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Abstract

The importance of the right ventricle (RV) in pulmonary arterial hypertension (PAH) has been gaining increased recognition. This has included a reconceptualization of the RV as part of an RV–pulmonary circulation interrelated unit and the observation that RV function is a major determinant of prognosis in PAH. Noninvasive imaging of RV size and function is critical to the longitudinal management of patients with PAH, and continued understanding of the pathophysiology of pulmonary vascular disease relies on the response of the RV to pulmonary vascular remodeling. Echocardiography, in particular the newer echocardiographic measurements and techniques, allows easy, readily accessible means to assess and follow RV size and function.

Keywords

imaging three-dimensional echocardiography tricuspid annular plane systolic excursion right heart failure right ventricular function

Pulmonary arterial hypertension (PAH) is characterized by severe remodeling of distal pulmonary arterioles due to a complex interplay between genetic and molecular factors.^1,2 This remodeling is characterized by intimal hyperplasia, vasoconstriction, medial hypertrophy, and the development of plexiform lesions, all of which contribute to and result in higher pulmonary artery pressure. The prevalence of PAH is 7–15 individuals per million people.^3,4 A diagnosis of PAH is initially suggested by symptoms including dyspnea, syncope, and exertional intolerance and is usually evaluated first with echocardiography.⁵ Echocardiography may suggest elevated pulmonary artery pressures (PAPs) and help formulate a working hypothesis regarding the etiology of the presumed pulmonary hypertension (PH), but right heart catheterization remains essential to provide final hemodynamic classification of PH and, with that knowledge in hand, to guide appropriate World Health Organization (WHO) PH group–specific therapy.⁶ Once the diagnosis of PAH is established (mean PAP ≥ 25 mmHg and pulmonary capillary wedge pressure ≤ 15 mmHg), most clinicians rely on a combination of frequent clinical evaluations and echocardiography to follow therapeutic response and to give insight into the effects of elevated PAP on the structure and function of the right ventricle (RV). The right ventricle's adaptation or maladaptation to the increased afterload is often a sign of the severity of PH.⁷

The relevance of the relationship between the RV and the pulmonary circulation in PAH has been gaining increased recognition.⁸ As a pump, the RV generates the same stroke volume as the left ventricle (LV) with one-fourth the stroke work because of the lower resistance of the normal pulmonary vasculature.⁹ The RV is thin walled, with the free wall measuring 2–5 mm, and contains one-sixth the muscle mass of the LV.⁹ It is a crescent-shaped chamber with a high capacitance and a greater ability to handle changes in preload than in afterload. When chronically exposed to increased afterload, the RV can adapt with myocardial hypertrophy, since increase in wall pressure leads to increase in wall stress that, by way of LaPlace's law, can be tempered by increased wall thickness. However, maladaptive changes can subsequently occur that lead to RV dilation and a decreased contractility.⁷ Concomitant with the pressure burden, metabolic shifts, neurohormonal signal alterations, ischemia, oxidative stress, and inflammation have been proposed to adversely affect the RV in PAH and may play a role in the development of RV dysfunction.¹⁰ Ultimately, RV remodeling and RV dysfunction have been associated with a poor prognosis, and RV failure is a leading cause of death in PAH.^10,11

With the advances made in echocardiographic techniques, in particular 3-dimensional (3D) echocardiography and speckle-tracking right ventricular (RV) strain, RV imaging by transthoracic echocardiography (TTE) has improved considerably, enabling the acquisition of accurate assessment of RV function. Echocardiography is also more affordable for serial testing and more universally available than more advanced cardiac imaging tests such as cardiac magnetic resonance imaging (MRI) and positron emission tomography. In this review of using echocardiography to follow the RV in the setting of PAH, we outline the ability of Doppler, 2-dimensional (2D), and 3D echocardiography to assess RV structure and function, and we propose that echocardiography will remain the mainstay in the evaluation of the RV in PAH throughout patient management in developed and developing countries.

THE ROLE OF ECHOCARDIOGRAPHY IN THE DIAGNOSIS OF PAH

Doppler echocardiography represents the most accessible screening tool for PAH^12–14 with an estimation of the RV systolic pressure (RVSP). The RVSP is calculated from Bernoulli's principle on the basis of the velocity of the tricuspid regurgitant (TR) jet (4ν², where ν is the maximum velocity of the tricuspid valve regurgitant jet, plus the estimated right atrial [RA] pressure). Recognizing that the RVSP measurement is only an estimate and subject to error,¹⁵ the measurement should be interpreted in context of the information on the echocardiogram as a whole. In a meta-analysis, Janda and colleagues¹⁶ showed only modest sensitivity and specificity for the use of peak TR jet velocities to estimate the RVSP, in combination with RA pressures, to diagnose PH (sensitivity of 83% and specificity of 72%). In addition, Rich and colleagues¹⁵ have shown the tendency for misclassification of pressures by TR jet velocity with both underestimation and overestimation of pulmonary artery systolic pressures.

On the other hand, even when the estimated RVSP is normal, other echocardiographic parameters may suggest RV dysfunction, which ultimately may be related to undiagnosed PAH (Table 1). No significant tricuspid regurgitation (TR) or low/normal estimated RVSP has been noted in 10%–25% of patients with PH, as the TR Doppler profile may be insufficient to measure.^6,17 Thus, specific evaluation for evidence of RV dysfunction is of paramount importance if there is clinical suspicion of PH and should prompt the clinician to pursue further clinical workup.

Table 1.

