Download The Right Ventricular Function After Left Ventricular Assist Device

European Heart Journal – Cardiovascular Imaging (2016) 17, 429–437
doi:10.1093/ehjci/jev162
The Right Ventricular Function After Left
Ventricular Assist Device (RVF-LVAD) study:
rationale and preliminary results
Andreas P. Kalogeropoulos 1*, Raghda Al-Anbari 1, Ann Pekarek 1,
Kristin Wittersheim 1, Maria A. Pernetz 1, Amber Hampton 1, Jerilyn Steinberg 1,
Vasiliki V. Georgiopoulou 1, Javed Butler 2, J. David Vega 3, and Andrew L. Smith 1
1
Division of Cardiology, Department of Medicine, Emory Clinical Cardiovascular Research Institute, Emory University, 1462 Clifton Road NE, Suite 535B, Atlanta, GA, USA;
Division of Cardiology, Department of Medicine, Stony Brook University, Stony Brook, NY, USA; and 3Division of Cardiothoracic Surgery, Department of Surgery,
Emory University, Atlanta, GA, USA
2
Received 24 February 2015; accepted after revision 31 May 2015; online publish-ahead-of-print 9 July 2015
Aims
Despite improved outcomes and lower right ventricular failure (RVF) rates with continuous-flow left ventricular assist
devices (LVADs), RVF still occurs in 20-40% of LVAD recipients and leads to worse clinical and patient-centred outcomes and higher utilization of healthcare resources. Preoperative quantification of RV function with echocardiography
has only recently been considered for RVF prediction, and RV mechanics have not been prospectively evaluated.
.....................................................................................................................................................................................
Methods
In this single-centre prospective cohort study, we plan to enroll a total of 120 LVAD candidates to evaluate standard and
mechanics-based echocardiographic measures of RV function, obtained within 7 days of planned LVAD surgery, for preand results
diction of (i) RVF within 90 days; (ii) quality of life (QoL) at 90 days; and (iii) RV function recovery at 90 days post-LVAD.
Our primary hypothesis is that an RV echocardiographic score will predict RVF with clinically relevant discrimination (C
.0.85) and positive and negative predictive values (.80%). Our secondary hypothesis is that the RV score will predict
QoL and RV recovery by 90 days. We expect that RV mechanics will provide incremental prognostic information for
these outcomes. The preliminary results of an interim analysis are encouraging.
.....................................................................................................................................................................................
Conclusion
The results of this study may help improve LVAD outcomes and reduce resource utilization by facilitating shared decision-making and selection for LVAD implantation, provide insights into RV function recovery, and potentially inform
reassessment of LVAD timing in patients at high risk for RVF.
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Echocardiography † Ventricular mechanics † Ventricular assist devices † Right ventricular function † Risk
prediction models † Outcomes
Background
Ventricular assist devices for advanced
heart failure
The implantable left ventricular assist device (LVAD) is now a standard option as bridge-to-transplant (BTT) for patients with heart failure (HF) deteriorating while awaiting heart transplantation.1,2 Due
to (i) donor organ shortage, (ii) increasing number of patients
who are older or have comorbidities precluding transplantation,
and (iii) improving technology, LVAD is gaining momentum as destination therapy (DT) also.3,4 Currently, 40% of the LVADs are
implanted as DT,5 with 1-year survival exceeding 80% for
continuous-flow devices,5 which currently represent 100% of
the implants.5 An estimated 150 000–250 000 patients are potential
LVAD recipients in the USA.6 However, LVAD remains a high-risk,
high-cost option, necessitating careful patient selection.
Right ventricular failure and LVAD
outcomes
Outcomes after LVAD implantation are critically dependent on right
ventricular (RV) function, which provides flow through the pulmonary vascular bed to fill the LVAD for optimal function.7 Despite
* Corresponding author. Tel: +1 404 778 3652; Fax: +1 404 778 5285, E-mail: [email protected]
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: [email protected].
