Perioperative Changes of Right Ventricular Function in Cardiac Surgical Patients Assessed by Myocardial Deformation Analysis and 3-Dimensional Echocardiography

ARTICLE IN PRESS Journal of Cardiothoracic and Vascular Anesthesia 000 (2019) 111

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Original Article

Perioperative Changes of Right Ventricular Function in Cardiac Surgical Patients Assessed by Myocardial Deformation Analysis and 3-Dimensional Echocardiography Marcell Donauer, Dr. med. univ. Szeged*, y Jens Schneider, Medical Assistanty, Nikolaus Jander, MD , 1 z , * Friedhelm Beyersdorf, MD , Cornelius Keyl, MD *

Department of Anesthesiology, University Heart Center Freiburg - Bad Krozingen, Germany Department of Cardiology and Angiology II, University Heart Center Freiburg - Bad Krozingen, Germany z Department of Cardiovascular Surgery, University Heart Center Freiburg - Bad Krozingen, Germany

y

Objectives: To test the hypothesis that longitudinal strain of the right ventricle (RV) is significantly reduced in patients undergoing cardiac surgery with extracorporeal circulation and cardioplegic cardiac arrest at the end of surgery, whereas RV ejection fraction remains unchanged. Design: Prospective observational cohort study. Setting: Single university hospital. Participants: Thirty patients with normal myocardial function undergoing coronary artery bypass grafting with cardioplegic cardiac arrest. Interventions: Right ventricular 3-dimensional echocardiography and strain analysis were performed preoperatively, intraoperatively, and postoperatively. Measurements and Main Results: Peak longitudinal systolic strain of the RV lateral and inferior wall, RV outflow tract, and interventricular septum was reduced significantly at the end of surgery after sternal closure compared to preoperatively (lateral: 16 § 5 v 22 § 4, p < 0.001; inferior: 12 § 4 v 19 § 5, p < 0.001; outflow tract, 11 § 5 v . 20 § 6, p < 0.001; septum: 9 § 3 v 14 § 4, p < 0.001), whereas peak circumferential systolic strain of the RV lateral wall had increased significantly (16 § 4 v -12 § 5, p = 0.008). Right ventricular ejection fraction remained stable (51 § 6% v. 50 § 7%, p = 0.34). Conclusion: In patients undergoing coronary artery bypass grafting with cardioplegic cardiac arrest, the longitudinal contraction of the RV lateral and inferior wall, the RV outflow tract, and the interventricular septum is impaired at the end of surgery. This impairment is compensated by an increase in circumferential contraction without changes in RV ejection fraction. Ó 2019 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) Key Words: right ventricular function; echocardiography; strain analysis; cardiac surgery

THE COMPLEX geometry of the right ventricle (RV) makes echocardiographic assessment challenging. Previous reports suggested that the RV function evaluated by the tricuspid annular plane systolic excursion (TAPSE), or the systolic 1

Address reprint requests to Cornelius Keyl, MD, Department of Anesthesiology, University Heart Center Freiburg  Bad Krozingen, Suedring 15, 79189 Bad Krozingen, Germany. E-mail address: [email protected] (C. Keyl).

tricuspid annular velocity (RV S’), is impaired after cardiac surgery.1-4 These findings have been corroborated by deformation analysis assessing the longitudinal contraction of the RV lateral free wall.5,6 In contrast, RV ejection fraction (EF), or RV fractional area change (FAC), seems to remain stable immediately postoperatively.7-9 A preceding study suggested that the decrease in TAPSE may be compensated by an increase in RV transverse contraction after cardiac surgery, thus resulting in an unchanged RV EF.10

https://doi.org/10.1053/j.jvca.2019.08.026 1053-0770/Ó 2019 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

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The underlying cause of the changes in the RV contraction pattern after cardiac surgery is unknown. Phenomena, such as altered performance of the interventricular septum, mechanical effects of pericardiotomy, or postoperative adhesions of the RV, have been discussed previously as causative factors.5,6,11 To get further insights into changes of the RV contraction pattern in patients undergoing cardiac surgery with extracorporeal circulation, the authors evaluated circumferential and radial strain in addition to the conventional longitudinal strain analysis, and assessed the strain of the inferior and anterior wall of the inflow and outflow tract, which has not been investigated before in this context. The authors primarily hypothesized that peak longitudinal systolic strain (PLSS) of the RV would be diminished at the end of surgery after sternal closure while RV EF remained unchanged. The authors expected a reduction in PLSS of about the same relative magnitude as the decrease in TAPSE, that is, a reduction of about 25% of the preoperative control value. Secondarily, the authors hypothesized that pericardiotomy would not be accompanied by a decrease in strain. Methods The study was designed as a prospective observational trial. The protocol of the study complies with the Declaration of Helsinki and was approved by the Ethics Committee of the University of Freiburg (protocol 138/17 approved on May 23, 2017). All participants gave written informed consent. Patients The study cohort comprised 30 patients scheduled for coronary artery bypass grafting (CABG). Inclusion criteria were a sinus rhythm and a normal systolic RV and left ventricular (LV) function (visually normal RV and LV contractility, normal LV EF, the absence of regional wall motion abnormalities, normal atrial and ventricular diameter and volumes). Exclusion criteria were redo cardiac surgery, more than mild valvular heart disease, frequent ectopic beats, atrial fibrillation or flutter, postoperative newly developed pacemaker dependency requiring ventricular pacing owing to atrioventricular conduction disturbances, and insufficient quality of the echocardiographic assessment, that is, the predefined characteristic structures of the echocardiographic view could not be visualized. Anesthetic Management Anesthesia was induced with sufentanil, etomidate, and rocuronium, and maintained with sevoflurane and supplemental sufentanil, as required. After orotracheal intubation, the lungs were ventilated mechanically with a tidal volume of 7 to 8 mL/kg, a positive end-expiratory pressure of 5 mbar, an inspiratory:expiratory ratio of 1:1, and a frequency of 10 to 12 per minute to maintain an end-tidal PCO2 of 35 to 40 mmHg at an FIO2 of 0.4. All patients were monitored intraoperatively by transesophageal echocardiography (TEE) and by a pulmonary artery catheter. Hemodynamic and respiratory parameters