Right ventricular structural echocardiography parameters

Parameter	Echo view	Normal value
2D RV measurements
RV basal diameter, mm	RV focused apical 4CH	<41
RV midcavity diameter, mm	RV focused apical 4CH	<35
RV base-apex RV longitudinal diameter, mm	RV focused apical 4CH	≤83
Indexed RV end-diastolic area in men, cm²/m²	RV focused apical 4CH	≤12.6
Indexed RV end-diastolic area in women, cm²/m²	RV focused apical 4CH	≤11.5
RVOT proximal, mm	Parasternal short axis	≤35
RVOT distal, mm	Parasternal short axis	≤27
RVOT wall thickness, mm	Parasternal long or subcostal	≤5
3D RV measurements
Indexed RV end-diastolic volume in men, mL/m²		≤87
Indexed RV end-diastolic volume in women, mL/m²		≤74
RV EF, %		≥45
2D RA dimensions
Indexed RA volume in men, mL/m²	Apical 4CH	25 ± 7
Indexed RA volume in women, mL/m²	Apical 4CH	21 ± 6

Note: EF: ejection fraction; RA: right atrial; RV: right ventricular; RVOT: RV outflow tract; 2D: 2-dimensional; 3D: 3-dimensional; 4CH: 4-chamber. The 2D RV normal values, 2D RA normal values, and 3D normal volumes are from American Society of Echocardiography guidelines.³³

THE RELATIONSHIP BETWEEN THE RV AND PROGNOSIS IN PAH

Many echocardiographic RV parameters have been shown to be key determinants in the prognosis in PAH¹⁰ as the RV adapts to the elevated pulmonary vascular resistance (PVR), with poor adaptation significantly contributing to mortality.^18,19 Parameters that have correlated with an increased mortality risk in PAH include evidence of right-sided pressure overload with secondary abnormal RV systolic and diastolic function, the presence of pericardial effusion, increased RA area indexed to height, increased RV diameter, decreased tricuspid annular plane systolic excursion (TAPSE), decreased Tei index, alterations in RV free-wall strain, and decreased isovolumic contraction velocity (IVCv).^20–29 These are reflective of increasing RV and RA size and decreased RV contractility. A thorough discussion of how to obtain these parameters and the limitations of each one are outlined below.

Interestingly, the presence of a mild-to-moderate pericardial effusion has also long been associated with chronic severe PAH³⁰ and has consistently been shown to correlate with increased mortality.^20–23 The development of a pericardial effusion in PAH is proposed to be the result of high RA pressures from RV dysfunction. This subsequently inhibits lymphatic drainage via the thoracic duct and may increase in proportion to the elevated RA pressure.

ASSESSMENT OF RV STRUCTURE

The differences between the RV and the LV include structural, embryological, genetic, and neurohormonal responses.^9,31,32 Structurally, the healthy RV is an anterior, thin-walled, trabeculated, crescent-shaped structure with a complex geometry that wraps around the ellipsoid LV and has been delineated anatomically into the inlet, the trabeculated apex, and the infundibulum. The RV contracts in a peristolic (“bellows”) motion,⁹ which is the result of contraction from predominantly longitudinal muscle fibers. The structure and orientation of the RV in the anterior chest, as well as its unique shape, have made it challenging to fully characterize the RV by 2D echocardiography. The RV sits close to the anterior chest wall and may be subject to poorer near-field resolution, and there is no one echocardiographic view that is able to completely visualize the whole of the RV. Thus, different probe orientations are used to assess the RV in piecemeal fashion, including the parasternal long- and short-axis views, the RV inflow view, the apical 4-chamber view, and the subcostal views (Fig. 1).³³

Figure 1.

Segmental anatomy of the right ventricle (RV), as shown in representative echocardiographic views. The colors indicate the different subdivisions of the interventricular septum. AO: aorta; LA: left atrium; LV: left ventricle; RA: right atrium; RVOT: right ventricular outflow tract. Adapted from Jiang³⁴ with permission from the publisher (copyright 1994, Lippincott Williams & Wilkins).

Figure 1 summarizes the segmental anatomy of the RV in different echocardiographic views.³⁴ To assess RV size and volume, the American Society of Echocardiography proposes the use of standard 2D size measurements from parasternal short-axis and apical 4-chamber views of the heart (Figs. 2, 3).³³ However, these measurements correlate poorly with 3D volumes obtained with echocardiography and are highly dependent on probe and patient positions^35,36 and therefore have been the subject of criticism of the true assessment of RV size.³⁷ Use of 2D methods, such as Simpson's method of disks, underestimates volumes of the RV because of the crescentic shape of the RV.³⁸ The size and shape of the RV are also intrinsically linked to those of the LV, and visual estimation of RV size is often made relative to that of the LV.⁸ However, qualitative measurements of the RV size and function have wide interobserver variability, compared with quantitative assessment.³⁹

Figure 2.

Examples of 2-dimensional echocardiographic chamber dimensions and RV wall thickness. A, Parasternal long-axis view and the proximal RVOT diameter. B, Basal parasternal short-axis view and the proximal RVOT diameter. C, Parasternal short-axis view of the pulmonary bifurcation and the main PA measurement. The RVOT distal measurement is made in this view just above the pulmonary valve. D, Right atrial volume in the apical 4-chamber view in end-systole when the RA has the largest area. E, RV wall thickness, measured in the subcostal view at end-diastole. PA: pulmonary artery; RA: right atrium; RV: right ventricular; RVOT: RV outflow tract.

Figure 3.

RV dimension and area measurements in the apical 4-chamber view. A, Basal, midcavity, and longitudinal RV dimensions. B, The upper panel shows an RV with normal systolic function and a normal FAC. The lower panel shows a markedly dilated RV with decreased function and an abnormal FAC. The calculation of percentage FAC is [(area at ED – area at ES)/area at ED)] × 100. ED: end-diastole; ES: end-systole; FAC: fractional area change; RV: right ventricle.

