Comprehensive Invasive and Noninvasive Approach to the Right Ventricle–Pulmonary Circulation Unit
2009; Lippincott Williams & Wilkins; Volume: 120; Issue: 11 Linguagem: Inglês
10.1161/circulationaha.106.674028
ISSN1524-4539
AutoresHunter C. Champion, Evangelos D. Michelakis, Paul M. Hassoun,
Tópico(s)Cardiovascular Function and Risk Factors
ResumoHomeCirculationVol. 120, No. 11Comprehensive Invasive and Noninvasive Approach to the Right Ventricle–Pulmonary Circulation Unit Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBComprehensive Invasive and Noninvasive Approach to the Right Ventricle–Pulmonary Circulation UnitState of the Art and Clinical and Research Implications Hunter C. Champion, Evangelos D. Michelakis and Paul M. Hassoun Hunter C. ChampionHunter C. Champion From the Pulmonary Vascular Disease Center, Department of Medicine, University of Pittsburgh Medical Center, Pa (H.C.C.); Pulmonary Hypertension Program and Division of Pulmonary and Critical Care Medicine (P.M.H.), Johns Hopkins Medical Institutions, Baltimore, Md; Pulmonary Hypertension Program, Department of Medicine (Cardiology), University of Alberta, Alberta, Edmonton, Canada (E.D.M.); and Pulmonary Vascular Research Institute, Chicago, Ill (H.C.C., E.D.M., P.M.H.). , Evangelos D. MichelakisEvangelos D. Michelakis From the Pulmonary Vascular Disease Center, Department of Medicine, University of Pittsburgh Medical Center, Pa (H.C.C.); Pulmonary Hypertension Program and Division of Pulmonary and Critical Care Medicine (P.M.H.), Johns Hopkins Medical Institutions, Baltimore, Md; Pulmonary Hypertension Program, Department of Medicine (Cardiology), University of Alberta, Alberta, Edmonton, Canada (E.D.M.); and Pulmonary Vascular Research Institute, Chicago, Ill (H.C.C., E.D.M., P.M.H.). and Paul M. HassounPaul M. Hassoun From the Pulmonary Vascular Disease Center, Department of Medicine, University of Pittsburgh Medical Center, Pa (H.C.C.); Pulmonary Hypertension Program and Division of Pulmonary and Critical Care Medicine (P.M.H.), Johns Hopkins Medical Institutions, Baltimore, Md; Pulmonary Hypertension Program, Department of Medicine (Cardiology), University of Alberta, Alberta, Edmonton, Canada (E.D.M.); and Pulmonary Vascular Research Institute, Chicago, Ill (H.C.C., E.D.M., P.M.H.). Originally published15 Sep 2009https://doi.org/10.1161/CIRCULATIONAHA.106.674028Circulation. 2009;120:992–1007… And I ask, as the lungs are so close at hand, and in continual motion, and the vessel that supplies them is of such dimensions, what is the use or meaning of this pulse of the right ventricle? And why was nature reduced to the necessity of adding another ventricle for the sole purpose of nourishing the lungs?— —William Harvey, Exercitatio Anatomica de Motu Cordis et Sanguinis in Animalibus, 1628There is still no answer to William Harvey's rhetorical question. He included the right ventricle (RV), its "pulse," the large pulmonary arteries (PAs), and the lungs in the same sentence, emphasizing the concept of a "unit." Although Harvey realized the importance of the RV and its interactions with the pulmonary circulation, 4 centuries later, the RV is largely understudied. At the same time, there has been significant progress in our understanding of the pathology of pulmonary vascular disease and, over the past few years, an explosion of clinical therapeutic trials for PA hypertension (PAH).1 This unbalanced approach has generated a number of problems and controversies. For example, it is now becoming apparent that even if experimental therapies improve or reverse PAH pathology, this does not necessarily lead to clinical improvement and prolonged survival unless accompanied by a parallel improvement in RV function. The degree of pulmonary hypertension (ie, PA pressure [PAP]) does not strongly correlate with symptoms or survival, whereas RV mass and size and right atrial pressure reflect functional status and are strong predictors of survival.2 The 6-minute walk test, used as the primary end point in most PAH clinical trials, correlates better with RV function (ie, cardiac output) than with the degree of pulmonary pressure elevation. However, this test is being heavily criticized because of multiple inherent problems and the fact that it does not provide information on specific components of RV–pulmonary vascular function.3 Although therapies aiming at reversing pulmonary vascular remodeling might also have a positive effect on the RV (eg, sildenafil, which has been shown to increase RV inotropy4 and decrease RV hypertrophy,5 