Postoperative Right Ventricular Failure After Left Ventricular Assist Device Placement is Predicted by Preoperative Echocardiographic Structural, Hemodynamic, and Functional Parameters

Journal of Cardiac Failure Vol. 19 No. 1 2013

Clinical Investigations

Postoperative Right Ventricular Failure After Left Ventricular Assist Device Placement is Predicted by Preoperative Echocardiographic Structural, Hemodynamic, and Functional Parameters AMRESH RAINA, MD,1 HARISH RAJ SEETHA RAMMOHAN, MD, MRCP,2 ZACHARY M. GERTZ, MD,3 J. EDUARDO RAME, MD, MPhil,2 Y. JOSEPH WOO, MD,4 AND JAMES N. KIRKPATRICK, MD2 Pittsburgh and Philadelphia, Pennsylvania; and Richmond, Virginia

ABSTRACT Background: Right ventricular failure (RVF) after left ventricular assist device (LVAD) implantation results in significant morbidity and mortality. Preoperative parameters from transthoracic echocardiography (TTE) that predict RVF after LVAD implantation might identify patients in need of temporary or permanent right ventricular (RV) mechanical or inotropic support. Methods and Results: Records of all patients who had preoperative TTE before implantation of a permanent LVAD at our institution from 2008 to 2011 were screened, and 55 patients (age 54 6 16 years, 71% male) were included: 26 had LVAD implantation alone with no postoperative RVF, 16 had LVAD implantation alone but experienced postoperative RVF, and 13 had initial biventricular assist devices (BIVADs). The LVAD with RVF and BIVAD groups (RVF group) were pooled for comparison with the LVAD patients without RVF (No RVF group). RV fractional area change (RV FAC) was significantly lower in the RVF group versus the No RVF group (24% vs 30%; P 5 .04). Tricuspid annular plane systolic excursion was not different among the groups (1.6 cm vs 1.5 cm; P 5 .53). Estimated right atrial pressure (RAP) was significantly higher in the RVF group versus the No RVF group (11 mm Hg vs 8 mm Hg; P 5 .04). Left atrial volume (LAV) index was lower in patients with RVF versus No RVF (27 mL/m2 vs 40 mL/m2; P 5 .008). Combining RV FAC, estimated RAP, and LAV index into an echocardiographic scoring system revealed that the TTE score was highly predictive of RVF (5.0 vs 2.8; P 5 .0001). In multivariate models combining the TTE score with clinical variables, the score was the most predictive of RVF (odds ratio 1.66, 95% confidence interval 1.06e2.62). Conclusions: Preoperative RV FAC, estimated RAP, and LAV index predict postoperative RVF in patients undergoing LVAD implantation. These parameters may be combined into a simple echocardiographic scoring system to provide an additional tool to risk-stratify patients being evaluated for LVAD implantation. (J Cardiac Fail 2013;19:16e24) Key Words: Right ventricular failure, ventricular assist device, echocardiography, risk prediction.

Left ventricular assist devices (LVADs) are increasingly used for the management of severe systolic heart failure, both as a bridge to cardiac transplantation and as destination therapy in patients who are not transplantation

candidates. Preoperative right ventricular (RV) dysfunction and postoperative right ventricular failure (RVF) negatively affect post-LVAD morbidity and mortality.1e4 Predicting which patients with preoperative RV dysfunction will

From the 1Cardiovascular Institute, Allegheny General Hospital, Pittsburgh, Pennsylvania; 2Cardiovascular Division, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania; 3Division of Cardiology, Virginia Commonwealth University, Richmond, Virginia and 4Division of Cardiac Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania. Manuscript received June 15, 2012; revised manuscript received October 17, 2012; revised manuscript accepted November 1, 2012.

Reprint requests: Amresh Raina, MD, Gerald McGinnis Cardiovascular Institute, Allegheny General Hospital, 320 East North Avenue, Pittsburgh, PA 15212-4772. Tel: 412-359-4760; Fax: 412-359-6544. E-mail: araina@ wpahs.org See page 23 for disclosure information. 1071-9164/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cardfail.2012.11.001

16

Echo Predictors of RV Failure After LVAD

develop postoperative RVF is important both in terms of appropriate patient selection for destination therapy LVADs and in selecting the most appropriate type of mechanical circulatory support (LVAD, biventricular assist device [BIVAD] or total artificial heart) in those who are being bridged to cardiac transplantation. In addition, earlier data from our center has suggested that planned up-front biventricular mechanical support is associated with decreased morbidity and mortality compared with urgent placement of an right ventricular assist device (RVAD) for RVF after isolated LVAD implantation.5 A number of preoperative risk-scoring algorithms have been published to predict RVF after LVAD implantation, using commonly available clinical and laboratory markers.6e8 However, these scoring systems can be cumbersome, and some have not been validated in the era of continuous-flow LVADs. Furthermore, most existing RV risk-scoring systems have not used detailed imaging parameters to aid in risk stratification. Studies have suggested that tricuspid annular plane systolic excursion (TAPSE) is predictive of postoperative RVF in LVAD patients.9 However, the value of TAPSE is uncertain in patients who have had previous cardiac surgery, as is the case in many patients evaluated for LVAD, given changes in the RV contractile pattern after cardiac surgery.10,11 Recently published data from the use of intraoperative transesophageal echocardiography (TEE) suggested that the ratio of RV to LV end-diastolic diameter was highly predictive of short-term RVF in the first 48 hours after LVAD.12 However, TEE is an invasive procedure which is often not performed until the patient is already in the operating room under general anesthesia, when loading conditions are different than in the pre- and postoperative settings. Transthoracic echocardiography (TTE) is a widely available noninvasive imaging modality that can assess RV structure and function in patients with heart failure with a variety of quantitative measures, such as fractional area change (FAC), strain, tricuspid annular motion, and tissue Doppler of the tricuspid annulus.13e16 We sought to evaluate baseline echocardiographic parameters from standard preoperative clinical TTE, which might identify patients at risk for prolonged RVF or the need for BIVADs in patients being evaluated for mechanical circulatory support.