Over time in PAH, with the associated chronic afterload elevation, the RV dilates. This is noted when an end-diastolic RV area approximates or is greater than that of the LV in the apical 4-chamber view (Fig. 4A, 4B). Ghio and colleagues²⁶ showed that patients with an RV end-diastolic diameter greater than 36.5 mm, measured on the parasternal long-axis view, had a higher mortality than patients with an RV end-diastolic diameter of up to 36.5 mm, with a hazard ratio of 2.64. Similarly, increased RA area indexed to height, a reflection of high atrial pressures, has been shown to predict increased mortality.^20,40

Figure 4.

Two-dimensional echocardiography of RV and LV size and ventricular interdependence. A, Apical 4-chamber view showing an enlarged RV, where the RV is larger than the LV. B, Parasternal long-axis view with an enlarged RV and bowing of the septum into the LV chamber. C, Flattening of the ventricular septum, forming a D-shaped short-axis LV appearance. D, Representation of the end-diastolic eccentricity index, which is the ratio between the LV anteroposterior dimension (D1) and LV septolateral dimension (D2). LV: left ventricle; RA: right atrium; RV: right ventricle.

RV WALL THICKNESS

Chronic RV pressure overload seen in PAH can induce RV hypertrophy (RVH), which is an adaptive change to the increased afterload. The increased RV thickness is a reflection of an increase in total RV mass. Using subcostal views of the RV, an end-diastolic free-wall thickness greater than 5 mm indicates hypertrophy and remodeling in response to chronically elevated afterload.⁴¹ No studies have shown survival benefit or hazard with increased RV hypertrophy in PAH. Ghio and colleagues⁴² looked at RV wall thickness in a small study of 59 patients with severe PH (mean PAP = 54 mmHg and PVR = 14 Wood units) from idiopathic PAH, followed these patients for an average of 52 months, and found that the mean RV free-wall thickness in this group was 3.8 mm. Although in the general population and in heart failure with preserved ejection fraction (EF), RVH has been found to be predictive of worse outcomes,^43,44 in idiopathic PAH there was no significant association with survival or mortality based on wall thickness. However, the finding of normal wall thickness in severe PAH suggests that there may be a predominance of maladaptive RV remodeling or a mix of adaptive and maladaptive remodeling responses.¹²

ABNORMAL INTERVENTRICULAR WALL MOTION AS A SIGN OF VENTRICULAR INTERDEPENDENCE

Despite the differences between the LV and the RV, their functions are not independent of each other.⁴⁵ The RV has a critically important anatomic and physiologic interdependence with the LV that must be understood to appreciate the effects of RV dysfunction and failure. Anatomically, the RV shares the septum with the LV, with attachments at the anterior and posterior septum; has mutually encircling epicardial fibers; and is jointly enclosed within the intrapericardial space.³⁵ This interdependence is evident in many cardiac disease processes, including restrictive and constrictive pathophysiology.⁴⁶ With RV pressure or volume overload, a bowing and flattening of the interventricular septum (IVS) toward the LV is noted (Fig. 4C; Video 1, available online). A greater degree of septal shift occurs toward end-systole in chronic pressure overload. RV volume overload may also result in septal flattening and shifting of the IVS, predominantly during diastole and especially toward end-diastole. This leftward bowing of the IVS contributes to decreased LV filling and a reduction in stroke volume. The ratio of the end-diastolic anteroposterior distance to the septal-lateral distance on short-axis views of the LV at end-diastole is referred to as the LV eccentricity index, and a ratio greater than 1 is indicative of RV overload (Fig. 4D).⁴⁷ Physiologically, with RV dilation and a septum shift leftward, the RV loses the normal LV septal contractile force's contribution to RV stroke work, amounting to approximately one-third of the work. This septal flattening may in turn negatively affect LV filling and RV perfusion from decreased peak LV pressures.⁹

Video 1.

Image from a video, available online, showing an example of severe right ventricular volume and pressure overload with flattening of the interventricular septum throughout the cardiac cycle.

RV FUNCTION

As discussed above, survival in PAH and the severity of symptoms are strongly associated with RV function.⁴⁸ Historically, since the RV has been so difficult to visualize by 2D echocardiography, numerous ways were developed to assess RV function (Table 2). The traditional surrogate measures of RV performance are fractional area change (FAC), which is defined as [(RV end-diastolic area – RV end-systolic area)/RV end-diastolic area] × 100 and measured in the apical 4-chamber view; TAPSE, which is the M-mode measurement of the longitudinal displacement of the tricuspid annulus; and RV myocardial performance index (RV-MPI), which is the ratio of total isovolumic time to ejection time. Newer 2D echocardiographic methods to quantify RV function include the RV free-wall longitudinal systolic tissue velocity (S'), measured with pulse-wave or color Doppler tissue imaging (DTI); the first derivative of RV pressure (dP/dt_max); IVCv; and RV strain imaging.

Table 2.

