ISSN 0903-1936

explains why the diagnosis may be delayed. In theNational Institutes of Health (NIH) primary PHregistry, the mean interval from onset of symptoms todiagnosis was 2 yrs [7]. The most common presentingsymptom is dyspnoea, followed by fatigue, syncope ornear syncope and chest pain. The clinical presentationof PH critically depends upon its cause, but it is notwithin the scope of the present review to detail thispoint. The general diagnostic approach includes physicalexamination, exercise capacity testing (6-min walk test),chest radiograph, electrocardiography, laboratory tests(blood tests, arterial blood gases, pulmonary functiontests), noninvasive cardiac and pulmonary imagingand cardiac catheterisation [1–8]. Cardiac cathe-terisation allows for the precise establishment of thediagnosis and the type of PH, the severity of thedisease, the consequences on right heart function, andthe amount of pulmonary vasodilatation in reserve.Echocardiography is especially valuable in the serialassessment of PAP and right and left heart function.

The early initiation of treatments at a time whendynamic or reversible pathogenic mechanisms arepresent may increase the likelihood of a successfultreatment outcome [1]. A screening transthoracicechocardiogram is therefore recommended in asymp-tomatic patients with scleroderma or liver disease/

portal hypertension evaluated for liver transplanta-tion, and in asymptomatic subjects with a familyhistory of primary PH (first degree relatives). Recentstudies have identified mutations in the genes whichencode for receptor members of the transforminggrowth factor-b family in familial (and sporadic)primary PH, and in PH associated with hereditaryhaemorrhagic telangiectasia, and this provides pro-mising perspectives to genetic testing in PH [9].

Table 1. – World Health Organization diagnosticclassification

Pulmonary arterial hypertensionPrimary pulmonary hypertension

SporadicFamilial

Related to:Collagen vascular diseaseCongenital systemic to pulmonary shuntsPortal hypertensionHIV infectionDrugs/toxins

AnorexigensOther

Persistent pulmonary hypertension of the newbornOther

Pulmonary venous hypertensionLeft-sided atrial or ventricular heart diseaseLeft-sided valvular heart diseaseExtrinsic compression of central pulmonary veins

Fibrosing mediastinitisAdenopathy/tumours

Pulmonary veno-occlusive diseaseOther

Pulmonary hypertension associated with disorders of therespiratory system and/or hypoxaemiaChronic obstructive pulmonary diseaseInterstitial lung diseaseSleep-disordered breathingAlveolar hypoventilation disordersChronic exposure to high altitudeNeonatal lung diseaseAlveolar-capillary dysplasiaOther

Pulmonary hypertension due to chronic thrombotic and/orembolic diseaseThromboembolic obstruction of proximal pulmonaryarteries

Obstruction of distal pulmonary arteriesPulmonary embolism (thrombus, tumour, ova and/orparasites, foreign material)

In situ thrombosisSickle cell disease

Pulmonary hypertension due to disorders directly affectingthe pulmonary vasculatureInflammatory

SchistosomiasisSarcoidosisOther

Pulmonary capillary haemangiomatosis

Although this clinical classification is primarily concernedwith causes and thus prevention and treatment, theclassification is in keeping with the pathological character-isation of pulmonary hypertensive states; Pulmonary hyper-tension (PH) that results from identifiable causes (secondaryPH) is far more common than pulmonary hypertension withno apparent cause (primary PH); HIV: human immuno-deficiency virus.

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Fig. 1. – Typical pulmonary artery curve tracing a) at rest and b)during exercise (workload 45 W) in a patient with primarypulmonary hypertension. The noise is minimal with the use of ahigh-fidelity pressure-measuring catheter. PAP: pulmonary arterypressure.

1315HAEMODYNAMICS OF PULMONARY HYPERTENSION

Pathophysiology of haemodynamic changes inpulmonary hypertension

Pulmonary artery pressure

The pressure drop across the pulmonary circulation(i.e. the driving pressure) is often referred to as thetranspulmonary pressure gradient (TPG):

TPG~mean PAP{downstream pressure ð1ÞIn analogy with the electric Ohm9s law, TPG equalsPVR times cardiac output [10–13]:

mean PAP{downstream pressure~

PVR|cardiac outputð2Þ

The equation can be rewritten as follows:

mean PAP~(PVR|cardiac output)z

downstream pressureð3Þ

The normal pulmonary circulation is a low resistancecircuit, with little or no resting vascular tone, and themost important factors influencing mean PAP arehydrostatic pressure, intra-alveolar pressure, left atrialpressure and alveolar gases.

PH is most often defined as a mean PAPw25 mmHgat rest. According to the mechanistic classification[12], increases in mean PAP may be passive (as a resultof increased downstream pressure), hyperkinetic (as aresult of increased cardiac output through the lungs)or due to increased PVR resulting from changes in thepulmonary circulation itself. Granted that varioushypertensive mechanisms can work jointly, two formsof PH have been defined. Postcapillary PH (orpulmonary venous hypertension) is a passive formcharacterised by an increased downstream pressure o15 mmHg and a normal TPG. Precapillary PH (orpulmonary arterial hypertension) is characterised by anormal downstream pressure (v15 mmHg). TPG isincreased because of increased cardiac output orincreased PVR. Increases in PVR are due to asignificant reduction in the area of the distal (mainlyresistive) and/or proximal (mainly capacitive) PAs.This classification illustrates the crucial role of cardiaccatheterisation in determining not only the mean PAPand cardiac output but also the downstream pressure.

Pulmonary vascular resistance

The PVR is used to characterise PH in a morerestricted sense and to quantify abnormalities of thepulmonary vasculature according to the followingequation:

PVR~(mean PAP{downstream pressure)=

cardiac outputð4Þ

PVR is expressed in Wood units=(1 WU=1 mmHg?min?L-1

=80 dyne?s?cm-5).The PVR is mainly related to the geometry of small

distal resistive pulmonary arterioles. According toPoiseuille9s law, PVR is inversely related to the fourth

power of arterial radius. PVR is therefore consideredto mainly reflect the functional status of pulmo-nary vascular endothelium/smooth muscle cell coupledsystem [10–13]. PVR is also positively related to bloodviscosity and may be influenced by changes in periva-scular alveolar and pleural pressure.

Pressure is independent of the size of the system,and PAP from various subjects can therefore becompared without the need to take into accountpotential differences in their body size. Conversely,variables such as volume are proportional to the sizeof the system. For comparative purposes, the PVRIis therefore defined as the pressure drop across thecircuit divided by cardiac index (in WU?m2 or inmmHg?L-1?min?m2 or in dyne?s?cm-5?m2). In patientswith high BMI, the use of PVR instead of PVRI hasbeen responsible for significant underestimation ofPH, and for the occurrence of haemodynamic andrespiratory failure following heart transplantation.The use of PVRI must be recommended in studiesevaluating new therapeutic strategies in PH.

Pulmonary arterial hypertension results from threemain elements: vascular wall remodelling, thrombosisand vasoconstriction [8]. The increases in PVRI maybe fixed and/or potentially reversible. Arterial obstruc-tion, obliteration and remodelling are responsible forthe fixed component, while active increases in vasculartone are responsible for the reversible component,which may account for w50% PVRI. The pulmonaryvascular tone results from a complex interplay betweenthe pulmonary endothelium, smooth muscle cells,extracellular matrix, and circulating blood cells andblood components. In PH, the dysfunction of pulmo-nary arterial endothelium plays a key role, whetherdue to external stimulus (e.g. shear stress, shear rate,hypoxia, acidosis) or to the disease process itself (e.g.primary PH).

