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© The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Right ventricular function in pulmonary hypertension: physiological concepts

Robert Naeije^* and Sandrine Huez

Department of Pathophysiology, Faculty of Medicine, Free University of Brussels, Erasme Campus, CP 604, 808, Lennik Road, B-1070 Brussels, Belgium

^* Corresponding author. Tel: +32 2 5553322; fax: +32 2 5554124. E-mail address: rnaeije{at}ulb.ac.be

	Abstract

Top Abstract Cardiac limitation to exercise... Right ventricular failure in... Conclusions Acknowledgements References

 
The symptoms of pulmonary hypertension are explained by a decrease in cardiac output caused by an afterload-induced right ventricular (RV) failure. However, the standard haemodynamic evaluation of pulmonary hypertension, with measurements of mean pulmonary vascular pressures and cardiac output, does not capture the determinants of RV function. Right ventricular afterload can be measured either as a hydraulic load calculated from spectral analysis of pulmonary artery pressure and flow waves, or as a maximal wall tension estimated from instantaneous ventricular pressure, volume, and wall thickness measurements. The adequacy of ventricular adaptation to afterload can be assessed by a measurement of the matching of systolic function to arterial elastance. The difficulty in measuring instantaneous RV volume is overcome using a single-beat method, which derives a systolic pressure–volume relationship from instantaneous RV pressure and an integration of pulmonary arterial flow. On such a pressure–volume curve, it is easy to determine graphically end-systolic elastance (E_es, end-systolic pressure on end-systolic volume), as a load-independent measure of contractility, and arterial elastance (E_a, end-systolic pressure on stroke volume), as a measure of afterload. The optimal value of the E_es/E_a ratio, compatible with flow output at a minimal energy cost, is between 1 and 2. Patients with severe pulmonary hypertension present with a decreased elastance ratio, in spite of an adaptative increase in systolic function, which underscores that RV failure in the face of increased afterload is a relative notion. Further studies are needed to confirm that right ventriculo-arterial decoupling accounts for a decreased aerobic exercise capacity by a limitation of cardiac output adaptation to peripheral demand.

Key Words: Pulmonary vascular resistance • Pulmonary vascular impedance • Right ventricular function • Arterial elastance • Contractility • Pulmonary hypertension

	Cardiac limitation to exercise capacity in pulmonary hypertension

Top Abstract Cardiac limitation to exercise... Right ventricular failure in... Conclusions Acknowledgements References

 
Pulmonary hypertension, as defined by an increase in mean pulmonary artery pressure (PAP) >25 mmHg at rest and/or 30 mmHg at exercise, complicates a variety of cardiac and pulmonary conditions, but may occur as a consequence of an isolated pulmonary arteriolar vasculopathy and is then called pulmonary arterial hypertension (PAH).¹ The condition is either idiopathic (IPAH, formerly primary pulmonary hypertension) or occurs in association with a variety of diseases or circumstances, which include human immuno-deficiency syndrome, intake of fenfluramines, connective tissue disease, portal hypertension, and congenital cardiac shunts.¹ Increased pulmonary vascular resistance (PVR) in PAH is associated with a progressively severe symptomatology of dyspnea, fatigue, chest pain, syncope, and right heart failure.

It is remarkable that extensive vascular remodelling in PAH has actually little effect on pulmonary gas exchange. Studies using the sophisticated multiple inert gas elimination technique have shown that the distribution of ventilation/perfusion (VA/Q) relationships in these patients is close to normal,^2,3 the low normal arterial PO₂ being essentially to be accounted for by a low-mixed venous PO₂, consequence of a low cardiac output.^2,3 In some patients, there is hypoxaemia because of a right-to-left shunt through a patent foramen ovale.³ In spite of vascular obliteration, physiological dead space remains normal, at rest as well as at exercise.⁴ Patients with PAH hyperventilate, accounting for a typically low arterial P_CO2, at rest as well as at exercise, but still do not present with a ventilatory limitation to exercise capacity.^5,6