430
improved outcomes and lower right ventricular failure (RVF) rates
with continuous-flow over pulsatile-flow LVADs,3 RVF still occurs in
13 –40% of the recipients.8 The aetiology of RVF, which is characterized by systemic hypoperfusion with elevated right-sided pressures,
is multifactorial. Intrinsic RV dysfunction,9 ischaemia,10 ventricular
interaction,11 worsening tricuspid regurgitation,12,13 intraoperative
events,14,15 and LVAD management strategies16 have all been implicated. Patients who develop RVF have (i) reduced survival and progression to transplant17 – 24 and worse outcomes thereafter18,22; (ii)
higher resources utilization with longer intensive care stays,15,21,23
more transfusions,23 use of inotropes,15,20 and need for right ventricular assist devices (RVADs)15,21; and (iii) long-term poor exercise capacity and quality of life (QoL).25
Risk for RVF and clinical decision-making
Although RVADs are available for short-term support, long-term
mechanical circulatory support of the RV is still under development.26 Thus, identification of patients at high risk for RVF is of paramount importance, especially for DT implants. Elective, planned
biventricular support is feasible and leads to better outcomes compared with ‘bailout’ RV support.27 Also, surgical series suggest that
reduction of tricuspid regurgitation during LVAD surgery in patients
with severe RV dysfunction may improve outcomes.28,29 Therefore,
assessment of RVF risk has direct implications for patient selection
and planning of surgical strategy.
A.P. Kalogeropoulos et al.
relevant discrimination (C ≥ 0.85) and positive and negative predictive values (.80%). Our secondary hypotheses are that the RV
echocardiographic score will predict (i) poor QoL at 90 days
(C ≥ 0.85) and (ii) the degree of recovery of RV function at 30
and 90 days after LVAD. We expect longitudinal myocardial
mechanics to have incremental value.
Study overview
We plan to enrol 120 adults scheduled to receive an LVAD as
BTT or DT at Emory Healthcare (Atlanta, GA, USA) with Interagency Registry for Mechanically Assisted Circulatory Support
(INTERMACS) Profiles 2 – 7 (Box 1), without plans for mechanical RV support or unresponsive severe pulmonary hypertension
(Table 1). We opted not to include INTERMACS Profile 1
patients because these patients receive an LVAD in emergent
situations, some as a bridge-to-decision after cardiogenic shock.
These conditions are not conducive to complete evaluation for
research purposes. Currently, Profiles 2 – 7 constitute 86% of
the implants.5
Patients undergo complete echocardiography at baseline and
then at 30 and 90 days after implant (Table 2). QoL is assessed
with the Kansas City Cardiomyopathy Questionnaire (KCCQ)
and Euro-QoL 5D-3L at baseline and 90 days. Clinical outcomes
are recorded through 90 days. Blood samples are drawn at baseline
and 30 days for future analyses. Sonographers with extensive
Predicting RVF
Current risk prediction schemes for RVF take into account HF severity, end-organ damage, right-heart haemodynamics, and history
of cardiac procedures.8 No scheme to date includes quantitative
RV variables. Of note, these schemes were primarily developed in
older, pulsatile-flow LVAD cohorts. Notably, although a C-statistic
of 0.73 – 0.74 was reported for clinical scores in derivation cohorts,30,31 substantially lower values (C ¼ 0.61 – 0.66) were observed in external cohorts.30,32
Quantitative RV function has only recently been studied for RVF
prediction.8 However, most studies were retrospective and either
included patients with pulsatile-flow devices or included preimplant decision for biventricular support as RVF.8 RV mechanics
have allowed for early detection of RV dysfunction in various settings. Retrospective studies in continuous-flow LVAD populations
report that RV free wall strain predicted RVF independently of clinical risk scores and better than standard echocardiographic RV variables.32 – 34 However, prospective data are lacking.
Study design and methods
Study objectives and hypotheses
The Right Ventricular Function After Left Ventricular Assist Device
(RVF-LVAD) is a prospective, single-centre cohort study (www.
clinicaltrials.gov NCT01999712) initiated in Q3 2012. In this study,
we evaluate echocardiographic measures of RV function for prediction of (i) RVF, (ii) QoL, and (iii) RV function recovery at 90 days
after LVAD implantation.
Our primary hypothesis is that an echocardiographic score will
predict RVF (occurring within 90 days of implantation) with clinically
Box 1.
INTERMACS Profiles Classification
Profile
Description
1
2
Critical cardiogenic shock
Progressive decline on inotropic support
3
Stable but inotrope-dependent
4
5
Resting symptoms home on oral therapy
Exertion-intolerant
6
Exertion-limited
7
Advanced NYHA Class III symptoms
................................................................................
