1 INTRODUCTION

Right ventricular failure (RVF) is recognized as a major cause of morbidity and mortality following left ventricular assist device (LVAD) implantation.1 The prevalence of post-LVAD RVF is variable and reported in between 13 and 44% of cases dependent on criteria applied.2-5 Although several prediction models have been published to aid advanced heart failure (HF) teams, identifying patients at risk of RVF after LVAD implantation remains a significant challenge.1, 6 Despite being most widely used during pre-operative screening, the assessment of RV function using two-dimensional trans-thoracic echocardiography (2D-TTE) does have inherent limitations.3 Given the structural complexity of the RV, with inlet, outlet and apical regions it is not possible to visualize the entire chamber from a single 2D-TTE acoustic window.7 Furthermore, current quantitative functional parameters assessed with 2D-TTE are limited to one free wall region of the RV, namely the lateral wall. This is a limitation which may result in an over or under estimation of global RV function.8 Whilst three-dimensional (3D) TTE is able to overcome the geometrical assumptions made with 2D-TTE, poor spatial resolution or artefacts arising from adjacent structures may limit measurement feasibility.9 In order to address some of these issues, our research group previously introduced a novel imaging approach utilizing 2D multi-plane echocardiography (MPE) performed using a 3D ultrasound transducer. Whilst maintaining a fixed RV apical transducer position, with the RV apex centered, four different RV walls based on anatomic landmarks (lateral, anterior, inferior and inferior coronal)–(Figure 1), can be imaged using electronic plane rotation.10 Crucially, an RV centered view enables rotation through the true RV apex rather than the LV and permits optimal visualization of the entire RV free wall. This new method, also known as iRotate mode, therefore allows for a more detailed, quantitative assessment of global and regional RV wall function than presently performed with 2D-TTE. The main aim of this study was to evaluate RV function using this multi-plane method in a cohort of patients with end stage HF prior to LVAD implantation. A secondary aim was to identify which trends emerge amongst the multi-plane parameters in patients who develop post-LVAD RVF.

Multi-plane imaging of the right ventricle (RV). Views obtained by electronic plane rotation around a single RV focused apical echocardiographic position. 0° rotation: lateral wall; +40°: anterior wall; -40°: inferior wall; -90°: inferior wall coronal view also visualizing the right ventricular outflow tract

2 METHODS

End-stage HF patients undergoing echocardiographic screening prior to elective continuous flow LVAD implantation at our center between 2016 and 2019 were included in this study. These individuals underwent transthoracic echocardiography (TTE), including comprehensive 2D MPE RV assessment, right heart catheterization (RHC) and full clinical and laboratory evaluation. Emergency LVAD implantation cases were excluded. All echocardiograms were performed by DB or MS, imaging experts trained in LVAD echocardiography, using an iE33 or EPIQ7 ultrasound system (Phillips Medical Systems, Best, The Netherlands) equipped with an X5-1 matrix array transducer. 2D/3D echocardiographic parameters for left and right ventricular size and function were collected in addition to the grading of any valvular lesions. RV basal and longitudinal linear dimensions alongside fractional area change (FAC – calculated as end-diastolic area – end-systolic area/end-diastolic area x 100) were measured in the standard focused RV apical four chamber view conforming to international guidelines.11 RHC data was included if performed within 31 days of the TTE. To be able to compare the multi-plane RV parameters with a healthy population, we used a control group matched for age and sex. For this control group, self-declared healthy volunteers were prospectively recruited through advertisements, the details of which have been published previously.10 The study was carried out according to the principles of the Declaration of Helsinki and approved by the local medical ethics committee (METC) and written informed consent was obtained from all subjects.

2.1 Post-LVAD outcomes

Early clinical outcome data (≤30 days post implantation) was collected on each subject post LVAD implantation, namely cases of death; acute kidney injury (defined by an increase in serum creatinine by ≥ .3 mg/dl [≥ 26.5 μmol/l] within 48 h or ≥ 1.5 times the recorded baseline value)12; and length of ICU/hospital stay post implantation. Significant RVF post-LVAD implantation was defined as moderate-severe in length by a post-operative requirement for sustained inotropic support > 7 days and/or implantation of a RV assist device (RVAD).

