Right Ventricular Myocardial Work Characterization

in Patients With Pulmonary Hypertension and Relation

to Invasive Hemodynamic Parameters and Outcomes
Steele C. Butcher, MD, MPhila,b, Christos Feloukidis, MDc, Vasileios Kamperidis, MD, PhDa,c,
Idit Yedidya, MDa,d, Jan Stassen, MDa, Federico Fortuni, MDa,e, Elena Vrana, MDc,
Sophia A. Mouratoglou, MD, PhDc, Afroditi Boutou, MD, PhDc, George Giannakoulas, MD, PhDc,
David Playford, MD, PhDf, Nina Ajmone Marsan, MD, PhDa, Jeroen J. Bax, MD, PhDa, and
Victoria Delgado, MD, PhDa,*

Noninvasive evaluation of indexes of right ventricular (RV) myocardial work

(RVMW) derived from RV pressure-strain loops may provide novel insights into RV
function in precapillary pulmonary hypertension. This study was designed to evaluate
the association between the indexes of RVMW and invasive parameters of right heart
catheterization and all-cause mortality. Noninvasive analysis of RVMW was com-
pleted in 51 patients (mean age 58.1 § 12.7 years, 31% men) with group I or group
IV pulmonary hypertension. RV global work index (RVGWI), RV global constructive
work (RVGCW), RV global wasted work (RVGWW), and RV global work efficiency
(RVGWE) were compared with parameters derived invasively during right heart
catheterization. Patients were followed-up for the occurrence of all-cause death. The
median RVGWI, RVGCW, RVGWW, and RVGWE were 620 mm Hg%, 830 mm
Hg%, 105 mm Hg% and 87%, respectively. Compared with conventional echocardio-
graphic parameters of RV systolic function, RVGCW and RVGWI correlated more
closely with invasively derived RV stroke work index (R = 0.63, p <0.001 and
R = 0.60, p <0.001, respectively). Invasively derived pulmonary vascular resistance
correlated with RVGWW (R = 0.63, p <0.001), RVGWE (R = 0.48, p <0.001), and
RV global longitudinal strain (R = 0.58, p <0.001). RVGCW (hazard ratio 1.42 per
100 mm Hg% <900 mm Hg%, 95% confidence interval 1.12 to 1.81, p = 0.004) and
RVGWI (hazard ratio 1.46 per 100 mm Hg% <650 mm Hg%, 95% confidence inter-
val 1.09 to 1.94, p = 0.010) were significantly associated with all-cause mortality,
whereas RV global longitudinal strain, RVGWE, and RVGWW were not. In conclu-
sion, indexes of RVMW were more closely correlated with invasively derived RV
stroke work index and peripheral vascular resistance than conventional echocardio-
graphic parameters of RV systolic function. Decreased values of RVGCW and
RVGWI were associated with all-cause mortality, whereas conventional echocardio-
graphic parameters of RV function were not. © 2022 The Author(s). Published by
Elsevier Inc. This is an open access article under the CC BY license (http://
creativecommons.org/licenses/by/4.0/) (Am J Cardiol 2022;177:151−161)

A recently developed echocardiographic method of provide an estimate of right ventricular (RV) myocardial
evaluating left ventricular (LV)1 myocardial work to work,2 using noninvasively derived pressure-strain loops,
provides a quantitative estimate of ventricular deforma-
a
Department of Cardiology, Leiden University Medical Center, Lei-
tion that accounts for afterload, dyssynchrony, and post-
den, The Netherlands; bDepartment of Cardiology, Royal Perth Hospital, systolic shortening. The quantitative integration of these
Perth, Western Australia, Australia; cDepartment of Cardiology, AHEPA important components of RV function may provide the
University Hospital, Aristotle University, Thessaloniki, Greece; dDepart- clinician a more comprehensive evaluation of the status
ment of Cardiology, Rabin Medical Center, Petah-Tikva, Israel; eDivision of the right ventricle than standard echocardiographic
of Cardiology, "Citta della Salute della Scienza" University Hospital, evaluation of RV function. However, this novel method
Turin, Italy; and fSchool of Medicine, University of Notre Dame, Freman- has not been investigated in patients with precapillary
tle, Western Australia, Australia. Manuscript received December 23, 2021; pulmonary hypertension. Therefore, this study was
revised manuscript received and accepted April 23, 2022. designed to (1) evaluate the association between the novel
Dr. Butcher received funding from European Society of Cardiology, Eng
indexes of RV myocardial work and the invasively derived
Sci Research grant App000080404, Brussels, Belgium.
See page 160 for disclosure information.
parameters and (2) to evaluate the association of RV myo-
*Corresponding author: Tel: +31 71 526 2020; fax: +31 71 526 6809. cardial work parameters with all-cause mortality in
E-mail address: v.delgado@lumc.nl (V. Delgado). patients with precapillary pulmonary hypertension.

