Clinical Significance of Right Ventricular Function in Pulmonary Hypertension

Abstract

Pulmonary hypertension (PH) is a progressive disease characterized by increased pulmonary vascular resistance that leads to right ventricular (RV) failure, a condition that determines its prognosis. This review focuses on the clinical value of the evaluation of RV function in PH. First, the pathophysiology of PH, including hemodynamics, RV function, and their interaction (known as ventriculoarterial coupling), are summarized. Next, non-invasive imaging modalities and the parameters of RV function, mainly assessed by echocardiography, are reviewed. Finally, the clinical impacts of RV function in PH are described. This review will compare the techniques that yield comprehensive information on RV function and their roles in the assessment of PH.

Introduction

Right ventricular (RV) function is an independent predictor of clinical outcomes in patients with cardiovascular diseases such as myocardial infarction,¹ chronic heart failure,² and pulmonary hypertension (PH).^3,4 Because of these findings, scientific interest in RV function is increasing, although the RV used to be called “the forgotten ventricle.” The response of the RV to increased afterload in the pulmonary circulation is complex and often maladaptive.⁵ The basic responses of the ventricle to afterload are modified by a large Frank–Starling reserve, in which an increase in afterload is matched by an increase in preload.⁶ This phenomenon is called “the preload reserve.” Progressive dilatation occurs when the increase in afterload cannot be compensated by the Frank–Starling mechanism, and ventricular function deteriorates. The aim of this review is to summarize the existing noninvasive measures of RV function and their clinical value in PH.

Pathophysiology of Pulmonary Hypertension

Hemodynamics

Under normal conditions, the RV is coupled with a low impedance, highly distensible pulmonary vascular system. Compared to the systemic circulation, the pulmonary circulation has a much lower vascular resistance, greater pulmonary artery distensibility, and a lower peripheral pulse wave reflection coefficient.⁷ Moreover, right-sided pressures are significantly lower than comparable left-sided pressures. The RV isovolumic contraction time is short because the RV systolic pressure rapidly exceeds the low pulmonary artery diastolic pressure. Consequently, RV pressure tracings demonstrate an early peak and rapid decline in pressure, in contrast to the rounded contour seen in LV pressure tracing.⁸ A careful study of hemodynamic tracing and flow dynamics also reveals that the end-systolic flow may continue in the presence of a negative ventricular–arterial pressure gradient. This interval, which is referred to as the hangout interval, is most likely explained by the momentum of the blood in the outflow tract.

The crucial hemodynamic change in PH is the increase in pulmonary vascular resistance (PVR) as a consequence of pulmonary vascular remodeling. PVR may increase by a factor of four or more, rather than the 50% increase seen in systemic hypertension. As a consequence of this increased resistance, pulmonary artery pressure (PAP) increases. One of the most striking features of the pulmonary circulation in PH is that the pulmonary artery systolic and diastolic pressures are proportional to mean pulmonary artery pressure (mPAP).⁹ This proportionality follows from the unique properties of the pulmonary vascular system, resulting from an inverse relationship between the two major components of the vascular load: PVR and total arterial compliance.¹⁰ An increase in PAP leads to the elevation of RV wall stress (RV afterload), which is proportional to the pressure during RV ejection. The responses of the RV to afterload are modified by the preload reserve, in which an increase in afterload is matched by an increase in preload.⁶ As a result, progressive RV dilatation occurs if the increase in afterload cannot be compensated by this mechanism, and RV function deteriorates.

RV function in pressure overload

In the setting of pressure overload, the RV initially responds with adaptive remodeling (characterized by relatively preserved volumes and function) and compensatory concentric hypertrophy. However, compared with the LV, the RV muscle is thinner and much more sensitive to changes in afterload; it is therefore less likely to compensate by concentric hypertrophy.