Raina et al

17

Definition of RV Failure Prolonged RVF after LVAD implantation was defined as the need for inotropes for $14 days after LVAD implantation or need for temporary RVAD placement after LVAD implantation.1,7,17,18 Standard clinical criteria at our institution for initial BIVAD placement included any of the following: 1) qualitative evidence of concomitant severe RV dysfunction on preoperative TTE or TEE; 2) severe pulmonary hypertension with pulmonary vascular resistance (PVR) O5 Wood units or persistently elevated invasive right atrial pressure O15 mm Hg; or 3) sustained ventricular arrhythmias causing hemodynamic compromise. Ultimately, the final decision regarding upfront BIVAD placement was at the discretion of the treating heart failure cardiologist and cardiac surgeon. We calculated the Michigan RV risk score, the University of Pennsylvania BIVAD risk score, and a modified Model for End-Stage Liver Disease (MELD) score for each individual patient cohort and the combined BIVAD and LVAD with RVF group as a whole.6,7,19 Echocardiography Two-dimensional color flow and Doppler TTE was performed with the use of Phillips IE33 (Phillips Medical Systems, Andover, Massachusetts) and GE Vivid 7 (GE Healthcare, Milwaukee, Wisconsin) machines according to the standard clinical protocol at the Hospital of the University of Pennsylvania. Images were then downloaded and analyzed offline with the use of commercially available software (Prosolv Cardiovascular; Fujifilm, Valhalla, New York) by a single research reader blinded to patient outcomes. Quantitative assessment of RV function was made with the use of TAPSE and RV FAC, measured from the apical 4-chamber view according to the following formula: (RV enddiastolic area RV end-systolic area)/RV end-diastolic area (Fig. 1). A subset of 15 studies was reviewed by a second blinded reader to assess the reproducibility of RV FAC measurement. Noninvasive hemodynamic measurements included estimated pulmonary artery systolic pressure with the use of tricuspid regurgitant jet velocity, estimates of PVR with the use of RV outflow tract (RVOT) acceleration time, and right atrial pressure estimation with the use of inferior vena cava size and collapsibility (Fig. 2). RV and LV dimensions were measured with the use of apical 4-chamber and parasternal long-axis views, respectively (Fig. 3). The quantitative assessment of RV structure and function described above was performed according to the American Society of Echocardiography guidelines for RV chamber quantification.20 Statistical Analysis

Methods Patient Selection All patients with long-term LVAD or BIVAD implantation at our institution from May 2008 to June 2011 were screened retrospectively for inclusion in the study. Patients were excluded if they did not have a preoperative TTE at our institution before VAD implantation or if image quality on the TTE precluded accurate RV assessment. Detailed demographic and clinical data were obtained from the electronic medical record of each subject, with baseline laboratory data collected on the day of LVAD implantation. The study was approved by the Institutional Review Board at the Hospital of the University of Pennsylvania.

The BIVAD and LVAD with RV failure groups were pooled for comparison with the LVAD group without RV failure. Continuous variables were compared with the use of a Student t test and categoric variables with the use of Fisher exact test. Receiver operator curve analysis was used to evaluate the properties of specific echocardiographic variables in predicting RV failure. Echocardiographic variables that were predictive of RVF in univariate analysis were combined to generate an echocardiographic scoring system for predicting RVF. Multivariate models were constructed with the use of binary logistic regression to determine echocardiographic variables independently predictive of RVF and to compare the echocardiographic scoring system with clinical variables in predicting RVF. Only variables with univariate P !.1 were

18 Journal of Cardiac Failure Vol. 19 No. 1 January 2013

Fig. 1. Measurement of right ventricular (RV) fractional area change from apical 4-chamber view. Fractional area change 5 [RV enddiastolic area (outlined area, left panel) RV end-systolic area (outlined area, right panel)]/RV end-diastolic area. included in the multivariate models. All significance tests were 2 tailed, and P !.05 was considered to be statistically significant.

Results A total of 55 patients (age 54 6 16 years, 71% male) were included in the study. Of these, 26 patients had LVAD implantation alone with no postoperative RVF, 16 patients had LVAD implantation alone but subsequently experienced postoperative RVF, and 13 patients had initial BIVAD implantation with Thoratec paracorporeal devices (Thoratec Corp, Pleasanton, California). Among the 42 patients with solitary LVAD implantation, the majority (39 patients, 93%) had continuous-flow devices implanted and of these, most were Thoratec Heartmate II (32 patients, 82%) or Heartware devices (6 patients, 15%). Most patients in the

study (82%) had chronic heart failure. Though the incidence of acute heart failure was higher in the BIVAD group, there was no significant overall difference in the incidence of acute heart failure in the LVAD with RVF versus the LVAD with no RVF group. Baseline clinical and demographic characteristics of the study cohorts are presented in Table 1. Univariate comparisons of the clinical variables from the LVAD group without RV failure (No RVF) with the combined BIVAD and LVAD group with RV failure (RVF) revealed that higher body surface area (2.18 vs 1.98 m2; P 5 .03), lower albumin (2.9 vs 3.5 mg/dL; P ! .001), higher number of preoperative inotropes/vasopressors (1.6 vs 0.9; P ! .001), lower Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) score (1.6 vs 2.4; P 5 .002) and higher baseline heart rate during echocardiogram (98 vs 84 beats/min; P 5 .03) were all