Pulmonary arterial hypertension is associated with a decrease in exercise capacity and a low cardiac output. The maximum capacity of an individual to perform aerobic work is defined by the maximum O₂ consumption (VO_2max), the product of maximum cardiac output by the arterio-venous O₂ content difference (Ca_O2 – Cv_O2). Because of the sigmoid shape of the oxyhaemoglobin dissociation curve, with high affinities for O₂ at high and at low saturations, there is an inferior limit of Cv_O2 attained at the highest level of exercise. On the other hand, a VO_2max is achieved on a bicycle with about half of the body's muscles, and there is no data to suggest a skeletal muscle limitation to exercise capacity in cardiac or in pulmonary patients. It is therefore reasonable to assume that aerobic exercise capacity in PAH patients is essentially limited by cardiac output, or in case of exercise-induced hypoxaemia, by the product of cardiac output by Ca_O2.⁷ As there is a linear relationship between the running or walking speed and VO₂, a 12 min run⁸ or a 6 min walk⁹ distance can be used as a surrogate of VO_2max.⁷ Both the VO_2max and the 6 min walk distance reflect the ability of the RV to increase flow output in response to peripheral O₂ demand; exercise testing in PAH provides an indirect estimate of RV performance.

The gold standard for the evaluation of patients with PAH is a right heart catheterization with measurements of pulmonary vascular pressures and cardiac output, and calculation of PVR.¹ These measurements allow for the quantification of the severity of pulmonary vascular disease, but PVR provides only partial description of all the forces that oppose RV flow output (or afterload),¹⁰ and cardiac output is determined by loading conditions in addition to intrinsic changes in RV function.¹¹ It is therefore understandable that standard haemodynamic measurements in patients with PAH are only loosely correlated to clinical state, functional class, exercise capacity, and prognosis, and often fail to reach significance on mean PAP.^9,12–15 Measurements at exercise may provide more clinically meaningful results,¹⁶ probably because an exercise-induced increase in cardiac output may more closely reflect the functional capability of the afterloaded RV.

	Right ventricular failure in pulmonary hypertension

Top Abstract Cardiac limitation to exercise... Right ventricular failure in... Conclusions Acknowledgements References

 
Right ventricular (RV) afterload results from a dynamic interplay between resistance, elastance, and wave reflection.¹⁰ An acceptable measurement of RV afterload is given by pulmonary arterial input impedance (PVZ), which is the ratio of pulsatile PAP to pulsatile flow.¹⁰ The calculation of PVZ requires a spectral analysis of pressure and flow waves and a mathematical elaboration to derive a PVZ spectrum, which is expressed as a ratio of pressure and flow moduli and a phase angle, both as a function of frequency. The method has been applied to patients with PAH,^17,18 but is complicated, and requires expensive high-fidelity technology that is not available in most catheterization laboratories. The clinical relevance of PVZ determinations is unknown.

Right ventricular afterload can easily be evaluated by PAP and flow waveform analysis in the time domain. Increased pulmonary arterial elastance and wave reflection decrease the acceleration time, cause late or mid-systolic deceleration of pulmonary arterial flow waves, and increase pulse pressure and late systolic peaking of pulmonary arterial pressure waves.¹⁰ Shortened acceleration times of pulmonary arterial flow have been associated with decreased survival in a small series of PAH patients.¹⁹ Increased pulse pressure has been reported to help in the differential diagnosis between PAH and chronic thrombo-embolic pulmonary hypertension, whether pressures are directly measured during a right heart catheterization,²⁰ or re-calculated from tricuspid and pulmonary regurgitant waves and the simplified form of the Bernouilli equation.²¹ Refined indices of wave reflection such as the time to inflection point of the upstroke of RV pressure or the (peak pressure minus inflection point pressure) referred to mean PAP (called the ‘augmentation index’) may also be useful.²² However, discrepant results have been reported^22,23 and therefore the diagnostic value of pulmonary pressure waveform analysis remains uncertain.