2.2 Right ventricular assessment by 2D multi-plane echocardiography

2D MPE assessment of the RV has been previously demonstrated by our group and allows for multiple RV walls to be assessed from one echocardiographic position.8, 10 The main advantage of MPE is the ability to combine the multiplane scanning ability of 3D-TTE whilst maintaining the temporal resolution (> 60 Hz) of 2D-TTE at almost the same spatial resolution. To acquire the four additional RV views, a focused, non-foreshortened RV view is required with the RV apex and inter-ventricular septum centered along or as near to the midline of the imaging sector as possible. This allows for a full electronic rotation around the RV apex whilst maintaining a fixed probe position. The first view at 0˚ shows the lateral RV wall with the left sided landmark being the mitral valve. The second view at approximately +40˚ shows the anterior RV wall and the coronary sinus, thirdly at approximately -40˚ the inferior RV wall and the aortic valve and lastly at approximately -90˚ the inferior coronal view (CV) with the inferior wall and the right ventricular outflow tract (RVOT) (Figure 1 and supplementary Movies 1-4). With correct alignment and complete RV wall visualization, it is possible to perform quantitative analysis of RV function on all walls (Figure 2). Feasibility and values of the established RV functional echo parameters, tricuspid annular plane systolic excursion (TAPSE); tissue Doppler imaging derived tricuspid annular peak systolic velocity (RV-S’) and RV wall longitudinal strain (RV-LS) were assessed offline by an experienced sonographer (DB) on each of the four RV walls, by averaging three to five successive measurements. TAPSE and RV-S’ parameters were deemed feasible to measure if the respective M-mode or tissue Doppler tracing was adequately optimized for the measurement to be performed accurately. In addition to the values from the individual RV walls, a four-wall average of both TAPSE and RV-S’ was calculated when measurements from all four-walls from one individual were feasible.

Echocardiographic images of the four multi-plane right ventricular (RV) views (A-D) with corresponding quantitative functional parameters of the respective free wall segments (L-R panels). (A) – Focused four chamber view (0°), lateral wall; (B) – coronary sinus view (+40°), anterior wall; (C) – aortic view (-40°), inferior wall; (D) – coronal view (-90°), inferior wall and RVOT anterior wall. Second panel (center left): tricuspid annular plane systolic excursion (TAPSE); third panel, (center right): tricuspid annular peak systolic velocity (RV-S’); fourth panel (far right): RV wall longitudinal strain (RV-LS). LV - left ventricle; CS - coronary sinus; AoV - aortic valve; RVOT - right ventricular outflow tract

2.3 RV speckle tracking analysis

To assess RV wall peak systolic longitudinal strain (RV-LS) an RV algorithm wall motion tracking software was used (2D CPA, Image-Arena version 4.6; TomTec Imaging Systems, Munich, Germany) and data analysis was performed offline by one observer (DB). The endocardial border of the RV free wall and septum was manually traced at end systole and adjusted accordingly at end diastole if required. This was performed in each of the four multi-plane views previously described. RV-LS refers to a single segment value of the free wall, with the inter-ventricular septum excluded. A measurement was considered feasible if all portions of the RV wall tracked accurately throughout the cardiac cycle. In cases where the automated tracking was not accurate, attempts were made to re-adjust the endocardial border manually.

2.4 Statistical analysis

The distribution of data was assessed using histograms and the Shapiro–Wilk test. Depending on the data distribution, continuous data is presented as mean ± standard deviation (SD) or median [inter-quartile range (IQR)], whilst categorical data is presented as frequencies and percentages. For comparison of normally distributed continuous variables the independent samples T-test was used and in case of skewed distribution, the Mann–Whitney U-test was applied. For comparison of frequencies the Fisher's exact test was used. All statistical analyses were performed using the Statistical Package for Social Sciences version 25.0 (SPSS, Armonk, NY, USA: IBN corp.). The statistical tests were two-sided and a p value < 0.05 was considered statistically significant.

3 RESULTS

Twenty-five patients with end-stage HF (mean age 58.9 ± 6.8 years; 76.0% male) were included in the study. Detailed RV assessment by 2D MPE was feasible in all patients and performed 9 [5.0–28.5] days prior to LVAD implantation. 3D RV full volume datasets were acquired in 12 (48%) patients although only three cases were considered of sufficient quality to analyze and therefore no data was reported. Pre-implant RHC data was available in 19 (76.0%) patients and hemodynamic values alongside other clinical, laboratory and echocardiographic data are detailed in Table 1. Twenty-five age and gender matched healthy subjects (mean age – 58.9 ± 7.1 years, 76.0% male), who were recruited for a separate study at our center, underwent the same echocardiographic imaging and were used as a control group.