Fig. 2. Noninvasive estimation of right atrial pressure (RAP) from inferior vena cava (IVC) collapsibility assessed from the subcostal view. Top: small IVC with O50% collapse (RAP 3 mm Hg). Bottom: dilated IVC with minimal collapsibility (RAP 15 mm Hg). RAP may be assumed at 8 mm Hg when the IVC is not well visualized. See table:

RAP Estimate 3 mm Hg 8 mm Hg 8 mm Hg 15 mm Hg IVC diameter Collapse

<2.1 cm

<2.1 cm

>2.1 cm

>2.1 cm

>50%

<50%

>50%

<50%

Echo Predictors of RV Failure After LVAD



Raina et al

19

predictive of postoperative RVF (Table 1). In addition, there was a trend toward higher intraoperative invasive RA pressure in the RVF group (12 vs 9 mm Hg; P 5 .06). Notably, invasive pulmonary artery pressures and cardiac index were similar between groups. RV stroke work index was lower in the RVF group compared with the No RVF group (367 6 221 vs 603 6 286 mm Hg$mL/m2; P 5 .003) and was lowest in the BIVAD group (220 6 197 mm Hg$mL/m2). Baseline echocardiographic parameters of the RVF and No RVF groups are presented in Table 2. The RVF and No RVF groups had similar LV dimensions and LV ejection fraction. Quantitative assessment of RV function revealed that RV FAC was significantly lower in the RVF group versus the No RVF group (24% vs 30%; P 5 .04). However, TAPSE was not significantly different among the 2 groups (1.6 vs 1.5 mm; P 5 .53). Receiver operator curve analysis revealed that RV FAC !31% had a sensitivity of 82% but a specificity of 52% in predicting RV failure (area under curve 0.67; P 5 .04; Fig. 4). In the 15 patients reviewed by a second blinded reader to assess reproducibility of RV FAC, the mean difference in RV FAC between the 2 readers was 7%, and only 3 of 15 patients (20%) were reclassified as having RV FAC O31%.

Fig. 3. Measurement of basal (RVD1), middle (RVD2) and longaxis (RVD3) right ventricular dimensions from the apical 4-chamber view.

Table 1. Preoperative Clinical and Demographic Characteristics of the Study Population LVAD With No LVAD With RVF (n 5 26) RVF (n 5 16) Age (y) Male sex Ischemic DT Acute heart failure* Mechanical ventilation Prior sternotomy INTERMACS score BSA (m2) Heart rate (beats/min) No. of vasopressors Invasive RA (mm Hg) PA systolic pressure (mm Hg) PA systolic pressure (mm Hg) Cardiac index (L min 1 m 2) RV stroke work index (mm Hg$mL/m2) MAP (mm Hg) BUN (mg/dL) Cr (mg/dL) Albumin (mg/dL) Total bilirubin (mg/dL) INR AST ALT Michigan RV risk score Penn BIVAD risk score Modified MELD score Echo score (0e7)

56 6 17 77% 42% 46% 12% 7% 19% 2.4 6 0.9 1.98 6 0.26 84 6 21 0.92 6 0.56 965 51 6 16 25 6 8 1.96 6 0.27 603 6 286 76 30 1.39 3.53 1.32 1.39 129 68 1.1 26 15 2.8

6 6 6 6 6 6 6 6 6 6 6 6

14 18 0.52 0.54 0.58 0.28 387 191 2.1 13 5 2.0

52 6 18 63% 38% 44% 6% 13% 13% 1.9 6 0.5 2.22 6 0.32 94 6 23 1.12 6 0.66 12 6 5 52 6 12 25 6 5 1.86 6 0.36 457 6 205 72 33 1.78 3.01 2.12 1.56 166 71 1.8 29 20 4.9

6 6 6 6 6 6 6 6 6 6 6 6

11 22 0.81 0.59 3.36 0.50 302 111 3.0 12 8 1.9

BIVAD (n 5 13) 51 6 15 69% 31% 0% 45% 30% 38% 1.3 6 0.8 2.13 6 0.49 103 6 22 2.20 6 1.1 13 6 7 38 6 13 20 6 7 1.76 6 0.42 220 6 197 71 31 1.68 2.78 2.48 1.50 353 283 4.3 51 22 5.2

6 6 6 6 6 6 6 6 6 6 6 6

14 29 1.1 0.72 2.46 0.30 731 556 2.7 16 8 1.7

Combined BIVAD P Value, No RVF P Value, No RVF and LVAD With vs Combined RVF vs LVAD With RVF RVF (n 5 29) Group only 52 6 16 66% 34% 24% 24% 21% 24% 1.6 6 0.7 2.18 6 0.40 98 6 23 1.62 6 1.01 12 6 6 46 6 14 23 6 7 1.81 6 0.38 367 6 221