in addition to its effects on the pulmonary circulation), others might have untoward effects on the RV. For example, imatinib, an antiproliferative/proapoptotic agent that shows preliminary promise in reversing pulmonary vascular remodeling,6 is potentially associated with primary negative (ie, proapoptotic) effects on the myocardium.7As our knowledge of RV physiology and biology increases, it is becoming apparent that a comprehensive approach to the RV, the pulmonary circulation, and their interactions will be beneficial in both clinical management of PAH patients and clinical research. The evolution of RV pathology from the normal to a compensated (hypertrophied) and then decompensated state parallels the evolution of pulmonary vascular pathology from a vasodilated high-capacitance state to vasoconstricted arteries and early loss of endothelial cells/capillaries to an end-stage proliferative and obliterative vascular remodeling (Figure 1). Therefore, it is important to study the RV and the PAs comprehensively and simultaneously as a unit. Here, we discuss standard clinical tests (eg, right heart catheterization and echocardiography) and evolving technologies (eg, magnetic resonance [MR] imaging [MRI] and positron emission tomography [PET]) that have the ability to study the RV–proximal PAs–PA microcirculation unit comprehensively and provide quantitative data. Such data promise to be very relevant to the clinical management of PAH patients and might prove to be ideal end points for future clinical research. Download figureDownload PowerPointFigure 1. Schematic showing the theoretical progression of pulmonary vascular disease and the subsequent effect on RV function from normal physiological conditions (top) to severe pulmonary vascular remodeling and subsequent RV failure (bottom). Note that in the compensated state clinical studies as currently used might miss the disease because in that stage cardiac output (CO) is preserved (ie, no symptoms) and the hemodynamics are minimally if at all affected. In contrast, accurate measurements of the RV mass, PA stiffness, or lung perfusion, as discussed in this review, might clearly identify this stage of disease.Hemodynamic Assessment of RV Function and Ventricular-Vascular InteractionsStandard Hemodynamic ApproachesCardiac catheterization remains the gold standard for diagnosing pulmonary hypertension, assessing disease severity, and determining prognosis and response to therapy. By directly measuring pressures and indirectly measuring flow, right heart catheterization allows determination of prognostic markers such as right atrial pressure, cardiac output, and mean PAP.8 Importantly, this procedure has been shown to be safe, with no deaths reported in the National Institutes of Health registry study8 and a recent study showing a procedure-related mortality of 0.055%.9 Right heart catheterization determines the presence or absence of pulmonary hypertension, may allow definition of the underlying cause, and allows prognostication. The most critical aspect to right heart catheterization is that it should be performed appropriately and the data interpreted with accuracy and precision. Because the end-expiratory intrathoracic pressure most closely correlates with atmospheric pressure, it is important that all RV, PA, pulmonary wedge, and left ventricular (LV) pressures be measured at end expiration.10–12 This is especially true in patients in whom there can be significant variation between inspiratory and end-expiratory vascular pressures (obese patients and patients with intrinsic lung disease). After determination of the presence of pulmonary hypertension, pulmonary venous pressures should be evaluated by the pulmonary capillary wedge pressure (PCWP). PAH is defined by a PCWP of ≤15 mm Hg at rest or with exertion to exclude LV dysfunction, mitral valve disease, or other conditions of pulmonary venous hypertension.12,13 This value was based on the normal PCWP or LV end-diastolic pressure of 15 mm Hg in response to exercise or fluid challenge suggests the presence of pulmonary venous hypertension (Figure 2), a condition with dramatically different management than PAH. Because cardiac output can increase up to 5 times baseline, pulmonary vascular resistance (PVR) normally decreases with exercise (Figure 2).17,18 Poor prognostic signs in exercise right heart catheterization are the inability of the RV to augment in response to exercise (ie, lack of a significant increase in cardiac output), failure to reduce PVR with exercise, angina, and