were recorded continuously in 1-minute intervals in the electronic patient database (Metavision, IMDsoft, Tel Aviv, Israel). Mean pulmonary artery pressure (PAPm), pulmonary artery occlusion pressure (PAOP), central venous pressure (CVP), and cardiac output were assessed simultaneously with the echocardiographic recordings. Cardiac output was measured as the average of 3 measurements, randomly distributed over the respiratory cycle, using 10 mL of 0.9% sodium chloride solution at room temperature. Surgical Management Coronary artery bypass grafting was carried out under normothermic conditions via median sternotomy. Full myocardial revascularization was performed using single or bilateral internal thoracic artery grafting and aortocoronary vein grafts, according to the decision of the cardiac surgeon. Pericardial incision was performed before preparation of the internal thoracic arteries. Cardiac arrest was achieved using only antegrade cold blood cardioplegia (Buckberg/Beyersdorf cardioplegic solution, Dr. F. K€ohler Chemie, Benzheim, Germany) after aortic cross-clamping. Cardioplegic reinfusions were delivered every 20 minutes. Neither antegrade vein graft nor retrograde perfusion was delivered systematically. The pericardium was closed at the end of surgery in all patients. Echocardiographic Assessment Standardized transthoracic echocardiography (TTE) was performed in accordance with recent recommendations12,13 by a single observer (J.S.) at 2 sample points: in the week before the intervention, and on the fourth or fifth postoperative day (GE ultrasound system E95, 4V-D probe, GE Healthcare, Solingen, Germany). Standardized TEE (GE ultrasound system E95, 6VT-D probe, GE Healthcare) was performed intraoperatively by 2 observers (M.D., C.K.) at 3 sample points: after induction of anesthesia before surgical incision (pre-incision, A), approximately 15 minutes after opening the pericardium (after pericardiotomy, B), and after pericardial and sternal closure (after sternal closure, C). All measurements were performed under stable hemodynamic conditions. Systolic RV function was assessed by measuring the systolic displacement of the lateral tricuspid annulus (TAPSE)14,15 and the RV S’,15 using the apical 4-chamber view during TTE examination. During TEE measurements, TAPSE was assessed in the midesophageal RV-focused 4-chamber view by measuring the displacement of the tricuspid annulus in the 2D mode. The RV S’ was assessed at the inferior tricuspid annulus, which was visualized using the transgastric RV inflow-outflow view, either at 0˚ or at about 130˚. The RV index of myocardial performance (RIMP) and RV myocardial acceleration during isovolumic contraction (IVA) were calculated using the tissue Doppler method at the lateral annulus of the tricuspid valve in the apical 4-chamber view (TTE), or at the inferior tricuspid annulus in the transgastric RV inflow-outflow view at 0˚ (TEE).12 The RV FAC was measured in the RV-focused 4-

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chamber view, and the RV transversal shortening fraction was assessed at the midlevel of the RV-focused 4-chamber view. The central venous pressure (CVP) was estimated during the TTE examination by assessing the diameter and inspiratory collapse of the inferior vena cava.12 Three-dimensional assessment of the RV was obtained from a modified 4-chamber view with the RV apex centered during TTE, as well as TEE examinations. A full volume scan was acquired from 4 to 6 consecutive cardiac cycles, which were registered during expiration breath hold. Right ventricular myocardial deformation analyses and RV 3D analyses were performed by 2 observers (M.D. analyzed TEE registrations, J.S. analyzed TTE registrations). Speckle tracking echocardiography was computed using the GE EchoPAC PC software 201 (GE Healthcare). Loops consisting of 3 cardiac cycles were recorded at frame rates of more than 60 Hz. End-diastolic and end-systolic time markers were defined, dependent on the peak of the R wave and the pulmonic valve closure, derived from spectral Doppler measurements, respectively. Longitudinal deformation was analyzed at the RV lateral free wall and the interventricular septum from a RV-focused 4-chamber view. Applying the software originally designed for longitudinal strain analysis of the LV, the RV lateral free wall and the interventricular septum each were divided automatically into 3 segments, the region of interest was adjusted manually to the myocardial wall, and PLSS and time to PLSS were computed for the basal, middle, and apical segments. The mean PLSS of the RV lateral free wall, and of the interventricular septum, was calculated as the arithmetic mean of the PLSS in the 3 segments of the RV lateral free wall and the septum, respectively.13 Additionally, the PLSS of the RV inflow-outflow tract was assessed from the transgastric RV inflow-outflow view at about 130˚. This view was preferred to the transesophageal RV inflowoutflow view, because the image quality of the RV outflow tract, visualized in the transesophageal view, frequently was disturbed by artifacts generated by calcification of the aortic annulus or aortic root. By adapting the “APLAX” mode of the GE software for strain analysis, the authors obtained information on the RV basal inferior free wall, the RV mid inferior wall, the RV anterolateral free wall, and the anterior free wall of the right ventricular outflow tract (RVOT). The mean strain of the inflow tract and the outflow tract was calculated as the arithmetic mean of the individual wall segments. The peak radial and circumferential systolic strain of the interventricular septum was assessed from the transgastric LV short-axis view. The peak radial and circumferential systolic strain of the RV was measured from the transgastric RV short-axis view, analyzing the inferolateral and anterolateral segments of the RV free wall. Again, mean values of radial and circumferential strain were calculated as arithmetic mean of the specific wall segments. Software presets, which originally were designed for LV deformation analysis, were applied for analysis. The LV systolic function was measured as the LV EF, calculated by the Simpson biplane formula.16 Segmental wall motion abnormalities were assessed visually. The LV diastolic function was obtained as the ratio of the early diastolic transmitral flow velocity, and the lateral mitral annulus velocity, during the early diastolic filling inflow (LV