TABLE 1. Clinical, hemodynamic, and echocardiographic characteristics of end stage heart failure patients prior to left ventricular assist device implantation and matched healthy controls End stage heart failure patients (n = 25) Healthy controls (n = 25) p-value Clinical data Age (years) 58.9 ± 6.8 58.9 ± 7.1 0.98 Male gender (n, %) 19 (76) 19 (76) 1.00 Body mass index (kg/m2) 25.9 [22.3, 28.1] 26.0 [23.6, 27.6] 0.73 Sinus rhythm (n, %) 15 (60) 25 (100) <0.001 Ischemic etiology (n, %) 10 (40) Non-ischemic etiology (n, %) 16 (64) Previous cardiac surgery (n, %) 3 (12) INTERMACS (n, %) Class 1 1 (4) Class 2 9 (36) Class 3 8 (32) Class 4 and up 7 (28) Indication (n, %) Bridge to transplant 8 (32) Destination therapy 12 (48) Bridge to decision 5 (20) Laboratory data* Creatinine (μmol/L) 152.2 ± 45.1 eGFR (ml/min) 41 [32.5–48.5] Total bilirubin (μmol/L) 18.0 [10.5–29] Albumin (g/L) 38.3 ± 6.7 Hb (mmol/L) 7.7 ± 1.2 RHC parameters (n – 19) Right atrial pressure (mm Hg)  11.2 ± 5.5 Mean pulmonary artery pressure (mm Hg)  30.4 ± 11.8 Pulmonary capillary wedge pressure (mm Hg)  18.1 ± 9.9 RA/PCWP ratio  .6 [.4–.8] Pulmonary vascular resistance (wood units) 2.6 ± 1.3 Trans pulmonary gradient (mm Hg)  9.8 ± 4.0 Pulmonary artery pressure indexed (mm Hg/m2)  2.3 ± .9 Diastolic pulmonary gradient (mm Hg)  2.0 ± 4.8 Cardiac output (l/m)  3.7 [3.3–4.5] Cardiac index (l/m/m2) 1.8 [1.6–2.1] Echocardiographic parameters Left ventricle LV end diastolic diameter (mm) 73.9 ± 11.9 44.4 ± 4.5 <0.001 LV end systolic diameter (mm) 68 ± 13.6 27.8 ± 5.5 <0.001 LV ejection fraction (%) 19.3 ± 6.0 59.5 ± 4.4 <0.001 Left atrial volume index (ml/m2) 62.7 [52.5, 90.7] 26.4 [23.8, 32.7] <0.001 Right ventricle RV basal dimension (mm) 46.7 ± 8.8 39.4 ± 5.6 0.001 RV mid dimension (mm) 33.8 ± 7.6 30.6 ± 5.1 0.10 RV outflow tract 1 dimension (mm) 41.3 ± 6.0 32.0 ± 3.0 <0.001 RV end diastolic area (cm2) 29.1 ± 10.3 25.3 ± 5.4 0.13 RV end systolic area (cm2) 21.1 ± 9.2 14.3 ± 4.1 0.002 RV fractional area change (%) 29.2 ± 11.7 44.5 ± 7.9 <0.001 RA area (cm2) 24.2 ± 8.5 17.4 ± 3.6 0.001 Valvular ≥ Moderate mitral regurgitation (n, %) 14 (56) ≥ Moderate aortic regurgitation (n, %) 2 (8) ≥ Moderate tricuspid regurgitation (n, %) 10 (40) Tricuspid regurgitation velocity (m/s) 2.8 ± .6 Data presented as mean ± SD, median [IQR] or n (%). RA/PCWP ratio - right atrial/pulmonary capillary wedge pressure ratio. Cardiac output and cardiac index measured by thermodilution method. *Laboratory data collected 2 ± 1.5 days prior to implant. 3.1 Multi-plane parameters for RV function