.37 .39 .57 .09 .30 .29 .75 .002 .03 .03 .002 .06 .20 .29 .13 .003

.53 .48 .99 .98 .99 .62 .69 .04 .02 .22 .30 .15 .82 .94 .36 .09

6 6 6 6 6 6 6 6 6 6 6 6

.36 .68 .10 .001 .09 .16 .35 .23 .01 .02 .01 .0001

.44 .63 .10 .01 .36 .24 .74 .94 .43 .60 .05 .003

72 32 1.74 2.90 2.28 1.53 249 166 2.9 39 21 5.0

12 25 0.95 0.65 2.9 0.42 535 388 3.1 18 8 1.8

ALT, alanine transaminase; AST, aspartate transaminase; BIVAD, biventricular assist device; BSA, body surface area; BUN, blood urea nitrogen; Cr, creatinine; DT, destination therapy; INR, international normalized ratio; INTERMACS, Interagency Registry for Mechanically Assisted Circulatory Support; LVAD, left ventricular assist device; MAP, mean arterial pressure; MELD, Model for End-Stage Liver Disease; PA, pulmonary artery; RA, right atrium; RVF, right ventricular failure. *Acute heart failure defined as diagnosis of heart failure within 30 days of ventricular assist device implantation.

20 Journal of Cardiac Failure Vol. 19 No. 1 January 2013 Table 2. Preoperative Echocardiographic Characteristics of the Study Population LVAD With No RVF (n 5 26) LVEDD (cm) LVEF (%) LA volume index (mL/m2) RVD1 (cm) RVD2 (cm) RVD3 (cm) RV EDA (cm2) RV/LV ratio, apical RV/LV ratio, parasternal RVOT acceleration time (ms) RVOT VTI (cm) RV FAC (%) TAPSE (cm) RA pressure (mm Hg)

6.30 18 40 4.67 3.1 8.74 22.7 0.88 0.55 102 10.8 30 1.5 8

6 6 6 6 6 6 6 6 6 6 6 6 6 6

0.99 13 21 0.91 0.62 0.92 6.3 0.15 0.12 29 3.7 10 0.4 5

LVAD With RVF (n 5 16) 6.54 17 31 5.09 3.29 9.05 25.4 0.91 0.58 89 9.85 22 1.7 10

6 6 6 6 6 6 6 6 6 6 6 6 6 6

1.04 8 13 1.08 0.81 1.36 8.75 0.10 0.09 24 2.91 15 0.4 5

BIVAD (n 5 13) 5.24 17 23 4.35 3.19 8.70 22.5 0.88 0.63 92 11.1 25 1.5 12

6 6 6 6 6 6 6 6 6 6 6 6 6 6

1.19 13 17 1.07 0.91 1.21 10.1 0.21 0.16 20 2.58 7 0.5 4

Combined BIVAD and LVAD With RVF (n 5 29)

P Value

6 6 6 6 6 6 6 6 6 6 6 6 6 6

.26 .09 .008 .79 .45 .63 .55 .77 .08 .10 .70 .04 .53 .04

5.9 17 27 4.8 3.24 8.9 24.1 0.89 0.61 90 10.4 24 1.65 11

1.28 10 15 1.1 0.85 1.28 9.34 0.16 0.13 22 2.8 10 0.5 5

LA, left atrial; LV, left ventricle; LVEDD, left ventricular end-diastolic dimension; LVEF, left ventricular ejection fraction; RA, right atrial; RV, right ventricle; RV EDA, right ventricular end-diastolic area; RVD, right ventricular dimension (see Fig. 3); RVOT, right ventricular outflow tract; TAPSE, tricuspid annular plane systolic excursion; VTI, velocity time integral.

Echocardiographic measures of pulmonary vascular resistance and pulmonary artery (PA) pressures did not predict RVF after LVAD implantation. RVOT acceleration time (90 vs 101 ms; P 5 .10), RVOT velocity time integral (10 vs 11 cm; P 5 .70), and estimated pulmonary artery systolic pressure (40 vs 45 mm Hg; P 5 .50) were not significantly different in the RVF versus No RVF group. Estimated right atrial pressure from inferior vena cava collapsibility was significantly higher in the RVF versus No RVF group (11 vs 8 mm Hg; P 5 .04; Table 2). In terms of assessment of RV structure and morphology, there was no significant difference between the RVF and No RVF groups in any RV dimension or in RV enddiastolic area. As a result, the calculated ratio of RV to LV end-diastolic diameter measured from the apical 4-chamber view was not different between the 2 groups (0.89 vs 0.88; P 5 .77). However, there was a trend toward higher ratio of RVOT to LV end-diastolic diameter measured from the

parasternal long-axis view in the RVF vs No RVF group (0.61 vs 0.54; P 5 .07). In addition, there was no significant difference in the ratio of short-axis to long-axis dimension of the RV between the RVF and No RVF groups. However, in evaluating left atrial morphology, left atrial volume indexed for body surface area was significantly lower in patients with RVF versus those without (27 vs 40 mL/m2; P 5 .008). Receiver operator curve analysis revealed that at a cutoff of 38 mL/m2, left atrial volume index had a sensitivity of 86% but a specificity of 56% in predicting RVF (area under the curve 0.71; Fig. 5). In a multivariate model of the 3 echocardiographic variables predictive of RVF in univariate analysis, only left atrial volume index remained independently predictive on multivariate analysis (odds ratio [OR] per 5-mL/m2 increment 0.77, 95% confidence interval [CI] 0.63e0.95; P 5 .015). We then combined the echocardiographic variables of RV FAC, LA volume index, and estimated right atrial

Fig. 4. Receiver operating characteristic curve for right ventricular fractional area change in predicting post operative right ventricular failure.

Fig. 5. Receiver operating characteristic curve for left atrial volume index in predicting postoperative right ventricular failure.