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E/E’ ratio). The LV eccentricity index (LVEI), which indicates an alteration in the circular short-axis geometry of the left ventricle, was measured at end-diastole and at end-systole as the anteroposterior-to-septolateral diameter ratio of the LV.17 Statistical Methods Statistical analysis was performed using commercially available software (IBM SPSS Statistics, version 20, IBM Corporation, Armonk, NY). Data were checked for normal distribution by visual assessment of histograms and q-q plots. Normally distributed data are reported as mean with standard deviation. Owing to the limited comparability of TEE and TTE for strain analysis, the authors analyzed the data assessed by TEE and TTE separately.18 Normally distributed paired data were compared by the paired samples t test. Repeated-measures data assessed at 3 sample points were compared by a general linear model procedure for repeated measures (ie, a repeated-measures analysis of variance), using a simple contrast with sample point A as reference. Mauchly’s test was used to test for sphericity. The Greenhouse-Geisser adjustment was used when data violated the assumption of sphericity. Categorical data were compared between 2 sample points using McNemar’s test. All tests were performed as 2-sided tests with alpha = 0.05. The intraobserver reproducibility of peak systolic strain measured at the RV lateral free wall was assessed in 15 randomly selected patients in accordance with the suggestions of Bland and Altman.19 The repeatability coefficient, which reports the range in which 95% of replicate measurements are expected to lie, was calculated for 3 measurements in each patient.19 To adjust for multiple hypothesis testing, the false discovery rate was controlled using the Benjamini-Hochberg procedure.20 A false discovery rate <0.05 was considered significant. The p values, which are statistically significant using the Benjamini-Hochberg procedure, are indicated in the tables. Endpoint and Sample Size Calculation The endpoint of the study was the change in RV PLSS after sternal closure, compared to the baseline values. Bitcon et al. observed a reduction in PLSS of the RV lateral free wall with an effect size of 1.0 in patients undergoing CABG after chest closure.21 Kempny et al. reported a reduction in RV PLSS with an effect size of 0.9 in patients undergoing surgical aortic valve replacement in the postoperative period.5 To be able to assess less pronounced effects, expressed by an effect size of 0.5 with alpha of 0.05 (2-sided) and beta of 0.2, and expecting a dropout rate of 20%, the authors enrolled 30 patients in the study. Results Patients A total of 39 patients met the inclusion criteria and gave their written informed consent to participate in the study. Nine patients were excluded from the study owing to newly developed pacemaker dependency at the end of surgery, or owing to

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insufficient quality of the intraoperative TEE assessment. Owing to this procedure, 30 patients were included in the study. The patients’ characteristics are presented in Table 1. At the final TTE examination 4 to 5 days postoperatively, 3-dimensional recordings were of minor quality in 5 patients, so that the presented data of 3-dimensional TTE were obtained in only 25 patients. Complete anatomic revascularization was achieved in all but 1 patient. This patient had a left-dominant coronary circulation and a chronically obstructed small right coronary artery, which was not revascularized. The clinical course of this patient was uneventful without any signs of myocardial ischemia. Blood flow of coronary bypass grafts was measured in all patients at the end of surgery using transit-time ultrasound technology without indicating any blood flow obstruction. The patients did not show wall motion abnormalities or pathologically increased plasma levels of creatine kinase-MB or cardiac troponin in the intraoperative or postoperative period. At the end of surgery, 9 patients required atrial pacing without showing any alteration in AV conduction. All patients presented with a sinus rhythm at the postoperative TTE

Table 1 Characteristics of Patients (n = 30) Male (n) Age (y) Height (cm) Weight (kg) BMI (kg/m) STS score Hypertension (n) Diabetes (n) Smoking (n) Peripheral arterial vascular disease (n) Stroke/TIA (n) Chronic obstructive lung disease (n) Creatinine clearance (mL/min) Bilirubin (mg/dL) Preoperative medication (n) Beta-adrenergic blocker ACE inhibitor/angiotensin II blocker Calcium channel blocker Diuretic Diseased coronary artery LMCA (n) LAD (n) LCX (n) RCA (n) Number of non-left main diseased vessels 0 (n) 2 (n) 3 (n)