Right ventricle functional echocardiography parameters, prognostic significance

Parameter	Echo view	Normal value^a	Prognosis	Limitation
RV FAC,^b %	Apical 4CH	>35		Difficult endocardial delineation due to trabeculations; delineation of anterior wall; identification of infundibular plane; load dependent
TAPSE, mm (Fig. 5A)	Apical 4CH M-mode of lateral tricuspid annulus	≥17	TAPSE < 18 associated with increased RV dysfunction, increased 1- and 2-year mortality and hazard ratio of 5.7²⁵	Load dependent; angle dependent; cannot use if tricuspid annuloplasty; assesses only RV inflow
dP/dt_max, mmHg/s	Apical 4CH pulse Doppler TR	<400		Preload dependent; angle dependent; not as reliable in significant TR
Tei index, or MPI^c	Apical 4CH pulse Doppler TR or DTI of lateral tricuspid annulus	Doppler: ≤0.43; DTI: ≤0.54	MPI of <0.83 had a 5-year survival free of death or lung transplantation of 74%, compared to 4% for MPI ≥ 0.83, with a hazard ratio of 1.3 for every 0.1 unit increase²⁴	Less affected by load dependence and heart rate; arrhythmia sensitive in the pulse-wave Doppler method; may be underestimated in high RAPs (as IVRT decreases)
DTI S', cm/s (Fig. 5 c )	Apical 4CH DTI of lateral tricuspid annulus	≥9.5		Angle dependent; less load dependent; can calculate MPI at the same time
IVA, m/s²	Apical 4CH DTI of lateral tricuspid annulus	1.4–3.0		Angle dependent; HR dependent; low reproducibility
IVCv, cm/s	Apical 4CH DTI of the lateral tricuspid annulus	≥9	Independent predictor of mortality with 1-year survival of 95% if IVCv > 9 and 80% if IVCv ≤ 9; hazard ratio: 3.68²⁸	Angle dependent
RV diastolic function	Apical 4CH Doppler of RV inflow at tips of tricuspid valve	E/e’ > 6 predicts RAP > 10 mmHg;		Angle dependent; load dependent; not well studied in severe TR;arrhythmia sensitive; expected to show small E/A decrease with increasing age
		E/A < 0.8: impaired relaxation;
		E/A = 0.8–2.0 and diastolic predominance in hepatic veins: pseudonormal filling;
		E/A > 2.0 and DT < 119: restrictive filling
Strain imaging	Speckle-tracking strain		RV free-wall strain of <-12.5% was associated with decreased 1 year survival (61%, vs. 89% if strain > −12.5%);²⁷	Requires additional processing; vendor specific
			RV strain predicted outcome with a 1.46 higher risk of death (95% CI: 1.05–2.12) for every 6.7% decline in strain⁶⁶

Note: A: tricuspid peak A-wave velocity; CI: confidence interval; DTI: Doppler tissue imaging; E: tricuspid peak E-wave velocity; e': tricuspid early myocardial velocity; ET: ejection time; FAC: fractional area change; IVA: isovolumic acceleration; IVCv: isovolumic contraction velocity; IVCT: isovolumic contraction time; IVRT: isovolumic relaxation time; MPI: myocardial performance index; RAP: right atrial pressure; RV: right ventricle; S': systolic velocity; TAPSE: tricuspid annular plane systolic excursion; TR: tricuspid regurgitation; 4CH: 4-chamber view.

Based on Lang et al.³³

[(End-diastolic area – end-systolic area)/end-diastolic area] × 100.

(IVRT + IVCT)/(RV ET); Figure 5B.

The measurement of RV FAC is demonstrated in Figure 3. A good correlation has been observed between RV FAC and RVEF, and it appears to be the 2D measure of RV function that best correlates with RV systolic function measured on cardiac MRI.^49,50

TAPSE assesses longitudinal RV function through the use of the M-mode in the apical 4-chamber view (Fig. 5A). A focus on quantitative measures of RV function has centered on estimating the longitudinal shortening, or base-to-apex movement, of the RV, since this motion has been presumed to contribute more to the RV stroke volume than circumferential shortening.⁵¹ TAPSE has been shown to be a reliable predictor of prognosis in PAH and a measure of RV function, with a value of less than 18 mm predicting mortality from PAH.²⁵ Acquisition of TAPSE is angle dependent and preload and afterload dependent. Some concern has been raised about the accuracy of TAPSE when compared with EFs obtained with cardiac MRI, as TAPSE represents only basal RV systolic function and therefore is not reflective of global function as well as being influenced by passive translational or tethering forces.⁵⁰

Figure 5.

Surrogate echocardiographic markers of right ventricle (RV) function. A, Tricuspid annulus plane systolic excursion (TAPSE). M-mode cursor placed through the RV apex to the lateral tricuspid annulus in the apical 4-chamber view for the purpose of measuring the distance traveled by the annulus in centimeters from end-diastole to end-systole. Abnormal TAPSE of 1.3 cm is noted by cross-hatching. B, RVMPI (Tei index). Top, representation of the two ways to calculate RVMPI: on tissue Doppler and on pulsed-wave Doppler. Bottom, isovolumic contraction and relaxation times (IVCT and IVRT, respectively) and ejection time (ET), where right ventricular myocardial performance index (RVMPI) = (IVCT + IVRT)/ET. C, Doppler tissue imaging (DTI) of the tricuspid annulus after pulsed-wave interrogation of the lateral wall of the tricuspid annulus. These measurements can be made after high-frame-rate acquisition with color-coded Doppler offline (not shown). IVCv: isovolumic contraction velocity; S': highest systolic velocity. D: Rate of pressure rise in the RV, or the dP/dT. On the ascending limb of the continuous Doppler image of the tricuspid regurgitation jet, the time for the velocity to increase from 1 to 2 m/s is measured, and the dP/dT is 12 mmHg/time in seconds.

Forfia and colleagues²⁵ evaluated TAPSE in a prospective study of 63 patients with PAH. Patients with TAPSE no greater than 1.8 cm had a survival estimate of 50% at 2 years, compared with 88% 2-year survival in patients with TAPSE greater than 1.8 cm.²⁵ In all, TAPSE is likely the most widely used and reproducible technique to follow RV function, although the timing of the deterioration in TAPSE relative to the onset of RV failure is ill defined.⁵²

The RV-MPI, also known as the Tei index, incorporates elements of both systolic and diastolic phases in the assessment of global ventricular function (Fig. 5B). The Tei index is defined as the sum of the isovolumic contraction and the isovolumic relaxation times divided by ejection time.⁵³ These measurements can be obtained on either DTI of the tricuspid annulus or pulsed-wave Doppler imaging of the RV outflow for the ejection time and from either tricuspid valve inflow or regurgitation for the tricuspid valve opening time. Values greater than 0.55 by DTI and greater than 0.40 by pulsed-wave Doppler reflect RV dysfunction.³⁷ The Tei index correlates well with RVEF⁵⁴ and is less affected by heart rate or loading conditions, thereby making it more reproducible. In a series of 53 patients studied by Yeo and colleagues,²⁴ a Tei index cut-off value of at least 0.83 was associated with decreased 1-, 2-, and 5-year survival of 71%, 28%, and 4%, respectively, compared to a Tei index of less than 0.83, which had 1-, 2-, and 5-year survival of 96%, 87%, and 73%, respectively.