Echo Predictors of RV Failure After LVAD

pressure into an echocardiographic scoring system for predicting RVF. Receiver operator curve analysis was used to derive optimal cutoffs in terms of sensitivity and specificity for RV FAC (!31%) and left atrial volume index (!38 mL/m2). Three points were assigned to LA volume index !38 mL/m2, 2 points to RV FAC !31%, and 2 points to estimated RA pressure O8 mm Hg. Thus, the score could range from 0 to 7 points, with a higher score being more predictive of RVF. When comparing the RVF and No RVF groups, the echocardiographic score was significantly higher in the RVF group (5.0 6 1.8 vs 2.8 6 2.0; P 5 .0001; Table 1). Moreover, when comparing the echocardiographic score in the No RVF and LVAD with RVF group only (excluding the upfront BIVAD group), the echocardiographic score remained significantly predictive of RVF (4.9 6 1.9 vs 2.8 6 2.0; P 5 .003). A scatterplot showing the individual echocardiographic scores in the RVF and No RVF groups is shown in Figure 6. In multivariate analysis of the clinical variables for predicting RVF, including body surface area, albumin, heart rate, and INTERMACS score, only INTERMACS score remained independently predictive. In a multivariate model combining left atrial volume index with these clinical variables, no single variable remained independently predictive of RVF. However, in a third model combining the echocardiographic score with the clinical variables, the echo score remained independently predictive (OR 1.66, 95% CI 1.06e2.62), and the model itself was stronger than that using clinical variables alone. Receiver operator curve analysis of the echocardiographic score in predicting RVF revealed that an

Fig. 6. Scatterplot of individual echocardiographic (echo) scores in the right ventricular failure (RVF) and No RVF groups. Arrow indicates optimal cutoff.



Raina et al

21

echocardiographic score of $5 had a sensitivity of 63% and specificity of 78% for predicting RVF (Fig. 7). In patients with an echocardiographic score of $5, 77% had RVF, whereas only 36% of patients with an echocardiographic score of !5 had RVF (P 5 .005). The Michigan RV risk score (2.9 6 3.1 vs 1.1 6 2.1; P 5 .01), Penn BIVAD score (39 6 18 vs 26 6 13; P 5 .02) and modified MELD score (21 6 8 vs 15 6 5; P 5 .01) were all higher in the RVF group versus the No RVF group (Table 1). Using the highest-risk cutoff of O5.5, the Michigan RV risk score had a sensitivity of 28% for predicting the combined RVF group and 13% for predicting the LVAD with RVF group only, with a high overall specificity of 96%. Lowering the prediction cutoff to O3.0, the sensitivity rose to 38% for predicting the combined RVF group, but remained only 19% for predicting the LVAD with RVF group only, with overall specificity of 88%. The Penn BIVAD prediction score had a sensitivity of 70% for predicting the BIVAD group, but at a cutoff of 50 it did not predict any of the LVAD with RVF group only, with overall sensitivity of 33% for predicting the combined RVF group. Specificity was high at 92%. The modified MELD score had an overall sensitivity of 54% and specificity of 64% for predicting the combined RVF group. Discussion The clinical data from our study revealed that a number of commonly measured clinical parameters, such as number of preoperative vasopressors, heart rate, INTERMACS score, albumin, and body surface area, predicted RVF after LVAD placement. Many of these clinical parameters have been previously described as predictive of RVF,6,7,21 and the present data suggests that our clinical stratification of patients into RVF and No RVF groups was appropriate and likely similar to earlier study populations of RVF after LVAD implantation. Though we pooled the BIVAD group with the LVAD with RVF group to derive the echocardiographic scoring system, we noted that the BIVAD cohort

Fig. 7. Receiver operating characteristic curve for echocardiographic score in predicting postoperative right ventricular failure.

22 Journal of Cardiac Failure Vol. 19 No. 1 January 2013 had the lowest RV stroke work index and highest Michigan risk score, Penn BIVAD score, and modified MELD score, suggesting that these patients had an appropriate ‘‘phenotype’’ of RV failure. Moreover, no patient had their RVAD explanted in the 30 days after implantation, and 30-day mortality was 46% in the BIVAD group, arguing for the need for continued RV support in these patients. Earlier studies using echocardiography to predict prolonged RV failure after LVAD placement centered around assessment of RV function and noninvasive hemodynamic measurements with the use of Doppler echocardiography, or they evaluated the RV geometry.9,12,22,23 Although qualitative assessment of RV function is the most commonly used echocardiographic method to characterize RV contraction, it is inherently subjective, with risk for significant inter- and intraobserver variability. Of the quantitative measures of RV function, TAPSE is perhaps the easiest to perform. TAPSE has been shown to correlate well with RV ejection fraction by radionuclide angiography14 and is predictive of outcomes in pulmonary arterial hypertension and nonischemic cardiomyopathy.24,25 Puwanant et al evaluated tricuspid annular motion in 33 patients with LVAD placement, 11 of whom developed RVF after LVAD and 2 of whom required RVAD support. They demonstrated that TAPSE was significantly lower in patients who developed RVF.9 However, TAPSE was not significantly different in the RVF and No RVF groups in our study. The reason may relate in part to the larger more heterogeneous population in our study, with higher number of patients requiring up-front biventricular support; it may also be explained by the fact that a significant number of patients in our study (22%) had prior cardiac surgery. Emerging data has suggested that TAPSE is reduced after cardiac surgery, despite the presence of normal global RV function, in large part secondarily to a change in the geometry of RV contraction, with a relative increase in transverse versus longitudinal contraction.10,11 However, changes in the geometry of RV contraction are variable from patient to patient, and this may explain why TAPSE does not correlate well with RV ejection fraction in several postsurgical populations, such as patients who have had pulmonary thromboembolectomy, repaired congenital heart disease, and cardiac transplantation.10,26,27 RV FAC appeared to be a better predictor of RVF in our study population. FAC has the benefit of accounting for both longitudinal and transverse shortening of the RV, giving a more balanced overall assessment of RV function. The drawback of this measure is that it requires appropriate endocardial definition to circumscribe RV end-systolic and end-diastolic areas from the apical 4-chamber view, which can be technically difficult in critically ill mechanically ventilated patients. Our data did suggest that there was significant interobserver variability in assessing RV FAC (mean difference 7% between observers), but this only led to change in classification of RVF in 3 of 15 patients. Nevertheless, overall our data support the routine assessment of RV FAC in patients evaluated for LVAD.