NYHA, New York Heart Association.
Table 1
Inclusion and exclusion criteria
Inclusion criteria
Exclusion criteria
(1) Age 18–75 years
(1) INTERMACS Profile 1 (critical
cardiogenic shock)
(2) Pre-operative advanced right
ventricular dysfunction, defined
as planned or anticipated need
for right ventricular support or
extracorporeal membrane
oxygenation at surgery
(3) Unresponsive pulmonary
vascular resistance .6 Wood
units
................................................................................
(2) INTERMACS Profiles 2 –7
(3) Willing to participate and
able to provide informed
consent
431
The RVF-LVAD study
Table 2
work may redefine RVF, we will be able to update estimates for
RVF and predictive parameters.
Summary of study procedures
Procedure
Baseline
Day 30
Day 90
Clinical assessment
×
×
×
Echocardiography
Blood drawn
×
×
×
×
×
Kansas City Cardiomyopathy
Questionnaire
×
................................................................................
×
Outcomes surveillance
×
×
RVF definition elements
×
×
experience in research echocardiography have been designated to
perform all echo studies. All data are entered into a REDCapw electronic data capture database securely hosted at Emory. The study
has been approved by the Emory University Institutional Review
Board and has been registered in clinicaltrials.gov with identifier
NCT01999712.
Study outcomes and definitions
Right ventricular failure
Following the INTERMACS definition, RVF is defined as symptoms
and signs of persistent RV dysfunction (defined as central venous
pressure .18 mmHg with a cardiac index ,2.0 L/min/m2 in the absence of pulmonary capillary wedge pressure .18 mmHg, tamponade, ventricular arrhythmias, or pneumothorax), requiring RVAD or
inhaled nitric oxide (or other pulmonary vasodilator) or inotropic
therapy for .7 days any time after LVAD implantation.
Quality of life
Health status and QoL are assessed with KCCQ, which has been established as a valid, reliable, and responsive health status tool in HF,
including LVAD recipients.1,35 KCCQ scales are summarized into a
single score (0–100), with higher scores reflecting better status. A
KCCQ , 45 at 90 days will be considered to be indicative of poor
QoL.36 Euro-QoL 5D-3L is used as an adjunct tool.37
Changes in RV function
We will report changes in (i) standard RV function parameters and
(ii) RV mechanics from baseline to 30 and 90 days post-implant. For
binary definition purposes, improvement of RV free wall strain by
≥5% units will be considered indicative of RV recovery.38
Quality of life
In the pivotal HeartMate II clinical trials, most QoL improvement
after LVAD implantation has taken place by 90 days.40 A KCCQ
summary score ,45 has been associated with worse outcomes
and health status in HF patients and has been used in previous studies in advanced HF41; therefore, we opted for this cut-off point for
the binary definition of poor QoL.
Recovery of RV function
The recovery of RV after LVAD has variable course, but most of the
improvement is seen by 90 days.42 We quantify RV recovery at 30
and 90 days. However, we will also report RV recovery as a binary
response, considering improvement in RV free wall strain ≥5% as
evidence of RV recovery. In a serial study in pulmonary arterial
hypertension,38 this degree of RV recovery was associated with
lower mortality.
Research procedures
Echocardiography
All studies are performed by registered sonographers on Vivid 7 and
E9 systems (GE Healthcare, WI, USA) and transferred in uncompressed raw DICOM for offline analysis. Parameters of LV and RV
functions and haemodynamics are recorded according to the
American Society of Echocardiography (ASE) recommendations.