25 67.6 § 9.1 172 § 7 81.2 § 12.2 27.5 § 4.4 8.1 § 3.1 25 3 3 2 1 1 77 § 16 0.6 § 0.2 13 19 8 5

assessment. No patient developed more than mild regurgitation of the tricuspid or mitral valve. Strain Analysis After Pericardiotomy Results of strain analysis are presented in Table 2, and a graphical presentation is provided in Figure 1. Peak longitudinal systolic strain of the RV lateral free wall and the interventricular septum did not change significantly after pericardiotomy. The analysis of the different wall segments showed a significant increase in PLSS of the basal RV lateral free wall by 4%, whereas PLSS of the outflow tract decreased by 4%. Right ventricular circumferential and radial contraction did not change. Pericardiotomy did not affect the time to PLSS or the synchronicity of contraction of the RV lateral free wall and the interventricular septum (Fig 2). Conventional and 3D Echocardiographic Assessment After Pericardiotomy Details of conventional and 3D echocardiographic assessment are presented in Table 3. Right ventricular EF increased significantly by a mean value of 8% after pericardiotomy. As the end-diastolic and end-systolic volume decreased by about 10 mL each, RV stroke volume remained unchanged. The IVA increased significantly by a mean value of 42%, whereas the other parameters of RV systolic function, such as TAPSE, RV S’, and RIMP, did not change. Hemodynamic Changes After Pericardiotomy Heart rate and CI increased after pericardiotomy by a mean value of 9 beats/min and by 33%, respectively, compared to the baseline conditions. Right and left ventricular filling pressures, estimated by CVP and PAOP, decreased significantly after pericardiotomy, each by a mean value of 3 mmHg. The PAPm remained unchanged (Table 4). Strain Analysis After Sternal Closure

25 27 27 27 1 6 23

NOTE. Values are presented as mean § standard deviation, categorical variables as number. Creatinine clearance was calculated by the CKD-EPI formula. ACE, angiotensin-converting enzyme; BMI, body mass index; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; LAD, left anterior descending coronary artery; LCX, left circumflex artery; LMCA, left main coronary artery; RCA, right coronary artery, STS score, The Society of Thoracic Surgeons adult cardiac surgery risk score; TIA, transient ischemic attack.

Peak longitudinal systolic strain of the RV lateral free wall, as well as of the free wall of the RV inflow-outflow tract, had decreased significantly by a mean percentage value of 23% (lateral free wall), 34% (inflow tract), and 41% (outflow tract) after sternal closure (Table 2, Fig 1). The RV circumferential contraction had increased significantly by a mean percentage value of 4%. Peak longitudinal systolic strain of the interventricular septum had decreased significantly by a mean percentage value of 31%, whereas the septal circumferential and radial contraction pattern remained unchanged. Time to PLSS had shortened similarly in all wall segments at the end of surgery without changes in the sequence or in the synchronicity of contraction of the RV lateral free wall and the interventricular septum (Fig 2).

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Table 2 Results of Strain Analysis: Peak Strain TTE In the week before surgery

4 to 5 days after surgery

Right ventricular free lateral wall longitudinal strain (%) Basal 19 § 3 9 § 4 Mid 24 § 3 10 § 3 Apical 22 § 3 13 § 4 Lateral free wall 22 § 2 10 § 2 Interventricular septum longitudinal strain (%) Basal 15 § 2 11 § 2 Mid 17 § 2 12 § 2 Apical 18 § 2 12 § 4 Interventricular septum 17 § 2 12 § 1 Right ventricular inflow-outflow tract longitudinal strain (%) Inflow basal inferior Inflow mid inferior Inflow Outflow anterolateral Outflow anterior Outflow Right ventricular circumferential strain (%) Inferolateral free wall Anterolateral free wall Lateral free wall Right ventricular radial strain (%) Inferolateral free wall Anterolateral free wall Lateral free wall Interventricular septum circumferential strain (%) Inferior Anterior Septum Interventricular septum radial strain (%) Inferior Anterior Septum

TEE p Value

Pre-incision (A)

After pericardiotomy (B)

After sternal closure (C)

<0.001* <0.001* <0.001* <0.001*

25 § 6 23 § 5 18 § 6 22 § 4

29 § 8 23 § 6 20 § 7 24 § 4

22 § 6 17 § 7 10 § 6 16 § 5

0.009* 0.79 0.08 0.026

0.12 0.001* <0.001* <0.001*

<0.001* <0.001* <0.001* <0.001*

13 § 3 15 § 4 15 § 6 14 § 4

15 § 4 16 § 4 17 § 7 16 § 3

9 § 4 10§ 4 9 § 5 9 § 3

0.11 0.19 0.07 0.046

<0.001* <0.001* <0.001* <0.001*

17 § 7 19 § 6 19 § 5 20 § 6 19 § 8 20 § 6

19 § 6 21 § 5 20 § 5 16 § 5 17 § 8 16 § 5

13 § 4 11 § 6 12 § 4 10 § 6 12 § 7 11 § 5

0.42 0.28 0.38 0.002* 0.28 0.043

0.001* <0.001* <0.001* <0.001* 0.002* <0.001*

10 § 6 13 § 8 12 § 5

10 § 7 10 § 6 10 § 5

14 § 6 17 § 6 16 § 4

0.87 0.093 0.15

0.045 0.012* 0.008*

16 § 11 15 § 9 16 § 10

0.49 0.39 0.41

0.012* 0.004* 0.005*

22 § 14 20 § 15 21 § 14

1.0 0.09 0.33

0.51 0.23 0.33

31 § 15 33 § 15 32 § 15

0.49 0.70 0.59

0.024 0.056 0.036

22 § 10 21 § 10 22 § 10 20 § 7 17 § 9 18 § 7 41 § 17 42 § 18 42 § 17

20 § 11 19 § 11 20 § 10 20 § 9 21 § 9 20 § 8 45 § 22 45 § 22 45 § 22

p Value B versus A

p Value C versus A

NOTE. Data are reported as mean § standard deviation. The RV lateral free wall and the interventricular septum were visualized using the RV-focused 4-chamber view; the longitudinal strain of the free wall of the RV inflow-outflow tract was assessed using the transgastric RV inflow-outflow view either at 0˚ or at about 130˚; the radial and circumferential strain of the RV lateral free wall and the interventricular septum were obtained from a transgastric short-axis view. * Indicates the p values that are significant using the Benjamini-Hochberg procedure for control of the false discovery rate in multiple testing. A false discovery rate <0.05 was considered significant. RV, right ventricle; TEE, transesophageal echocardiography; TTE, transthoracic echocardiography.

