Eur Respir J 2002; 20: 1314–1331
`DOI: 10.1183/09031936.02.00068002
`Printed in UK – all rights reserved
`
`Copyright #ERS Journals Ltd 2002
`European Respiratory Journal
`ISSN 0903-1936
`
`SERIES 0ADVANCES IN PATHOBIOLOGY, DIAGNOSIS, AND TREATMENT OF
`PULMONARY HYPERTENSION0
`Edited by A.T. Dinh-Xuan, M. Humbert and R. Naeije
`Number 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 of
`pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) leading to
`right ventricular enlargement and hypertrophy. Pulmonary hypertension may result
`from 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 rest
`or w30 mmHg during exercise, the pressure being measured invasively with a pulmonary
`artery catheter. Doppler echocardiography allows serial, noninvasive follow-up of PAPs
`and right heart function. When the adaptive mechanisms of right ventricular dilatation
`and hypertrophy cannot compensate for the haemodynamic burden, right heart failure
`occurs and is associated with poor prognosis.
`The haemodynamic profile is the major determinant of prognosis. In both primary
`and secondary pulmonary hypertension, special attention must be paid to the assessment
`of pulmonary vascular resistance index (PVRI), right heart function and pulmonary
`vasodilatory reserve.
`Recent studies have stressed the prognostic values of exercise capacity (6-min walk
`test), right atrial pressure, stroke index and vasodilator challenge responses, as well as
`an interest in new imaging techniques and natriuretic peptide determinations. Overall,
`careful haemodynamic evaluation may optimise new diagnostic and therapeutic
`strategies in pulmonary hypertension.
`Eur Respir J 2002; 20: 1314–1331.
`
`*Dept of Cardiac and Respiratory
`Physiology, Biceˆtre Hospital, Faculty
`of Medicine, University of Paris XI,
`Le Kremlin-Biceˆtre and, #Dept of
`Thoracic and Vascular Surgery, Marie
`Lannelongue Hospital,
`le Plessis-
`Robinson, France. }Intensive care unit,
`Erasme Hospital, Brussels, Belgium.
`
`Correspondence: D. Chemla, Service
`EFCR, Broca 7, Hoˆ pital de Biceˆtre, 78
`rue du Ge´ne´ral Leclerc, 94 275 Le
`Kremlin Biceˆtre, Paris, France.
`Fax: 33 145213778
`E-mail: denis.chemla@bct.ap-hop-paris.fr
`
`Keywords: Cor pulmonale
`pulmonary hypertension
`pulmonary vasodilatory reserve
`right atrial pressure
`right ventricle
`walk test
`
`Received: July 29 2002
`Accepted after revision: August 5 2002
`
`The normal adult pulmonary vascular bed is a
`low-pressure, low-resistance, highly distensible system,
`and is capable of accommodating large increases in
`blood flow with minimal elevations of PAP. Pulmo-
`nary hypertension (PH) is characterised by the chronic
`elevation of PAP and PVR leading to right ventricular
`enlargement and hypertrophy [1–8]. At first, PAP is
`normal at rest but rises abnormally high with exercise.
`In more evolved stages, PH occurs at rest (fig. 1).
`When the adaptive mechanisms of right ventricular
`dilatation and hypertrophy cannot compensate for the
`haemodynamic burden, right heart failure occurs and
`is associated with poor prognosis. PH may result from
`respiratory and cardiac diseases,
`the most severe
`forms occurring in thromboembolic PH and primary
`PH. The World Health Organization (WHO) has
`recently proposed a revised diagnostic classification
`(table 1) [1].