Standard echocardiographic RV function parameters
The ASE has suggested that RV function be quantified by twodimensional and pulsed-wave tissue Doppler echocardiography.43
Based on previous experience and a thorough literature review,8 we
have selected tricuspid annular plane systolic excursion (TAPSE), peak
systolic velocity (s′ ) at the tricuspid annulus by tissue Doppler, RV
myocardial performance index (MPI), and RV fractional area change
(FAC) as the most representative standard measures of RV function
(Table 3). TAPSE is acquired in the apical four-chamber view by aligning
an M-mode cursor with the tricuspid annulus and measuring the longitudinal motion of the annulus; colour M-mode can facilitate tracking
of motion (Figure 1 A). In the same view, we obtain peak systolic velocity (s′ ) by placing a pulsed tissue Doppler sample volume in the
Table 3 Main echocardiographic parameters of RV
function in the study
Rationale for outcomes and definitions
Standard echocardiography
Echocardiographic
mechanics
Definition of RVF
In previous studies, the definition of RVF has been variable, including
need for RVAD alone or combined with need for prolonged use of
inotropes.8 Need for pulmonary vasodilators following surgery has
also been considered.8 All these components of RVF definition have
been associated with worse outcomes.8 Although no time frame
was specified in previous studies, most of the RVF develops immediately after implantation (,90 days). We have opted for the
INTERMACS definition to facilitate comparison with INTERMACS
registry data.39 However, we collect detailed data on post-LVAD
haemodynamics and use of medications. Therefore, as ongoing
................................................................................
Tricuspid annular plane systolic
excursion (cm)
Pulsed tissue Doppler peak systolic
velocity (s′ ) at the tricuspid
annulus (cm/s)
STE: global strain (%)
RV myocardial performance index
RV fractional area change (%)
STE: free wall strain (%)
STE: free wall systolic strain
rate (1/s)
STE: global systolic strain
rate (1/s)
RV, right ventricle; STE, speckle-tracking echocardiography.
432
A.P. Kalogeropoulos et al.
Figure 1 Evaluation of standard RV function parameters. (A) Evaluation of TAPSE with two-dimensional-guided colour M-mode, which facilitates
tracking of motion. TAPSE is 1.6 cm in this patient (normal: ≥1.6 cm). (B) Pulse tissue Doppler assessment of longitudinal myocardial velocities of the
basal RV free wall. The systolic peak (s′ velocity) is 11 cm/s in this patient (normal: ≥10 cm/s). (C) The RV MPI is calculated from the tissue Doppler
trace as: [tricuspid closure-to-opening (TCO) time minus pulmonary valve ejection time (PVET)] divided by PVET. Lower RV MPI values reflect worse
RV function. In this patient, RV MPI is 0.54 (normal: ≤0.55). (D) The RV FAC is calculated as: [RV area in diastole (34.4 cm2 in this patient) minus RV
area in systole (32.8 cm2, data not shown)] divided by RV area in diastole. The RV FAC in this patient was 5% (normal: ≥35%).
middle of the RV free wall basal segment (Figure 1B). We use a carefully
acquired tissue Doppler trace at the tricuspid annulus to measure MPI
as this is the most reliable approach (Figure 1C). Finally, we measure the
RV FAC from a dedicated RV apical four-chamber view, i.e. adjusting
the transducer angle to focus on the RV chamber, with the goal of
maximizing its chamber size (Figure 1D). On the basis of pathophysiology and previous data, we also consider estimated RV systolic pressure and tricuspid regurgitation44 as potential RVF predictors obtained
with conventional echocardiography.
RV mechanics
In addition to standard measures of RV function, we use speckle tracking to assess longitudinal RV mechanics (strain and strain rate), which
have shown promise in RVF prediction (Table 3). The RV is imaged
from a dedicated apical view with an adequate field to image the entire
RV throughout the cardiac cycle with high frame rate (.40 frames/s),
as described previously.45,46 To assess RV longitudinal deformation,
we adopt the six-segment RV model.45,46 Briefly, the endocardial
border is manually outlined and the myocardium is then tracked by
the algorithm and divided into six segments (Figure 2). The speckletracking algorithm detects the QRS onset from the electrocardiographic signal to define the point of zero strain, amenable to correction, and
calculates segmental and global strain. By temporal derivation of
strain, the corresponding strain rate is obtained. Global parameters
refer to the total deformation of the chamber during the cardiac
cycle in the selected view; the entire length of the tracked myocardium is considered as baseline length. We recorded global peak systolic strain (GS) and global systolic strain rate (GSRs) of the RV in
the longitudinal direction as the main RV mechanics parameters of
interest. We calculate GS and GSRs using the entire length of the RV
myocardium, as shown in Figure 2A. The free wall RV strain and strain
rate are calculated using the three free wall segments (Figure 2B).
