CONGENITAL HEART DISEASE
Insights into the Evolution of Myocardial Dysfunction in the Functionally Single Right Ventricle between Staged Palliations Using Speckle-Tracking Echocardiography Edythe B. Tham, MBBS, Jeffery F. Smallhorn, MBBS, Sachie Kaneko, MD, Sabira Valiani, MD, Kimberley A. Myers, MD, Timothy M. Colen, MBBS, Shelby Kutty, MD, and Nee S. Khoo, MBChB, Edmonton and Calgary, Alberta, Canada; Omaha, Nebraska
Background: The long-term prognosis of hypoplastic left heart syndrome is limited by progressive right ventricular dysfunction. The aim of this study was to determine the trends in single right ventricular systolic function between staged palliative surgeries using speckle-tracking and conventional echocardiography. Methods: There were 76 patients with functionally single right ventricles at the (1) pre-Norwood (n = 26), (2) pre–bidirectional cavopulmonary anastomosis (BCPA; n = 19), (3) pre-Fontan (n = 16), and (4) postFontan (n = 15) stages, compared with 30 controls of similar ages. Speckle-tracking-derived longitudinal and circumferential strain and strain rate, postsystolic strain index, and mechanical dyssynchrony index were compared with conventional measures of ventricular function. Differences between stages were analyzed using analysis of variance (P < .05). Results: Strain rate was highest at the pre-Norwood stage and decreased at the other stages (longitudinal P < .0001, circumferential P = .0002), as opposed to controls, in whom strain rate was maintained. Longitudinal strain was significantly decreased at the pre-BCPA stage compared with the pre-Norwood stage (P = .004), but circumferential strain was maintained, resulting in a corresponding decrease in the ratio of longitudinal to circumferential strain, which failed to resemble that of controls. Longitudinal (P = .003) and circumferential (P = .002) postsystolic strain indices were greatest at the pre-BCPA stage. Conclusions: A decline in contractility occurred at the pre-BCPA stage. Although there was evidence of adaptation of the single right ventricle, this failed to resemble the normal left ventricle and may be insufficient to handle the chronic volume load or insult from previous surgery. These findings suggest an intrinsic inability of the single right ventricular myocardium to fully adapt to chronic systemic pressures. (J Am Soc Echocardiogr 2014;27:314-22.) Keywords: Speckle-tracking imaging, Single ventricle, Ventricular function, Strain, Echocardiography
Advances in surgical techniques and perioperative care over the past decade have been associated with improved early and long-term survival of patients with hypoplastic left heart syndrome (HLHS).1,2 Even patients with less favorable hemodynamics than those outlined by the original selection criteria are now undergoing the Fontan procedure.3 However, single right ventricular (RV) function may deteriorate over time.4-6 Understanding the mechanisms of myocardial dysfunction may allow the early optimization of medical management.4 Risk factors for long-term outcomes include tricuspid From the Stollery Children’s Hospital, Edmonton, Alberta, Canada (E.B.T., J.F.S., S.K., S.V., T.M.C., N.S.K.); Alberta Children’s Hospital, Calgary, Alberta, Canada (K.A.M.); and University of Nebraska College of Medicine/Children’s Hospital and Medical Center, Omaha, Nebraska (S.K.). Reprint requests: Edythe B. Tham, MBBS, Stollery Children’s Hospital, Division of Pediatric Cardiology, 4C2.28 WMC HSC, 8440-112 Street, Edmonton, AB T6G 2B7, Canada (E-mail: [email protected]). 0894-7317/$36.00 Copyright 2014 by the American Society of Echocardiography. http://dx.doi.org/10.1016/j.echo.2013.11.012
314
regurgitation, unfavorable ventricular morphology, diastolic dysfunction, and afterload mismatch.7 Other postulated mechanisms include impaired coronary flow reserve and mechanical dyssynchrony.8-12 Serial assessment of ventricular function is important in the longterm care of these patients.13,14 However, there is no widely accepted technique by which to quantify single RV function, because of the right ventricle’s complex asymmetric geometry.4 Conventional echocardiographic indices of ventricular function are largely qualitative, while quantitative methods are limited by their load dependency and geometric assumptions. Systolic function as assessed by cardiac magnetic resonance imaging is reliable and accurate, but it provides only a global index of ventricular function, and it does not assess the complex contraction mechanics in the single right ventricle.15-17 Speckle-tracking echocardiography measuring ventricular function using strain and contractility from strain rate (SR) are angle-independent and reproducible methods of quantifying ventricular deformation.18 Furthermore, as shown in our previous longitudinal study of HLHS between the pre-Norwood and pre–bidirectional cavopulmonary anastomosis (BCPA) stages, these methods enable the assessment of both longitudinal and circumferential contractility,
Journal of the American Society of Echocardiography Volume 27 Number 3
Abbreviations
BCPA = Bidirectional cavopulmonary anastomosis
EDAi = Indexed right ventricular end-diastolic area FAC = Fractional area change HLHS = Hypoplastic left heart syndrome
Tham et al 315
providing important insights into the adaptive changes that occur within the single right ventricle when facing systemic pressures.18 The aim of this study was to gain insight into the evolution of systolic dysfunction in functionally single right ventricles between the stages of palliative surgery using speckletracking echocardiography.