`PH is most often defined as a mean PAPw25 mmHg
`at rest or w30 mmHg during exercise, the PAP being
`
`artery
`measured invasively with a pulmonary
`(PA) catheter. However, there is no clear consensus
`as to what level of PAP constitutes PH [1–8]. Pro-
`posed upper normal values for mean PAP range
`18–25 mmHg at
`rest. Other definitions of PH
`have been used, which either include a systolic PAP
`w30 mmHg, or rely on the level of PVR. During
`exercise, a mean PAP threshold w30 mmHg may
`apply in healthy older subjects. Doppler echocardio-
`graphy allows the noninvasive assessment of PAP,
`and systolic PAP is most commonly used. Proposed
`upper normal values range 40–50 mmHg at rest,
`which correspond to a tricuspid regurgitant velocity
`of 3.0–3.5 m?s-1 [1]. However, Doppler-derived PAP
`critically depends upon age, body mass index (BMI)
`and right atrial pressure (RAP).
`PH may be identified during testing of symptomatic
`patients, during screening of patients at risk (table 1),
`or it may be discovered incidentally [1–8]. PH is a rare
`condition 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 J
`2002; 20: 741–749. No. 2: Galie` N, Manes A, Branzi A. The new clinical trials on pharmacological treatment in pulmonary arterial
`hypertension. Eur Respir J 2002; 20: 1037–1049.
`
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`

`HAEMODYNAMICS OF PULMONARY HYPERTENSION
`
`1315
`
`Table 1. – World
`classification
`
`Health
`
`Organization
`
`diagnostic
`
`Pulmonary arterial hypertension
`Primary pulmonary hypertension
`Sporadic
`Familial
`Related to:
`Collagen vascular disease
`Congenital systemic to pulmonary shunts
`Portal hypertension
`HIV infection
`Drugs/toxins
`Anorexigens
`Other
`Persistent pulmonary hypertension of the newborn
`Other
`Pulmonary venous hypertension
`Left-sided atrial or ventricular heart disease
`Left-sided valvular heart disease
`Extrinsic compression of central pulmonary veins
`Fibrosing mediastinitis
`Adenopathy/tumours
`Pulmonary veno-occlusive disease
`Other
`Pulmonary hypertension associated with disorders of the
`respiratory system and/or hypoxaemia
`Chronic obstructive pulmonary disease
`Interstitial lung disease
`Sleep-disordered breathing
`Alveolar hypoventilation disorders
`Chronic exposure to high altitude
`Neonatal lung disease
`Alveolar-capillary dysplasia
`Other
`Pulmonary hypertension due to chronic thrombotic and/or
`embolic disease
`Thromboembolic obstruction of proximal pulmonary
`arteries
`Obstruction of distal pulmonary arteries
`Pulmonary embolism (thrombus, tumour, ova and/or
`parasites, foreign material)
`In situ thrombosis
`Sickle cell disease
`Pulmonary hypertension due to disorders directly affecting
`the pulmonary vasculature
`Inflammatory
`Schistosomiasis
`Sarcoidosis
`Other
`Pulmonary capillary haemangiomatosis
`
`Although this clinical classification is primarily concerned
`with causes and thus prevention and treatment,
`the
`classification is in keeping with the pathological character-
`isation of pulmonary hypertensive states; Pulmonary hyper-
`tension (PH) that results from identifiable causes (secondary
`PH) is far more common than pulmonary hypertension with
`no apparent cause (primary PH); HIV: human immuno-
`deficiency virus.
`
`portal hypertension evaluated for liver transplanta-
`tion, and in asymptomatic subjects with a family
`history of primary PH (first degree relatives). Recent
`studies have identified mutations in the genes which
`encode for receptor members of the transforming
`growth factor-b family in familial (and sporadic)
`primary PH, and in PH associated with hereditary
`haemorrhagic telangiectasia, and this provides pro-
`mising perspectives to genetic testing in PH [9].
`
`Time 500 ms
`
`Time 500 ms
`
`a)
`
`140
`
`70
`
`0
`
`PAP mmHg
`
`b)
`
`140
`
`70
`
`0
`
`PAP mmHg
`
`Fig. 1. – Typical pulmonary artery curve tracing a) at rest and b)
`during exercise (workload 45 W)
`in a patient with primary
`pulmonary hypertension. The noise is minimal with the use of a
`high-fidelity pressure-measuring catheter. PAP: pulmonary artery
`pressure.