0002-9149/© 2022 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license www.ajconline.org
(http://creativecommons.org/licenses/by/4.0/)
https://doi.org/10.1016/j.amjcard.2022.04.058
152 The American Journal of Cardiology (www.ajconline.org)

Methods Transthoracic echocardiography was performed with a

Vivid 7, E9 or E95 ultrasound system (General Electric
Between January 2016 and March 2020, patients with Vingmed Ultrasound, Milwaukee, Wisconsin) equipped
pulmonary arterial hypertension (group I) or chronic with a 3.5-MHz or M5S transducer, with patients at rest in
thromboembolic pulmonary hypertension (group IV) who the left lateral decubitus position. Electrocardiogram-trig-
underwent right heart catheterization (RHC) at the gered echocardiographic data were stored offline in a cine-
AHEPA University General Hospital (Thessaloniki, loop format for analysis with EchoPac software (EchoPac
Greece) were identified. Patients who underwent echocar- 204, General Electric Vingmed Ultrasound). LV ejection
diography within 6 weeks of the RHC were included for fraction, LV end-diastolic, and LV end-systolic volumes
further evaluation. Diagnostic confirmation of group I or were calculated using the biplane Simpson method, with
group IV pulmonary hypertension was performed accord- LV mass calculated using a linear 2-dimensional approach.8
ing to the European Society of Cardiology guidelines on Tricuspid annular plane systolic excursion (TAPSE) was
pulmonary hypertension, including RHC (pulmonary derived from M-mode recordings of the lateral tricuspid
hypertension was defined by a mean pulmonary artery annulus in an RV-focused apical view according to guide-
pressure [mPAP] ≥25 mm Hg), nuclear ventilation/perfu- line recommendations.8 RV end-systolic and end-diastolic
sion scan, pulmonary function tests, and the diffusing areas were measured in an RV-focused apical view,
capacity of the lung for carbon monoxide.3 Patients with whereas RV fractional area change (FAC) was calculated
pulmonary hypertension because of left heart disease with the following equation: ([RV end-diastolic area − RV
(group II, n = 7) or because of lung diseases and/or end-systolic area]/RV end-diastolic area) £ 100. Pulmonary
chronic hypoxia (group III, n = 4) and patients with an artery systolic pressure (PASP) was estimated from the tri-
echocardiogram performed outside the specified time cuspid regurgitation jet peak velocity using the modified
window (n = 2) or where RV myocardial work could not Bernoulli equation (PASP = 4 £ [tricuspid regurgitation jet
be analyzed (n = 6) were excluded. Because this study velocity]2 + estimated right atrial pressure). Estimated right
was designed to evaluate the effect of isolated elevated atrial pressure was calculated on the basis of the evaluation
pulmonary pressure on RV work and invasive hemody- of the inferior vena cava diameter and its collapsibility.9
namics, patients with group II pulmonary hypertension All other standard measurements were performed according
were excluded. Additionally, patients with group III pul- to the European Association of Cardiovascular Imaging and
monary hypertension were excluded because of the American Society of Echocardiography guidelines.8
important association between hyperinflation, impaired The quantification of parameters of RV myocardial
LV filling, and reductions in stroke volume.4 work was performed using proprietary software (Echo-