presyncopal symptoms or frank syncope. Download figureDownload PowerPointFigure 2. Confrontational assessment of cardiopulmonary function by exercise and fluid challenge during right heart catheterization. Top, Johns Hopkins University protocol for exercise right heart catheterization and fluid challenge and an example of the results of an exercise challenge in a patient with nonsystolic heart failure (heart failure with preserved ejection fraction, diastolic dysfunction) in which the patient's baseline mean PAP is borderline elevated and PCWP is elevated at 12 mm Hg. With exercise, the PCWP increased significantly to 25 mm Hg with a concomitant increase in mean PAP that resulted from the elevated PCWP. Bottom, The Johns Hopkins University protocol for fluid challenge and an example of data from a patient with pulmonary hypertension and nonsystolic heart failure. At baseline, PAP was elevated (29 mm Hg), as was PCWP (12 mm Hg; note that measures are appropriately measured at end expiration). With fluid challenge, PCWP increased to 22 mm Hg, thus confirming the diagnosis of nonsystolic heart failure. CO indicates cardiac output.Novel Hemodynamic TechniquesPA Wave Reflection as a Component of RV Load and Measurement of PA Input ImpedanceChronic pulmonary hypertension results from an increase in PVR, which is a simple measure of the opposition to the mean component of flow. However, given the low-resistance/ high-compliance nature of the pulmonary circulation, the pulsatile component of hydraulic load is also critical to consider. The fact that the mean and the pulsatile components of flow are dependent on different portions of the pulmonary circulation suggests that they could be controlled separately without much overlap. The pulmonary circulation is pulsatile with multiple bifurcations, and wave reflection is an inevitable consequence. When the forward pressure wave from the heart collides with the backward pressure wave that was reflected from the bifurcations, pressure increases and flow decreases. Because the often-used PVR takes only mean flow into account, it does not allow for changes in pulsatility of the pulmonary circuit (Figure 3).20–23 One must consider the elastic properties of the pulmonary circulation/left atrium and impedance on RV performance rather than the pure resistive properties because the heart could not function if it were not for the elastic properties of pulmonary vasculature. During systole, the pulmonic valve is open at a time when the mitral valve is closed. Thus, if it were not for the elastic properties of the pulmonary vasculature, the heart could not develop forward flow.21–23Download figureDownload PowerPointFigure 3. Assessment of pulmonary circulation-RV interactions using impedance analysis and augmentation index. A, Outline of technique used to measure simultaneous PAP and flow to compute PA input impedance. B, Schematic highlighting key features of summary impedance spectra. Impedance, the opposition to blood flow by the pulmonary circulation, is frequency dependent on and modulated by heart rate, vessel dimensions, vessel stiffness, and wave reflections. Z0 is total resistance that does not take into account frequency and represents total PVR. C, Sample impedance spectra from a patient with normal pulmonary circulation (dashed line) showing a baseline Z0 (PVR) and frequency of first minimal impedance modulus (pulse-wave velocity [PWV]) of ≈2 to 3 Hz. Solid line shows impedance spectra from a patient with severe pulmonary vascular disease and RV dysfunction in which Z0 is elevated and there is significant delay in Z1, indicating poor RV-pulmonary circulation coupling. In addition, the patient with pulmonary vascular disease displays a significant shift in the frequency of first minimal harmonic and in elevated characteristic impedance, suggesting increased large-vessel stiffness. D, Measurement of augmentation index using PA tracing (time-domain analysis). An increase in augmentation index suggests increased wave reflection in the pulmonary circulation. sPAP indicates systolic pulmonary arterial pressure; Pi, input pressure; PAPP, pulmonary arterial pulse pressure.Frequency-Domain Analysis of the Pulmonary Circulation: PA Input ImpedanceThe concept of the RV-pulmonary circulation operating as a unit is best demonstrated by the change in hydraulic load that occurs in the setting of PA stiffening and is an early and important component of the vascular remodeling in PAH. As the RV is met with increased hydraulic wave reflection (largely from