We have previously reported on the reproducibility of RV myocardial deformation parameters in our laboratory; the mean absolute
percentage error for measurements performed in random order
by two observers was 6.9 and 8.9% for GS and GSRs, respectively.47
433
The RVF-LVAD study
Figure 2 Evaluation of RV longitudinal mechanics with speckle tracking. The algorithm creates a six-segment model of the RV after manual
delineation of the endocardial border. Global right of RV strain (A) in this LVAD candidate is depressed (211.0%). The segmental RV strain
(B) map reveals that the impairment of contractility is more prominent in interventricular septum. RV, right ventricular.
Blood draws
To facilitate future biomarker studies, we draw blood samples
during the pre-operative assessment (baseline) and at 30 days after
implant. One serum and one plasma tube are centrifuged at 2500 g,
48C for 10 min, and the supernatant is stored at 2808C in cryovials.
Analytic plan
Sample size determination
We plan to enrol 120 patients, based on a conservative 25% rate at
90 days. This sample provides 80% power to detect a difference at
P ¼ 0.05 between receiver operating characteristic (ROC) curve
with C ≥ 0.85 (echocardiographic or combined clinical and echocardiographic score) vs. C ¼ 0.70 (old clinical scores).
Primary hypothesis
Because of relatively short follow-up, we will work in the logistic regression framework. For echocardiographic variable selection, we
will use backwards elimination guided by clinical rationale. The final
set of variables will be converted into a simple score. To assess the
performance of the echocardiographic score, we will calculate (i)
the C-statistic, (ii) sensitivity and specificity, and (iii) positive and
negative predictive values for RVF. Because predictive models overperform in the derivation cohort (‘optimism’),48 we will correct for
optimism by bootstrapping.48 To assess the incremental value over
previous models for RVF prediction, we will enter the score in multivariable models with (i) risk factors identified previously8 and (ii)
existing RVF risk models.8
Secondary hypotheses
The association of the RV echocardiographic score with poor QoL
(KCCQ Summary Score ,45) will be assessed using logistic regression. To assess whether baseline RV parameters can predict the
course of RV function over time (30 and 90 days), we will use multilevel mixed models. We will also assess RV response as a binary variable (DRV free wall strain by ≥5%).
Preliminary results
Study population and outcomes
As of Q2 2014, 41 patients have been enrolled, one-third of the total
planned sample. At this point, we did an interim analysis for futility,
evaluating the predictive value of echocardiography for the primary
endpoint (RVF at 90 days). The pre-operative patient characteristics
are summarized in Table 4. Pre-operative echocardiograms were performed a median of 4 days (1, 14) prior to implantation. Complete RV
assessment was possible in 38 patients (feasibility 92.7%). Three
patients had inadequate echocardiographic views for complete RFV
assessment and therefore were excluded from the analysis.
At 90 days, 15 of 38 patients (39.5%) had developed RVF (with 2
deaths) and 3 (11.5%) had died from sepsis. Median hospital stay was
15 days (25th and 75th percentiles: 12, 18), and intensive care stay
was 7 days (6, 10). The median duration of inotrope use was 7 days
(5, 12). Seven patients (18.4%) required inhaled or oral pulmonary
vasodilators, and one patient required mechanical RV support.
Echocardiographic parameters and RVF
Among pre-operative echocardiographic parameters, smaller LV diameters, lower RV global longitudinal strain, moderate or higher degree
of semi-quantitatively assessed tricuspid regurgitation, and shorter pulmonary acceleration time and acceleration-to-ejection-time ratio
were associated with RVF (Table 5). TAPSE, tissue Doppler RV
velocities, and RV FAC did not differ significantly between RVF groups.
Predictive value of echocardiographic
parameters
Using stepwise elimination (P to enter 0.1 and P to leave 0.05) in a
model with only echocardiographic parameters, the three parameters that remained in the final model were the semi-quantitative
tricuspid regurgitation grade, LV systolic diameter, and RV global
longitudinal strain. The echocardiographic score deriving from these
three parameters had a C-statistic of 0.88 [95% confidence interval
434
A.P. Kalogeropoulos et al.
Table 4 Pre-operative clinical and haemodynamic
characteristics (N 5 41)
Characteristic
Value
Age (years)
Female, N (%)
51.8 + 13.5
16 (39.0)
................................................................................