Additionally, to create a control group with no structural PAC version 204, GE Healthcare, Horten, Norway), which
cardiac disease to compare values of RV myocardial work was originally developed for the assessment of LV myo-
with invasive hemodynamics, patients with systemic sclero- cardial work by 2-dimensional speckle-tracking echocar-
sis referred for RHC at Leiden University Medical Center diography,1 adapted for RV work analysis, as previously
with normal diastolic function,5 normal systolic function described.2 Initially, an RV-focused apical 4-chamber
(LV ejection fraction ≥50%), no significant (≥moderate) view was used to derive RV global longitudinal strain
valvular heart disease, and with an mPAP <25 mm Hg on (RVGLS) (including the regions of the RV free wall and
RHC were selected. Demographic and clinical data were interventricular septum) (Figure 1). Pulsed-wave Doppler
prospectively collected. Due to the retrospective study was used to define the pulmonary valve opening and clo-
design, the institutional review boards of AHEPA Univer- sure timings, whereas event timings of the tricuspid valve
sity General Hospital and Leiden University Medical Cen- were derived from direct visualization of the valve leaflets
ter waived the need for written informed consent. on an RV-focused apical 4-chamber view. Subsequently,
All RHC procedures were performed by an experienced RVGLS and pulmonary arterial pressures were synchro-
interventional cardiologist. A 7.5 French triple lumen Swan nized by valvular event timings, producing pressure-strain
Ganz CCOmbo V thermodilution catheter (Edwards Life- loops of the right ventricle. RV myocardial work was then
sciences) was inserted by way of an 8 French introducer calculated by integrating the product of the rate of seg-
sheath through the right femoral or internal jugular vein mental shortening and instantaneous RV pressure over
under fluoroscopic guidance. Right atrial pressure, pulmo- time to obtain myocardial work as a function of time dur-
nary artery wedge pressure, mPAP, systolic pulmonary ing isovolumic contraction, ejection, and isovolumic
artery pressure, and diastolic pulmonary artery pressure relaxation. A total of 4 parameters of RV function were
were obtained at end-expiration. Cardiac output was deter- then derived from the analysis of the RV pressure-strain
mined by thermodilution, according to guideline recom- loops: (1) RV global work index (RVGWI), derived from
mendations.3 Stroke volume was calculated by dividing the area within the global RV pressure-strain loop; (2) RV
cardiac output by heart rate, whereas cardiac index and global constructive work (RVGCW), equal to the work
stroke volume index were calculated by indexing cardiac contributing to myocardial shortening during systole and
output and stroke volume by body surface area. RV stroke lengthening during isovolumic relaxation; (3) RV global
work index was calculated using the following equation6: wasted work (RVGWW), equal to the work contributing
stroke volume index £ (mPAP right atrial to myocardial lengthening during systole and shortening
pressure) £ 0.0136. Peripheral vascular resistance (PVR) during isovolumic relaxation; and (4) RV global work effi-
was calculated as7: (mPAP − pulmonary artery wedge pres- ciency (RVGWE), calculated by the following formula:
sure)/cardiac output. (RVGCW/[RVGCW + RVGWW]) £ 100%.
 Miscellaneous/RV Myocardial Work in Pulmonary Hypertension 153