`
`explains why the diagnosis may be delayed. In the
`National Institutes of Health (NIH) primary PH
`registry, the mean interval from onset of symptoms to
`diagnosis was 2 yrs [7]. The most common presenting
`symptom is dyspnoea, followed by fatigue, syncope or
`near syncope and chest pain. The clinical presentation
`of PH critically depends upon its cause, but it is not
`within the scope of the present review to detail this
`point. The general diagnostic approach includes physical
`examination, exercise capacity testing (6-min walk test),
`chest radiograph, electrocardiography, laboratory tests
`(blood tests, arterial blood gases, pulmonary function
`tests), noninvasive cardiac and pulmonary imaging
`and cardiac catheterisation [1–8]. Cardiac cathe-
`terisation allows for the precise establishment of the
`diagnosis and the type of PH, the severity of the
`disease, the consequences on right heart function, and
`the amount of pulmonary vasodilatation in reserve.
`Echocardiography is especially valuable in the serial
`assessment of PAP and right and left heart function.
`The early initiation of treatments at a time when
`dynamic or reversible pathogenic mechanisms are
`present may increase the likelihood of a successful
`treatment outcome [1]. A screening transthoracic
`echocardiogram is therefore recommended in asymp-
`tomatic patients with scleroderma or liver disease/
`
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`
`

`

`1316
`
`D. CHEMLA ET AL.
`
`Pathophysiology of haemodynamic changes in
`pulmonary hypertension
`
`Pulmonary artery pressure
`
`The pressure drop across the pulmonary circulation
`(i.e. the driving pressure) is often referred to as the
`transpulmonary pressure gradient (TPG):
`TPG~mean PAP{downstream pressure
`
`ð1Þ
`In analogy with the electric Ohm9s law, TPG equals
`PVR times cardiac output [10–13]:
`mean PAP{downstream pressure~
`
`ð2Þ
`
`ð3Þ
`
`PVR|cardiac output
`
`The equation can be rewritten as follows:
`mean PAP~(PVR|cardiac output)z
`
`downstream pressure
`
`The normal pulmonary circulation is a low resistance
`circuit, with little or no resting vascular tone, and the
`most important factors influencing mean PAP are
`hydrostatic pressure, intra-alveolar pressure, left atrial
`pressure and alveolar gases.
`PH is most often defined as a mean PAPw25 mmHg
`at rest. According to the mechanistic classification
`[12], increases in mean PAP may be passive (as a result
`of increased downstream pressure), hyperkinetic (as a
`result of increased cardiac output through the lungs)
`or due to increased PVR resulting from changes in the
`pulmonary circulation itself. Granted that various
`hypertensive mechanisms can work jointly, two forms
`of PH have been defined. Postcapillary PH (or
`pulmonary venous hypertension) is a passive form
`characterised by an increased downstream pressure o
`15 mmHg and a normal TPG. Precapillary PH (or
`pulmonary arterial hypertension) is characterised by a
`normal downstream pressure (v15 mmHg). TPG is
`increased because of
`increased cardiac output or
`increased PVR. Increases in PVR are due to a
`significant reduction in the area of the distal (mainly
`resistive) and/or proximal (mainly capacitive) PAs.
`This classification illustrates the crucial role of cardiac
`catheterisation in determining not only the mean PAP
`and cardiac output but also the downstream pressure.
`
`Pulmonary vascular resistance
`
`The PVR is used to characterise PH in a more
`restricted sense and to quantify abnormalities of the
`pulmonary vasculature according to the following
`equation:
`PVR~(mean PAP{downstream pressure)=
`
`ð4Þ
`
`cardiac output
`
`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 to
`Poiseuille9s law, PVR is inversely related to the fourth
`
`power of arterial radius. PVR is therefore considered
`to mainly reflect the functional status of pulmo-
`nary vascular endothelium/smooth muscle cell coupled
`system [10–13]. PVR is also positively related to blood
`viscosity 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 be
`compared without the need to take into account
`potential differences in their body size. Conversely,
`variables such as volume are proportional to the size
`of the system. For comparative purposes, the PVRI
`is therefore defined as the pressure drop across the
`circuit divided by cardiac index (in WU?m2 or in
`mmHg?L-1?min?m2 or in dyne?s?cm-5?m2). In patients
`with high BMI, the use of PVR instead of PVRI has
`been responsible for significant underestimation of
`PH, and for the occurrence of haemodynamic and
`respiratory failure following heart transplantation.