Hypoxia, acidosis, endothelin, nitric oxide, thrombosis,neurohormones

Alveolar hypoxia is a major stimulus leading topulmonary vasoconstriction either via a direct pressoreffect or by causing mediators to discharge. Acidosisleads to pulmonary vasoconstriction as well as actingsynergistically with hypoxia. Hypoxic vasoconstrictionis the main mechanism explaining mild and moderatedegrees of PH in patients with chronic obstructivepulmonary disease (COPD), in whom severe chroniclong-standing hypoxia is observed. An oxygen tensionin arterial blood (Pa,O2)v7.98 kPa (v60 mmHg) and acarbon dioxide tension in arterial blood w5.32 kPa(w40 mmHg) are thought to be accurate thresholdsfor the development of PH in COPD [14]. A recentstudy has shown that mean PAP inversely correlatedwith arterial Pa,O2, forced expiratory volume inone second (%) and single-breath carbon monoxidediffusion capacity (%) and directly correlated withpulmonary wedge pressure in patients with severeemphysema [15]. Surprisingly, all factors but Pa,O2

remained significant determinants of mean PAPwhen multiple regression analysis was used. Although

1316 D. CHEMLA ET AL.

methodological explanations may be discussed, thisresult suggests that factors other than hypoxia areinvolved in PH of patients with severe emphysema[15]. In COPD patients with mild-to-moderate hypoxia,the progression of PAP is very slow (z0.4 mmHg?yr-1)and only initial values of resting and exercise meanPAP are independently related to the subsequentdevelopment of PH [16]. In patients with primary PHor chronic pulmonary thromboembolism, hypocapniais commonly observed; the Pa,O2 may be withinnormal limits or only slightly decreased at rest, whilehypoxaemia is observed with exercise [17, 18]. Right-to-left shunt is the main mechanism of hypoxia in theEisenmenger syndrome. Severe hypoventilation is asso-ciated with hypoxia and may lead to PH, particularlyif there is associated acidosis. This may explain the PHobserved in the setting of the obesity-hypoventilationPickwickian syndrome and in a number of musculardisorders [6]. In patients with PH, high resting PAPand PVRI values increase further following exercise oracute hypoxaemia (e.g. rapid eye movement (REM)sleep or respiratory failure in patients with COPD). Itis important to prevent, diagnose and treat pulmonaryinfections in PH patients. Altitudes w1500 m mustbe avoided without supplemental oxygen, and alti-tudes w3000 m must be discouraged.

The pathogenic role of endogenous endothelin-1has been stressed, together with impaired synthesis ofvasorelaxant nitric oxide, and this may have thera-peutic implications [19, 20]. PH is associated withactivation of the endothelin system, which has potentvasoconstrictive and mitogen properties. Thrombosiscan play a part in the pathophysiology of the disease,as attested to by the platelet activation, disturbancesof various steps of the coagulation cascade andabnormal thrombolysis described in PH [21]. Primaryor secondary endothelial dysfunction increase the riskof thrombotic events. Dilated right heart chambers,sluggish pulmonary blood flow and sedentary lifestylealso increase this risk. Adrenergic overdrive mayprecipitate right ventricle (RV) failure and highplasma noradrenaline is associated with increasedmortality in patients with primary PH, suggesting thatthe level of sympathetic activation relates to theseverity of the disease [22].

Other precipitating factors

Changes in the rheological blood properties mayaggravate PH. Erythrocytosis may be secondary tohypoxia, and is potentially responsible for increasedblood viscosity and changes in erythrocyte deform-ability. PH may be aggravated by increases in cardiacoutput in the setting of hyperadrenergic states, anaemiaand hyperthyroidism. Decreased diastolic time (e.g.tachycardia) or the loss of atrial contribution to leftventricle (LV) filling (e.g. atrial fibrillation) tend toincrease left atrial pressure and thus may also aggravatePH. Finally, permanent PH is self-aggravating, as itfavours several local pathological processes, includingthe remodelling of small distal arteries and the loss ofthe elastic properties of proximal arteries, thus leadingto a vicious circle.

The right ventricle in pulmonary hypertension

Right ventricular function

RV has a complex geometry and is characterisedby a crescentic shape and a thin wall [23]. The cristasupraventricularis divides the RV into inflow andoutflow regions. Inflow (sinus), which is located posteriorand inferior, has a greater fibre shortening and is theeffective flow generator, pumping w85% of the strokevolume. Outflow (conus), which is located anteriorand superior, is a resistive and pulsatile conduit with alimited ejection capacity. RV contraction proceedsfrom the sinus to the conus according to a peristalticmovement. Right ventricular output equals heart ratetimes stroke volume. For a given stroke volume, RVoutput increases when heart rate increases (chrono-tropic reserve). For a given heart rate, RV outputincreases when RV end-diastolic volume increases (pre-load reserve) or when RV end-systolic volume decreases.The RV end-systolic volume decrease can be due toincreased inotropy (inotropic reserve) or to decreasedRV end-systolic pressure. The latter mechanism maybe observed in some healthy subjects during exercise(distensibility, recruitment) and in a subgroup of PHpatients following vasodilators (pulmonary vasodila-tory reserve).

The thin-walled, highly compliant RV can accom-modate with high volumes at physiological pressures(e.g. exercise), thanks to its marked preload-dependenceand RV-LV interdependence [23]. However, the RVis unable to face an acute increase in PVRI, andworks inefficiently when confronted with PH [24].Thus, unlike the LV, the RV performance is markedlyafterload-dependent. In PH patients, the use of preloadreserve (Frank-Starling9s mechanism) helps preserveRV function. Furthermore, according to Laplace9slaw, an increase in afterload can be offset by anincrease in RV wall thickness (RV hypertrophy), andthis normalises RV wall stress and myocardial oxygenconsumption. There is a linear correlation between RVmass and free wall area, indicating that an increase inafterload causes RV enlargement with both dilatationand hypertrophy [25]. Chronic cor pulmonale is definedas dilatation and hypertrophy of the RV secondary toPH caused by diseases of the pulmonary parenchymaand/or pulmonary vascular system between the originsof the main PA and the entry of the pulmonary veinsinto the left atrium [26, 27].

Right ventricular ejection fraction (RVEF) is muchmore sensitive to changes in ventricular afterload thanLV ejection fraction [28]. The RVEF has been foundto augment with exercise in healthy subjects given thedecreased PVRI and increased contractility of the RVfree wall [29, 30]. In patients with PH, the decreases inRVEF are not indicative of decreased RV contractilitybut mainly reflect increased afterload [31]. In primaryPH studied at rest, cardiac function is characterisedby RV systolic overload due to PH and diastolic over-load with tricuspid regurgitation (TR), whereas theLV is subject to diastolic underloading and reducedcompliance [32, 33]. With exercise, RV systolic perfor-mance further declines with a reduction in strokevolume and ejection fraction, and consequently heart


rate becomes the mechanism by which cardiac outputincreases.

Right ventricular failure

RV failure may be related to the natural evolutionof the disease or to acute exacerbation of PH (e.g.following acute hypoxaemia). In both primary PHand thromboembolic PH, the main cause of death isRV failure [1–8]. COPD is the most commonpulmonary disease that culminates in RV dysfunction[24, 34]. An autopsy study suggests that cor pulmonaleis found in 40% COPD patients [35]. Cor pulmonale ismainly observed in "blue bloaters" who develop a lowcardiac output profile and severe hypoxaemia anderythrocytosis resulting in PH. Conversely, "pinkpuffers" exhibit less severe hypoxaemia, decreasedcardiac output and increased arteriovenous oxygencontent difference, and cor pulmonale is less likely todevelop despite increased PVRI [24]. In a number ofCOPD patients, peripheral oedema may not always beexplained by RV failure, but rather relate to hyper-capnia, acidosis and increased sympathetic and renin-angiotensin-aldosterone activities, and the relatedchanges in renal haemodynamics and redistributionof body water [36].