Repeatability of Strain Analysis The intraobserver repeatability coefficient of the assessment of PLSS was calculated with 2.7% for the RV lateral free wall, and was within 4.6% to 5.1% for the 3 lateral wall segments. Conventional and 3D Echocardiographic Assessment After Sternal Closure The RV EF was not significantly different from baseline values after sternal closure (Table 3, Fig 1). The TAPSE and RV S’ had decreased significantly by a mean value of 44% and 46%, respectively. Other measures of RV function, such as IVA and RIMP, did not change after sternal closure. Left

ventricular EF had increased significantly by a mean value of 4%; LV diastolic function was not different from the baseline values. The eccentricity index indicated a change in LV geometry with a significant increase in the end-systolic anteroposterior-to-septolateral diameter ratio by about 9% (Table 3). Hemodynamic Changes After Sternal Closure The heart rate had increased significantly with a mean value of 30 beats/min at the end of surgery, compared to preoperative conditions, accompanied by an increase in the mean value of CI by 41% (Table 4). The CVP and PAPm increased significantly with a mean value of 3 mmHg and 5 mmHg, respectively. The PAOP remained unchanged.

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Fig 1. Exemplary TEE views for strain analysis and 3D echocardiography. Indicated is the peak longitudinal systolic strain of the RV lateral free wall and the interventricular septum (A), the peak longitudinal systolic strain of the inferior free wall and the RV outflow tract (B), the peak circumferential systolic strain of the RV lateral free wall (C), the peak circumferential systolic strain of the interventricular septum (D), and the RVEF (E). TEE examinations were performed after anesthesia induction before incision, after pericardiotomy, and after sternal closure. The associated p values are presented in Tables 2 and 3. 3D, 3-dimensional; RV, right ventricle; RVEF, right ventricular ejection fraction; TEE, transesophageal echocardiography.

Strain Analysis 4 to 5 Days After Surgery At the postoperative TTE assessment, PLSS of the lateral free wall, and of the interventricular septum, had decreased significantly by a mean percentage value of 51% and 28%, respectively, compared to the preoperative values (Table 2). Conventional and 3D Echocardiographic Assessment 4 to 5 Days After Surgery All patients presented with a sinus rhythm at the TTE examination 4 to 5 days postoperatively. The heart rate had increased nonsignificantly compared to preoperative values by a mean value of 5 beats/min. The transversal contraction of the RV lateral free wall had increased significantly by a mean value of 13%, and the FAC had increased significantly by a mean value of 5%, compared to the preoperative values (Table 3). The RV EF and LV EF were identical with preoperative values, as well as the LV eccentricity index. The LV diastolic function was slightly, but statistically significantly, impaired postoperatively. Discussion The main findings of the present study are:  Peak longitudinal systolic strain of the RV lateral and inferior free wall, RV outflow tract, and interventricular septum were decreased significantly by a mean percentage value of 23% to 41% after sternal closure, while TAPSE was

decreased by 44%. Right ventricular EF did not change after sternal closure, thus confirming the primary hypothesis.  Right ventricular PLSS and RV EF were not reduced significantly after pericardiotomy, thus confirming the hypothesis that pericardiotomy is not associated with an immediate negative effect on RV PLSS and RV EF.

The Effect of Pericardiotomy on RV Function A previous study found that pericardiotomy was associated with an immediate decrease in TAPSE and RV S’.22 Bitcon et al., however, observed that TAPSE and RV S’, as well as PLSS of the RV lateral free wall, remained unchanged after pericardial incision.21 The authors’ results confirm these findings. Right ventricular EF and RV stroke volume, as well as PLSS of the RV lateral and inferior free wall, RV outflow tract, and interventricular septum, did not change after pericardiotomy. The relevance of significant changes in PLSS of 2 RV wall segments (RV basal lateral free wall and anterolateral outflow tract) remains unclear. Left ventricular EF did not change after pericardiotomy, nor did the position of the interventricular septum, as indicated by the eccentricity index. These results must be differentiated from long-term effects of pericardiotomy in patients without pericardial closure after cardiac surgery. In these patients, the RV geometry changed toward increased sphericity.23 The LV moved anteriorly during the systole, causing a septum displacement toward the RV,24 which was accompanied by reduced mobility of the RV lateral free wall.25,26 These findings may underline the beneficial effect of pericardial closure after cardiac surgery.