increased pulmonary stiffness, resulting in decreased pulsatility) in the diseased pulmonary vasculature, its workload is greater to maintain forward flow. Impedance is a measure of the opposition to the pulsatile components of flow. RV afterload is usually considered in terms of PVR. Yet, between one third and one half of the hydraulic power in the main PA is contained in the pulsatile components of flow. Therefore, measurement of arterial input impedance is needed to obtain a complete description of ventricular afterload. It is also likely that "early" or more severe pulmonary hypertension is missed simply because this contribution to the load on the RV is not accounted for in the mean PAP measurement at the time of right heart catheterization. Research in pulmonary vascular disease has so far focused essentially on the small PAs, which appear to be the main site of resistance. Impedance is dependent primarily on the mechanical properties and the geometry of the proximal PAs. The PA input impedance spectrum is dependent primarily on the first 5 orders of bifurcation from the main PA in decreasing levels of importance and lends credence to the idea that the "total resistance" does not lie solely at the level of arterioles that are <250 μmol/L in diameter.21–24 The changes in impedance resulting from large-artery stiffening or remodeling alone can markedly alter the load on the RV. Interestingly, this can occur in the absence of a change in PVR. Moreover, congenital cardiac disease with or without surgical correction (especially in repaired tetralogy of Fallot with transannular patch) can significantly increase the pulsatility of the PA waveform. Moreover, with the pulmonic valvular insufficiency that often accompanies congenital disease, there is an increased diastolic volume/load exerted on the RV. With diseases such as scleroderma-related PAH and idiopathic PAH (IPAH), both large-artery and small-artery remodeling occurs, which increases resistance and impedance. However, it is more likely that large-artery involvement (as seen in scleroderma-related PAH or cardiovascular aging) plays a more significant role compared with IPAH in increasing impedance. This abnormal pulsatile load may have detrimental effects on ventricular-vascular coupling by increasing the pulsatile part of ventricular power and thus unfavorably loading the still-ejecting RV.Several studies have documented the relationship between pulsatile pressure and flow (pulmonary input impedance; Figure 3).21,23,25–27 The first assessment of pulmonary vascular impedance dates back to 1961, shortly after impedance was first described in the systemic vascular bed.21,23,28 However, given the previous technical challenges in obtaining impedance spectra, its use has largely been relegated to the laboratory and reported in a few relatively small clinical trials. Only recently have we been able to measure PA input impedance routinely as a result of the ability to measure PA blood flow and PAP simultaneously with high-fidelity catheters at the time of routine right heart catheterization, adding only 5 to 10 minutes to each case.20,29 These measurements of simultaneous pressure and flow are then used to calculate the arterial input impedance spectra and have been greatly facilitated by software that can accomplish this task quickly, although the software is not currently commercially available (eg, Matlab-based custom software). This calculation of impedance allows a more accurate quantification of RV hydraulic load from a spectral analysis of pressure and flow waves. The results of this analysis are expressed as an impedance spectrum, consisting of a pressure-to-flow ratio and a phase angle, both of which are expressed as a function of frequency. As shown in Figure 4B, the impedance spectrum includes a measure of total PVR; indexes of wave reflection such as the first minimum of the ratio of pressure and flow moduli or low-frequency phase angle; characteristic impedance (Zc), which corresponds to the ratio of inertance to compliance; and hydraulic load, as evaluated by low-frequency impedance and the amplitude of impedance oscillations. Prior studies have shown that the pulsatile load is also increased in chronic pulmonary hypertension, as suggested by the increased characteristic impedance and enhanced wave reflection that have generally been attributed to decreased PA compliance and complex changes in reflection sites. Moreover, pulmonary vascular impedance has been studied in the pediatric population, in which it was found to