When pulmonary arterial impedance is chronicallyincreased, RV function and output are preserved thanksto RV dilation and hypertrophy, increased inotropyand faster heart rate. Both increased impedance andincreases in RV size and annulus diameter lead to TR,which further compromise RV function. DecreasedRV function is observed when the limits of cardiacreserves are reached or when significant RV-LVinterdependence or chronic RV ischaemia are present(fig. 2). The mechanisms for RV ischaemia includeincreased pressure work leading to increased myocar-dial oxygen consumption; reduced systemic pressureleading to decreases in the coronary perfusion drivingpressure; and higher sensitivity to hypoxia andreduced vasodilatory reserve of the hypertrophiedRV [23, 34]. In patients with end-stage RV failure, the

maintenance of a sufficiently high systemic pressure isof major importance to prevent RV ischaemia, andthis may require high doses of vasoconstrictive agents(e.g. noradrenaline).

Numerous factors may precipitate RV failure [23,24, 34]. Factors related to preload include impairedvenous return (e.g. mechanical ventilation), decreasedpreload reserve (e.g. hypovolaemia) and mechanicallimitation (e.g. effusive pericarditis). Factors relatedto afterload include acute load increases (althoughpulmonary embolism-related RV failure is observedonly for acute systolic pressurew60–70 mmHg), increasedpulsatile load (e.g. proximal obstruction with mark-edly increased pulse wave reflections), and factorsrelated to transpulmonary pressure, lung complianceand mechanical ventilation. Major tricuspid valveinsufficiency may precipitate RV failure, and theanatomical and functional status of the tricuspidvalve has a key role in preserved RV function. Otherfactors potentially precipitating RV failure aredecreased inotropy, RV ischaemia, REM sleep andobstructive sleep apnoea syndrome. The deleteriousrole of hypoxia and neurohormonal factors has alsobeen demonstrated.

Therapeutic implications

The main goals in the prevention and treatmentof RV failure include: 1) reducing RV afterload bydecreasing PVRI; 2) limiting pulmonary vasoconstric-tion (e.g. prevention of hypoxaemia); 3) optimisingRV preload; and 4) preserving coronary perfusionthrough maintenance of systemic blood pressure.Other strategies may depend upon the cause of PH(e.g. recipient selection for preventing acute RVfailure following cardiac transplantation) [37].

Exercise capacity

During exercise, the pulmonary vascular bed ofnormal subjects shows a minimal rise in PAP despitethe doubling or tripling of cardiac output, thanks tothe substantial reserve of pulmonary circulation. Thefall in PVRI reflects passive distension of compliantsmall vessels and/or recruitment of additional vesselsin the superior portions of the lung [10–13, 38].

According to the New York Heart Association(NYHA) functional classification, symptoms may becaused by ordinary physical activity (Class II), lessthan ordinary activity (Class III) or may even bepresent at rest (Class IV) in PH patients [1–8]. Recentguidelines focus on the rational management ofpatients without any limitation of their physical activity(Class I) [1]. It must be remembered that clinicalsymptoms poorly correlate with resting mean PAP[39]. The degree of preservation of systolic perfor-mance of the RV is the main factor governing theclinical presentation.

In patients with primary PH, impaired cardiacreserve during exercise is reflected in reduced peak O2

uptake (V9O2) [40, 41]. The NYHA functional classbest correlates with % predicted peak V9O2, which

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Fig. 2. – Main pathophysiological factors involved in right and leftheart failure in patients with pulmonary hypertension. RV: rightventricle; LV: left ventricle.


allows a precise grading of the severity of the disease[42]. A reduction of the anaerobic threshold alsoappears to be an independent marker of the diseaseseverity. The O2 pulse can be calculated as the V9O2

divided by heart rate ratio, and equals the product ofstroke volume times the O2 content difference betweenarterial and mixed venous blood. The progressivelydecreasing peak O2 pulse reflects a progressivereduction (or inadequate increase) in peak strokevolume paralleling disease severity [42]. Patientswith primary PH exhibit hyperventilatory responseto exercise, i.e. impaired ventilatory efficiency, asattested to by the increased slope relating minuteventilation to carbon dioxide output (V9E/V9CO2) [42].However, the fitting of a linear slope is somewhatarbitrary in patients with primary PH as the ventila-tion of underperfused alveoli causes an increase indead space ventilation, and also because a significantnumber of patients may have a patent foramen ovale,both conditions leading to nonlinearities of the V9E-V9CO2 relationship. Finally, in patients with primaryPH, exercise stroke volume response is related toresting haemodynamics, namely diastolic PAP (inver-sely), PVRI (inversely) and pulse wave reflectionfactor (directly) [43].

Maximal exercise testing must be prohibited inPH patients, as syncope and sudden death have beenreported. Submaximal exercise testing may be lessunpleasant for the patient and is more representativeof daily life activity [44]. In primary PH, MIYAMOTO

et al. [39] have reported that the distance walked in6 min was decreased in proportion to the severityof the NYHA functional class, and was stronglycorrelated with peak V9O2 and oxygen pulse. Thedistance walked in 6 min has a strong, independentassociation with mortality and patients walkingv332 m had a significantly lower survival than thosewalking farther [45]. In primary PH patients perform-ing the 6-min walk test, a distance f300 m andreduction in arterial oxygen saturation (Sa,O2) atmaximal distance o10% increased mortality risk by2.4 and 2.9, respectively [18]. The distance walked in6 min may serve as a safe prognostic indicatorthroughout the survey. Finally, in patients withadvanced heart failure, RVEF o0.35 at rest andduring exercise is a more powerful predictor ofsurvival than V9O2 [46].

Cardiac catheterisation: standard procedures

Right heart and PA catheterisation remains thegold standard used to establish the diagnosis and thetype of PH. This procedure helps quantify the severityof the disease, the consequences on right heartfunction and the amount of vasodilatation in reserve.Furthermore, the haemodynamic profile is the majordeterminant of prognosis in PH. Initial studies havereported that catheterisation carries an increased riskin patients with PH, which is why it is importantto ensure that catheterisation is performed by anexperienced team, familiar with PH patients. Theprevention of vasovagal reaction and pain, andextreme caution in Class IV patients, are needed.

There were no deaths during catheterisation proce-dures in the NIH registry study (n=187) [40].

Pulmonary artery pressure

Cardiovascular textbooks indicate a 9–19 mmHgrange for normal mean PAP at sea level [47, 48]. Inresting healthy subjects aged 6–45 yrs, mean PAPremains constant at 14¡3 mmHg [2, 4]. Althoughmean PAP increases slightly to 16¡3 mmHg between60–83 yrs, it is generally agreed that mean PAP is littleinfluenced by age in healthy subjects [2, 4, 49, 50].There is no clear consensus as to what resting meanPAP level constitutes PH. Pressure valuesw18 mmHg[4, 51], 20 mmHg [5, 6, 38, 52] and 25 mmHg [5] havebeen proposed, the latter cut-off value being the onemost often used in recent clinical trials. Otherdefinitions of PH include a systolic PAP w30 mmHgat rest and a mean PAPw30 mmHg on exercise [5, 51,52]. The cause and type of PH also influence thehaemodynamic profile, which is the major determi-nant of PH prognosis. For example, PH of mild (meanPAP=25–35 mmHg) and moderate (mean PAP=35–45 mmHg) intensity are more common in PH second-ary to cardiac diseases or COPD, whereas severe PH(mean PAP o45 mmHg) is generally found in primaryPH and in chronic pulmonary thromboembolism [1–8].