Pulsed DTI of the tricuspid annulus records the peak systolic tricuspid lateral annular velocity (S'; Fig. 5C), which is a reflection of systolic longitudinal RV myocardial contractility. An S’ of less than 9.7 cm/s is associated with abnormal RV contractility, and S’ has been shown to be potentially useful in the early detection of RV dysfunction.^12,55 The S’ is inversely related to PVR and correlates with RVEF.⁵⁶ Acquisition is limited by angle dependence and tethering effects, similar to TAPSE, as this measurement is taken at the same angle and is focused on the same lateral segment of the tricuspid annulus as TAPSE.

The dP/dt_max as the RV pressure changes by 12–15 mmHg (depending on the measurement of velocities from 1 to 2 m/s or from 0.5 to 2 m/s) is a useful measure in the assessment of RV systolic function and contractility (Fig. 5D).⁵⁷ This index can be noninvasively estimated by continuous-wave Doppler echocardiography using TR.⁵⁸ However, the Doppler-derived dP/dt_max has not been used routinely as a clinical index because it depends on preload and is sensitive to the incident angle. The dP/dt_max is independent of afterload. Some investigators contend that dividing the derivative of the RV pressure by the maximum pressure (dP/dt_max) is a more accurate measure of RV contractility because it does not have the load- and angle-dependent features.⁵⁹

The IVCv is the peak velocity by DTI measurement at the level of the tricuspid annulus that is taken during isovolumic contraction, a period in the cardiac cycle in early systole when the RV contracts and pressures rise acutely without any change in ventricular volume (a brief period after the tricuspid valve is closed and before the pulmonic valve is open). It is the velocity deflection seen just before the S’ deflection on DTI. This contractility is relatively preload and afterload independent and may reflect a more global ventricular contractility.⁶⁰ Ernande and colleagues²⁸ found IVCv to be an independent predictor of mortality in PAH by multivariate analysis, with a 1-year survival of 95% if IVCv exceeds 9 cm/s and 80% if it does not, with an associated hazard ratio of 3.68.

FUTURE DIRECTIONS OF RV ASSESSMENT

As acquisition of RV physiology improves and our understanding of RV function changes, the aforementioned descriptions of RV function may become obsolete. Looking at the movement of one side of the tricuspid annulus and measuring DTI from this region may not be as valuable once RV strain and 3D RVEF become more advanced and adopted.⁶¹ However, many echocardiographic laboratories are currently using the conventional measures along with the newer methods described below for complete RV echocardiographic analysis.⁶²

RV STRAIN

Advances in echocardiographic evaluation of the RV have improved the ability to assess RV strain. Strain is a measurement of tissue deformation as the myocardium contracts in systole as a result of sarcomere shortening. The myocardial tissue deforms as the myocardial tissue changes 3D shape, with longitudinal shortening, circumferential shortening, and radial thickening. This deformation results in a smaller RV cavity and forward ejection of blood from the ventricle. We describe this myocardial deformation as strain, the percent change from the initial length in end-diastole or onset of the cardiac cycle.⁶³ Longitudinal shortening resulting in a negative strain can be measured with DTI in the apical 4-chamber view, and circumferential shortening strain, which is also a negative strain, is obtained in the short-axis view but is less standardized than longitudinal strain in the acquisition methods. Color DTI strain is limited by different ranges of “normal” provided by different echocardiogram vendors and is dependent on complex postprocessing, image acquisition, frame rate, and angle of acquisition.

Speckle tracking is a technique where the unique speckled back-scatter of the reflected ultrasound beam in the myocardium is followed frame by frame.⁶³ This is a more reliable measure of RV strain than DTI⁶⁴ and uses algorithms that identify and follow speckles in the myocardium on sequential frames, and strain values are derived from this movement. Unlike color DTI, speckle tracking is angle dependent, but it is dependent on image quality and frame rate. This method also allows for short-axis and long-axis strain measurement reliably.⁶⁴ The normal and abnormal values still vary, depending on the vendor providing the strain software, which makes comparison between centers very difficult.⁶¹

Worsening of RV longitudinal strain has been associated with increased pulmonary artery pressures, decreased TAPSE, worsened functional class, and increased mortality from PAH (Fig. 6).^65,66 RV strain has been shown to improve with vasodilator therapy,⁶⁷ and an improvement in strain in response to therapy is predictive of a favorable prognosis.⁶⁸

Figure 6.

A, B, Velocity vector imaging showing normal (A) and abnormal (B) segmental patterns of longitudinal displacement, velocity, and strain. LA: left atrium; LV: left ventricle; RA: right atrium; RV: right ventricle. Adapted from Sanz et al.³⁷ with permission. C, A severe reduction in RV free-wall systolic strain at follow-up (<-12.5%) was associated with a poor prognosis over 4 years of subsequent follow-up (P = 0.002). D, An improvement in RV free-wall systolic strain by 5% was associated with a better survival over 4 years of follow-up (P = 0.006). C and D are adapted from Hardegree et al.⁶⁸ with permission.