Figure 1. Method of acquisition of RV myocardial work parameters. RV myocardial work incorporates speckle-tracking echocardiography-derived RV
strain, pulmonary pressures, and cardiac valve opening and closure events to generate noninvasive pressure-strain loops of the right ventricle. Panel A depicts
the acquisition of RV global longitudinal strain utilizing speckle-tracking echocardiography. The upper image in Panel B demonstrates an image used for the
estimation of PASP from the TR jet peak velocity using the modified Bernoulli’s equation. The lower image in Panel B demonstrates the synchronization of
cardiac valvular event timings, performed through either direct visualization of the two-dimensional image presented, or using event timings established by
pulsed-wave Doppler interrogation. Panel C demonstrates the noninvasive estimation of RV myocardial work indexes and a pressure-strain loop of the basal
segment of the free wall of the right ventricle. TR = tricuspid regurgitation.

The primary end point of the study was all-cause mortal- log-rank test was used to compare groups. The association
ity at follow-up. Mortality data were complete for all of clinical, RHC, and echocardiographic variables with all-
patients. Follow-up began from the date of echocardiogra- cause mortality was investigated by univariable Cox pro-
phy and data for all patients were included up to the last portional hazards regression models. To optimize the bal-
date of follow-up. ance between bias and variance while accounting for
Statistical analyses were performed using SPSS version nonlinearity, RVGCW and RVGWI were refitted in the
25.0 (IBM Corporation, Armonk, New York) and R version Cox proportional hazards regression models with linear
4.0.1 (R Foundation for Statistical Computing, Vienna, spline terms, reducing variance and minimizing model
Austria). Adherence to normality was verified through overfitting.10 The proportional hazards assumption was ver-
visual assessment of histograms of the sample data. Nor- ified through the assessment of scaled Schoenfeld residuals.
mally distributed continuous variables are presented as The HR and 95% confidence intervals (CIs) were calculated
mean § SD, whereas non-Gaussian variables are presented and reported for each variable. To examine the reproduc-
as median and interquartile range. Categoric variables are ibility of indexes of RV myocardial work, 10 individuals
expressed as numbers and percentages. Spearman correla- were randomly selected for the evaluation of intra- and
tion was used to evaluate the association between prespeci- interobserver agreement using ICCs. The second observer
fied invasive RHC (RV stroke work index, stroke volume was blinded to the measurements of the first observer for
index, and PVR) and echocardiographic variables (includ- interobserver measurements. All tests were 2-sided and p
ing indexes of RV myocardial work, standard parameters of <0.05 were considered statistically significant.
RV systolic function, and PASP). Additionally, to evaluate
the difference in the estimation of RV myocardial work
Results
indexes with invasively derived pulmonary pressures versus
echocardiographically derived pulmonary pressures, intra- A total of 57 patients (mean age 58 § 13 years, 31%
class correlation (ICC) coefficients were calculated. All men) fulfilled the study inclusion criteria, with RV myocar-
analyses were performed only in patients in whom RV dial work analysis feasible in 51 patients. The median time
myocardial work analysis was feasible. For the evaluation between echocardiogram and RHC was 1 (0 to 10) day. A
of the end point of all-cause mortality, restricted cubic total of 21 patients with systemic sclerosis and without
spline curve analysis was used to investigate the hazard structural cardiac disease were included to facilitate com-
ratio (HR) change for all-cause mortality across a range of parison with the precapillary pulmonary hypertension
values of RV myocardial work parameters. Likelihood ratio group. A summary of clinical and RHC characteristics of
tests were used to determine the significance of nonlinear- both groups are presented in Table 1.
ity. A threshold of RVGCW and RVGWI to dichotomize Table 2 provides a summary of the echocardiographic
the population for Kaplan−Meier analysis was estimated characteristics of the study population. Conventional
using the fitted spline curves. Cumulative survival rates parameters of RV systolic function were decreased, with a
were calculated using the Kaplan−Meier method and the mean RVFAC of 30 § 11% and mean RVGLS of 15.5 §
154 The American Journal of Cardiology (www.ajconline.org)

Table 1
Clinical and right heart catheterization characteristics
Overall Precapillary pulmonary No structural cardiac
Variable (N = 72) hypertension (N = 51) disease (N = 21) P-value
Age (years) 56 (§13) 58 (§13) 49 (§10) 0.003
Men 27 (38%) 16 (31%) 11 (52%) 0.094
Systolic blood pressure (mmHg) 124 (20) 126 (21) 116 (16) 0.044
PDE-5 inhibitor 18 (25%) 18 (35%) 0 (0%) 0.002
Endothelin receptor antagonist 17 (24%) 17 (33%) 0 (0%) 0.002
Guanylate cyclase stimulator 7 (9.9%) 7 (14%) 0 (0%) 0.18
Prostacyclin 3 (4.2%) 3 (5.9%) 0 (0%) 0.55
Right atrial pressure (mmHg) 7 (4 to 9) 7 (5 to 10) 6 (4 to 7) 0.033
sPAP (mmHg) 56 (§25) 67 (§20) 28 (§5) <0.001
dPAP (mmHg) 20 (13 to 27) 23 (18 to 30) 11 (9 to 13) <0.001
mPAP (mmHg) 34 (20 to 45) 41 (34 to 48) 16 (14 to 19) <0.001
Stroke volume index (ml/m2) 38 (§11) 38 (§12) 40 (§7) 0.34
Cardiac index (L/min/m2) 2.95 (§0.90) 2.92 (§1.00) 3.02 (§0.63) 0.62
RV stroke work index (ml.mmHg/m2) 12 (7 to 17) 16 (12 to 20) 6 (5 to 7) <0.001
PVR (WU) 4.1 (2.0 to 6.8) 5.4 (4.0 to 8.2) 1.5 (1.0 to 1.8) <0.001
PAWP (mmHg) 10 (8 to 12) 10 (8 to 12) 9 (6 to 11) 0.089
Values are presented as mean § SD, median (IQR) or n (%).
dPAP = diastolic pulmonary artery pressure; mPAP = mean pulmonary artery pressure; PAWP = pulmonary artery wedge pressure;
PDE5 = phosphodiesterase type 5 inhibitor; PVR = peripheral vascular resistance; sPAP = systolic pulmonary artery pressure; WU = Wood units.