Pulmonary occlusion pressure, pulmonary vascularresistance index, total peripheral resistance index andpulmonary hypertension classification

Downstream pressure is approximated on the basisof the pulmonary occlusion pressure (PA,op). PA,op

provides a more accurate estimate of left atrial pressurethan mean PA capillary wedge pressure (PA,wp),which overestimates left atrial pressure when pulmo-nary venous resistance is increased [53, 54]. In normoxichealthy subjects, the difference between mean PAPand PA,wp is 5–9 mmHg [4]. The PA,op value allowsdiagnosis of the type of PH, namely pulmonary venous(PA,op o15 mmHg) or arterial (PA,op v15 mmHg)hypertension. Measurements of mean PAP, PA,op andcardiac index allow the calculation of PVRI accordingto standard formula. Unlike mean PAP, PVRIincreases significantly with age [4, 49, 50]. The upperlimit for PVRI (in mmHg?L-1?min?m2) in normalsubjects increases fromy2.8 (6–10 yrs) to 3.2 (32–45 yrs)to 4.6 (60–83 yrs) [2, 4]. There is no consensus as towhat resting PVRI level constitutes PH, and thresholdvalues ranging from 3–6 mmHg?L-1?min?m2 have beenused previously. Although it has often been reportedthat an accurate PA,op may be unobtainable inpatients with severe PH, this is rarely the case inexperienced teams. Total peripheral resistance (TPR;equal to mean PAP/cardiac output) and total peri-pheral resistance index are calculated in cases wherereliable PA,op recordings are not obtained.

A PVR threshold value may be included in thediagnostic criteria of some forms of PH, e.g. porto-pulmonary hypertension (POPH) [55–57]. POPH canbe defined as a pulmonary arterial hypertension


associated with portal hypertension with or withouthepatic disease. A moderate increase in mean PAP(25–35 mmHg) is observed in up to 20% of patientswith cirrhosis and portal hypertension. This passiveincrease in mean PAP, which relates to increasedcardiac output and/or blood volume, is associatedwith near normal PVRI (i.e. minimum pulmonaryvascular remodelling) and normal or increased PA,op

(pulmonary venous hypertension). A severe pulmo-nary arterial hypertension with extensive pulmonaryvascular remodelling and elevated PVR is more rarelyobserved in patients with portal hypertension. Thislatter condition represents the entity of POPH and isassociated with poor outcome. To distinguish betweenthese two forms of PH, the following POPH criteriahave been proposed [55, 56] :1) mean PAPw25 mmHgat rest; 2) PVR w120 dyne?s?cm-5; and 3) PA,op v

15 mmHg.

Cardiac index, evaluation of intracardiac shunt,venous oxygen saturation, uric acid

The determination of cardiac index is essentialfor the diagnostic work-up and follow-up programmein patients with PH. The thermodilution technique isused in the vast majority of PH centres. In patientswith severe PH, a recent study indicates that thermo-dilution was equally accurate to the Fick method (thegold standard technique) over a broad range ofcardiac output values (1.7–7.8 L?min-1) [58]. Althoughconflicting results have been published, the agreementbetween the two methods was not affected by theseverity of tricuspid regurgitation [58]. In most casesof PH, the accuracy of the thermodilution technique isacceptable. However, in case of intracardiac shunt,as in the patients with patent foramen ovale, thethermodilution technique is inappropriate. Only theFick method, with measurement of pulmonary venousO2 content is able to measure pulmonary blood flow.

Oximetry (i.e. diagnostic saturation run and com-putation of the pulmonary to systemic flow ratio) isrequired to exclude intracardiac shunting. Furtherinvestigations (dye dilution curves and angiography)may also be required although they do not intrinsi-cally belong to the standard evaluation of PH. Thehigh pulmonary blood flow-related hyperkineticcomponent of PH is often associated with vasocon-striction (reactive component) and arterial remodelling(obstructive/obliterative component). The prevalenceof patent foramen ovale in PH is similar to the normalpopulation, and this finding provides no detectableinfluence on resting haemodynamics or exercise toler-ance in patients with PH [59].

Assuming normal haemoglobin content and normalSa,O2, the fall in mixed venous oxygen saturation(Sv,O2) is a reliable indicator of the fall in cardiacindex, as predicted from the Fick equation. It isimportant to compare Sv,O2 values between subjects atsimilar, optimal Sa,O2, and this may require supple-mental oxygen. Decreased Sv,O2 has been found to bea strong predictor of poor outcome in some studies [7,60] while others do not document such a link [40].PH patients with an Sv,O2 v60% are more likely to

respond to prostaglandin treatment [61]. An increasein Sv,O2 under treatment may indicate an improvedcardiac index and a decreased RV afterload both duringvasodilator challenge [62] and long-term therapy [63].

Tissue hypoperfusion and hypoxia resulting fromreduced cardiac output induce both overproductionand impaired excretion of uric acid, leading to increasedserum levels of uric acid in patients with severeprimary PH [64, 65]. Serum uric acid negativelycorrelates with cardiac output and positively corre-lates with TPR [64].

Right heart function

In the setting of PH, decreased cardiac index andelevated mean RAP and RV end-diastolic pressureindicate RV dysfunction. Although threshold valuesmay depend upon each laboratory and upon the typeof catheter used, mean RAP v6 mmHg and RV end-diastolic pressure v8 mmHg are generally considerednormal values [47, 48]. A mean RAP o8 mmHg andRV end-diastolic pressure o12 mmHg are abnor-mally high values highly suggestive of RV failure. Thedecreased compliance of the hypertrophied RV alsocontributes to increase RV end-diastolic pressure.In the case of typical TR, RAP rises throughoutRV systole, with pressure regurgitation waves. Inearly stages of PH, the RV contractility is increasedand the peak rate of RV pressure rise may beincreased by up to 10 times the normal value [66].Analysis of RV waveform in more severe forms of thedisease reveals RV systolic dysfunction with depressedupstroke and delayed relaxation.

Pulmonary arterial hypertension

Isolated arterial hypertension is characterised by aPA,op v15 mmHg and a diastolic PAP minus PA,op

gradient w10 mmHg. Major increases in PAP andPVRI are found in thromboembolic and primary PH.Vascular obstruction/obliteration is typically observedin thromboembolic [67] and primary PH [8, 68]. Inchronic pulmonary thromboembolism, the thrombifollow an aberrant path of organisation and recana-lisation, leaving endothelialised residua that narrowand stiffen major (main, lobar or segmental) PAs, i.e.elastic arteries. In primary PH, pulmonary obstructivevasculopathy involves distal, medium-to-small sizedmuscular (resistive) arteries. In the latter case, both afixed obstructive component and a reactive compo-nent (increased vascular tone) contribute to PH. InCOPD patients, hypoxia-induced vasoconstrictionplays a major role in producing PH, and destructionof the pulmonary vascular bed is also involved. Theincreased resistance to flow through the pulmonary vascu-lar bed may be due to several other diseases (table 1),including the Eisenmenger syndrome. In this syn-drome, the left-to-right shunts, mainly post-tricuspidshunts, lead to irreversible PH at systemic level whichsubsequently cause the shunt to be reversed [6].


Pulmonary venous hypertension

Increased resistance to pulmonary blood flow down-stream leads to passive PH, with elevation of PAP butno significant elevation of PVRI. In patients withincreased left heart filling pressure, pulmonary venoushypertension is characterised by a PA,op o15 mmHg.Although the diastolic PAP minus PA,op gradientis v10 mmHg, diastolic PAP must not be used as asurrogate of downstream pressure. In a recent study,diastolic PAP was w5 mmHg higher than PA,wp in21% and 57% of cardiac patients with mean PAP of21–40 mmHg andw40 mmHg, respectively [69]. Acuteincreases in pulmonary flow (e.g. exercise) worsenspulmonary venous hypertension when blood flowthrough the left atria or LV filling are impeded.Additional reactive vasoconstriction and vascularremodelling may occur, especially in cases where leftheart filling pressure is markedly and durably increased.A decrease in left heart filling pressure usually reversesboth the passive and vasoreactive components of PHand therefore tends to normalise PAP.