When this homeometric adaptation is exhausted and contractility can no longer increase to match the afterload, “maladaptive” remodeling takes place with “eccentric” hypertrophy, progressive RV dilatation and dyssynchrony, and maintenance of stroke volume through Frank–Starling mechanisms. This comes at the price of increased filling pressures and, eventually, clinical decompensation.^11,12 With worsening PH, the RV becomes less dependent on longitudinal shortening and more dependent on transverse wall motion.^13,14 An important component of RV contractile dysfunction in pressure overload is dyssynchrony. Intraventricular RV dyssynchrony may be present in the early stages of disease,¹⁵ leading to loss of peristaltic motion¹⁶ and heterogeneous increases in RV free wall workload,¹⁷ and is associated with clinical worsening.⁴ In addition, interventricular dyssynchrony (delay in RV free wall peak shortening when compared to the septum or LV free wall) occurs in the more advanced stages. Eventual RV dilatation causes additional deleterious ventricular interaction in diastole (see the section on volume-overloaded RV). For these reasons, knowledge of both RV dimensions and function is relevant in PH.

Right ventricular–pulmonary arterial coupling

Right heart failure in PH is caused by increased afterload; consequently, the cardiopulmonary unit is indispensable for the assessment of RV function. Recently, close relationships between RV coupling and the transition to RV maladaptation (dilatation) have been demonstrated.¹⁸ RV coupling is usually described as the interplay between RV contractility (Ees) and arterial elastance (Ea). As the afterload increases in the course of PH, RV contractility (Ees) increases to maintain right ventricular–pulmonary arterial (RV-PA) coupling (Ees/Ea). When Ees/Ea reduces to the point of uncoupling (at a value of approximately 0.8), RV begins to dilate to maintain stroke volume.

Noninvasive Imaging of RV Function

There are several modalities for the evaluation of RV function, including cardiac magnetic resonance imaging (CMR) and echocardiography. However, it may not be realistic to perform all modalities for every investigation. CMR is suitable for understanding the patient’s condition at the first visit. In contrast, echocardiography can be repeatedly performed and is useful as an evaluation during repeated examinations in the acute phase and for regular examinations. RV strain and three-dimensional echocardiography (3DE) are desired for pathological evaluation and the prediction of prognosis through detailed RV functional analysis for moderate and severe cases, whereas conventional echocardiographic evaluation is sufficient for mild cases.

Assessment of RV function by CMR

A previous study demonstrated that, among imaging modalities, CMR provided the most accurate measurements of RV volume.¹⁹ Therefore, CMR-based RV analysis is the gold standard in PH for its high spatial resolution and reproducibility. One of the advantages of CMR is that it allows the non-invasive measurement of RV-PA coupling without the need for an invasive process.^20,21 Furthermore, CMR provides qualitative information, including the detection of RV myocardial fibrosis. Although CMR-derived RV remodeling parameters such as chamber enlargement, wall thickening, myocardial fibrosis, and ejection decline have shown independent prognostic value for all-cause mortality and the composite endpoint, the right ventricular ejection fraction (RVEF) was found to be the strongest prognostic factor among all the RV parameters in patients with PH.²²

Assessment of RV function by echocardiography

Echocardiography is routinely used for the assessment of RV size and function. Compared to CMR, echocardiography can be easily performed both at the bedside in critical inpatients and at the outpatient clinical laboratory; echocardiography is less expensive and is therefore available for repeated examinations.

Quantitation of RV dimensions is critical for accurate measurements of RV function. However, evaluation of RV function by two-dimensional echocardiography (2DE) is challenging because of the complex geometry of the right ventricle and the absence of specific right-sided anatomic landmarks for use as reference points.²³ The conventional apical four-chamber view results in considerable variability in how the right heart is sectioned, and, consequently, RV linear dimensions and areas may vary widely in the same patient with relatively minor rotations in transducer position. In this regard, RV function should be estimated from an RV-focused apical four-chamber view displaying the largest basal RV diameter. Despite these concerns, the usefulness of 2D RV parameters has been established in PH. Furthermore, recent advances in 3DE have enabled more accurate measurements of RV volume and RV function. The features of several RV parameters are summarized in Table 1.