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which found a reduction in the longitudinal contraction of the RV lateral free wall, assessed either as TAPSE or as longitudinal strain, after cardiac surgery, whereas RV EF remained stable.23,30 The authors’ present data expand the abovementioned findings: the longitudinal contraction was reduced not only at the RV lateral free wall, but also at the RV inflow-outflow tract and at the interventricular septum after sternal closure. Simultaneously, RV circumferential contraction was increased. An increase in RV circumferential contraction has been described previously in patients with systemic RV, and has been interpreted as an adaptive response to a decrease in longitudinal contraction.31 The authors’ data support the hypothesis that an increase in transversal contraction may compensate for the decrease in longitudinal contraction.10,26 The RV shortening fraction and RV FAC, determined by longitudinal as well as transversal contraction of the RV lateral free wall, had increased at the TTE assessment 4 to 5 days postoperatively in the authors’ patients. This phenomenon was not present during the TEE assessment after sternal closure, which may have been caused by the reduction in RV ED volume and in RV stroke volume at that time. As discussed above, a causative effect of pericardiotomy on the observed modification of the RV contraction pattern could be ruled out in the present study. Furthermore, the pericardium was closed at the end of surgery. Thus, the underlying cause of the observed changes in the RV contraction pattern remains unclear. The discussion, as to whether or not the impairment of the longitudinal contraction of the interventricular septum may contribute to the decreased longitudinal contractility of the RV, remains speculative as well.32 Fig 2. Time to peak longitudinal systolic strain, assessed at the RV lateral free wall and the interventricular septum (A), and at the free wall of the RV inflowoutflow tract (B). Time to peak strain did not differ between the different wall segments of the RV lateral free wall, and of the interventricular septum, respectively (RV lateral wall, p = 0.44; interventricular septum, p = 0.80). At the free wall of the RV inflow-outflow tract, time to peak strain was significantly different between the basal inferior segment and the other segments (mid inferior segment, p = 0.002*; anterolateral segment, p < 0.001*; RVOT, p < 0.001*). Time to peak longitudinal systolic strain differed between sample points (RV lateral free wall: B v A, p = 0.008*; C v A, p < 0.001*; interventricular septum: B v A, p = 0.059; C v A, p < 0.001*; RV inflow-outflow tract: B v A, p = 0.41; C v A, p < 0.001*). RVOT, right ventricular outflow tract; sample point A, after anesthesia induction before incision; sample point B, after pericardiotomy; sample point C, after sternal closure. *Indicates the p values that are significant using the Benjamini-Hochberg procedure for control of the false discovery rate in multiple testing. A false discovery rate <0.05 was considered significant.

RV Function After Sternal Closure and in the Postoperative Period Several authors observed a tight correlation between RV longitudinal strain and RV EF in nonsurgical patients referred to cardiac magnetic resonance imaging of the heart.27-29 The authors’ data demonstrate that this relationship cannot be applied to the patient cohort investigated in the present study. The authors’ results are in accordance with previous studies,

Contraction Pattern of the Interventricular Septum After Sternal Closure and in the Postoperative Period Several authors reported an impairment of the longitudinal contraction of the interventricular septum after cardiac surgery,30,33 whereas a recent study observed that the interventricular septum remained postoperatively unaffected.26 The cause of these controversial findings is unclear. Reynolds et al. noticed a paradoxical motion of the septum after CABG in about one-third of patients and considered the dislocation of the heart owing to pericardiotomy, as well as ischemic myocardial injury, as possible underlying mechanisms.24 Lindqvist et al. excluded a relevant effect of pericardiotomy, as the abnormality in septal motion persisted after pericardial closure in patients undergoing aortic valve replacement.33 The current study showed a decrease in the longitudinal contraction of the interventricular septum, as well as an impaired thickening at the end of surgery. The circumferential contraction, however, was not impaired, which normally would be expected in the case of a paradoxical septal motion toward the RV. Likewise, the LV ES eccentricity index should have decreased in the case of a septal bulging toward the RV, but the authors observed the opposite. Buckberg et al. hypothesized that a septal injury may be prevented by the use of adequate blood cardioplegic methods.34 Therefore, it might be hypothesized that differences in cardioprotection contributed to the different

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Table 3 Results of Conventional and 3D Echocardiography TTE In the Week Before Surgery Right ventricular systolic function TAPSE (mm) 25 § 3 RV S’ (mm/s1) 13 § 3 RIMP 0.48 § 0.14 IVA (m/s2) 4.0 § 0.5 RV EDD basal (mm) 37 § 4 RV EDD midcavity (mm) 27 § 4 RV FS (%) 29 § 11 RV FAC (%) 45 § 3 Right ventricular 3-dimensional analysis RV EDV (ml) 136 § 17 RV ESV (ml) 73 § 12 RV stroke volume (mL) 62 § 9 RV EF (%) 46 § 3 Left ventricular systolic function LVEF 61 § 3 Left ventricular diastolic function LV E/E’ ratio 10 § 2 Left ventricular eccentricity index LVEI ES 1.01 § 0.12 LVEI ED 1.07 § 0.10

TEE

4 to 5 Days After Surgery

p Value

Pre-incision (A)

After Pericardiotomy (B)

After Sternal Closure (C)