A PA,opw15 mmHg may be observed together witha diastolic PAP minus PA,op gradient w10 mmHg. Insuch combined venous and arterial PH, PAP does notnormalise following the alleviation of the high down-stream pressure, given the fixed arterial component ofPH (e.g. evolved mitral stenosis). In these patients,high levels of PVRI are sometimes referred to as the"second stenosis" and may have both deleteriouseffects (by increasing the strain put on the RV), andprotective effects (by limiting RV output and thus theoccurrence of episodes of pulmonary oedema) [23].Finally, some catheterisation findings may be evoca-tive of pulmonary veno-occlusive disease (e.g. thefailure to obtain a PA,wp tracing) [70].

Vasodilator testing

The potentially treatable vasoconstrictive compo-nent may be found in numerous forms of PH andthus must be sought during catheterisation by acutereversibility testing [71]. The vasodilator challengeresponse is the first step of the algorithm currentlyused for the management of primary PH [8]. Vasodilatorchallenge must be performed by an experienced teamand requires intensive care equipment. Indeed, drug-induced systemic hypotension (e.g. with prostacyclin)may reduce RV coronary blood flow and result inacute RV ischaemia. There is no advantage in testingmore than one drug. The most specific short-actingvasodilator for pulmonary vessels is inhaled nitricoxide (iNO), the maximal effect being obtained after5–10 min at the dose of 10 parts per million (ppm).Since iNO has no systemic effects, the resulting dropin PVRI reliably indicates the amount of pulmonaryvasodilatation in reserve [72]. Other vasodilators havebeen proposed, including i.v. iloprost (epoprostenolsodium), a prostacyclin analogue with fewer systemiceffects, and i.v. adenosine.

There is no clear consensus as to what criteria mayindicate beneficial response to vasodilator challenge.Because mean PAP and PVRI may vary spontaneously

by f20–25%, measurements must be performed afterstabilisation, and only changes greater than sponta-neous haemodynamic variability must be taken intoaccount. A significant response to vasodilator testingis currently defined as a drop in mean PAP or PVRIbyw20% [60, 73–76]. Other definitions include aw30%threshold [62, 77, 78] or a reduction in mean PAPw10 mmHg [1], or an increase in cardiac index byo30% [61].

In most studies on primary PH, the proportion ofresponders to vasodilators ranges from 12–40% depend-ing on the patient9s age, RV function, the cause ofhypertension and the protocol used [79]. The absenceof pulmonary vasodilatory reserve has been associatedwith a poor outcome [60, 71, 80–82]. A decrease inPVRI by o20% predicts good response to long-termvasodilator therapy with calcium channel blockers[83]. BARST et al [74] found it safer to prescribe long-term chronic calcium channel blocker therapy only inpatients exhibiting a decrease in PVR of o50%.

In PH patients evaluated for cardiac transplanta-tion, some authors have defined irreversible (or fixed)PH as those patients who, after provocative vasodi-lator therapy, have either a PVR o4 mmHg?L-1?min,a PVRI o6 mmHg?L-1?min?m2, a systolic PAPo60 mmHg or a tranpulmonary pressure gradiento15 mmHg [37]. Patients with reversible (or reactive)haemodynamics have better prognosis than patientswith irreversible PH. Serial aggressive sequences oflong-term inotropic support followed by provocativevasodilatory testings may convert fixed PH into thereactive category and condition the pulmonary vascula-ture into a maximally dilated state ("vasodilatorconditioning") [37].

Cardiac catheterisation: recent issues

Pulmonary resistance partitioning

More insight into the pulmonary circulation can beobtained by estimating the effective pulmonarycapillary pressure, in order to discriminate betweenincreases in arterial resistance and in venous resis-tance. Clinically, capillary pressure is computed byanalysing the PAP decay after single arterial occlusionby an intravascular balloon [53, 84, 85] (fig. 3). Recentstudies have confirmed a predominant increase inarterial resistance in thrombo-embolic disease, asignificant increase in arterial but also in venousresistance in primary PH, and the expected majorincrease in venous resistance in pulmonary veno-occlusive hypertension [38, 53].

Pulmonary arterial pressure/flow relationship

The transposition of Poiseuille9s law to pulmonarycirculation rests on the main assumptions that thePAP-flow relationship is linear, and that the PAP isequal to downstream pressure at zero flow. The firstassumption appears valid in both normal and diseasedpulmonary circulation over physiological ranges offlows [38, 53, 86, 87] (fig. 4). Initial work by JANICKI


et al. [38] suggested that the second assumptionwas also valid in normal subjects and in the majorityof PH patients. However, in one fourth of the PHpatients in this study, the average closure pressureexceeded PA,wp [38]. More recent experiments haveshown that the pressure axis intercept of the mean PApressure/flow relationship (i.e. the closing pressure) ishigher than PA,op or left atrial pressure in primary PH[53, 88] (fig. 3). In such conditions, a change in PVRIcan be interpreted unequivocally only when cardiac

output remains unchanged, or when driving pressureand cardiac output change in opposite direction.

Increased driving pressure with decreased pulmo-nary flow attests to vasoconstriction, while decreaseddriving pressure with increased pulmonary flow atteststo vasodilatation (fig. 5). Other haemodynamic pat-terns are not easy to interpret [86] (fig. 6). Forexample, increases in PAP and decreases in PVRI(e.g. after drug administration) can result fromincreases in cardiac output without any modificationin pulmonary vascular tone. Therefore, the determi-nation of multipoint mean PAP-flow plots provides

Fig. 3. – Typical pulmonary artery occlusion recording used toestimate pulmonary capillary pressure (PCP) and the arterialsegment of pulmonary vascular resistance (PVRa) in a patientwith pulmonary arterial hypertension [16, 89]. A balloon-tippedflow-directed pulmonary catheter was used. PCP (time=0) wascomputed from the exponential pressure decay by fitting the databetween the moment of occlusion of the balloon of the pulmonarycatheter and the stabilisation of the pressure level (pulmonaryartery occlusion pressure (PA,op)) (dotted line). Mean pulmonaryartery pressure=53 mmHg; PA,op=13 mmHg; PCP=31 mmHg;PVRa=55% PVR. $: PCP=30 mmHg.

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Fig. 4. – Mean pulmonary artery pressure (PAP)-flow plots (n=6,#) obtained at rest (1 plot), during exercise (4 plots, the work-load being increased stepwise to 15, 30, 45 and 60 W) and duringrecovery (1 plot) in a patient with primary pulmonary hyper-tension. High-fidelity PAP measuring catheter was used. Pulmo-nary artery occlusion pressure (PA,op)=12 mmHg at rest and18 mmHg at peak exercise. The solid line indicates the regressionline applied to the data set and the dotted line indicates thepressure-flow relationship extrapolated below the lowest datapoint. The pressure intercept at zero-flow (closure pressure=27 mmHg) was markedly higher than PA,op.

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Fig. 5. – Schematic of pressure-flow changes typical of pulmonaryvasoconstriction and vasodilatation. Pulmonary vasoconstrictionis diagnosed on the basis of transpulmonary pressure gradientversus pulmonary flow relationship showing increased drivingpressure with decreased flow. Pulmonary vasodilatation is diag-nosed on the basis of transpulmonary pressure gradient versuspulmonary flow relationship showing decreased driving pressurewith increased flow.