3D ECHOCARDIOGRAPHIC ASSESSMENT OF THE RV

Although RVEF is highly dependent on loading conditions, it remains the most commonly used index of RV contractility. Under normal conditions, RVEF is lower than LVEF, because the RV chamber is larger than the LV chamber, with a normal range of RVEF varying between 40% and 76%, depending on the technique used.⁶⁹ A decline in RVEF is predictive of mortality and correlates with worsening functional class.^70,71

RV volumes acquired with 3D TTE correlate considerably better than 2D TTE with the reference standard of cardiovascular MRI, but in the past this has been limited by suboptimal image quality.⁷² In patients with dilated RV, the exclusion of the free wall from the imaging sector can lead to inaccuracy of RV volumes. Improvements in image acquisition technology are making this less prevalent and have overcome many of the difficulties surrounding 3D reconstruction of the RV. Currently, in order to acquire 3D volumes of the RV, tracings of anatomical landmarks are made at the end of diastole, and then, akin to speckle tracking, these sites are followed over the course of systole in order to reconstruct the 3D images. There remains a need to obtain 3–6 cardiac cycles to create full-volume imaging, and therefore this can be subject to increased error in the setting of arrhythmia. However, this method does facilitate imaging of the entire RV and can therefore measure RV volumes. These volume acquisitions and subsequent RVEF measurements have been validated compared to in vivo volumes and function, have demonstrated minimal interobserver variability (˜4%), and have been found to be accurate and reproducible (Fig. 7A–7C).^73–75 Changes in RV function and volume based on 3D TTE correlate with symptoms in patients with PAH. Interestingly, Leary and colleagues⁷⁵ observed that RVEF obtained with 3D TTE did not correlate well with TAPSE. This likely reflects a limitation of TAPSE due to other influences on this parameter, such as LV function and respiration.

The technique of knowledge-based reconstruction has been applied to PAH in 3D echocardiography with some success. In the published versions of knowledge-based reconstruction in PAH, the technique involves the acquisition of 2D images localized in 3D space by a magnetic-field generator. A magnetic-field sensor is attached to the echocardiographic transducer, and the specific anatomic landmarks are identified and recorded by the user. A reconstruction algorithm uses these landmarks to generate a 3D model by cataloging them against patients with similar pathologies (Fig. 7D, 7E).⁷⁶ The generation of a 3D RV model from 2D transthoracic echocardiographic has been validated in vitro and against cardiac MRI in patients with congenital heart disease.^77,78 The RV end-diastolic volumes and RVEF in patients with PAH obtained through this technique correlate well with those seen in CMR.⁷⁹

Figure 7.

A–C, Three-dimensional (3D) reconstructions from patients with a normal heart (A), idiopathic pulmonary arterial hypertension (iPAH; B), or connective tissue disease related pulmonary hypertension (ctd-PH; C), demonstrating apical rounding (asterisks) and basal bulging (plus signs). Adapted from Leary et al.⁷⁵ with permission. av: aortic valve; LV: left ventricle; mv: mitral valve; pv: pulmonic valve; RV: right ventricle; tv: tricuspid valve. D, Transthoracic echocardiographic images with points placed to define anatomic landmarks and borders of 3D model superimposed (yellow outlines): parasternal long-axis view (A), Parasternal short-axis view at the level of the papillary muscles (B), RV inflow view (C), RV inflow-outflow view (D), standard apical 4-chamber view (E), and focused RV apical view (F). Colors of points are as follows: red for RV endocardium, cyan for interventricular septum, green for RV septal edge, violet for tricuspid annulus, blue for conal septum, orange for pulmonic annulus, brown for basal bulge, and light pink for RV apex. E, 3D model of the RV at end-diastole, with endocardial points placed during multiplane initialization. F, Bland-Altman analysis comparing TTE-derived measurements with cardiac magnetic resonance imaging (CMR) reference values for end-diastolic volume (EDV). TTE: transthoracic echocardiogram. G, Scatterplot analysis comparing TTE-derived measurements with CMR reference values for ejection fraction (EF). D–G are adapted from Bhave et al.⁷⁹ with permission.

ECHOCARDIOGRAPHY AND RV HEMODYNAMICS

To understand how and why the RV adapts to the changes in the pulmonary circulatory system, one should take a thoughtful look at RV hemodynamics, including the afterload (PVR), preload (central venous pressure [CVP]), and contractility, as assessed in invasive RV pressure-volume loops or conceptualized in a calculated RV stroke-work index.⁸⁰ Just as worsening echocardiographic parameters of RV function have correlated with a worse prognosis, so have worsening cardiac hemodynamics indicative of the struggling RV (RA pressure >15 mmHg and cardiac index < 2.0 L/min/m²).⁸¹

Doppler echocardiography can estimate the afterload and preload of the RV and can help clinicians understand the hemodynamic significance of any RV dysfunction.⁸² The estimation of CVP can be made by assessing the size and collapsibility of the inferior vena cava (IVC) proximal to the hepatic veins.⁸³ An IVC that has a size greater than 2.1 cm and is also not collapsible by more than 50% suggests an RA pressure higher than 15 mmHg (range: 10–20 mmHg).^84,85 The collapsibility, or “sniff test, “ is assessed on inspiration because the intrapleural pressure drop leads to an increase in central venous return, a decrease in CVP, and an IVC that should collapse. The caveat is that young patients may have dilated IVCs at baseline and that assessment of high RA pressures cannot be made on positive pressure ventilation, although a collapsible IVC is indicative of low RA pressure on positive pressure ventilation. Afterload is most commonly evaluated as PVR, with PVR = (mean PAP—pulmonary capillary wedge pressure)/cardiac output.⁸⁶

Other measures of the right-sided pressures estimated by Doppler echocardiography are noted in Table 3. Despite the advances in the assessment of right-sided hemodynamics noninvasively, right heart catheterization continues to be the gold standard to determine hemodynamic parameters. However, some advocate a future time when hemodynamic parameters will confidently be measured by noninvasive methods, including echocardiography. It remains unclear how current hemodynamics measurements by echocardiography are influencing day-to-day clinical practice.

Table 3.