`The use of PVRI must be recommended in studies
`evaluating new therapeutic strategies in PH.
`Pulmonary arterial hypertension results from three
`main elements: vascular wall remodelling, thrombosis
`and vasoconstriction [8]. The increases in PVRI may
`be fixed and/or potentially reversible. Arterial obstruc-
`tion, obliteration and remodelling are responsible for
`the fixed component, while active increases in vascular
`tone are responsible for the reversible component,
`which may account for w50% PVRI. The pulmonary
`vascular tone results from a complex interplay between
`the pulmonary endothelium, smooth muscle cells,
`extracellular matrix, and circulating blood cells and
`blood components. In PH, the dysfunction of pulmo-
`nary arterial endothelium plays a key role, whether
`due 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 to
`pulmonary vasoconstriction either via a direct pressor
`effect or by causing mediators to discharge. Acidosis
`leads to pulmonary vasoconstriction as well as acting
`synergistically with hypoxia. Hypoxic vasoconstriction
`is the main mechanism explaining mild and moderate
`degrees of PH in patients with chronic obstructive
`pulmonary disease (COPD), in whom severe chronic
`long-standing hypoxia is observed. An oxygen tension
`in arterial blood (Pa,O2)v7.98 kPa (v60 mmHg) and a
`carbon dioxide tension in arterial blood w5.32 kPa
`(w40 mmHg) are thought to be accurate thresholds
`for the development of PH in COPD [14]. A recent
`study has shown that mean PAP inversely correlated
`with arterial Pa,O2,
`forced expiratory volume in
`one second (%) and single-breath carbon monoxide
`diffusion capacity (%) and directly correlated with
`pulmonary wedge pressure in patients with severe
`emphysema [15]. Surprisingly, all factors but Pa,O2
`remained significant determinants of mean PAP
`when multiple regression analysis was used. Although
`
`1316
`
`

`

`HAEMODYNAMICS OF PULMONARY HYPERTENSION
`
`1317
`
`methodological explanations may be discussed, this
`result suggests that factors other than hypoxia are
`involved 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 mean
`PAP are independently related to the subsequent
`development of PH [16]. In patients with primary PH
`or chronic pulmonary thromboembolism, hypocapnia
`the Pa,O2 may be within
`is commonly observed;
`normal limits or only slightly decreased at rest, while
`hypoxaemia is observed with exercise [17, 18]. Right-
`to-left shunt is the main mechanism of hypoxia in the
`Eisenmenger syndrome. Severe hypoventilation is asso-
`ciated with hypoxia and may lead to PH, particularly
`if there is associated acidosis. This may explain the PH
`observed in the setting of the obesity-hypoventilation
`Pickwickian syndrome and in a number of muscular
`disorders [6]. In patients with PH, high resting PAP
`and PVRI values increase further following exercise or
`acute hypoxaemia (e.g. rapid eye movement (REM)
`sleep or respiratory failure in patients with COPD). It
`is important to prevent, diagnose and treat pulmonary
`infections in PH patients. Altitudes w1500 m must
`be avoided without supplemental oxygen, and alti-
`tudes w3000 m must be discouraged.