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Fig. 6. – Schematic of complex pressure-flow changes. Currentproblems may be encountered in interpreting single measurementof indexed pulmonary vascular resistance (PVRI) calculated as thetranspulmonary pressure gradient over indexed pulmonary flowratio (slope of the dotted line). The solid line indicates themultipoint pulmonary artery (PA) pressure-flow relationship, withclosure pressure greater than PA occlusion pressure. From 1 to 2,PVRI decreases while functional state of the pulmonary circula-tion (as described by the transpulmonary pressure gradient-pulmonary flow relationship) remains essentially unchanged. From1 to 3, PVRI is unchanged while the increased slope of therelationships attests to worsening of pulmonary hypertension.


more accurate insight into the nature of increasedPVRI [38, 53, 86–89].

Thus, in PH, both closing pressure and the capillarypressure determined from the analysis of the PAPdecay curve after balloon occlusion are increased [86,88]. The main site of increased resistance may be at theperiphery of the pulmonary arterial tree, and this ispossibly a cause of increased closing pressure [86].Greater venous involvement than previously assumedhas also been suggested recently [88]. In patients withPH, recent data using two-point curves have suggestedthat exercise is associated with some pulmonaryvasoconstrictive effect, while dobutamine at dosesf10 mcg?kg-1?min-1 allows cardiac output to increasewithout affecting pulmonary vascular tone [86, 89].Finally, in patients with primary PH, mean PAP-flowplots have indicated that the improvement in exercisetolerance seen after 6 weeks of prostacyclin therapymay be ascribable to a decrease in incremental PVRduring exercise through a vasodilator effect [87].

Pulmonary vascular impedance

The pulmonary vascular impedance (PVZ) is afrequency-dependent function encompassing informa-tion about resistive, capacitive and inertial compo-nents of vascular hydraulic load, as well as the extentof pulse wave reflection [10, 43]. Few studies havebeen performed in patients, due to a requirement forsimultaneous recordings of high-fidelity pressure andflow signals. Results are reported as spectra of PVZamplitude and PVZ phase versus frequency. PVZspectra in patients with PH demonstrate increases ofboth the steady component (increased resistance) andoscillatory component (elevated PA characteristicimpedance and increased pulse wave reflection) ofhydraulic load [43]. Decomposition of pressure andflow into forward and backward components show anincreased amplitude and early arrival of the reflectedpressure wave, contributing to unfavourable loadingof the still-ejecting RV [43]. A preliminary report hassuggested that high characteristic impedance couldpredict better than PVR the occurrence of severe rightventricular failure after cardiac transplantation [90].

Pressure pulsatility

For a given stroke volume, the TPG and thus meanPAP reflect the steady component of potential energy,i.e. the heat dissipated in the microcirculation[10]. Mean PAP and PVRI are useful measurementsreflecting the opposition to the mean component offlow and the functional status of the distal (resistive)pulmonary vasculature. However, they do not takeinto account the pulsatile component of hydraulicload, which is mainly related to the proximal (elastic)PAs. The precise measurements of instantaneous pul-satile pressure and wave reflections require the use ofexpensive, high-fidelity pressure catheters instead ofthe commonly used fluid-filled catheters.

In the normal pulmonary vasculature, proximalPAs are highly distendable. The normal pulmonary

circulation exhibits very little wave reflection, and thecomposite reflected pressure wave arrives during theearly diastolic period [10]. Earlier, increased wavereflection may impede the ongoing RV ejection andthus impair right ventricular-arterial coupling in bothprimary PH and chronic pulmonary thromboembo-lism. In patients with primary PH, the extent of wavereflection is large at rest and the composite reflectedpressure wave arrives during the mid-portion of RVejection [43]. Patients with chronic pulmonary thrombo-embolism have increased anticipated wave reflectioncompared with patients with primary PH, probablybecause the functional reflection site is more proximalin the former patient group [91, 92]. In PH, increasedPVR, decreased PA compliance and complex changesin the pulse wave reflection site lead to increasedpulsatile load, as attested to by increased PA pulsepressure (PP; equal to systolic minus diastolic PAP)and increased wave reflection [43, 91]. Some authorshave suggested that patients with chronic pulmonarythromboembolism have a higher PP than patientswith primary PH [93]. Others have shown that nocut-off PP value could help distinguish these twopopulations when the mean PAP level was accountedfor [91, 94]. In hyperkinetic/high-flow states, increasedpulsatile load may be explained by increased strokevolume.

Echocardiography

Systolic pulmonary artery pressure: tricuspid regurgitationpeak jet velocity

Continuous-wave Doppler transthoracic echocardio-graphy can be used in subjects with TR to determinethe RV systolic pressure minus RAP gradient with thesimplified Bernouilli equation:

RV systolic pressure{RAP~4 VTR2 ð5Þwhere VTR is the TR peak jet velocity. Assumingthat systolic PAP equates RV systolic pressure inthe absence of pulmonic stenosis and outflow tractobstruction the following is obtained:

Systolic PAP~4 VTR2zRAP ð6ÞPatients must be in sinus rhythm to ensure stableVTR recordings. According to the WHO recommenda-tions, mild PH is defined as a resting systolic PAPof 40–50 mmHg, which corresponds to a tricuspidregurgitant velocity of 3.0–3.5 m?s-1 [1], assuming afixed 5 mmHg RAP. In a recent large-scale, echocardio-graphic study of 3,790 healthy subjects (2,432 females)from 1–89 yrs of age, a 37.9 mmHg 95% upper limitwas documented for systolic PAP at rest, whichcorresponds to a VTR of 2.64 m?s-1 assuming a fixed10 mmHg RAP [95]. This study supports the use ofage- and BMI-corrected values in establishing thenormal pressure range, since a systolic PAPw40 mmHgwas found in 6% of healthy subjects w50 yrs of ageand 5% of healthy subjects with BMIw30 kg?m-2 [95].Male sex and LV septal and posterior wall thicknessare also predictive of systolic PAP [95]. The level ofphysical training is also important to consider. In


resting healthy males v23 yrs, the 95% upper limit ofmean VTR is 1.93 and 2.41 m?s-1 in nonathletes (n=14)and athletes (n=26), respectively [96].

Tricuspid regurgitation is common in healthysubjects, and increases in prevalence and severity asPAP increases. It is widely accepted that continuouswave Doppler echocardiography is a valuable tool fordiagnosing PH, with interobserver variability ofv5%.However, some investigators were unable to docu-ment VTR in 40–70% of patients with proven PH,mainly in cases of moderately elevated PAP or becauseof poor acoustic windows [97]. Finally, as Dopplerestimates of systolic PAP are operator-dependent,inter- and intra-observer reproducibility must be checked.

Doppler-derived systolic PAP values are stronglycorrelated with pressure measured with catheterisa-tion in numerous studies [98, 99]. In other studies,Doppler values markedly underestimated systolicPAP [45, 96, 100, 101]. Systolic PAP values measuredby catheterisation and estimated by Doppler werepoorly related during dynamic changes [45]. Cathe-terisation therefore remains the gold standard inestablishing the diagnosis of PH, while Doppler allowsa serial, noninvasive follow-up of PA haemodynamics.

Diastolic pulmonary artery pressure

The simplified Bernouilli equation also allowsdetermination of diastolic PAP in normal subjectsand subjects with PH:

Diastolic PAP~4 VEDIP2zRAP ð7Þwhere VEDIP is the end-diastolic velocity of thepulmonic insufficiency jet and RAP is a surrogatefor the RV end-diastolic pressure [102]. Satisfactorypulmonary flow recordings are obtained in a majorityof normal subjects and in w90% of subjects with PH.