Race, N (%)
White
Black
15 (36.6)
24 (58.5)
Body mass index (kg/m2)
26.2 + 6.1
Indication, N (%)
Bridge to transplantation
17 (41.5)
Destination therapy
LVAD type, N (%)
HeartMate II
HeartWare
24 (58.5)
20 (48.8)
measures of RV function for prediction of (i) RVF within 90 days;
(ii) QoL at 90 days; and (iii) RV recovery at 90 days after LVAD implantation. For this purpose, we perform echocardiography within 7
days of planned LVAD surgery to evaluate the association of prespecified RV parameters with RVF and QoL at 90 days, in the belief that
an RV echocardiographic score will provide clinically relevant discrimination (C ≥ 0.85) and positive and negative predictive values
(.80%) for RVF. We also repeat echocardiograms at 30 and 90
days after LVAD surgery to examine the trajectory of RV recovery
and how baseline RV function is associated with RV recovery. We
expect RV mechanics to have incremental values for these outcomes. These results may help improve LVAD outcomes and reduce resource utilization by facilitating shared decision-making and
selection for LVAD implantation vs. alternative option; provide insights into RV function recovery; and inform reassessment of
LVAD timing.
21 (51.2)
Ischaemic aetiology, N (%)
Prior cardiac surgery, N (%)
14 (34.1)
21 (51.2)
Cardiogenic shock prior to implantation, N (%)
5 (12.2)
Need for intra-aortic balloon pump pre-op, N (%)
Need for inotropes pre-op, N (%)
11 (26.8)
41 (100)
Need for pressors, N (%)
3 (7.3)
Bilirubin (mg/dL)
Alanine aminotransferase (U/L)
1.4 (1.1, 1.7)
19 (15, 29)
Aspartate aminotransferase (U/L)
27 (23, 30)
International normalized ratio
Creatinine (mg/dL)
1.54 + 0.48
1.61 (1.44, 2.05)
Sodium (mEq/L)
131 (127, 133)
Systolic blood pressure (mmHg)
Cardiac index (Fick) (L/m2)
100 + 12
1.71 + 0.43
Right atrial pressure (mmHg)
13.5 + 5.7
Systolic pulmonary artery pressure (mmHg)
Mean pulmonary artery pressure (mmHg)
55 + 14
39 + 9
Pulmonary capillary wedge pressure (mmHg)
29 + 9
Pulmonary vascular resistance, Wood units
Right ventricular stroke work index
(mmHg × mL/min2)
3.2 + 1.6
462 + 204
Values for continuous variables are either mean + standard deviation or median
(25th and 75th percentiles).
(CI): 0.75 –1.00; P , 0.001] for RVF prediction (Figure 3). Sensitivity
was 86.7% (95% CI: 59.5 – 98.3); specificity was 87.0% (95% CI:
66.4 – 97.2); and the positive and negative predictive values were
81.3% (95% CI: 54.4–96.0) and 90.9% (95% CI: 70.8–98.9), respectively. In comparison, the reference clinical score (Michigan) had C ¼
0.63 (95% CI: 0.47–0.78; P ¼ NS), and P ¼ 0.009 for the difference
between the two curves. We did not include clinical covariates in
the model, as the power was not sufficient at this point.
Discussion
Study summary
In this study, we are prospectively enrolling 120 LVAD candidates
to evaluate standard and mechanics-based echocardiographic
Preliminary findings
In our preliminary analysis in the first 41 patients, in which only
echocardiographic variables were considered, we identified three
domains of potential importance for RVF prediction: tricuspid regurgitation, poor RV function, and smaller LV size. These parameters have been identified previously,8 but not in the context of
a comprehensive assessment. Although both tricuspid regurgitation
and RV function are ‘expected’ predictors of RVF, smaller LV size is
perplexing. One potential explanation is that a smaller LV is prone
to suction effects from the outflow cannula and therefore unfavourable ventricular interaction.
In contrast to tricuspid regurgitation severity and RV free wall
strain, conventional RV function parameters were not predictors
of RVF in our preliminary analysis. There are several potential explanations for this finding. In the USA, patients with INTERMACS Profiles 1–3 (corresponding to critical cardiogenic shock, progressively
declining despite inotropic support, or stable but inotropedependent patients, respectively) represent currently the majority
of LVAD recipients.49 This reflects also the current practice in our
institution. Most of these really sick patients are imaged under severe haemodynamic stress a few days before planned surgery. As
a result, all linear, load-dependent measures of RV function yield exaggerated values due to intense motion that does not actually represent true RV contraction. In our experience, TAPSE and RV
tissue Doppler’s values are the most vulnerable parameters to
this phenomenon (this was the case in the patient imaged in Figure 1).