`The pathogenic role of endogenous endothelin-1
`has been stressed, together with impaired synthesis of
`vasorelaxant nitric oxide, and this may have thera-
`peutic implications [19, 20]. PH is associated with
`activation of the endothelin system, which has potent
`vasoconstrictive and mitogen properties. Thrombosis
`can play a part in the pathophysiology of the disease,
`as attested to by the platelet activation, disturbances
`of various steps of
`the coagulation cascade and
`abnormal thrombolysis described in PH [21]. Primary
`or secondary endothelial dysfunction increase the risk
`of thrombotic events. Dilated right heart chambers,
`sluggish pulmonary blood flow and sedentary lifestyle
`also increase this risk. Adrenergic overdrive may
`precipitate right ventricle (RV)
`failure and high
`plasma noradrenaline is associated with increased
`mortality in patients with primary PH, suggesting that
`the level of sympathetic activation relates to the
`severity of the disease [22].
`
`Other precipitating factors
`
`Changes in the rheological blood properties may
`aggravate PH. Erythrocytosis may be secondary to
`hypoxia, and is potentially responsible for increased
`blood viscosity and changes in erythrocyte deform-
`ability. PH may be aggravated by increases in cardiac
`output in the setting of hyperadrenergic states, anaemia
`and hyperthyroidism. Decreased diastolic time (e.g.
`tachycardia) or the loss of atrial contribution to left
`ventricle (LV) filling (e.g. atrial fibrillation) tend to
`increase left atrial pressure and thus may also aggravate
`PH. Finally, permanent PH is self-aggravating, as it
`favours several local pathological processes, including
`the remodelling of small distal arteries and the loss of
`the elastic properties of proximal arteries, thus leading
`to a vicious circle.
`
`The right ventricle in pulmonary hypertension
`
`Right ventricular function
`
`RV has a complex geometry and is characterised
`by a crescentic shape and a thin wall [23]. The crista
`supraventricularis divides the RV into inflow and
`outflow regions. Inflow (sinus), which is located posterior
`and inferior, has a greater fibre shortening and is the
`effective flow generator, pumping w85% of the stroke
`volume. Outflow (conus), which is located anterior
`and superior, is a resistive and pulsatile conduit with a
`limited ejection capacity. RV contraction proceeds
`from the sinus to the conus according to a peristaltic
`movement. Right ventricular output equals heart rate
`times stroke volume. For a given stroke volume, RV
`output increases when heart rate increases (chrono-
`tropic reserve). For a given heart rate, RV output
`increases 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 to
`increased inotropy (inotropic reserve) or to decreased
`RV end-systolic pressure. The latter mechanism may
`be observed in some healthy subjects during exercise
`(distensibility, recruitment) and in a subgroup of PH
`patients 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-dependence
`and RV-LV interdependence [23]. However, the RV
`is unable to face an acute increase in PVRI, and
`works inefficiently when confronted with PH [24].
`Thus, unlike the LV, the RV performance is markedly
`afterload-dependent. In PH patients, the use of preload
`reserve (Frank-Starling9s mechanism) helps preserve
`RV function. Furthermore, according to Laplace9s
`law, an increase in afterload can be offset by an
`increase in RV wall thickness (RV hypertrophy), and
`this normalises RV wall stress and myocardial oxygen
`consumption. There is a linear correlation between RV
`mass and free wall area, indicating that an increase in
`afterload causes RV enlargement with both dilatation
`and hypertrophy [25]. Chronic cor pulmonale is defined
`as dilatation and hypertrophy of the RV secondary to
`PH caused by diseases of the pulmonary parenchyma
`and/or pulmonary vascular system between the origins
`of the main PA and the entry of the pulmonary veins
`into the left atrium [26, 27].
`Right ventricular ejection fraction (RVEF) is much
`more sensitive to changes in ventricular afterload than
`LV ejection fraction [28]. The RVEF has been found
`to augment with exercise in healthy subjects given the
`decreased PVRI and increased contractility of the RV
`free wall [29, 30]. In patients with PH, the decreases in
`RVEF are not indicative of decreased RV contractility
`but mainly reflect increased afterload [31]. In primary
`PH studied at rest, cardiac function is characterised
`by RV systolic overload due to PH and diastolic over-
`load with tricuspid regurgitation (TR), whereas the
`LV is subject to diastolic underloading and reduced
`compliance [32, 33]. With exercise, RV systolic perfor-
`mance further declines with a reduction in stroke
`volume and ejection fraction, and consequently heart
`
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`
`

`

`1318
`
`D. CHEMLA ET AL.