5.5%. Median RVGWI, RVGCW, and RVGWW were 620 for RVGWI and 0.97 for RVGCW, indicating excellent
(446 to 848) mm Hg%, 830 (660 to 1,201) mm Hg%, and agreement, whereas the interobserver variability was 0.87
105 (56 to 166) mm Hg%, respectively; whereas median for RVGWE and 0.76 for RVGWW, indicating good reli-
RVGWE was 87 (82 to 93)%. The ICCs for intraobserver ability (Supplementary Table 1).
variability were 0.96 for RVGWI, 0.92 for RVGCW, and Compared with PASP and conventional echocardio-
0.90 for RVGWE demonstrating excellent reliability graphic parameters of RV systolic function (including
(Supplementary Table 1). The ICC for intraobserver vari- RVGLS, TAPSE, and RVFAC), RVGCW and RVGWI cor-
ability for RVGWW was 0.78, signifying good reliability. related more closely with invasively derived RV stroke
Similarly, the ICCs for interobserver variability were 0.97 work index (R = 0.63, p <0.001 and R = 0.60, p <0.001,

Table 2
Echocardiographic characteristics
Overall Precapillary pulmonary No structural cardiac
Variable (N = 72) hypertension (N = 51) disease (N = 21) P-value
RV basal diameter (mm) 44 (§10) 46 (§10) 39 (§7) <0.001
RV mid-diameter (mm) 36 (§11) 39 (§10) 27 (§7) <0.001
Tricuspid annulus diameter (mm) 32.7 (§6.3) 32.3 (§6.6) 33.7 (§5.6) 0.39
Moderate or severe tricuspid regurgitation 7 (9.7%) 7 (14%) 0 (0%) 0.10
Right atrial volume index (ml/m2) 32 (21 to 44) 37 (26 to 49) 23 (18 to 33) 0.001
RV end-diastolic area (cm2) 26 (20 to 31) 30 (22 to 36) 21 (15 to 24) <0.001
RV FAC (%) 36 (§14) 30 (§11) 51 (§7) <0.001
TAPSE (mm) 20.3 (§4.4) 19.2 (§4.4) 22.8 (§3.1) <0.001
RV GLS (%) -17.0 (§5.4) -15.5 (§5.5) -20.7 (§2.8) <0.001
RV FWLS (%) -20 (§7) -18 (§7) -24 (§4) <0.001
PASP (mmHg) 48 (39 to 74) 65 (47 to 81) 29 (25 to 39) <0.001
Right ventricular global work index (mmHg%) 564 (442 to 691) 620 (446 to 848) 544 (403 to 591) 0.047
Right ventricular global constructive work (mmHg%) 708 (592 to 998) 830 (660 to 1,201) 588 (489 to 651) <0.001
Right ventricular global wasted work (mmHg%) 68 (38 to 134) 105 (56 to 166) 38 (21 to 51) <0.001
Right ventricular global work efficiency (%) 90 (85 to 94) 87 (82 to 93) 93 (91 to 96) 0.001
LV mass index (g/m2) 77 (§22) 77 (§23) 77 (§18) 0.88
LV end-diastolic volume (ml) 99 (§33) 96 (§34) 104 (§30) 0.34
LV end-systolic volume (ml) 38 (27 to 50) 39 (28 to 55) 34 (26 to 47) 0.45
LV ejection fraction (%) 63 (55 to 68) 60 (53 to 65) 66 (62 to 70) 0.006
Left atrial volume index (ml/m2) 32 (21 to 38) 29 (21 to 38) 35 (25 to 38) 0.57
Values are presented as mean§SD, median (IQR) or n (%).
LV = left ventricular; LVEF = left ventricular ejection fraction; PASP = pulmonary artery systolic pressure; RV = right ventricular; RV FAC = right ven-
tricular fractional area change; RV FWLS = right ventricular free wall longitudinal strain; RV GLS = right ventricular global longitudinal strain;
TAPSE = tricuspid annular plane systolic excursion.
 Miscellaneous/RV Myocardial Work in Pulmonary Hypertension 155