echocardiographic parameters, were recruited from the Stollery Children’s Hospital and the University of Nebraska. Because the pre-Fontan and post-Fontan stages were of the same age, we divided the controls into only three age groups of similar ages to patients with single right ventricles. All controls had no histories of cardiac pathology or respiratory disease and no family histories of cardiomyopathy. They had normal results on physical examination, 12-lead electrocardiography, and echocardiography. The parents of all subjects enrolled gave informed consent to participate in the study, which was approved by the health research ethics boards of both institutions.
METHODS
Echocardiographic Protocol All echocardiographic studies were performed using a Vivid 7 ultrasound machine (GE Medical Systems, Milwaukee, WI) with electrocardiographic and respiratory gating and stored on an offline EchoPAC (version 7.1) system (GE Medical Systems) for later analysis. A standard anatomic evaluation and functional examination were performed only by technicians or physicians experienced with our institution’s detailed single-ventricle functional protocol. All preBCPA patients were sedated for their studies, most receiving chloral hydrate (60–80 mg/kg); three studies were performed during general anesthesia in association with other procedures.
IVA = Isovolumic acceleration MDI = Mechanical dyssynchrony index
Study Subjects Since 2007, we have embarked index on a prospective, longitudinal study of ventricular function in RV = Right ventricular patients with HLHS and its SR = Strain rate variants (i.e., functionally single 2D = Two-dimensional right ventricle) at the Stollery Children’s Hospital, University of Alberta. This cross-sectional study was performed in patients selected from our study population at four different stages of surgical palliation, and thus each patient was only included once. PSSi = Postsystolic strain
Clinical Variables Demographic and clinical data collected included age, body surface area, oxygen saturation, blood pressure, and medications at the time of echocardiography. Note was made if patients were sedated at the time of the study. At the pre-Norwood stage, mechanical ventilation, blood pH and lactate, antenatal diagnosis, and modified inotrope score were recorded.19 The use of angiotensin-converting enzyme inhibitors was noted. Subjects Patients with functionally single right ventricles presenting to the Stollery Children’s Hospital were included. Patients were studied at a single time point at one of four possible surgical stages: the (1) pre-Norwood (pre–surgical intervention), (2) pre-BCPA, (3) preFontan, and (4) post-Fontan stages. These were chosen to represent different volume-loading conditions. Echocardiography was performed shortly after diagnosis at the pre-Norwood stage and at the time of presurgical assessment at the pre-BCPA or pre-Fontan stage. If the post-Fontan echocardiographic assessment was close to the time of discharge, it was performed once chest tubes were removed and there were no pleural effusions. All patients with the intent to proceed to the next stage of surgery were included whether they subsequently underwent the surgical procedure or not (i.e., an ‘‘intentionto-treat’’ approach). The type of Fontan procedure performed (lateral tunnel or extracardiac conduit) and the presence of a fenestration were recorded, as well as the time frame between the Fontan procedure and post-Fontan echocardiography. Exclusion criteria were arrhythmias, pacemakers, and inability to cooperate for an adequate functional echocardiographic study. Patients who did not undergo stage I procedures under cardiopulmonary bypass were excluded. Control Population Healthy volunteers between day 1 of life to 3.5 years of age, to represent the normal maturational changes for speckle-tracking
Two-Dimensional Echocardiography. Traditional parameters for the assessment of ventricular systolic function applicable to the single right ventricle were measured as described in previous studies.4,15,20 These included (1) tricuspid annular plane systolic excursion of the RV free wall indexed to body surface area, a measure of longitudinal systolic function; (2) Doppler tissue imaging assessment of tricuspid annular velocity to determine S0 velocity and myocardial performance index; (3) isovolumic acceleration (IVA) from color tissue Doppler; (4) indexed RV enddiastolic area (EDAi) and systole, from the apical ‘‘four-chamber’’ view, as surrogates for ventricular volumes, as we have previously shown a good correlation between these two-dimensional (2D) measures and magnetic resonance imaging–derived volumes18; and (5) calculated 2D fractional area change (FAC). The presence of tricuspid regurgitation was classified subjectively as none, mild, moderate, or severe. Speckle-Tracking