Commonly used right atrial, right ventricular, and pulmonary pressure estimates by echocardiography

Estimate, formula/method	Concept	Limitations	Sources
1. RAP estimates, normal range of 1–7 mmHg	Elevated RAP is transmitted to the IVC and is visualized by increase in end-expiratory diameter just proximal to junction of hepatic veins and reduced collapse on inspiration
From IVC diameter and collapsibility: ≤2.1 cm and >50% collapsible = low (<3 mmHg); ≤2.1 cm and <50% collapsible or >2.1 cm and >50% collapsible = intermediate (5–10 mmHg); >2.1 cm and <50% collapsible = high (>15 mmHg)		Not accurate in positive pressure ventilation; less reliable for intermediate pressures values; unknown whether altered by impaired compliance of IVC itself	Brennen et al.;⁸⁴ Kircher et al.⁸⁷
Multiple other RA estimates by evaluating systemic veins, hepatic veins, tissue Doppler, and RA size			Review in Beigel et al.⁸⁸
2. RVSP
Modified Bernoulli equation 4ν², where the ν is the peak velocity of the TR jet + RAP	Based on the pressure gradient between the right atrium and the right ventricle; first correlated to PASP by Yock and Popp,⁹¹ in the absence of pulmonic stenosis, RVSP can be representative of PASP; in PH screening, PASP > 37 mmHg may indicate need for further invasive measurements	Need TR to estimate pressure; alignment is crucial, maximum TR must be identified from multiple views; subtract gradient across PV if pulmonic stenosis present; avoid arrhythmia; recognition that RVSP elevation may be seen in high-flow states (anemia, high-output high flow) and that the modified Bernoulli equation does not account for abnormal viscosity (as in anemia)	Berger et al.;¹³ Currie et al.;¹⁷ Hatle et al.;⁸⁹ Skjaerpe and Hatle;⁹⁰ Yock and Popp⁹¹
3. PADP	The end-diastolic pulmonary pressure has been calculated with Bernoulli's formula to the end pulmonic regurgitation pressure + RAP or the RV pressure (based on TR jet) at time of PV opening
End-diastolic point of the PR jet			Ge et al.;⁹² Lee et al.;⁹³ Ristow et al.⁸⁵
Velocity of the TR jet at time of PV opening			Lanzarini et al.;⁹⁴ Reynolds et al.;⁹⁵ Stephen et al.⁹⁶
4. mPAP	There are many ways to calculate mPAP from Doppler echocardiography; mPAP currently dictates the severity of PH and has formed the basis of our definition of vasoreactivity	Multiple techniques to establish mPAP
From PASP: using Doppler-estimated PASP and PADP, mPAP = PADP + (PASP -PADP/3); mPAP = 0.61 (PASP) + 2 mmHg; mPAP = 0.65 (PASP) + 0.55 mmHg; mPAP = 0.6 (PASP)			Chemla et al.;⁹⁷ Steckelberg et al.;⁹⁸ Syyed et al.⁹⁹
From AcT of the RVOT (also known as PAAT): mPAP = 79 – 0.45 (RVOT AcT) or 90 – 0.62 (RVOT AcT); >100 ms less indicative of PH, <70 ms more indicative of PH			Kitabatake et al.¹⁰⁰
From tricuspid VTI: mPAP = tricuspid VTI + RAP			Aduen et al.¹⁰¹
From PR: 4 × PVR² + RAP			Abbas et al.,¹⁰² from work by Masuyama et al.
5. Total pulmonary resistance and PVR TR velocity/VTI of RVOT × 10 + 0.16; normal: <1.5 WU (120 dynes × cm/s²); noninvasive PVR = (RVSP – E/e')/RVOT VTI	Calculation of PVR helps distinguish whether pressure is due to increased flow or from intrinsic pulmonary disease	Not reliable in PVR > 8 WU	Abbas et al.;⁸⁶ Dahiya et al.¹⁰³
6. PAC SV: LVOT area × LV VTI)/PASP – PADP = SV/4 × (TR² – PR²)	Compliance of the pulmonary vasculature is a measure of workload on the RV; change in volume/change in pressure of SV/pulse pressure gives compliance	Reliance on several pressure estimations	Mahapatra et al.¹⁰⁴

Note: AcT: acceleration time; E: tricuspid peak E-wave velocity; e': tricuspid early myocardial velocity; IVC: inferior vena cava; LV: left ventricle; LVOT: left ventricular outflow tract; mPAP: mean pulmonary artery pressure; PAAT: pulmonary artery acceleration time; PAC: pulmonary artery compliance; PADP: pulmonary artery diastolic pressure; PASP: pulmonary artery systolic pressure; PH: pulmonary hypertension; PR: pulmonary regurgitation; PV: pulmonic valve; PVR: pulmonary vascular resistance; RA; right atrial; RAP: right atrial pressure; RV: right ventricular; RVOT: RV outflow tract; RVSP: RV systolic pressure; SV: stroke volume; TR: tricuspid regurgitation; VTI: velocity time integral; WU: Wood units.

RV CONTRACTILE RESERVE ASSESSED BY ECHOCARDIOGRAPHY

The concept of using stress, whether during exercise or induced pharmacologically, to evaluate ventricular contractile reserve or the ability to augment function is not new. Most consistently, contractile reserve is evaluated in aortic stenosis and low-flow, low-gradient conditions where the reduced LV systolic function is the focus. However, this framework is analogous in the RV and has been explored in a few disease states, looking at the ability of the RV to improve function as a favorable prognostic sign.^105–108

Two recent studies have applied the idea of RV reserve to PAH. Blumberg and colleagues¹⁰⁹ took an invasive approach and looked at the ability to increase cardiac index (and thus augmentable RV function) in 26 patients with severe PH from PAH or inoperable chronic thromboembolic pulmonary hypertension. In this study, patients with right ventricle reserve, defined invasively as an increase in RV cardiac index with exercise, had a better prognosis. Grünig and colleagues¹¹⁰ used a noninvasive approach with Doppler echocardiography to assess RV contractile reserve during exercise, as measured by an increase in pulmonary artery systolic pressure (PASP) of at least 30 mmHg.