In fact, patients who developed RVF to date in our study (Table 5)
had slightly higher TAPSE and RV tissue Doppler’s values at baseline,
highlighting this issue. RV FAC is less affected, but it becomes increasingly difficult to accurately assess RV FAC under severe
haemodynamic stress and high heart rates, and it is therefore difficult to rely on RV FAC for patient classification and clinical
decision-making.
Interestingly, RV global longitudinal strain was the most important
predictor of RVF (among RV function parameters) in our preliminary analysis. In a retrospective study of 117 LVAD recipients, RV free
wall longitudinal strain by velocity vector imaging (a variant of
speckle tracking) predicted RVF with 76% specificity and 68% sensitivity at a cut-off of 29.6% and had incremental predictive value
435
The RVF-LVAD study
Table 5
Pre-operative echocardiographic parameters (N 5 38)
Characteristics
Total (N 5 38)
RVF (N 5 15)
No RVF (N 5 23)
P-value
...............................................................................................................................................................................
Left ventricular ejection fraction (%)
Left ventricular diastolic diameter (cm)
Left ventricular systolic diameter (cm)
Left atrial volume index (cm3/m2)
Mitral regurgitation moderate or higher, N (%)
RV fractional area change (%)
Tricuspid annular plane excursion (cm)
Tricuspid annular s′ (cm/s)
Tricuspid regurgitation moderate or higher, N (%)
16.7 + 6.9
16.9 + 6.5
16.6 + 7.3
0.87
7.4 + 1.0
6.8 + 1.0
7.0 + 1.1
6.4 + 1.0
7.6 + 0.8
7.0 + 0.9
0.043
0.085
70 + 27
65 + 24
73 + 29
0.37
27 (71.0)
22.5 + 8.9
10 (66.7)
21.1 + 7.6
17 (73.9)
23.3 + 9.7
0.72
0.46
1.7 + 0.5
1.9 + 0.4
1.6 + 0.6
0.11
10.1 + 3.4
22 (57.9)
10.7 + 3.7
13 (86.7)
9.7 + 3.3
9 (39.1)
0.42
0.006
RV myocardial performance index
0.70 + 0.30
0.71 + 0.31
0.69 + 0.31
0.84
Pulmonary acceleration time (ms)
Pulmonary acceleration to ejection time ratio
81 + 16
0.35 + 0.10
75 + 13
0.30 + 0.07
84 + 17
0.38 + 0.11
0.097
0.013
RV global longitudinal strain (%)
RV global longitudinal strain rate systolic (1/s)
RV global longitudinal strain rate diastolic (1/s)
RV systolic pressure (mmHg)
28.1 + 3.6
26.7 + 2.7
29.0 + 3.8
0.047
20.59 + 0.22
0.62 + 0.26
20.57 + 0.18
0.68 + 0.25
20.60 + 0.24
0.57 + 0.27
0.61
0.23
54 + 15
57 + 13
52 + 16
0.33
Values are mean + standard deviation. RVF, right ventricular failure.
Limitations
Figure 3 ROC curves for RVF prediction with an echocardiographic score vs. a clinical score. An echocardiographic score combining elements of RV systolic function (RV longitudinal strain),
tricuspid regurgitation (semi-quantitative grade), and LV size endsystolic diameter achieved an area under the curve (C-statistic) of
0.88 (95% CI: 0.75 – 1.00) for RVF prediction, in comparison to
C ¼ 0.63 (95% CI: 0.47 – 0.78) achieved with a clinical score.
over a clinical score.32 In another study of 68 patients undergoing
elective LVAD placement, RV longitudinal strain was significantly impaired pre-operatively (212.6 + 3.3 vs. 216.2 + 4.3%, P , 0.001)
in 24 patients (35.3%) who experienced RVF by 14 days.34 Thus, we
need to prospectively validate the role of echocardiographic mechanics of RV function in post-LVAD RVF prediction.