Instead of trying to quantify the RV afterload by pulmonary pressure wave analysis, it might be more appropriate to quantify the RV function directly and to couple to the pulmonary circulation. Sunagawa et al.¹¹ showed that this can be done graphically using a ventricular pressure–volume diagram. The diagram allows for the determination of maximal or end-systolic ventricular elastance (E_es), which is the best possible load-independent measurement of contractility, of arterial elastance, E_a, as a measurement of afterload as it is ‘seen’ by the ventricle, and of the calculation of an E_es/E_a ratio as a measurement of the coupling of ventricular to arterial function. Complex mathematical modelling shows that the optimal matching of systolic ventricular and arterial elastances occurs at an E_es/E_a ratio of 1.5. Isolated increase in E_a, or decrease in E_es, decreases the E_es/E_a ratio, indicating uncoupling of the ventricle from its arterial system. Everything else being the same, a decrease in E_es/E_a is accompanied by a decrease in stroke volume. On the other hand, an isolated increase in preload is associated with an increase in stroke volume with unaltered ventriculo-arterial coupling.

However, the complex geometry of the RV makes functional evaluations with measurement of instantaneous volume changes technically difficult, and the determination of E_es may be unreliable because of the triangular shape of the RV pressure–volume loop resulting from the fact that RV ejection continues after end-systole. This problem can be overcome by measuring pressure–volume loops at several levels of preload,²⁴ but bedside manipulations of venous return are too invasive to be ethically acceptable. In addition, when applied to intact animals, changes in venous return are associated with reflex sympathetic nervous system activation, which affects the ventricular function that is measured. These concerns have been addressed by a most recently reported single-beat method allowing for a direct quantification of the coupling of the RV to the pulmonary circulation.²⁵ The approach had initially been proposed for the left ventricle by Sunagawa et al.²⁶ In its principle, the method avoids absolute volume measurements and related technical complexities, to calculate E_es and E_a from instantaneous RV pressure and flow output measurements. As shown in Figure 1, a P_max is estimated from a non-linear extrapolation of the early and late systolic isovolumic portions of the RV pressure curve. This estimated P_max has been shown to be tightly correlated with P_max directly measured during a non-ejecting beat.²⁵ A straight line drawn from P_max to the RV pressure vs. relative change in volume curve allows for the determination of E_es. A straight line drawn from the E_es point to the end-diastolic relative volume point allows for the determination of E_a.

View larger version (24K): [in this window] [in a new window] [Download PowerPoint slide]   Figure 1 Instantaneous measurements of right ventricular pressure and relative changes in volume in a dog, with calculation of a maximum ventricular pressure (Pmax) and graphical determinations of end-systolic elastance (Ees) and arterial elastance (Ea), leading to a ratio of elastances of 1.7. (Adapted from Brimioulle et al.25, with permission.)

 
The E_es/E_a ratio determined by the single-beat method is 1.5, which is similar to values reported for left ventricular-aortic coupling, and compatible with an optimal ratio of mechanical work to oxygen consumption.¹¹ The E_es/E_a ratio is decreased by propranolol and increased by dobutamine, and maintained in the presence of increased E_a because of hypoxic pulmonary vasoconstriction.²⁵ In fact, E_es increases adaptedly to increased E_a in hypoxia, even in the presence of adrenergic blockade, which is compatible with the notion of homeometric adaptation of RV contractility.²⁵ On the other hand, the approach allows for the demonstration that clinically relevant doses of dobutamine do not affect pulmonary arterial hydraulic load.^25,27 The single beat approach has also already been used to show the superiority of dobutamine over norepinephrine to restore right ventriculo-arterial coupling in acute right heart failure produced by a brisk increase in PAP.²⁷ Also, the optimal values for the E_es/E_a ratio were shown to be well maintained in piglets with PAH induced by 3 months systemic to pulmonary shunting, without or with endothelin receptor blocker therapy.²⁸ Furthermore, the method showed that, in contrary to the current belief,²⁹ prostacyclin iv has no intrinsic positive inotropic effects on the right ventricle.³⁰ The single-beat method was also applied to an asymptomatic patient with congenitally corrected transposition of the great arteries.³¹ The coupling between the native RV and the systemic arterial system was shown to be altered, with an E_es/E_a ratio down to 1.16, whereas the native LV was perfectly coupled to the pulmonary arterial system with an E_es/E_a of 1.67 (Figure 2). This observation suggested that an RV coupled to a high-pressure arterial system from birth is nevertheless chronically uncoupled, probably because of inherent structural characteristics, accounting for eventual clinical heart failure and decreased life expectancy.