The feasibility of multi-plane TAPSE and RV-S’ measurements was high across all RV walls (84–100%) and compared favorably with the control group (92–100%). A four-wall average TAPSE measurement was feasible in 22 (88%) patients whilst RV S’ measurement was feasible in 21 (84%) patients. RV-LS feasibility was 80% for the lateral wall, but much lower for the other walls (32–60%). In contrast, RV-LS feasibility was higher across all walls in the control group (lateral wall – 92%; inferior - 88%; anterior - 64%; inferior CV - 68%). Table 2 presents all multi-plane values from the patient cohort in addition to comparative values from the healthy control group. The highest TAPSE/RV-S’ values were seen in the lateral (16.3 ± 4.5 mm/10.0 ± 2.9 cm/s) and anterior walls (16.0 ± 4.5 mm/10.0 ± 2.6 cm/s), with lower values measured in the inferior (14.2 ± 4.6 mm/9.0 ± 2.9 cm/s) and inferior CV walls (12.3 ± 5.0 mm/8.7 ± 2.8 cm/s). Four-wall averaged TAPSE was 14.6 ± 4.4 mm, whilst four-wall averaged RV-S’ was 9.5 ± 2.7 cm/s. Lateral wall longitudinal strain was -12.1% ± 4.2%. Compared to the cohort of healthy controls, all multi-plane TAPSE and RV-LS parameters were significantly reduced (p = < 0.001). Differences in multi-plane RV-S’ measurement were less pronounced and not significantly different in the inferior walls (p > 0.05).

TABLE 2. Multi-plane RV quantitative parameters in end stage heart failure patients compared with healthy age and gender matched controls End stage heart failurepatients (n = 25) Healthy controls (n = 25) Multi-plane echo parameters Feasibility (%) Values Feasibility (%) Values p-value TAPSE (mm) Lateral wall 100.0 16.3 ± 4.5 100.0 26.0 ± 5.4 <0.001 Anterior wall 100.0 16.0 ± 4.5 100.0 26.6 ± 4.2 <0.001 Inferior wall 96.0 14.2 ± 4.6 96.0 22.8 ± 3.5 <0.001 Inferior coronal wall 88.0 12.3 ± 5.0 92.0 21.7 ± 4.1 <0.001 Four-wall average 88.0 14.6 ± 4.4 92.0 24.4 ± 3.7 <0.001 RV-S’ (cm/s) Lateral wall 96.0 10.0 ± 2.9 100.0 11.8 ± 2.0 0.014 Anterior wall 100.0 10.0 ± 2.6 100.0 12.0 ± 1.7 0.002 Inferior wall 96.0 9.0 ± 2.9 96.0 10.4 ± 1.6 0.06 Inferior coronal wall 84.0 8.7 ± 2.8 92.0 9.3 ± 1.8 0.42 Four-wall average 84.0 9.5 ± 2.7 92.0 10.9 ± 1.5 0.047 RV-LS (-%) Lateral wall 80.0 −12.1 ± 4.2 92.0 −27.1 ± 7.0 <0.001 Anterior wall 44.0 −12.5 ± 6.1 64.0 −24.4 ± 4.2 <0.001 Inferior wall 60.0 −12.6 ± 4.8 88.0 −22.6 ± 3.9 <0.001 Inferior CV wall 32.0 −12.1 ± 4.1 68.0 −19.7 ± 4.9 0.001 Data presented as mean ± SD. Abbreviations: TAPSE, tricuspid annular plane systolic excursion; RV-S’, tricuspid annular systolic velocity by tissue Doppler imaging; RV-LS, right ventricular wall longitudinal strain. 3.2 Comparison with mean pulmonary artery pressure

Swan Ganz catheter derived mean pulmonary artery pressure (mPAP) was used as a clinical measurement of RV afterload of which to compare RV multi-plane functional values against. Median mPAP was 31 [21, 40] mm Hg. Table 3 and Figure 3 present RV multi-plane functional parameters using this value to divide the cohort. TAPSE measurement of the lateral and inferior coronal view walls, in addition to the four-wall averaged value were significantly lower in patients with mPAP ≥31 mm Hg (lateral: 14.7 ± 3.8 mm vs 19.0 ± 4.2 mm, p = 0.03; inferior coronal view: 9.4 ± 5.3 mm vs 15.8 ± 3.7 mm, p = 0.01; average: 12.1 ± 3.9 mm vs 17.5 ± 3.8 mm, p = 0.01). Lateral RV-LS was lower in the ≥31 mm Hg mPAP group, but this difference was not statistically significant (-10.3 ± 2.9% vs -14.5 ± 4.7%; p = 0.06). There were no statistically significant differences between the groups for RV-S’ values.