Of noninvasive hemodynamic parameters, there was no significant difference between estimated PA systolic pressure between the RVF and No RVF groups. Similarly, noninvasive estimate of PVR with the use of RVOT acceleration time was not predictive of RVF. This finding is in keeping with earlier studies using invasive hemodynamics which suggested that elevated pulmonary artery pressure and PVR were not predictive of RVF.8 Our data did show that noninvasive estimate of right atrial pressure via inferior vena cava collapsibility was predictive of RVF after LVAD implantation. Earlier studies have shown that elevated invasive right atrial pressure is predictive of outcomes in pulmonary arterial hypertension,28,29 and that the ratio of right atrial pressure to wedge pressure is predictive of RVF after LVAD implantation.30 However, other data have suggested that invasive right atrial pressure does not in and of itself predict RVF after LVAD implantation.31 The right atrial pressure estimate via inferior vena cava collapsibility may simply reflect differences in actual right atrial pressure between groups (our invasive data showed a trend toward higher right atrial pressure in the RVF group), but it could also reflect a more global measure of right-side heart function, including tricuspid regurgitation and venous congestion.32 Our evaluation of RV geometry failed to demonstrate a difference in the ratio of RV to LV end-diastolic dimension from the apical 4-chamber view between the RVF and No RVF groups. This view is the transthoracic equivalent of the midesophageal 4-chamber view from TEE used by Kukucka et al to measure the RV in their study showing the predictive value of RV/LV end-diastolic ratio.12 Even using the parasternal long-axis view, the standard TTE view used to measure LV dimensions, and the apical 4-chamber view to measure the RV dimensions, the RV/LV end-diastolic ratio showed at most a modest trend toward a higher ratio in the RVF group (0.81 vs 0.75; P 5 .14). Overall, the present study suggests that the data regarding the predictive value of RV/LV diastolic dimension ratio seen with TEE are not as readily applicable to TTE. This may be due to technical differences in the imaging planes obtained via TTE and TEE, but may be equally attributable to differences in definition of RV failure in the 2 studies. The definition of RVF in the TEE study by Kukucka et al was over a shorter time course (48 h) rather than the more standard definition that we used of 14 days of postoperative inotropes.1,17,18 Finally, the present study also demonstrated that lower left atrial volume, indexed for body surface area, was significantly predictive of patients with RVF compared with those without RVF. Although it may initially seem counterintuitive that an absence of left-side structural heart disease would predict RVF after LVAD implantation, left atrial enlargement has previously been linked to LV diastolic dysfunction, left atrial congestion, and pulmonary venous hypertension.33 Therefore, our finding may reflect the fact that patients with larger left atria have had more chronic and/or severe left atrial congestion and LV diastolic dysfunction, which

Echo Predictors of RV Failure After LVAD

would be ameliorated with LVAD placement, leading to improvement or preservation of RV function. Alternatively, increased left atrial size may reflect an increased likelihood of functional mitral regurgitation (ie, that is highly responsive to increased volume), a lesion that is known to affect pulmonary vascular resistance and right ventricular dysfunction in left-side heart disease and is responsive to mechanical unloading with an LVAD. Patients with smaller left atria, conversely, may derive less benefit after left-sided decongestion. In those patients, perhaps the increased cardiac output demand and increased venous return to the RV after LVAD implant is not counterbalanced by the benefit of reduced left-side congestion. Although differences in response to decongestion do not appear to be reflected in an isolated measurement of pulmonary artery pressures, the effect of an LVAD on the processes which lead to left atrial enlargement are poorly understood and warrant further study. Left atrial size, along with inferior vena cava size and collapsibility, may represent a ‘‘downstream’’ effect of congestion that could be a good predictor of RV dysfunction. It is conceivable that lower left atrial volumes were a manifestation of atrial septal shifting due to right atrial congestion in the RVF cohort. However, it seems unlikely that this alone could explain the striking difference in left atrial volumes that we detected, and this mechanism seems to be less likely in the context of similar measured right atrial areas in the RVF and No RVF groups. Finally, combining echocardiographic variables into a simple easily interpreted echocardiographic scoring system significantly improved prediction of RVF versus any one echocardiographic variable alone, and, importantly, the echocardiographic score remained incrementally predictive after inclusion of clinical variables in our multivariate models, despite the small sample size in the present study. The Challenge of RV Risk Prediction