`
`rate becomes the mechanism by which cardiac output
`increases.
`
`Right ventricular failure
`
`RV failure may be related to the natural evolution
`of the disease or to acute exacerbation of PH (e.g.
`following acute hypoxaemia). In both primary PH
`and thromboembolic PH, the main cause of death is
`RV failure [1–8]. COPD is
`the most common
`pulmonary disease that culminates in RV dysfunction
`[24, 34]. An autopsy study suggests that cor pulmonale
`is found in 40% COPD patients [35]. Cor pulmonale is
`mainly observed in "blue bloaters" who develop a low
`cardiac output profile and severe hypoxaemia and
`erythrocytosis resulting in PH. Conversely, "pink
`puffers" exhibit less severe hypoxaemia, decreased
`cardiac output and increased arteriovenous oxygen
`content difference, and cor pulmonale is less likely to
`develop despite increased PVRI [24]. In a number of
`COPD patients, peripheral oedema may not always be
`explained by RV failure, but rather relate to hyper-
`capnia, acidosis and increased sympathetic and renin-
`angiotensin-aldosterone activities, and the related
`changes in renal haemodynamics and redistribution
`of body water [36].
`When pulmonary arterial impedance is chronically
`increased, RV function and output are preserved thanks
`to RV dilation and hypertrophy, increased inotropy
`and faster heart rate. Both increased impedance and
`increases in RV size and annulus diameter lead to TR,
`which further compromise RV function. Decreased
`RV function is observed when the limits of cardiac
`reserves are reached or when significant RV-LV
`interdependence or chronic RV ischaemia are present
`(fig. 2). The mechanisms for RV ischaemia include
`increased pressure work leading to increased myocar-
`dial oxygen consumption; reduced systemic pressure
`leading to decreases in the coronary perfusion driving
`pressure; and higher
`sensitivity to hypoxia and
`reduced vasodilatory reserve of the hypertrophied
`RV [23, 34]. In patients with end-stage RV failure, the
`
`Increased RV
`afterload
`
`RV dilation
`
`Limit of preload
`reserve, tricuspid
`insufficiency
`
`Leftward septal
`shift, decreased
`LV compliance
`
`Decreased
`LV output
`
`Increased
`free wall tension
`
`RV hypertrophy
`
`RV ischaemia
`
`Decreased
`RV output
`
`Fig. 2. – Main pathophysiological factors involved in right and left
`heart failure in patients with pulmonary hypertension. RV: right
`ventricle; LV: left ventricle.
`
`maintenance of a sufficiently high systemic pressure is
`of major importance to prevent RV ischaemia, and
`this may require high doses of vasoconstrictive agents
`(e.g. noradrenaline).
`Numerous factors may precipitate RV failure [23,
`24, 34]. Factors related to preload include impaired
`venous return (e.g. mechanical ventilation), decreased
`preload reserve (e.g. hypovolaemia) and mechanical
`limitation (e.g. effusive pericarditis). Factors related
`to afterload include acute load increases (although
`pulmonary embolism-related RV failure is observed
`only for acute systolic pressurew60–70 mmHg), increased
`pulsatile load (e.g. proximal obstruction with mark-
`edly increased pulse wave reflections), and factors
`related to transpulmonary pressure, lung compliance
`and mechanical ventilation. Major tricuspid valve
`insufficiency may precipitate RV failure, and the
`anatomical and functional status of the tricuspid
`valve has a key role in preserved RV function. Other
`factors potentially precipitating RV failure are
`decreased inotropy, RV ischaemia, REM sleep and
`obstructive sleep apnoea syndrome. The deleterious
`role of hypoxia and neurohormonal factors has also
`been demonstrated.