12 § 2 8§3 0.48 § 0.15 4.1 § 0.4 39 § 6 29 § 5 42 § 9 50 § 5

<0.001* <0.001* 0.81 0.38 0.052 0.086 <0.001* <0.001*

18 § 3 8§2 0.45 § 0.18 2.4 § 0.8 44 § 6 39 § 6 23 § 8 37 § 6

19 § 5 9§3 0.54 § 0.22 3.3 § 1.5 44 § 6 39 § 6 27 § 10 40 § 10

12 § 3 5§2 0.54 § 0.18 2.1 § 1.1 42 § 5 36 § 7 23 § 11 36 § 10

139 § 21 75 § 12 64 § 11 45 § 3

0.31 0.27 0.50 0.58

134 § 33 65 § 17 69 § 19 51 § 6

125 § 30 55 § 16 70 § 18 56 § 6

61 § 3

0.56

54 § 7

12 § 4

0.008*

1.01 § 0.12 1.05 § 0.12

0.98 0.31

p Value B versus A

p Value C versus A

0.66 0.12 0.092 0.001* 0.65 0.70 0.025 0.041

<0.001* <0.001* 0.073 0.27 0.034 0.005* 0.92 0.59

115 § 29 59 § 16 51 § 16 50 § 7

0.13 <0.001* 0.78 0.002*

<0.001* 0.029 0.001* 0.341

56 § 10

58 § 10

0.21

0.012*

7§2

8§2

8§3

0.74

0.26

1.09 § 0.09 1.05 § 0.09

1.10 § 0.13 1.05 § 0.09

1.17 § 0.16 1.09 § 0.13

0.39 0.71

0.006* 0.069

NOTE. Results are expressed as mean § standard deviation or as number of patients (n). p values are reported for within-subject comparisons between sample points B and A, and between sample points C and A. E, peak early diastolic filling flow velocity; E’, peak early diastolic annulus velocity; EDV, end-diastolic volume; EF, ejection fraction; ESV, end-systolic volume; FAC, fractional area change; FS, fractional shortening; IVA, isovolumic acceleration; LVEF, left ventricular ejection fraction; LVEI ED, end-diastolic left ventricular eccentricity index; LVEI ES, end-systolic left ventricular eccentricity index; RIMP, right ventricular index of myocardial performance; RV EDD, right ventricular end-diastolic transverse diameter; RVEF, right ventricular ejection fraction; RV ESD, right ventricular end-systolic transverse diameter; RV S’, peak systolic tricuspid annulus velocity; TAPSE, tricuspid annular plane systolic excursion; TEE, transesophageal echocardiography; TTE, transthoracic echocardiography. * Indicates the p values which are significant using the Benjamini-Hochberg procedure for control of the false discovery rate in multiple testing. A false discovery rate <0.05 was considered significant.

findings mentioned above. Further studies should investigate the association between the delivery of cardioplegia (ie, antegrade, retrograde, ante- and retrograde, as well as flow, duration, and perfusion pressure) and the contraction pattern of the interventricular septum and the RV after cardiac surgery. The contractions of the RV lateral free wall and the interventricular septum are synchronized in healthy participants without significant differences between the base and apex.35 Meris et al. observed in patients with impaired RV function that the time to PLSS was prolonged, compared to healthy participants, with a marked scattering of values.35 In view of these findings, the authors’ data do not indicate disturbances in the coordination of the longitudinal contraction, or in the synchronization of the RV free lateral wall and the interventricular septum, in the authors’ patients at any time. The time to PLSS had shortened similarly in all wall segments at the end of surgery, which should be interpreted as an effect of increased heart rate at that point. Methodological Aspects and Limitations of the Study Previous studies showed that strain analysis of the RV provides reliable information on the performance of the RV.28,36 Right ventricular strain analysis has been recommended for

application at the RV lateral free wall, which may be visualized using a RV centered 4-chamber view.37 Currently, RV strain analysis is performed using software that originally was designed for the analysis of the LV function, and which only can be adapted for the RV geometry in a limited way.38 In addition to the RV lateral free wall, the authors analyzed the strain of the free wall of the RV inflow-outflow tract. The strain analysis using the midesophageal RV inflow-outflow view frequently was disturbed by artifacts causing a low imaging quality, especially in the region of the outflow tract. The transgastric view of the RV inflow-outflow tract at about 130˚ offered a better imaging quality in the authors’ patients than the midesophageal view. As the RV apex frequently cannot be tracked in the transgastric RV inflow-outflow view, data for this wall segment are not provided. The software, originally designed for the LV, was applied for the assessment of the RV circumferential strain in the short-axis view, thus allowing the assessment of the circumferential strain for the RV inferolateral and anterolateral free wall segments. Regarding the sharp angle of the junction between the RV wall and interventricular septum in the short-axis view, and owing to difficulties in delineating these wall segments correctly, the strain of the interventricular septum was measured as the segmental strain

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Table 4 Hemodynamic and Respiratory Parameters and Intravenous Drug Therapy During the Echocardiographic Examinations In the Week Before Surgery

4 to 5 Days After Surgery

Hemodynamic and respiratory parameters HR (min) 71 § 10 SR (n) 30 Atrial pacing (n) 0 CVP (mmHg) 5 § 0.4 CI (mL/min/m2) MAP (mmHg) PAPm (mmHg) PAOP (mmHg) RVSWI (g/m/beat/m2) Mean airway pressure (mbar) PEEP (mbar) Intraoperative drug therapy Nitroglycerine (n) Norepinephrine (n) Dobutamine (n)

76 § 11 30 0 5 § 1.2

p Value

Pre-incision (A)

After Pericardiotomy (B)

After Sternal Closure (C)

p Value B versus A

p Value C versus A

0.07 -

52 § 8 30 0 13 § 4 1.9 § 0.4 75 § 11 22 § 4 15 § 4 4.7 § 2.0 11 § 2 6§1

61 § 10 30 0 10 § 3 2.5 § 0.5 75 § 10 21 § 4 12 § 4 6.4 § 2.5 10 § 2 6§2

82 § 10 21 9 16 § 4 2.6 § 0.4 76 § 13 27 § 7 16 § 4 4.8 § 2.0 12 § 2 7§2

<0.001* -

<0.001* 0.008*

0.001* <0.001* 0.75 0.15 0.005* 0.001*

<0.001* <0.001* 0.74 0.001*

0 12 0

1 12 0

29 13 8

0.36

0.28 0.09

0.07 0.90 <0.001* 0.001*

1.0 1.0 -

<0.001* 1.0 0.008*

NOTE. Results are expressed as mean § standard deviation or as number of patients (n). p values are reported for within-subject comparisons between sample points B and A, and between sample points C and A. CI, cardiac index; CVP, central venous pressure; HR, heart rate; MAP, mean arterial pressure; PAOP, pulmonary artery occlusion pressure; PAPm, mean pulmonary artery pressure; PEEP, positive end-expiratory pressure; RVSWI, right ventricular stroke work index; SR, sinus rhythm. * Indicates the p values that are significant using the Benjamini-Hochberg procedure for control of the false discovery rate in multiple testing. A false discovery rate < 0.05 was considered significant.