The prediction of RV failure after LVAD implantation continues to be a considerable challenge, particularly in the current era of growing use of LVADs as terminal heart failure therapy. Unfortunately, none of the current risk prediction methods have very high sensitivity in predicting RV failure in clinical practice, which may be due in part to the fact that several risk scores were derived in the era of pulsatile LVADs, whereas most LVADs presently implanted use continuous flow. Although our limited sample size could affect the performance of any individual risk score, and it was not our intention to rigorously compare the various existing risk scores, the echocardiographic scoring system we derived appeared to compare favorably in terms of sensitivity and specificity with other existing risk scoring systems in our small patient cohort. Though promising, the echocardiographic scoring system requires further prospective validation in additional larger LVAD cohorts before becoming routinely used in clinical practice. In the absence of other echo-based RV risk scoring systems, we suggest that the echocardiographic



Raina et al

23

components of this scoring system be routinely measured in patients being evaluated for LVAD implantation. Study Limitations

This study was designed as a retrospective cohort study and as such is subject to the same substantial limitations as any such study regarding potential bias in patient selection and data acquisition. However, all existing RV risk-scoring systems to date have been derived from single-center retrospective cohort studies. The TTEs used for the present study were performed for clinical indications and were often not obtained immediately before LVAD placement (median time from TTE to VAD implantation 7 days). In addition, they did not all have sufficient data for more complex RV assessment such as RV strain, strain rate, or spectral Doppler and tissue Doppler assessment of myocardial performance index. The decision to implant a BIVAD versus an LVAD alone was ultimately at the discretion of the treating cardiac surgeon and heart failure cardiologist per standard criteria at our institution. This fact could have affected the characteristics of the patients in the RVF group. Moreover, use of a priori BIVADs could have affected the analysis because the ‘‘outcome’’ was determined at the outset from the implantation of the BIVAD. However, as noted in the discussion, these patients were stratified as highest risk of RV failure based on RV stroke work index and the other risk-scoring systems, such that we thought that they had an appropriate phenotype of RV failure. Though our study was larger than many other studies evaluating echocardiographic parameters in LVAD patients, there were relatively few patients (n 5 13) with BIVADs, such that we were unable to further delineate characteristics that predicted need for BIVADs as an initial strategy. Conclusion Right ventricular FAC, estimated right atrial pressure, and left atrial volume are predictive of postoperative RVF in patients undergoing VAD implantation. These parameters can be easily measured from standard clinical TTEs and combined into a simple echocardiographic scoring system that may provide an additional noninvasive tool to further risk-stratify patients being evaluated for mechanical circulatory support. Disclosures Dr Rame has been a primary investigator in clinical trials sponsored by Thoratec Corporation and Heartware. Dr Kirkpatrick has received a grant from the Greenwall Foundation to examine caregiver stress in LVAD recipients. The other authors report no potential conflicts of interest.

References 1. Dang NC, Topkara VK, Mercando M, Kay J, Kruger KH, Aboodi MS, et al. Right heart failure after left ventricular assist device implantation

24 Journal of Cardiac Failure Vol. 19 No. 1 January 2013

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

in patients with chronic congestive heart failure. J Heart Lung Transplant 2006;25:1e6. Deng MC, Edwards LB, Hertz MI, Rowe AW, Keck BM, Kormos R, et al. Mechanical circulatory support device database of the International Society for Heart and Lung Transplantation: third annual reportd2005. J Heart Lung Transplant 2005;24:1182e7. Farrar DJ, Hill JD, Pennington DG, McBride LR, Holman WL, Kormos RL, et al. Preoperative and postoperative comparison of patients with univentricular and biventricular support with the thoratec ventricular assist device as a bridge to cardiac transplantation. J Thorac Cardiovasc Surg 1997;113:202e9. Morgan JA, John R, Lee BJ, Oz MC, Naka Y. Is severe right ventricular failure in left ventricular assist device recipients a risk factor for unsuccessful bridging to transplant and post-transplant mortality. Ann Thorac Surg 2004;77:859e63. Fitzpatrick JR 3rd, Frederick JR, Hiesinger W, Hsu VM, McCormick RC, Kozin ED, et al. Early planned institution of biventricular mechanical circulatory support results in improved outcomes compared with delayed conversion of a left ventricular assist device to a biventricular assist device. J Thorac Cardiovasc Surg 2009;137:971e7. Fitzpatrick JR 3rd, Frederick JR, Hsu VM, Kozin ED, O’Hara ML, Howell E, et al. Risk score derived from pre-operative data analysis predicts the need for biventricular mechanical circulatory support. J Heart Lung Transplant 2008;27:1286e92. Matthews JC, Koelling TM, Pagani FD, Aaronson KD. The right ventricular failure risk score a pre-operative tool for assessing the risk of right ventricular failure in left ventricular assist device candidates. J Am Coll Cardiol 2008;51:2163e72. Ochiai Y, McCarthy PM, Smedira NG, Banbury MK, Navia JL, Feng J, et al. Predictors of severe right ventricular failure after implantable left ventricular assist device insertion: analysis of 245 patients. Circulation 2002;106:I198e202. Puwanant S, Hamilton KK, Klodell CT, Hill JA, Schofield RS, Cleeton TS, et al. Tricuspid annular motion as a predictor of severe right ventricular failure after left ventricular assist device implantation. J Heart Lung Transplant 2008;27:1102e7. Fields A, Raina A, Chambers S, Forfia P. The right ventricular contractile pattern is markedly different in transplanted compared to normal hearts. Implications for RV function assessment post cardiac transplant. J Card Fail 2011;17:S11. Tamborini G, Muratori M, Brusoni D, et al. Is right ventricular systolic function reduced after cardiac surgery? A two- and three-dimensional echocardiographic study. Eur J Echocardiogr 2009;10:630e4. Kukucka M, Stepanenko A, Potapov E, Krabatsch T, Redlin M, Mladenow A, et al. Right-to-left ventricular end-diastolic diameter ratio and prediction of right ventricular failure with continuous-flow left ventricular assist devices. J Heart Lung Transplant 2011;30:64e9. Fukuda Y, Tanaka H, Sugiyama D, Ryo K, Onishi T, Fukuya H, et al. Utility of right ventricular free wall speckle-tracking strain for evaluation of right ventricular performance in patients with pulmonary hypertension. J Am Soc Echocardiogr 2011;24:1101e8. Kaul S, Tei C, Hopkins JM, Shah PM. Assessment of right ventricular function using two-dimensional echocardiography. Am Heart J 1984; 107:526e31. Meluzin J, Spinarova L, Bakala J, Toman J, Krejci J, Hude P, et al. Pulsed Doppler tissue imaging of the velocity of tricuspid annular systolic motion; a new, rapid, and noninvasive method of evaluating right ventricular systolic function. Eur Heart J 2001;22:340e8. Pavlicek M, Wahl A, Rutz T, de Marchi SF, Hille R, Wustmann K, et al. Right ventricular systolic function assessment: rank of echocardiographic methods vs cardiac magnetic resonance imaging. Eur J Echocardiogr 2011;12:871e80. Kavarana MN, Pessin-Minsley MS, Urtecho J, Catanese KA, Flannery M, Oz MC, et al. Right ventricular dysfunction and organ failure in left ventricular assist device recipients: a continuing problem. Ann Thorac Surg 2002;73:745e50. Schenk S, McCarthy PM, Blackstone EH, Feng J, Starling RC, Navia JL, et al. Duration of inotropic support after left ventricular