Figure 2. Correlation between invasively derived right ventricular stroke work index and echocardiographic parameters. RV stroke work index assessed with
right heart catheterization demonstrated a significant association with RVGCW (A), RVGWI (B) and PASP (C). The association between RVGLS and RV
stroke work index was not significant (D). PHTN = pulmonary hypertension.

respectively) (Figures 2, Supplementary Figure 1). In con- for RVGCW and 500 mm Hg% for RVGWI were estimated
trast, RVGLS (R = 0.57, p <0.001) correlated more from the respective spline curves. Kaplan−Meier analysis
closely with invasively derived stroke volume index than demonstrated significantly worse survival for patients with
RVGCW, RVGWI and RVGWE (R = 0.34, p = 0.016, RVGCW <550 mm Hg% than patients with an RVGCW
R = 0.48, p <0.001 and R = 0.47, p <0.001, respectively) ≥550 mm Hg% (96% and 64% vs 71% and 14%, at 1 and
(Figure 3). Invasively derived PVR correlated with 5 years of follow-up, respectively, p = 0.0007; Figure 6).
RVGWW (R = 0.63, p <0.001), RVGWE (R = 0.48, p Additionally, patients with an RVGWI <500 mm Hg% had
<0.001), RVGLS (R = 0.58, p <0.001), and PASP significantly worse estimated survival than those with an
(R = 0.66, p <0.001) (Figure 4). Moreover, similar correla- RVGWI ≥500 mm Hg% (97% and 64% vs 81% and 34%,
tions were observed in the patient cohort without structural at 1 and 5 years of follow-up, respectively, p = 0.008;
cardiac disease: RVGCW and RVGWI demonstrated an Figure 6). Univariable Cox regression analysis demon-
association with RV stroke work index (R = 0.62, p = 0.003 strated an association between all-cause mortality and
and R = 0.48, p = 0.028, respectively), RVGLS showed an RVGCW (HR 1.42 per 100 mm Hg% <900 mm Hg%, 95%
association with invasively derived stroke volume index 1.12 to 1.81, p = 0.004) and all-cause mortality and RVGWI
(R = 0.49, p = 0.023), and RVGWW was correlated with (HR 1.46 per 100 mm Hg% <650 mm Hg%, 95% CI 1.09 to
invasively derived PVR (R = 0.51, p = 0.017). 1.94, p = 0.010). Additionally, an association was observed
Over a median follow-up of 35 (interquartile range 25 to between age, RV stroke work index, and all-cause mortal-
45) months, a total of 17 patients (33%) died. Spline curve ity. However, no association was observed between
analyses showed significant increases in the hazard for all- RVGLS, RVFAC, TAPSE, PASP, PVR, RVGWE, or
cause mortality with progressively lower values of RVGWW and all-cause mortality (Table 3).
RVGCW (Figure 5) and RVGWI (Figure 5), although not
for RVGWE, RVGWW, or RVGLS (Supplementary Figure
Discussion
2). Likelihood ratio tests demonstrated that there was sig-
nificant nonlinearity for RVGCW (p = 0.031) and RVGWI RV performance is a major determinant of prognosis in
(p = 0.043), with an increasing hazard for mortality, evident patients with precapillary pulmonary hypertension and may
from values of <900 mm Hg% for RVGCW and for values be evaluated with invasive techniques, including RHC or
of <700 mm Hg% for RVGWI. To dichotomize the popula- noninvasive methods, such as echocardiography or cardiac
tion for Kaplan−Meier analyses, cutoffs of 550 mm Hg% magnetic resonance.11 Current guidelines state that RHC is
156 The American Journal of Cardiology (www.ajconline.org)

Figure 3. Correlation between invasively derived stroke volume index and echocardiographic parameters. Stroke volume index assessed with right heart
catheterization demonstrated a significant association with RVGWI (A), RVGWE (B), RVGCW (C) and RVGLS (D). PHTN=pulmonary hypertension.