predict outcomes better than PVR.30 Impedance, in combination with compliance and resistance, has been studied with MR technology, which has shown that these techniques may differentiate between types of pulmonary hypertension.31 Finally, echocardiographic measurements of pulmonary vascular impedance have recently been shown to be feasible.20 It is hoped that the study of pulmonary vascular impedance will yield important information about the RV response to stress in pulmonary hypertension and may prove to be a more predictive measure of prognosis and response to treatment than current standards. Download figureDownload PowerPointFigure 4. RV PV loop relationship analysis in patients with pulmonary vascular disease. A, Outline of technique used to measure simultaneous RV pressure and volume. B, Sketch of placement of conductance catheter (Millar Instruments, Houston, Tex) in the RV to obtain PV data. C, Schematic of basic measures of pressure and volume relationships. The end-systolic PV loop relationship (ESPVR) and end-diastolic PV loop relationships (EDPVR) define the boundaries of the PV loops for a given contractile state of the ventricle. Changing the preload (as shown with dashed lines) or afterload will change the shape and position of the loops, but the end-systolic and end-diastolic points will always fall on the ESPVR and EDPVR. This is the reason why the ESPVR and EDPVR are used as load-independent measures of contractility. The ratio of end-systolic pressure (Pes) to stroke volume has the dimension of elastance (mm Hg/mL) and is called the arterial elastance (Ea) because it is linked to the afterload, which is determined by the arterial system and is represented in the PV loop by the slope of the line that links Pes and end-diastolic volume. D, Representative tracings of RV PV loops in borderline PAH with preserved ESPVR and stroke volume (left) and late PAH with higher RV end-diastolic pressure, end-diastolic volume, and RV end-systolic pressure with a lower stroke volume and decreased contractility (shifted ESPVR to the right).Time-Domain Analysis of PA Pressure WaveformsAlthough we believe that the measurement of pulmonary vascular impedance may, in the future, become a routine test in patients with PAH, the technology and necessary equipment may currently limit its widespread use outside tertiary care academic centers.32 Time-domain analysis of pulse pressure and pressure waveform may provide valuable information on pulsatile arterial load and may be a surrogate to the full assessment of RV input impedance (Figure 3).32 Pulse pressure indicates the amplitude of pulsatile stress. Pulse pressure is determined mainly by both the characteristics of ventricular ejection and arterial compliance; the lower the compliance is, the higher the pulse pressure is. Moreover, pressure waveform analysis performed in the time domain makes it possible to calculate the timing and extent of wave reflection in systemic and pulmonary circulation with measures such as augmentation index (as shown in Figure 3D), which roughly represents reflected wave summation (ΔP) in the pulmonary circuit and normalizes for the PA pulse pressure.32–40 These values can be obtained easily at the time of right heart catheterization, and future studies will compare both analyses as potential prognostic indicators in patients with pulmonary hypertension and correlate with the previously described concept of capacitance.41RV Pressure-Volume Loop RelationsThe use of pressure-volume (PV) loop analysis as a means of measuring load-independent contractility has largely been restricted to the study of LV hemodynamics and the interaction between the LV and the systemic vasculature.27,38,42–52 This has been due primarily to geometric differences between the 2 ventricles, the optimal conductance properties required for proper volume measurements, and the belief that it is difficult to obtain consistent data with conductance measurements in the crescent-shaped RV. Indeed, under conditions of normal PAP and RV function, RV PV loop analysis is somewhat complicated given the crescent shape of the normal RV (Figure 1) and the ellipsoid shape of the PV loop obtained under these conditions. However, under conditions of even only modestly increased load, the RV shape changes to one resembling the more spherical LV, allowing measurement of end-systolic elastance and effective arterial elastance, as well as the more accurate measurements of indexes of RV systolic and diastolic function and RV/PA coupling (Figure 4). As shown in