TABLE 3. Multi-plane RV quantitative parameters compared by mean pulmonary artery pressure as measured by right heart catheterization Multi-plane echo parameters Mean pulmonaryartery pressure <31 mm Hg (n = 9) Mean pulmonaryartery pressure ≥31 mm Hg (n = 10) p-value TAPSE (mm) Lateral wall 19.0 ± 4.2 14.7 ± 3.8 0.031 Anterior wall 17.5 ± 4.6 14.3 ± 4.4 0.15 Inferior wall 15.1 ± 6.0 11.4 ± 4.7 0.17 Inferior coronal wall 15.8 ± 3.7 9.4 ± 5.3 0.014 Four-wall average 17.5 ± 3.8 12.1 ± 3.9 0.011 RV-S’ (cm/s) Lateral wall 10.2 ± 2.4 10.2 ± 3.7 0.97 Anterior wall 10.8 ± 2.6 9.1 ± 2.5 0.17 Inferior wall 10.4 ± 2.9 8.3 ± 3.2 0.18 Inferior coronal wall 9.4 ± 2.4 8.2 ± 3.7 0.46 Four-wall average 10.2 ± 2.4 8.8 ± 3.4 0.32 RV-LS (-%) Lateral wall −14.5 ± 4.7 −10.3 ± 2.9 0.06 Data presented as mean ± SD. Mean pulmonary artery pressure of 31 mm Hg used to split cohort as this represented the median value of all patients. Abbreviations: TAPSE, tricuspid annular plane systolic excursion; RV-S’, tricuspid annular systolic velocity by tissue Doppler imaging; RV-LS, right ventricular wall longitudinal strain.

Box and whisker plots presenting comparison between multi-plane RV echocardiographic parameters by mean pulmonary artery pressure (mPAP). A value of 31 mm Hg was used to split the cohort as this represented the median value of all patients. Left panel - four-wall averaged tricuspid annular plane systolic excursion (TAPSE); Middle panel - four-wall averaged tricuspid annular peak systolic velocity (RV-S’); Right panel - RV lateral wall longitudinal strain (FW-LS)

3.3 Clinical outcomes post LVAD implantation

Post LVAD implantation, there were three (14.5%) deaths and twelve (48%) patients with acute kidney injury (AKI). Median length of stay in ICU and hospital was 5 (3.5–17) and 28 (21.5-49) days respectively. Seven (28%) patients required sustained inotropic support for moderate or severe post-operative right ventricular failure (RVF), including three (12%) RVAD implantations. Table 4 presents the values of all RV multi-plane functional parameters when the population was split by incidence of significant post-operative RVF. Four-wall averaged TAPSE was the parameter most significantly reduced pre-operatively in patients who developed RVF compared to those who did not (11.1 ± 3.4 mm vs 15.9 ± 4.0 mm; p = 0.02), in addition to the values from the lateral (13.2 ± 4.1 mm vs 17.5 ± 4.1 mm; p = 0.027), anterior (13.0 ± 3.7 mm vs 17.1 ± 4.3 mm; p = 0.037) and inferior walls (10.5 ± 4.6 mm vs 15.4 ± 4.1 mm; p = 0.020). Four-wall averaged RV-S’ was 7.3 [6.2-9.7] cm/s vs 10.0 [7.8-9.7] cm/s (p = 0.09) whilst lateral wall RV-LS was -9.7 ± 2.8% compared to -13.1 ± 4.3% (p = 0.10). Feasibility of strain measurement for the other RV walls was considered insufficient for data analysis. Of those who developed post-operative RVF, right heart dimensions were significantly increased pre-operatively (RV basal dimension - 53.7 ± 10.0 mm vs 43.9 ± 6.7 mm, p = 0.009; RA area – 31.2 ± 9.0 cm2 vs 21.5 ± 6.8 cm2, p = 0.008) and incidence of significant (≥ moderate) tricuspid insufficiency was also increased (71.4% vs 27.7%, p = 0.045). Additionally, this group were older (63.2 ± 5.1 vs 57.2 ± 6.7 years, p = 0.045) and there was a reduced prevalence of sinus rhythm (28.5% vs 72.2%, p = 0.05). Three (42.8%) patients died within the first 90 days post LVAD implantation in the group with RV failure, whilst acute kidney injury occurred in six patients in both groups (85.7% RVF vs 33.3% no RVF; p = 0.019). Length of ICU stay for the RVF group was 28 [10-43] days compared to 4 [3-9.3] days (p = 0.006), whilst length of hospital stay was 59 [22-86] days compared to 28 [21-39.3] days (p = 0.15).

TABLE 4. Comparison of multi-plane echocardiographic parameters by incidence of significant post-operative right ventricular failure (>7 days inotropic support or RVAD implantation) Right ventricular failure (n = 7) No right ventricular failure (n = 18) p-value Characteristics Age (years) 63.2 ± 5.1 57.2 ± 6.7 0.045 Gender (male) 6 (85.6) 13 (72.2) 0.48 BMI