Figure 4. Correlation between invasively derived PVR and echocardiographic parameters PVR assessed with right heart catheterization demonstrated a sig-
nificant association with RVGWW (A), RVGWE (B), RVGLS (C) and PASP (D). PHTN = pulmonary hypertension.
 Miscellaneous/RV Myocardial Work in Pulmonary Hypertension 157

Figure 5. Spline curves demonstrating the hazard ratio for all-cause mortality according to RVGCW (A) and RVGWI (B). The curves in (A) and (B) demon-
strate the hazard ratio change for all-cause mortality with 95% confidence intervals (blue shaded areas) in patients with precapillary pulmonary hypertension,
across a range of values of RVGCW (A) and RVGWI (B) at the time of echocardiography.
158 The American Journal of Cardiology (www.ajconline.org)

Figure 6. Kaplan−Meier curves for all-cause mortality for RV myocardial work parameters for patients with precapillary pulmonary hypertension. Panel A
demonstrates the Kaplan−Meier curve for RVGCW of 550 mm Hg%, while Panel B shows the Kaplan−Meier curve for RVGWI at a cutoff of 500 mm
Hg%.
 Miscellaneous/RV Myocardial Work in Pulmonary Hypertension 159

Table 3
Univariable Cox regression for association with all-cause mortality
Variable HR (95% CI) P-value
Age (per year) 1.05 (1.00 to 1.10) 0.045
PDE-5 inhibitor 0.73 (0.25 to 2.10) 0.55
Endothelin receptor antagonist 0.83 (0.30 to 2.30) 0.72
Guanylate cyclase stimulator 0.61 (0.14 to 2.72) 0.52
Right atrial pressure (per mmHg) 0.88 (0.74 to 1.06) 0.18
sPAP (per mmHg) 0.98 (0.95 to 1.01) 0.11
mPAP (per mmHg) 0.95 (0.90 to 1.00) 0.064
Stroke volume index (per ml/m2) 0.97 (0.92 to 1.02) 0.19
RV stroke work index (per ml.mmHg/m2) 0.89 (0.80 to 0.99) 0.038
PVR (per WU) 0.93 (0.83 to 1.05) 0.26
PAWP (per mmHg) 0.90 (0.74 to 1.10) 0.30
≥ Moderate tricuspid regurgitation 0.26 (0.03 to 2.14) 0.21
Right atrial volume index (per ml/m2) 0.99 (0.98 to 1.01) 0.59
RV end-diastolic area (per cm2) 1.03 (0.98 to 1.09) 0.19
RV FAC (per %) 0.98 (0.94 to 1.03) 0.45
TAPSE (per mm) 1.03 (0.92 to 1.16) 0.56
RV GLS (per %) 1.07 (0.98 to 1.17) 0.13
PASP (per mmHg) 0.99 (0.97 to 1.01) 0.21
LV ejection fraction (per %) 0.99 (0.95 to 1.04) 0.78
Left atrial volume index (per ml/m2) 1.01 (0.97 to 1.05) 0.77
Right ventricular global work index (RV GWI) (per 100mmHg% below 650mmHg%) 1.46 (1.09 to 1.94) 0.010
Right ventricular global constructive work (RV GCW) (per 100mmHg% below 900mmHg%) 1.42 (1.12 to 1.81) 0.004
Right ventricular global wasted work (RV GWW) (per mmHg%) 1.00 (0.99 to 1.00) 0.18
Right ventricular global work efficiency (RV GWE) (per %) 1.00 (0.95 to 1.07) 0.88
CI = confidence interval; HR = hazard ratio; LV = left ventricular; LVEF = left ventricular ejection fraction; mPAP = mean pulmonary artery pressure;
PASP = pulmonary artery systolic pressure; PAWP = pulmonary artery wedge pressure; PDE5 = phosphodiesterase type 5 inhibitor; PVR = peripheral vascu-
lar resistance; RV = right ventricular; RV FAC = right ventricular fractional area change; RV GLS = right ventricular global longitudinal strain;
sPAP = systolic pulmonary artery pressure; TAPSE = tricuspid annular plane systolic excursion; WU = Wood units.