`
`Therapeutic implications
`
`The main goals in the prevention and treatment
`of RV failure include: 1) reducing RV afterload by
`decreasing PVRI; 2) limiting pulmonary vasoconstric-
`tion (e.g. prevention of hypoxaemia); 3) optimising
`RV preload; and 4) preserving coronary perfusion
`through maintenance of systemic blood pressure.
`Other strategies may depend upon the cause of PH
`(e.g. recipient selection for preventing acute RV
`failure following cardiac transplantation) [37].
`
`Exercise capacity
`
`During exercise, the pulmonary vascular bed of
`normal subjects shows a minimal rise in PAP despite
`the doubling or tripling of cardiac output, thanks to
`the substantial reserve of pulmonary circulation. The
`fall in PVRI reflects passive distension of compliant
`small vessels and/or recruitment of additional vessels
`in the superior portions of the lung [10–13, 38].
`According to the New York Heart Association
`(NYHA) functional classification, symptoms may be
`caused by ordinary physical activity (Class II), less
`than ordinary activity (Class III) or may even be
`present at rest (Class IV) in PH patients [1–8]. Recent
`guidelines focus on the rational management of
`patients without any limitation of their physical activity
`(Class I) [1]. It must be remembered that clinical
`symptoms poorly correlate with resting mean PAP
`[39]. The degree of preservation of systolic perfor-
`mance of the RV is the main factor governing the
`clinical presentation.
`impaired cardiac
`In patients with primary PH,
`reserve during exercise is reflected in reduced peak O2
`uptake (V9O2) [40, 41]. The NYHA functional class
`best correlates with % predicted peak V9O2, which
`
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`
`

`

`HAEMODYNAMICS OF PULMONARY HYPERTENSION
`
`1319
`
`allows a precise grading of the severity of the disease
`[42]. A reduction of the anaerobic threshold also
`appears to be an independent marker of the disease
`severity. The O2 pulse can be calculated as the V9O2
`divided by heart rate ratio, and equals the product of
`stroke volume times the O2 content difference between
`arterial and mixed venous blood. The progressively
`decreasing peak O2 pulse reflects a progressive
`reduction (or inadequate increase) in peak stroke
`volume paralleling disease severity [42]. Patients
`with primary PH exhibit hyperventilatory response
`i.e.
`to exercise,
`impaired ventilatory efficiency, as
`attested to by the increased slope relating minute
`ventilation to carbon dioxide output (V9E/V9CO2) [42].
`However, the fitting of a linear slope is somewhat
`arbitrary in patients with primary PH as the ventila-
`tion of underperfused alveoli causes an increase in
`dead space ventilation, and also because a significant
`number of patients may have a patent foramen ovale,
`both conditions leading to nonlinearities of the V9E-
`V9CO2 relationship. Finally, in patients with primary
`PH, exercise stroke volume response is related to
`resting haemodynamics, namely diastolic PAP (inver-
`sely), PVRI (inversely) and pulse wave reflection
`factor (directly) [43].
`Maximal exercise testing must be prohibited in
`PH patients, as syncope and sudden death have been
`reported. Submaximal exercise testing may be less
`unpleasant for the patient and is more representative
`of daily life activity [44]. In primary PH, MIYAMOTO
`et al. [39] have reported that the distance walked in
`6 min was decreased in proportion to the severity
`of the NYHA functional class, and was strongly
`correlated with peak V9O2 and oxygen pulse. The
`distance walked in 6 min has a strong, independent
`association with mortality and patients walking
`v332 m had a significantly lower survival than those
`walking farther [45]. In primary PH patients perform-
`ing the 6-min walk test, a distance f300 m and
`reduction in arterial oxygen saturation (Sa,O2) at
`maximal distance o10% increased mortality risk by
`2.4 and 2.9, respectively [18]. The distance walked in
`6 min may serve as a safe prognostic indicator
`throughout
`the survey. Finally,
`in patients with
`advanced heart failure, RVEF o0.35 at rest and
`during exercise is a more powerful predictor of
`survival than V9O2 [46].