Table 1. Echocardiographic parameters indicating RV systolic function

Parameter	Methods for measurement	Features	Limitations
Two dimensional
TAPSE	Tricuspid annular excursion by M-mode	RV longitudinal motion Feasible, reproducible	Angle dependency Partial RV function
RV S’	Peak systolic velocity of tricuspid free wall annulus by pulse-wave tissue Doppler imaging	RV longitudinal motion Reproducible Easy to perform	Angle dependency Partial RV function
RVFAC	RV area in RV-focused apical four-chamber view	RV longitudinal and circumferential motion Good correlation with CMR-derived RVEF	Partial RV function (RV outflow not included) Less reproducible
RIMP	By pulse Doppler or tissue Doppler	Less affected by heart rate	Less reliable when RV pressure is elevated
RV global longitudinal strain	Speckle tracking-derived strain averaged over the three segments of the RV Free wall in RV-focused apical Four-chamber view	Angle independent Prognostic value	Vender and image quality dependent
Three dimensional
RVEF	Matrix array 3D transducer	Overall RV function Close correlation with CMR-derived RVEF Prognostic value	Dependent on adequate image quality Analysis software needed
ACR / Area strain	Matrix array 3D transducer 3D wall motion tracking	Overall RV function RV longitudinal and circumferential motion	Dependent on adequate image quality Analysis software needed

TAPSE, tricuspid annular plane systolic excursion; RVFAC, right ventricular fractional area change; RIMP, right ventricular index of myocardial performance; RVEF, right ventricular ejection fraction; ACR, area change ratio.

Conventional echocardiographic RV parameters

Conventional echocardiography can measure RV parameters such as the tricuspid annular plane systolic excursion (TAPSE), the tissue Doppler-derived tricuspid lateral annular systolic velocity wave (RV S’), RV fractional area change (RVFAC), and RV index of myocardial performance (RIMP).

TAPSE is easily measured and predominantly reflects the RV longitudinal function. It has shown significant but weak correlations with RVEF measured by CMR.²⁴ Despite its convenience, TAPSE may over- or underestimate RV function because of angle dependence and cardiac translation. TAPSE <17 mm is highly suggestive of RV systolic dysfunction. RV S’ also reflects the RV longitudinal function and is a reliable and reproducible parameter. Just as for TAPSE, RV S’ may be influenced by heart motion due to the measurement being relative to the transducer. An RV S’<9.5 cm/s indicates RV systolic dysfunction. RVFAC provides an estimate of global RV systolic function that reflects both longitudinal and circumferential function; consequently, it has shown good correlation with RVEF measured by CMR.²⁵ RVFAC<35% indicates RV systolic dysfunction. RIMP is an index of global RV function including both systolic and diastolic function. It should be noted that RIMP measurements can be falsely low in conditions associated with elevated right atrial pressure, which shortens the isovolumic relaxation time. RIMP >0.43 by pulsed-wave Doppler and >0.54 by tissue Doppler indicate RV dysfunction.

RV strain

RV strain is useful for estimating global and regional RV systolic function. Two-dimensional echocardiography can evaluate RV strain in the longitudinal direction. It is recommended that RV longitudinal strain be calculated as the percentage of systolic shortening of the RV free wall from base to apex.²³ Compared with the other parameters, RV strain is less confounded by overall heart motion.^26,27 RV global longitudinal strain (GLS) usually refers to either the average of the RV free wall and the septum or the RV free wall alone. Peak RVGLS should be measured using the RV free wall alone because of its prognostic value in various cardiovascular diseases, including heart failure,^28,29 acute myocardial infarction,³⁰ and PH.^31,32

Our group and another group previously found that RV dyssynchrony is often observed in patients with PH and could be an independent predictor of clinical worsening.^4,33 In some studies, RV dyssynchrony was assessed by analyzing the time to peak strain of the four RV segments; this was done because of the high variability, compared with the mid and basal segments, of the apical segments of both the RV free wall and the RV interventricular septum, even in healthy subjects.^3,4 Nevertheless, the RV apex was observed being pulled toward the left ventricle during systole as a result of LV traction in some patients with PH. This is called apical traction and may occur with impaired RV systolic function in PH patients.³⁴ Consequently, RV apical motion is an essential part of evaluating RV function. We reported that assessing RV dyssynchrony using six RV segments and incorporating apical motion provided a better correlation with hemodynamics and with clinical outcomes than assessments not incorporating apical motion.³⁵ Therefore, we recommend that RV apical strain should be included for optimal assessment of RV dyssynchrony.