Our study is conducted in a single centre and is therefore subject to
biases associated with our institutional practice in terms of patient
selection, surgical approaches, treatment of RVF (e.g. conservative
approach vs. RVAD implantation), duration of inotrope use, and
other potential considerations. Moreover, institutional practices
may affect course of RV recovery and serial echocardiographic measurements. We believe, however, that the consistent definition of
outcomes and the standardized echocardiographic approach will
still provide a valid direction and strength of association of echocardiographic parameters of interest with RVF and course of RV function over time.
Commensurate with the single-centre design, our planned sample
size of 120 patients is relatively small for multivariable analyses. On
the basis of the observed enrolment rates during the pilot period of
the study, we have powered the study to demonstrate prognostic
and decision-making superiority of quantitative echocardiography
over clinical scores for RVF. However, the number of events will
be relatively small to obtain reliable estimates for individual risk factors. Therefore, we expect our findings to demonstrate the direction and strength of association for important domains of
echocardiographic and clinical parameters with RVF, but not necessarily provide the ultimate estimates for each parameter. This would
require a multicentre approach. In contrast, our study is overpowered for detection of changes in echocardiographic parameters
with serial echocardiography and for clinically relevant correlations
with QoL.
Regardless of our ability to accurately quantify RV function, RVF
prediction is a moving target. Intraoperative events, concomitant
surgical procedures, and post-operative changes in pulmonary
haemodynamics and device settings are important (and unpredictable) confounders. Additional challenges include evolving
436
mechanical circulatory support technology and shifts in the target
population. However, the full potential of echocardiography has
not been fully used in the pre-operative assessment of candidates
with LVAD.
Our imaging approach to the RV is incomplete compared with
other clinical methods of RV imaging (e.g. cardiac magnetic resonance) and reflects our attempt to strike a balance between practical
considerations for clinical applicability in this patient population and
scientific rigour. For example, our imaging approach does not include the RV outflow tract. Although the outflow tract plays a lesser
role in RV output for adults without congenital heart disease, as the
infundibulum accounts for ,15% of RV stroke volume,50 it is still an
important limitation. Also, we did not attempt to incorporate multilayered strain analysis in our study. There are pathophysiological and
practical considerations when applying this approach to the RV.
From a pathophysiology perspective, the fibres in the RV free wall
lack the multilayered orientation of the LV, and therefore, the incremental benefit would be unclear. From a practical perspective, unless there is hypertrophy due to congenital heart disease, for
example, the RV free wall is too thin to track into three layers. However, such an approach could have provided insights for the interventricular septum. Finally, we did not consider short-axis RV
mechanics in our study. However, unless there is continuous overload during development, as in transposition of the great arteries,51
for example, the RV relies predominantly on longitudinal function to
produce output,52 whereas twisting and rotational movements do
not contribute significantly to RV contraction (in contrast to the
LV).53 In experimental animal models, longitudinal strain seems to
best quantify RV contractile function.54 An additional concern is
the difficulty in acquiring reliable short-axis images in enlarged and
displaced RVs, as is frequently the case in patients with advanced HF.
Conclusion
By identifying LVAD candidates at high risk for RVF and poor QoL,
our ultimate goal is to (i) facilitate shared decision-making for LVAD
vs. planned alternatives (e.g. biventricular support or concomitant
procedures),28,29 potentially improving outcomes and QoL, and
(ii) reduce resource utilization and costs. Finally, although improvement of RV function after LVAD implantation has been reported,42
recovery may not be feasible when baseline RV dysfunction exceeds
a certain threshold. This might be a signal for earlier LVAD implantation in some patients when RV is still ‘viable’. By investigating RV
function with serial echocardiography, we will provide mechanistic
insights into RV recovery and, in conjunction with pre-operative
evaluation, may inform LVAD timing for patients with similar degrees of LV dysfunction but varying degrees of RV dysfunction. In
this direction, our preliminary results from the interim analysis are
encouraging.
Conflict of interest: none declared.
Funding
This work was supported by (i) the American Heart Association
(13SDG15960001); (ii) an Emory University Research Committee and
Atlanta Clinical and Translational Science Institute Grant (supported
by NIH, National Center for Advancing Translational Sciences under
A.P. Kalogeropoulos et al.
Award No. UL1TR000454); and (iii) PHS Grant UL1 RR025008 from
the Clinical and Translational Science Award program, NIH, National
Center for Research Resources (Research and Woodruff Health
Sciences IT Division—REDCap).
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