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

assist device implantation: risk factors and impact on outcome. J Thorac Cardiovasc Surg 2006;131:447e54. Chokshi A, Cheema FH, Schaefle KJ, Jiang J, Collado E, Shahzad K, et al. Hepatic dysfunction and survival after orthotopic heart transplantation: application of the MELD scoring system for outcome prediction. J Heart Lung Transplant 2012;31:591e600. Rudski LG, Lai WW, Afilalo J, Hua L, Handschumacher MD, Chandrasekaran K, et al. Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. J Am Soc Echocardiogr 2010;23:685e713. Drakos SG, Janicki L, Horne BD, Kfoury AG, Reid BB, Clayson S, et al. Risk factors predictive of right ventricular failure after left ventricular assist device implantation. Am J Cardiol 2010;105:1030e5. Potapov EV, Stepanenko A, Dandel M, Kfoury AG, Reid BB, Clayson S, et al. Tricuspid incompetence and geometry of the right ventricle as predictors of right ventricular function after implantation of a left ventricular assist device. J Heart Lung Transplant 2008;27: 1275e81. Topilsky Y, Oh JK, Shah DK, Boilson BA, Schirger JA, Kushwaha SS, et al. Echocardiographic predictors of adverse outcomes after continuous left ventricular assist device implantation. JACC Cardiovasc Imaging 2011;4:211e22. Forfia PR, Fisher MR, Mathai SC, Housten-Harris T, Hemnes AR, Borlaug BA, et al. Tricuspid annular displacement predicts survival in pulmonary hypertension. Am J Respir Crit Care Med 2006;174: 1034e41. Ghio S, Recusani F, Klersy C, Sebastiani R, Laudisa ML, Campana C, et al. Prognostic usefulness of the tricuspid annular plane systolic excursion in patients with congestive heart failure secondary to idiopathic or ischemic dilated cardiomyopathy. Am J Cardiol 2000;85: 837e42. Giusca S, Dambrauskaite V, Scheurwegs C, D’Hooge J, Claus P, Herbots L, et al. Deformation imaging describes right ventricular function better than longitudinal displacement of the tricuspid ring. Heart 2010;96:281e8. Morcos P, Vick GW III, Sahn DJ, Jerosch-Herold M, Shurman A, Sheehan FH. Correlation of right ventricular ejection fraction and tricuspid annular plane systolic excursion in tetralogy of Fallot by magnetic resonance imaging. Int J Cardiovasc Imaging 2009;25:263e70. d’Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med 1991;115:343e9. Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, et al. Survival in patients with idiopathic, familial, and anorexigenassociated pulmonary arterial hypertension in the modern management era. Circulation 2010;122:156e63. Kormos RL, Teuteberg JJ, Pagani FD, Russell SD, John R, Miller LW, et al. Right ventricular failure in patients with the Heartmate II continuous-flow left ventricular assist device: incidence, risk factors, and effect on outcomes. J Thorac Cardiovasc Surg 2010;139: 1316e24. Fukamachi K, McCarthy PM, Smedira NG, Vargo RL, Starling RC, Young JB. Preoperative risk factors for right ventricular failure after implantable left ventricular assist device insertion. Ann Thorac Surg 1999;68:2181e4. Testani JM, Khera AV, St John Sutton MG, Keane MG, Wiegers SE, Shannon RP, et al. Effect of right ventricular function and venous congestion on cardiorenal interactions during the treatment of decompensated heart failure. Am J Cardiol 2010;105:511e6. Melenovsky V, Borlaug BA, Rosen B, Hay I, Ferruci L, Morell CH, et al. Cardiovascular features of heart failure with preserved ejection fraction versus nonfailing hypertensive left ventricular hypertrophy in the urban Baltimore community: the role of atrial remodeling/dysfunction. J Am Coll Cardiol 2007;49:198e207.