Mean pulmonary artery pressure

Mean PAP can be approximated either by measur-ing the early-diastolic velocity of the pulmonicinsufficiency jet (VeDIP) or by measuring time inter-vals. The first method [102] is based on the followingequation:

Mean PAP~4 VeDIP2zRAP ð8ÞThe correlation with catheterisation is weak, althoughit may improve in cases where only patients with heartrates of 60–100 beats?min-1 are considered [103].

The second method relies on the observation thatthe pulmonary flow velocity signal is dome shapedin normal subjects while it is more triangular, withan earlier peak flow, in patients with PH. In thesepatients, time-to-peak flow (i.e. acceleration time(AcT)) is decreased and KITAKABE et al. [104] havedocumented a high correlation (r=0.88) between AcTand log10 mean PAP. In some patients, prematuredeceleration of pulmonary systolic flow may result inmid-systolic notching, especially in severe PH or whenthere is an early return of the reflected wave (e.g.proximal obstruction) [105]. Consistently, patients

with chronic pulmonary thromboembolism (i.e. prox-imal obstruction) have a shorter time-to-peak pressurethan patients with primary PH (distal obstruction)[91, 92]. Finally, AcT may also be prolonged in pati-ents with decreased RV function and/or increasedpreload. Several studies have confirmed the predictivevalue of a decreased AcT for diagnosing PH, with a90–100 ms threshold [106, 107]. The pre-ejection time /AcT ratio is also increased and correlates with PAP inpatients with PH.

Right atrial pressure

The enlargement of the right atria reflects increasedRAP. A precise estimation of RAP is especiallyneeded in PH patients because increased RAP reflectsRV dysfunction and is a strong predictor of out-come, and also because Doppler estimates of PAPdepend upon the RAP value. This may be of criticalimportance for Doppler-derived diastolic PAP sinceRAP is a much higher percentage of diastolic thansystolic PAP. In practice, the RAP may be arbitrarilyfixed [102], clinically evaluated by the jugular venouspulse [2], or echocardiographically measured by theinferior vena cava collapse with spontaneous respira-tion [108]. KIRCHER et al. [108] have suggested that percent collapse o50% or v50% reflect RAP valuesof v10 mmHg or o10 mmHg, respectively. Giventhat RAP increases with PAP, a fixed RAP valuetends to overestimate or underestimate low and highPAP values, respectively [109]. Recently, a new indexof RV filling pressure has been described, namely thetricuspid E/Ea ratio, where E is Doppler tricuspidinflow velocity and Ea is the tissue-Doppler earlydiastolic velocity of the tricuspid annulus [110]. MeanRAP was linearly related to E/Ea, and E/Ea ratio w6has a sensitivity of 79% and a specificity of 73% formean RAP o10 mmHg [110]. Finally, Doppler-derivedhepatic vein systolic filling and filling fraction arenegatively related to mean RAP, but the specificityand sensitivity of these indices over a large RAP rangeare still under study.

Right ventricular function

Given the complex architecture of the RV, indicesquantifying RV diameter, area or volume are notalways reproducible and are highly operator- andmodel-dependent. Following pressure overload, RVenlargement is best evidenced on the apical four-chamber view, and is often associated with a roundedrather than triangular (physiological) shape. The RVfractional area change in the apical four-chamber viewis decreased. An RV/LV area ratio ranging from 0.6–1indicates mild RV dilation, while severe RV dilation isassociated with a ratiow1 [111]. The RV function maybe indirectly estimated by using the global RV functionindex and the velocity of the tricuspid annulus plane.The Doppler global RV function index is defined asthe sum of RV isovolumic contraction and relaxationtimes divided by ejection time [112]. The index iscalculated by dividing the TR jet duration minus


pulmonary jet duration difference by pulmonary jetduration. The global RV function index is a useful,independent predictor of adverse outcome in patientswith PH, and patients with an index v0.83 have amore favourable survivorship [113]. Doppler tissueimaging can be used to calculate the velocity of thetricuspid annulus plane which is positively correlatedwith RV systolic function [114].

Interventricular septum and left ventricle function

PH results in RV systolic overload characterised byleftward septal shift at end-systole and early diastole,the septum behaving has an intrinsic part of the RV[32, 111]. RV geometric changes influence LV func-tion, and prolonged LV isometric relaxation, reduc-tion in LV early diastolic filling and paradoxic septalmotion in systole are also observed [32, 111]. Decelera-tion time of early transmitral flow is decreased andnegatively correlates with LV deformity index andPVR [115]. Interventricular septum kinetics are bestevidenced on the parasternal short-axis view. Signi-ficant tricuspid insufficiency leads to RV diastolicoverload with the RV filling at the expense of the LV,together with leftward septal shift at end-diastole,unchanged LV isometric relaxation and a reduction inthe contribution of left atrial systole to LV diastolicfilling [32]. In PH, the underfilling of the LV may bedue to reduced pulmonary venous return, left-to-rightinteratrial shunting and/or interventricular septal shiftdue to RV overload. In patients with chronic throm-boembolic PH, the impairment of LV filling ispotentially reversible, as attested to by the increasesin the transmitral early to atrial filling velocity ratio(E/A) quickly after pulmonary thromboendarteriectomy,with postoperative E/A w1.5 correlating with theabsence of severe, residual PH [116].

Right ventricle hypertrophy and other findings

RV free wall thickness is measured at end-diastoleusing the subcostal view, and normal values are f4 mm.Marked (w10 mm), heterogeneous RV hypertrophy iscurrently found in chronic cor pulmonale, while mildRV hypertrophy (6–8 mm) or subnormal values arefound in acute cor pulmonale [111]. Echocardiographymay reveal effusive pericarditis. Transoesophagealechocardiography and contrast echocardiographymay be especially valuable for diagnosing a patentforamen ovale. Colour Doppler indices relying on thejet length into the RA allow the severity of TR to bequantified. Measurements of PA diameter (normalvalue v2.35 cm) belong to the systematic echocardio-graphic analysis of PH patients. Finally, echocardio-graphy may diagnose an underlying cardiac diseaseresponsible for secondary PH.

In primary PH, higher mean PAP are associatedwith more pronounced abnormalities in the septalcurvature and depressed RV contractile function [45].Patients with poor performance on the 6-min walk testexhibited a greater degree of RV dilation, morepronounced septal displacement in diastole, larger

pericardial effusions, and more severe TR [45].Patients with Class IV symptoms are more likely tohave pericardial effusions.

Other techniques

Imaging

Pulmonary magnetic resonance angiography (PMRA)is a promising imaging tool for the identification ofpatients with PH. In a recent study, gadolinium-enhanced PMRA showed that a right PA diameterw28 mm, along with the measurement of diameterof the proximal-to-distal tapering of the PAs andabsence of intravascular filling defects, allow thediagnosis of PH with a high sensitivity and highnegative predictive value [117]. These results confirmearlier studies with computed tomography scanning[118] and magnetic resonance (MR) angiograms [119,120]. The diameter of the descending right PA onchest radiography has been used for a long time toscreen for the prevalence of PH in populations [121],and others indices are currently used, namely the hilarwidth percent and hilar/thoracic index percent.

Classic pulmonary angiography and ventilation/perfusion scans help diagnose chronic pulmonarythromboemboli. In primary PH, quantitative analysisof the irregularities of lung perfusion scans could berelated to the severity of the disease [122]. Someauthors have used thallium scintigraphy and cineMR imaging to study RV pressure overload in PHpatients. Perfusion abnormalities suggestive of RVischaemia are associated with RV dysfunction [123].Finally, first-pass radionuclide angiography and gatedstress myocardial perfusion imaging [124] allow theroutine evaluation of RVEF, bearing in mind thatRVEF reflects afterload rather than RV contractility.