Three-dimensional echocardiography

Compared with 2DE, real-time 3DE enables the measurement of RV volume and RVEF irrespective of the ventricle shape; it also more reliably evaluates the morphology and function of RV in PH.³⁶ Many reports, including ours, have shown that RV end-diastolic volume (RVEDV), RV end-systolic volume (RVESV), and RVEF measured using 3DE were strongly correlated to those measured using CMR: indeed, their correlation coefficients were greater than 0.9.^37,38 However, it has also been reported that, compared with CMR, 3DE underestimated RV volumes. Normal values for RVEDV and RVESV are larger in men than in women, and the normal ranges for RVEDV and RVESV, both normalized to the body surface area, are 35–87 mL/m² in men and 32–74 mL/m² in women, and 10–44 mL/m² in men and 8–36 mL/m² in women, respectively.²³ In contrast, RVEF in women is larger than in men. The normal value of RVEF is 58 ± 6.5%, and the abnormal threshold is 45%, independent of gender.

Although the 2D RV strain has demonstrated its usefulness and superiority over conventional RV functional parameters for assessing RV performance in patients with PH,^39,40 2D-speckle tracking echocardiography (2D-STE) has some inevitable limitations, including inaccurate myocardial tracking because of the through-plane phenomenon and the availability of strain measurement only in the longitudinal direction. Moreover, evaluation is limited to an area within the RV, and information about RV outflow, in particular, is lacking. Three-dimensional RV wall motion tracking (3D RV WMT) is a recently developed 3D-STE technique for evaluating global and regional RV function that takes into account the complex anatomy of the RV.^41,42 The RV global area change ratio (ACR) and the area strain measured by 3D-STE have components of both longitudinal and circumferential strain. Consequently, ACR has the potential to provide more accurate information about global and regional RV dysfunction and could be of unprecedented benefit for the assessment of the RV in PH.

Clinical Impact of RV Function in PulmonaryHypertension

Effects of hemodynamics on RV function

High PAP leads to RV pressure overload and the elevation of RV wall stress. RV pressure overload results in various RV dysfunctions, including RV dilatation, reduced RV wall motion, intraventricular RV dyssynchrony, and interventricular dyssynchrony. In the early stages (borderline) of PH, intraventricular RV dyssynchrony may be present,¹⁵ leading to the loss of peristaltic RV motion. We also reported that the assessment of peak RV strain in mild PH revealed that intraventricular RV dyssynchrony induced a reduction in RVEF without RV contractile dysfunction. This reduction was restored after treatment, implying that intraventricular RV dyssynchrony may be the regulatory factor for RV function.⁴³ In the early stages of PH, the conventional RV functional parameters such as TAPSE, RV S’, and RVFAC remain normal; consequently, RV strain analysis is most favorable for detecting subtle hemodynamic changes.

As PH progress, the RV becomes less dependent on longitudinal shortening and more dependent on transverse wall motion,^13,14 resulting in reductions of TAPSE, RV S’, and peak RV strain. Furthermore, in more advanced stages of PH, the delay of RV free wall peak shortening compared to the septum, i.e., interventricular dyssynchrony, may occur with the leftward shift of the septum leading to LV underfilling and a subsequent reduction in stroke volume.⁴⁴ Although most echocardiographic RV functional parameters significantly correlated with hemodynamics such as mPAP and PVR, we demonstrated that 3DRVEF had the strongest correlation in PH.⁴⁵

Although there is no doubt that RV afterload is a critical factor affecting RV function in PH, damage to RV muscle by chronic RV pressure overload should be taken into account. RV strain may remain impaired even after normalization of the mPAP by balloon pulmonary angioplasty in patients with chronic thromboembolic pulmonary hypertension. This fact implies that the current therapeutic clinical guidelines that recommend the use of hemodynamic parameters such as mPAP and PVR for the evaluation of patients with PH may not be sufficient and that the assessment of RV analysis is also essential.