of the LV, as recommended in current guidelines.37 Although not established until now, the authors measured radial strain not only for the interventricular septum, but likewise for the RV lateral free wall in the short-axis view. Because of the surgical dressing and drainage, neither the subcostal view of the RV inflow-outflow tract nor the parasternal short-axis view could be assessed properly in TTE. Therefore, strain measurements for TTE were provided for the 4-chamber view only. The authors did not compare TTE with TEE measurements of RV myocardial function, as various studies showed that parameters, such as RV S’ and TAPSE, are not comparable between methods.39,40 Strain values, expressed as absolute values, were consistently lower in the authors’ patients under baseline conditions than those reported previously.36,41 Lang et al. stated that a strain >20% of the RV lateral free wall should be regarded as abnormal.13 Peyrou found that a value >17% indicated a pathologic RV function when measuring the strain at the basal lateral wall.42 It is unclear whether the observed differences are owing to specific software characteristics. A previous study showed that TTE and TEE assessments of strain are comparable only in a limited way, possibly owing to different echocardiographic views or image quality.43 Furthermore, it is unclear whether RV strain analysis is comparable between mechanically ventilated and spontaneously breathing patients, owing to different preload and afterload conditions. The repeatability coefficient, that is, the range in which 95% of measurements are expected to lie, was similar to previous studies, which reported a range of 4.3% and 4.8%, respectively.27,35 As these studies assessed RV global longitudinal strain, that is, the

average of 6 segments of the RV lateral free wall and the interventricular septum, using TTE, the results are comparable only in a limited way. Hemodynamic conditions differed preoperatively and postoperatively in the authors’ patients. At the end of surgery, the heart rate had increased compared to the baseline values; RV and LV filling pressures had increased; as had PAPm, which may serve as a determinant of RV afterload. Mean airway pressure and positive end-expiratory pressure had increased slightly but statistically significantly at the end of surgery. Previous studies found an impairment of RV function, determined as RV lateral free wall strain and as RV ED volume, respectively, with increasing levels of positive end-expiratory pressure.44,45 The same mechanism cannot be ruled out in the authors’ patients. This study cohort comprised mostly male patients. A recent study found sex-specific differences in RV longitudinal strain and reported that RV lateral free wall strain was 2% § 4% larger in women than in men.41 Sex-specific differences in strain analysis also may exist perioperatively and postoperatively in cardiac surgical patients. As this study was not designed to detect these phenomena, this issue should be explored in future studies. Conclusion In conclusion, the authors found in patients undergoing CABG with cardioplegic cardiac arrest a significant reduction in PLSS of the RV lateral and inferior wall, RV outflow tract, and interventricular septum by a mean percentage value between 23% and 41% at the end of surgery after sternal

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closure. Simultaneously, the circumferential contraction of the RV lateral wall increased significantly by a mean percentage value of 4%. The RV EF remained unchanged. Pericardial incision was not associated with an immediate negative effect on RV PLSS and RV EF. Conflict of Interest The authors have no conflicts of interest to declare. References 1 Korshin A, Gronlykke L, Nilsson JC, et al. Tricuspid annular plane systolic excursion is significantly reduced during uncomplicated coronary artery bypass surgery: A prospective observational study. J Thorac Cardiovasc Surg 2019;158:480–9. 2 David JS, Tousignant CP, Bowry R. Tricuspid annular velocity in patients undergoing cardiac operation using transesophageal echocardiography. J Am Soc Echocardiogr 2006;19:329–34. 3 Hedman A, Alam M, Zuber E, et al. Decreased right ventricular function after coronary artery bypass grafting and its relation to exercise capacity: A tricuspid annular motion-based study. J Am Soc Echocardiogr 2004;17: 126–31. 4 Alam M, Hedman A, Nordlander R, et al. Right ventricular function before and after an uncomplicated coronary artery bypass graft as assessed by pulsed wave Doppler tissue imaging of the tricuspid annulus. Am Heart J 2003;146:520–6. 5 Kempny A, Diller GP, Kaleschke G, et al. Impact of transcatheter aortic valve implantation or surgical aortic valve replacement on right ventricular function. Heart 2012;98:1299–304. 6 Roshanali F, Yousefnia MA, Mandegar MH, et al. Decreased right ventricular function after coronary artery bypass grafting. Tex Heart Inst J 2008;35:250–5. 7 Raina A, Vaidya A, Gertz ZM, et al. Marked changes in right ventricular contractile pattern after cardiothoracic surgery: Implications for post-surgical assessment of right ventricular function. J Heart Lung Transplant 2013;32:777–83. 8 Okada DR, Rahmouni HW, Herrmann HC, et al. Assessment of right ventricular function by transthoracic echocardiography following aortic valve replacement. Echocardiography 2014;31:552–7. 9 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;10:630–4. 10 Keyl C, Schneider J, Beyersdorf F, et al. Right ventricular function after aortic valve replacement: A pilot study comparing surgical and transcatheter procedures using 3D echocardiography. Eur J Cardiothorac Surg 2016;49:966–71. 11 Wranne B, Pinto FJ, Siegel LC, et al. Abnormal postoperative interventricular motion: New intraoperative transesophageal echocardiographic evidence supports a novel hypothesis. Am Heart J 1993;126:161–7. 12 Rudski LG, Lai WW, Afilalo J, 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;23:685–713. 13 Lang RM, Badano LP, Mor-Avi V, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: An update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 2015;16: 233–70. 14 Kaul S, Tei C, Hopkins JM, et al. Assessment of right ventricular function using two-dimensional echocardiography. Am Heart J 1984;107:526–31.

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41

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43

44

45

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