View larger version (10K): [in this window] [in a new window] [Download PowerPoint slide]   Figure 2 Right ventricular-aortic artery and left ventricular-pulmonary artery coupling in a patient with congenitally corrected transposition. The ratio of elastances is decreased for the native right ventricle (Ees/Ea = 1.2) and normal for the native left ventricle (Ees/Ea, 1.7). (Adapted from Wauthy et al.31, with permission.)

 
Practically, all that is needed to determine single-beat E_es/E_a ratios is measurements of instantaneous pulmonary blood flow and RV pressure. This is feasible by echocardiography. Doppler pulmonary flow measurements synchronized to invasively measured PAPs have been reported to allow for accurate pulmonary arterial impedance calculations.¹⁸ Right ventricular pressure can be re-calculated from the envelope of tricuspid regurgitant jets and point-by-point application of the simplified form of the Bernouilli equation.³² However, the entirely non-invasive Doppler echocardiographic determination of E_es/E_a ratios in patients has not yet been validated. Most recently, Kuehne et al.³³ used magnetic resonance imaging together with RV pressure measurements to generate pressure–volume loops and to determine E_es and E_a values in patients with PAH. As compared with controls, RV E_es was increased from 5.2 ± 0.9 to 9.2 ± 1.2 mmHg/mL per 100 g (P < 0.05), but RV E_es/E_a was decreased from 1.9 ± 0.4 to 1.1 ± 0.3 (P < 0.05), indicating an increased RV contractility in response to increased afterload that was, however, insufficiently coupled to its hydraulic load, with inefficient mechanical work production (Figure 3). It will be interesting to correlate these findings to newly developed tissue Doppler indices of RV function.

View larger version (55K): [in this window] [in a new window] [Download PowerPoint slide]   Figure 3 Right ventricular pressure–volume loops showing in a patient with pulmonary arterial hypertension and in a control, showing uncoupling of the right ventricle in the patient in spite of an increased contractility. The figure also shows MRI imaging of the right ventricle. (Adapted from Kuehne et al.33, with permission.)

 

	Conclusions

Top Abstract Cardiac limitation to exercise... Right ventricular failure in... Conclusions Acknowledgements References

 
A most recent report of a National Heart, Lung and Blood Institute Working Group on Cellular and Molecular Mechanisms of Right Heart Failure identified a series of markers of RV dysfunction associated with clinical status and prognosis.³⁴ The list included both load- and contractility-sensitive RV function measurements such as ejection fraction, tricuspid annular velocity or excursion, dP/dt, tricuspid regurgitation, and the index of performance (calculated as the sum of isovolumetric contraction and relaxation times divided by stroke volume), right heart chamber dimension measurements, which are determined by both systolic and diastolic function changes at given levels of load, circulating biomarkers such as brain natriuretic peptide, which are released by myocardial stretch, and even heart rate variability which is affected by neurohumoral activation in (right) heart failure. However, there was a mention of pressure–volume or pressure–area loops, much closer to intrinsic RV function and its adaptation to loading conditions, and the report evoked the interest of tissue Doppler imaging. The importance of the RV ventricle in cardiovascular diseases was underscored, and there was a call for more translational cellular and molecular research with improved definition of parameters of function.³⁴

Symptoms of pulmonary hypertension are predominantly caused by RV dysfunction. The evaluation of pulmonary hypertension by the steady flow haemodynamic approach and a calculation of PVR is essential to the accurate measurement of resistive vessel obstruction, but does not accurately explain the RV's adaptation to an associated increase in afterload. This can be accomplished using newer non-invasive methods, methods needing urgent validation.

	Acknowledgements

Top Abstract Cardiac limitation to exercise... Right ventricular failure in... Conclusions Acknowledgements References

 
The work was supported by Grant no. 3.4551.05 from the Fonds de la Recherche Scientifique Médicale and by the Foundation for Cardiac Surgery. S.H. is a fellow of the Fonds National de la Recherche Scientifique, Belgium.

Conflict of interest: none declared.

	References

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This Article Abstract FREE Full Text (PDF) E-letters: Submit a response Alert me when this article is cited Alert me when E-letters are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Add to My Personal Archive Download to citation manager Disclaimer Request Permissions Google Scholar Articles by Naeije, R. Articles by Huez, S. Search for Related Content PubMed Articles by Naeije, R. Articles by Huez, S. Social Bookmarking          What's this?

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