Prognostic impact of RV function

Previous studies have shown that mortality in patients with pulmonary arterial hypertension is associated with both the severity of symptoms and the extent of right heart failure.⁴⁶ Moreover, RV function is a predictor of mortality in these patients, as evidenced by the correlation between clinical outcomes and several RV parameters, including TAPSE, RV S’, RVFAC, and RV strain. RV strain is correlated with not only disease severity and/or clinical outcomes^31,39 but also with exercise capacity.^4,33,39

In addition, 3DRVEF may be a predictive parameter associated with the combined endpoint of hospitalization, death, or lung surgery.⁴⁷ Because RV systolic function is mediated by various factors such as RV contractility, RV synchronization, and PVR,⁴⁸ the mechanisms of RV dysfunction should be identified for each pathophysiological condition. We also previously reported that Cox proportional hazard analysis identified echocardiographic 3DRVEF, and not mPAP, as an independent predictor of clinical events in patients with pulmonary hypertension.⁴⁵ Furthermore, Kaplan–Meier analysis revealed that long-term outcomes for patients with 3DRVEF <38% were worse than for those with 3DRVEF ≥38%. These results emphasize the predominant significance of 3DRVEF compared with hemodynamic parameters. This might be because RVEF declines along with an almost parallel decrease in Ees/Ea during the course of PH,⁴⁹ implicating it as a marker of ventricular–arterial coupling over RV systolic function.⁵⁰ The importance of 3DRVEF is also supported by the fact that Ees/Ea is an independent prognostic factor in PH and that Ees/Ea and RVEF are inversely related, i.e., Ees/Ea=RVEF/(1–RVEF), and should contain similar prognostic information.

Regional RV dysfunction assessed by 3D speckle tracking echocardiography

Three-dimensional RV WMT is facilitated by recently developed 3D-STE software for evaluating global and regional RV function that takes into account the complex anatomy of the RV (Fig. 1).^41,42 We recently reported a case concerning a PH patient with heterogeneous RV functional abnormalities with hyperkinetic inlet motion and reduced contraction in the apical and outflow areas.⁵¹ Because the cross-section on 2D RV echocardiographic analyses, such as that using the four-chamber view, did not include the apical and outflow RV walls, 2D RV echocardiography could not detect the asynergy in the apical and outflow RV areas. In contrast, RV-specific 3D-STE could successfully detect heterogeneous RV functional abnormalities with hyperkinetic inlet motion and reduced contraction in the apical and outflow areas in patients with pulmonary arterial hypertension. Although assessment of RV function is useful in predicting the prognosis of patients with PH, inaccurate RV analysis may lead to misunderstanding the disease condition. In this regard, 3D RV WMT is specifically useful and essential for accurate evaluation of RV function. Further studies on the significance of RV regional analysis using 3D RV WMT are necessary.

Fig. 1.

Echocardiographic parameters for the evaluation of right ventricular systolic function. (A) Tricuspid annular plane systolic excursion (TAPSE), (B) right ventricular fractional area change (RVFAC), (C) peak systolic velocity of tricuspid annulus by pulsed-wave Doppler (RV S’), (D) right ventricular strain, and (E) three-dimensional right ventricular image by 3D speckle tracking echocardiography. Using the latter, both longitudinal and circumferential systolic function can be evaluated. TV, tricuspid valve; PV, pulmonic valve.

Acknowledgments

I thank Dr. Hidenori Moriyama for reading this manuscript.

Conflicts of Interest

The author declares that no conflict of interest exists.

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