the gold standard for the evaluation and diagnosis of group I provide an evaluation of RV performance that accounts for
and group IV pulmonary hypertension.3,12 PVR and mPAP afterload and myocardial work efficiency.
provide an evaluation of RV afterload and stroke volume In the future, the noninvasive evaluation of RV myocar-
index provides an indirect estimate of RV contractility, dial work may have the potential to enhance echocardio-
whereas RV stroke work index estimates RV workload graphic monitoring of patients with precapillary pulmonary
through the incorporation of both RV function and hemody- hypertension. Hemodynamic parameters derived from RHC
namics.13 However, because of cost, training requirements, during follow-up after treatment (such as PVR and stroke
and associated risks, there is a driving interest in the devel- volume index) have been shown to be independently associ-
opment of noninvasive alternatives for the serial monitoring ated with adverse prognosis.18,19 Monitoring with serial
and assessment of RV performance in pulmonary hyperten- RHC may improve the risk stratification and management
sion.14 Although conventional echocardiographic parame- of patients with group I pulmonary hypertension.3,20 How-
ters of RV function have been demonstrated to be ever, with a rate of serious complications of approximately
prognostically important in precapillary pulmonary hyper- 1%, cheaper, noninvasive alternatives to serial RHC are
tension,15 they reflect the interaction between pulmonary needed.21 Changes in conventional echocardiographic
vascular load and the contractility of the right ventricle, parameters of RV performance, such as RVGLS, have been
providing a significantly afterload-dependent evaluation of independently associated with clinical deterioration and all-
RV performance.16 Indeed, because right heart failure is cause mortality in patients with group I pulmonary hyper-
often a direct consequence of increased afterload and not tension, implying a possible role for the monitoring of these
only the consequence of primary myocardial disease, a full patients with speckle-tracking echocardiography.22 How-
physiologic analysis of the cardiopulmonary unit is neces- ever, simultaneous evaluation of indexes of RV myocardial
sary to correctly interpret clinical and imaging data.16 For work may contextualize any changes in RVGLS by provid-
instance, parameters such as RV ejection fraction and ing an estimate of RV performance that also accounts for
TAPSE are typically decreased in patients with group I pul- afterload and mechanical work efficiency.
monary hypertension, despite evidence of increased con- Several studies have demonstrated that pressure-strain
tractility when RV end-systolic elastance is evaluated.17 loops of the left ventricle derived from speckle-tracking
Contrarily, RV myocardial work derived noninvasively echocardiography strongly correlate with myocardial glu-
from pressure-strain loops provides an estimate of RV per- cose metabolism by 18F-fluorodeoxyglucose positron emis-
formance that accounts for afterload and mechanical effi- sion tomography.1,23 RV myocardial work may also
ciency. Unlike RVGLS, TAPSE, and RVFAC, these novel provide a noninvasive estimate of regional myocardial ener-
indexes do not only reflect system function16 but also getics and could be useful for the evaluation of the right
160 The American Journal of Cardiology (www.ajconline.org)

ventricle, considering that the extent of RV glucose uptake invasive assessment of right ventricular function. Eur Heart J Cardio-
on 18F-fluorodeoxyglucose positron emission tomography vasc Imaging 2021;22:142–152.
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RVGCW and RVGWI were associated with all-cause mor- Zompatori M, Hoeper M. 2015 ESC/ERS Guidelines for the diag-
tality, and that this relation was significantly nonlinear. nosis and treatment of pulmonary hypertension: the Joint Task
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tional parameters of RV function, were not associated with Respiratory Society (ERS): endorsed by: Association for European
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Disclosures European Association of Echocardiography, a registered branch of the
European Society of Cardiology, and the Canadian Society of Echo-
The Department of Cardiology of the Leiden University cardiography. J Am Soc Echocardiogr 2010;23:685–713.
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cular, Bayer, Bioventrix, Medtronic, Biotronik, Boston Sci- tional Publishing; 2019.
entific, GE Healthcare (Horten, Norway), and Edwards 11. Lahm T, Douglas IS, Archer SL, Bogaard HJ, Chesler NC, Haddad F,
Lifesciences (Irvine, California). Drs. Bax and Marsan Hemnes AR, Kawut SM, Kline JA, Kolb TM, Mathai SC, Mercier O,
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A, Voelkel NF, Vonk-Noordegraaf A, Hassoun PM. American Tho-
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