Figure 4, the performance of such studies is relatively easy and can be made in the same acquisition time as measurements of impedance spectra with Food and Drug Administration–approved equipment. Because essentially all of the currently used PAH therapies (particularly prostaglandin analogs,53 phosphodiesterase inhibitors,4,54–57 and endothelin receptor antagonists58–60) and many of the emerging experimental therapies (eg, imatinib) have primary effects on the myocardium (whether positive or negative), a study of the intrinsic contractility of the RV is perhaps the only reliable way to separate the effects of these therapies on the PAs from those on the RV myocardium. In that sense, studies of RV contractility are not only relevant to the clinical management of PAH patients but also critical for the interpretation of the clinical trial data. Moreover, many of the measurements taken with conductance catheterization can be reproduced using measures of RV pressures and cardiac output/stroke volume by right heart catheterization and ventricular volumes as measured by echocardiography, CT, or MRI using standard equations.EchocardiographyStandard Echocardiographic ApproachesEstimating Pulmonary Pressures and ResistanceDoppler echocardiography is the most commonly used screening modality for the assessment of RV structure and function, and it allows exclusion of valvular, primary myocardial, and congenital causes of increased right heart pressures. The tricuspid regurgitant jet is generally used to estimate RV systolic pressure via the Bernoulli equation (4v2, where v is the maximum velocity of the tricuspid valve regurgitant jet; Figure 5). An estimated right atrial pressure (based on collapsibility of the inferior vena cava best visualized in the subcostal window61) is added to the peak systolic pressure gradient of the tricuspid regurgitant flow to obtain RV systolic pressure (which approximates PA systolic pressure in the absence of pulmonary valve stenosis and RV outflow tract obstruction). Although mean PAP can be estimated by measuring the early diastolic velocity of the pulmonary insufficiency jet, the correlation with invasive measures is weak because of difficulty in accurately visualizing the velocity regurgitant profile at the pulmonary valve. More recently, formulas for estimating mean PAP from the RV systolic pressure have been developed.62,63 In addition, Doppler echocardiography allows noninvasive estimation of PVR, measured as the ratio of the tricuspid regurgitant velocity to the velocity-time interval of the RV outflow tract. The ratio of tricuspid regurgitant velocity to the velocity-time interval of the RV outflow tract has recently been shown to predict mortality and adverse cardiovascular events in patients with stable coronary artery disease,64 but its usefulness in patients with pulmonary vascular disease65 remains to be determined. Download figureDownload PowerPointFigure 5. Use of echocardiography in assessing pulmonary hypertension. Top, Representative images of echocardiograph 2-dimensional imaging and Doppler assessments in PAH. Note the septum shift toward the LV from RV pressure overload, resulting in a decrease in LV volume and perhaps a secondary increase in LV filling pressures. Middle, The standard tricuspid regurgitation velocity method currently used to estimate systolic PAP (see text) using continuous-wave Doppler. Bottom, Pulsed-wave Doppler interrogation of the main PA to measure PAAT (the time from the start of the envelope to its peak) in patients with severe PAH (left) and no PAH (right). In pulmonary hypertension, the peak velocity of the Doppler envelope decreases and the time to peak velocity (measured from the onset of flow) or PAAT shortens. In severe pulmonary hypertension, there may be "notching" or early systolic deceleration, which, like the premature partial closure of the pulmonic valve on M mode, reflects reflection of velocity waves and cancellation by reverse flow. EDV indicates end-diastolic volume; ESV, end-systolic volume; EF, ejection fraction; TAPSE, tricuspid annular plane systolic excursion; RA, right atrium; and RVD, RV dimension.Initial studies by Berger et al66 and Currie et al67 demonstrated good correlation between echocardiographic estimates and directly measured pressures. However, there are conflicting data as to the strength of this correlation between RV systolic pressure estimated by Doppler echocardiography and mean PAP measured via right heart catheterization. When RV and PAPs are estimated via ec
Referência(s)