Electrocardiogram criteria

Although the echocardiogram has decreased depen-dency on the electrocardiogram (ECG) and catheter-isation to diagnose PH and monitor RV function,certain ECG parameters nevertheless remain impor-tant in patient management. Those reflecting rightatrial and ventricular overload have been associatedwith decreased survival [125]. The p-wave amplitudein lead II, a p o0.25 mV in lead II, the presence ofa qR pattern in V1, and WHO criteria for RVhypertrophy are highly predictive of an adverseoutcome [125].

Natriuretic peptides

In patients with PH, a high level of plasma atrialnatriuretic peptide (ANP) and brain natriureticpeptide (BNP) negatively correlates with parametersof RV function [126–128]. Following prostacyclintreatment, the decreases in both ANP and BNP parallelpulmonary vasodilatation and haemodynamic improve-ment [127, 128]. During follow-up, a further increase


in plasma BNP is an independent predictor of mortality.Repeated plasma BNP measurement may well offer anoninvasive tool for identifying patients refractory totreatments [127], although it remains to be establishedhow the predictive value of BNP compares to that ofother indices, e.g. the walking distance.

Predictors of adverse outcomes in patients withpulmonary hypertension

The prognosis is related essentially to the under-lying illness, the severity of the PH and the RVfunction. Some diseases leading to secondary PH(table 1) carry a high specific risk, e.g. underlying liverfunction is a major prognosis factor in patients withPOPH. Predictors of prognosis cannot be detailed forall forms of PH, and only PH in the setting of primarydisease, COPD and heart failure will be detailedbelow.

Primary pulmonary hypertension

Several studies have focused on the haemodynamicpredictors of adverse outcomes in primary PH.Although the heterogeneity of the clinical course ofprimary PH has been acknowledged, the prognosisappears mainly related to both RV function (staticparameters) and to the amount of pulmonary vasodila-tation in reserve (dynamic parameter). Adverse prognosiscorrelates with the NYHA functional classification[40, 61], the distance walked during the 6-min walktest [18, 39], the mean RAP [40, 60, 65, 129, 130],cardiac or stroke volume index [40, 60, 61, 129–131]and systemic arterial and mixed Sv,O2 [60, 61, 64].Prognosis also relates to mean PAP and PVRI(or PVR) in most studies, although conflicting resultshave been reported in some studies. The lack ofpulmonary vasodilatory reserve is also associated withpoor prognosis [60, 71, 80–82, 132]. Echocardio-graphic predictors of adverse outcomes in primaryPH include pericardial effusion, right atrial enlarge-ment, septal displacement and an increased Dopplerglobal RV function index [113, 133, 134]. Numerousother prognostic factors have been described, includ-ing the forced vital capacity [60], pulmonary Sa,O2

[132], oxygen saturation at peak distance during the6-min walk test [18], anticoagulant therapy [132] andincreased serum uric acid [64, 65]. Overall, determin-ing the walking distance, stroke volume index, meanRAP, pulmonary vasodilatory reserve, serum uric acidand echocardiographic characteristics should help inpredicting primary PH clinical course.

The results of two recent studies deserve particularattention. SITBON et al. [135] have tested the predic-tive value of the responses to a 3-month continuousinfusion of epoprostenol in primary PH patients inNYHA functional class III-IV. In the Cox model ofmultivariate analysis including both baseline and 3-month clinical and haemodynamic variables, thepersistence of NYHA functional class III–IV and theabsence of fall in PVRIw30% relative to baseline at 3months, and a history of right heart failure, were

associated with a poor 5-yr survival. This suggeststhat haemodynamic responses to 3-month prostaglan-din I2 infusion may help diagnose a subset of primaryPH in whom lung transplantation could be proposed[135]. Furthermore, WENSEL et al. [65] have performedsymptom-limited exercise testing, pulmonary functiontest, cardiac catheterisation and uric acid measure-ments in primary PH. They reported that low peakV9O2 and low peak exercise systolic arterial pressurewere the strongest predictors of impaired survival.The predictive value of the V9E/V9CO2 slope was nottested due to the high percentage of patients with apatent foramen ovale [65]. Patients with two riskfactors, namely peak V9O2 f10.4 mL?kg-1?min-1 andpeak exercise systolic arterial pressure f120 mmHghad poor survival rates at 12 months (23%), whereaspatients with one or none of these risk factors had79% and 97% survival rates, respectively [65]. Theprognostic consequence of a low systemic pressurecould be explained by greater sensitivity and moresevere dysfunction of the RV as a result of ischae-mia [123]. Finally, amongst the new therapeuticapproaches for primary PH, several trials, eitherpublished or in progress, have suggested benefits fora patient assigned to a specific treatment group, andfurther studies are needed to confirm and summarisenew therapeutic guidelines.

Chronic obstructive pulmonary disease

In COPD patients, factors related to survivalinclude forced expiratory volume in one minute,Pa,O2 and mean PAP [24]. In patients receivinglong-term oxygen therapy, mean PAP is the bestprognostic factor [136]. Finally, the higher the meanPAP, the higher the risk of hospitalisation for acuteexacerbation [137].

Heart failure

As far as right heart failure is concerned, there is acomplex interplay between the severity and the causeof PH. Despite a tendency towards higher PAP,patients with Eisenmenger syndrome have lower meanRAP and greater systemic cardiac output than thosewith primary PH [138], and the preservation ofbiventricular function could explain the more favour-able outcome in the former group [138, 139]. Thedegree of hypoxaemia at baseline is a strong predictorof survival in the Eisenmenger syndrome.

The RVEF is an independent prognostic factor inpatients with PH complicating chronic heart failure[140]. In patients with advanced heart failure, RVEFo0.35 at rest and during exercise is a more powerfulpredictor of survival than V9O2 [46]. A few recentstudies have suggested that hyperventilatory responseto exercise, as measured by increased V9E/V9CO2 slope,may be a prognostic factor of poor survival, but thispoint remains to be confirmed in large populationstudies. Mean PAP is particularly important in strati-fying risk in cardiomyopathy caused by myocarditis[141]. Patients with PH are a particularly high-risk


group, probably because PH may develop more acutely,overwhelming compensatory mechanisms such as RVhypertrophy.

In PH patients evaluated for cardiac transplanta-tion, patients with reversible (or reactive) haemo-dynamics following provocative vasodilatory therapyhave better prognosis than patients with irreversible(or fixed) PH [37].

Conclusion

The rational management of patients with pulmo-nary hypertension relies on the careful assessment oftheir haemodynamic profile. Cardiac catheterisationallows for the precise establishment of the diagnosisand the type of pulmonary hypertension, the severityof the disease, the consequences on right heart function,and the amount of vasodilatation in reserve. Theprecise evaluations of exercise capacity (6-min walktest), right atrial pressure, stroke index and vaso-dilator challenge responses are of major importance,given their prognostic values. Echocardiography isespecially valuable in the serial assessment of pulmo-nary artery pressures and right and left heart function.The underlying cause of pulmonary hypertensionmust be recognised and any treatable factor poten-tially involved in pulmonary vasoconstriction andright ventricle failure must be prevented or treated.New developments in vascular biology have improvedunderstanding of the underlying causes of vascularobstruction, remodelling and vasoconstriction inpulmonary hypertension. Recent therapeutic strate-gies in primary pulmonary hypertension have reportedthe significant benefits of oral prostacyclin analoguesand oral endothelin-receptor antagonists. The outlookin the field of genetic testing is promising. Overall,the careful haemodynamic evaluation of pulmonaryhypertension patients may optimise new diagnosis andtherapeutic strategies.

Acknowledgements. The authors thankR. Naeije, F-X. Blanc and S. Carrodus fortheir helpful comments. The authors apologiseto many investigators whose work that couldnot be cited because of space limitation.

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