Patients with the ability to augment PASP had 1-, 3-, and 4-year survival of 96%, 92%, and 89%, respectively, compared to survivals of 92%, 69%, and 48% in patients with low contractile reserve.¹¹⁰

INTERNATIONAL ACCESS TO ECHOCARDIOGRAPHY

On the basis of data from the Intersocietal Accreditation Commission, the number of currently accredited adult echocardiography sites in 2013 in the United States is approximately 5,000. However, worldwide access to echocardiography remains limited in most developing countries because of the costs of the technique and the lack of highly specialized personnel to perform it. Echocardiography is portable and safe, uses a simple power supply, and does not require large amounts of maintenance; these characteristics make it the most suitable imaging technique in PAH for low-resource areas, especially those in sub-Saharan Africa. Coincident with this is the fact that more than 200 million people worldwide are infected with schistosomiasis and that approximately 1% of those chronically infected will develop PAH.¹¹¹ This is also localized to developing countries, particularly in sub-Saharan Africa. Rheumatic heart disease and endomyocardial fibrosis with subsequent PH are also common in these areas,^112,113 further necessitating the spread of echocardiography into these underserved areas (Fig. 8). Not only will a proliferation of echocardiography in developing countries assist in the diagnosis and characterization of PH, but it will also increase our understanding of these epidemic disease processes and form the basis of imaging and clinical research.¹¹⁴

Figure 8.

Researcher performing echocardiography in an African rural setting.

RELEVANCE OF RV IMAGING BY ECHOCARDIOGRAPHY IN CLINICAL DECISION MAKING

The American College of Cardiology/American Heart Association 2009 Expert Consensus Document on Pulmonary Hypertension and the recent Fifth World Symposium on PH recommend basing the initial therapeutic decision for PAH on vasoreactivity testing.^6,115 Subsequent decisions should be based on risk stratification of low- and high-risk PAH patients based on clinical assessment, which may include WHO functional class, physical examination, and/or echocardiography. The recognition of RV dysfunction, RA enlargement, and RV volume overload in PAH leads one to characterize these patients as high-risk, which necessitates consideration of parenteral prostacyclins.⁶ With patient outcomes closely tied to the fate of the RV, more knowledge about the effect currently available therapies have on RV dysfunction and investigating new therapies targeting RV dysfunction appears warranted. Our model for a noninvasive evaluation of the RV by echocardiogram is shown in Figure 9.

Figure 9.

Our approach to RV assessment in echocardiography is summarized. A measurement of size in the apical 4-chamber view evaluating minor and major right ventricular (RV) dimensions is reported, along with RV thickness from the subcostal window. Surrogate measures of RV function routinely evaluated include fractional area change (FAC), tricuspid annulus plane systolic excursion (TAPSE), myocardial performance index (MPI), and systolic velocity (S'), with others utilized in research or in times of measurement discrepancies. Comments about qualitative RV wall motion and the relationship between right and left ventricles, as evidenced by septal motion, are described. We highly recommend use of RV strain and three-dimensional (3D) RV assessment in all pulmonary arterial hypertension patients if the capability exists within the clinical setting. Recommended routine noninvasive hemodynamics that can be easily obtained include right ventricular systolic pressure (RVSP), central venous pressure (CVP), pulmonary artery acceleration time (PAAT), and pulmonary vascular resistance (PVR).

CONCLUSION

PAH continues to be a very challenging disease to diagnose and manage. Echocardiography has a clear and vital role in both the diagnosis and the management of this disease, and with improved RV imaging, additional ways will become available to evaluate RV structure and function. In particular, 3D echocardiographic imaging of the RV and RV speckle tracking provide accurate and reproducible measures of RV size and function that can be routinely used in clinical practice. In addition, surrogate markers of RV function have been validated against more invasive and extensive assessments of RV performance, such as nuclear ventriculography and cardiac MRI. Continuing advances in acquisition of RV imaging will increase the ability of echocardiography to prognosticate and potentially influence treatment options in PAH. These advances, lower cost, and worldwide availability make echocardiography more attractive as the predominant imaging modality in the longitudinal management of patients with PAH.

Footnotes

ACKNOWLEDGMENTS

We would like to thank Stephen Ishihara, from University of Utah Cardiovascular Imaging Center, for acquisition of images and Kenneth Peake RDCS, from Siemens Cardiovascular Ultrasound, for advice on image processing.

Source of Support: Nil.

Conflict of Interest: None declared.

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The Right Ventricle under Pressure: Evaluating the Adaptive and Maladaptive Changes in the Right Ventricle in Pulmonary Arterial Hypertension using Echocardiography (2013 Grover Conference Series)

Abstract

Keywords

THE ROLE OF ECHOCARDIOGRAPHY IN THE DIAGNOSIS OF PAH

THE RELATIONSHIP BETWEEN THE RV AND PROGNOSIS IN PAH

ASSESSMENT OF RV STRUCTURE

RV WALL THICKNESS

ABNORMAL INTERVENTRICULAR WALL MOTION AS A SIGN OF VENTRICULAR INTERDEPENDENCE

RV FUNCTION

FUTURE DIRECTIONS OF RV ASSESSMENT

RV STRAIN

3D ECHOCARDIOGRAPHIC ASSESSMENT OF THE RV

ECHOCARDIOGRAPHY AND RV HEMODYNAMICS

RV CONTRACTILE RESERVE ASSESSED BY ECHOCARDIOGRAPHY

INTERNATIONAL ACCESS TO ECHOCARDIOGRAPHY

RELEVANCE OF RV IMAGING BY ECHOCARDIOGRAPHY IN CLINICAL DECISION MAKING

CONCLUSION

Footnotes

ACKNOWLEDGMENTS

References