`
`Cardiac catheterisation: standard procedures
`
`Right heart and PA catheterisation remains the
`gold standard used to establish the diagnosis and the
`type of PH. This procedure helps quantify the severity
`of
`the disease,
`the consequences on right heart
`function and the amount of vasodilatation in reserve.
`Furthermore, the haemodynamic profile is the major
`determinant of prognosis in PH. Initial studies have
`reported that catheterisation carries an increased risk
`in patients with PH, which is why it is important
`to ensure that catheterisation is performed by an
`experienced team, familiar with PH patients. The
`prevention of vasovagal reaction and pain, and
`extreme 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 mmHg
`range for normal mean PAP at sea level [47, 48]. In
`resting healthy subjects aged 6–45 yrs, mean PAP
`remains constant at 14¡3 mmHg [2, 4]. Although
`mean PAP increases slightly to 16¡3 mmHg between
`60–83 yrs, it is generally agreed that mean PAP is little
`influenced by age in healthy subjects [2, 4, 49, 50].
`There is no clear consensus as to what resting mean
`PAP level constitutes PH. Pressure valuesw18 mmHg
`[4, 51], 20 mmHg [5, 6, 38, 52] and 25 mmHg [5] have
`been proposed, the latter cut-off value being the one
`most often used in recent clinical
`trials. Other
`definitions of PH include a systolic PAP w30 mmHg
`at rest and a mean PAPw30 mmHg on exercise [5, 51,
`52]. The cause and type of PH also influence the
`haemodynamic profile, which is the major determi-
`nant of PH prognosis. For example, PH of mild (mean
`PAP=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 primary
`PH and in chronic pulmonary thromboembolism [1–8].
`
`Pulmonary occlusion pressure, pulmonary vascular
`resistance index, total peripheral resistance index and
`pulmonary hypertension classification
`
`Downstream pressure is approximated on the basis
`of the pulmonary occlusion pressure (PA,op). PA,op
`provides a more accurate estimate of left atrial pressure
`than mean PA capillary wedge pressure (PA,wp),
`which overestimates left atrial pressure when pulmo-
`nary venous resistance is increased [53, 54]. In normoxic
`healthy subjects, the difference between mean PAP
`and PA,wp is 5–9 mmHg [4]. The PA,op value allows
`diagnosis 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 and
`cardiac index allow the calculation of PVRI according
`to standard formula. Unlike mean PAP, PVRI
`increases significantly with age [4, 49, 50]. The upper
`limit for PVRI (in mmHg?L-1?min?m2) in normal
`subjects 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 to
`what resting PVRI level constitutes PH, and threshold
`values ranging from 3–6 mmHg?L-1?min?m2 have been
`used previously. Although it has often been reported
`that an accurate PA,op may be unobtainable in
`patients with severe PH, this is rarely the case in
`experienced teams. Total peripheral resistance (TPR;
`equal to mean PAP/cardiac output) and total peri-
`pheral resistance index are calculated in cases where
`reliable PA,op recordings are not obtained.
`A PVR threshold value may be included in the
`diagnostic criteria of some forms of PH, e.g. porto-
`pulmonary hypertension (POPH) [55–57]. POPH can
`be defined as a pulmonary arterial hypertension
`
`1319
`
`

`

`1320
`
`D. CHEMLA ET AL.
`
`associated with portal hypertension with or without
`hepatic disease. A moderate increase in mean PAP
`(25–35 mmHg) is observed in up to 20% of patients
`with cirrhosis and portal hypertension. This passive
`increase in mean PAP, which relates to increased
`cardiac output and/or blood volume,
`is associated
`with near normal PVRI (i.e. minimum pulmonary
`vascular remodelling) and normal or increased PA,op
`(pulmonary venous hypertension). A severe pulmo-
`nary arterial hypertension with extensive pulmonary
`vascular remodelling and elevated PVR is more rarely
`observed in patients with portal hypertension. This
`latter condition represents the entity of POPH and is
`associated with poor outcome.