Echocardiography. Two-dimensional grayscale images captured at the equivalent apical ‘‘four-chamber’’ (longitudinal) and basal short-axis (circumferential) planes optimized for higher frame rate (115 6 33 Hz) were analyzed by a single observer. Speckle-tracking imaging measured global longitudinal and circumferential strain and SR. The ratio of longitudinal to circumferential strain was calculated to determine their relative contribution to contraction. The postsystolic strain index (PSSi) was calculated as [(peak strain peak systolic strain)/peak strain] and expressed as a percentage. Mechanical dyssynchrony in the longitudinal and circumferential dimensions was measured as the standard deviation of segmental time to peak strain. Measurements were made in the single right ventricle in the study patients and the normal left ventricles of controls. We previously reported low interobserver variability, a small 1.96 within-subject standard deviation, and high intraclass correlation coefficients for all the reported parameters, indicating good repeatability of these novel parameters in an anatomically similar cohort of patients with single right ventricles using the same equipment and analytic software.18 Because of the importance of accurate timing of these parameters, we noted the heart rate at the time of our
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Journal of the American Society of Echocardiography March 2014
Table 1 Types of single ventricular morphology Stage
HLHS
Critical AS
Heterotaxy/AVSD
Other*
Pre-Norwood Pre-BCPA Pre-Fontan Post-Fontan
85% 79% 94% 60%
4% 0% 0% 20%
11% 21% 0% 20%
0% 0% 6% 0%
AS, Aortic stenosis; AVSD, atrioventricular septal defect. *Double-outlet right ventricle plus hypoplastic left ventricle.
M-mode calculation of aortic valve closure, and at the strain image, and chose comparative images that had heart rate variability of 620 beats/min, noting that heart rate variation of 620 beats/min accounted for 69-msec error. Statistical Analysis Results are expressed as mean 6 SD. Differences between the stages for each parameter were analyzed using one-way analysis of variance with Tukey-Kramer or Dunn’s post hoc comparison test within groups (P < .05) using GraphPad Prism version 5.04 (GraphPad Software, San Diego, CA). The differences among the three control groups were analyzed in the same fashion to determine maturational trends. Differences between neonates who received ventilation or inotropes and patients who received angiotensin-converting enzyme inhibitors were compared with those without, using unpaired t tests. Pearson’s correlation coefficients were used to determine associations between speckle-tracking and 2D echocardiographic parameters. Although previous studies have used the normal left ventricle in a biventricular circulation as a control population for the single right ventricle, this is not a valid comparison, because of the different fiber architecture and orientation in the RV and left ventricular myocardium, so direct comparisons with controls at each stage were not evaluated.
RESULTS Subjects A total of 76 subjects formed the study group: (1) 26 at the pre-Norwood stage (3.0 6 3.5 days), (2) 19 at the pre-BCPA stage (5.3 6 2.1 months), (3) 16 at the pre-Fontan stage (3.5 6 1.0 year), and (4) 15 at the post-Fontan stage (3.7 6 1.2 years). Echocardiography was performed a mean of 4 6 9 months after the Fontan procedure. All patients had HLHS or its variants, as shown in Table 1. Thirty controls, with 10 in each group, were of similar ages to our patient group: (1) neonates (4 6 3.2 days), (2) 5.8 6 2.9 months, and (3) 3.8 6 0.7 years. Demographic data and clinical characteristics are displayed in Table 2. Clinical Data All neonates were in stable condition at the time of the study, with normal mean blood pH (7.4 6 0.1) and lactate (1.6 6 0.7 mmol/L). In the pre-Norwood group, 88% had prenatal diagnoses, 58% were ventilated (mostly because of apnea secondary to prostaglandin E1 infusion), and 54% received inotropes (milrinone or dobutamine), with a mean inotrope score of 3.7 6 3.6. Oxygen saturation varied significantly among the groups (P < .0001), as expected, with higher saturations at the pre-Norwood stage compared with the pre-BCPA and pre-Fontan stages and greater saturations at the post-Fontan stage
compared with the pre-BCPA and pre-Fontan stages. In the pre-BCPA group, all patients had undergone previous Norwood procedures with Sano shunts under cardiopulmonary bypass. In the post-Fontan group, 94% were fenestrated, 11 (73%) received extracardiac conduits, three (20%) underwent lateral tunnel Fontan procedures, and one (7%) had a Kawashima procedure. Effect of Medical Interventions Neonates receiving inotropes had increased longitudinal SRs compared with those who did not receive inotropes (1.9 6 0.52%/sec vs 1.5 6 0.19%/sec, P = .01). Inotropes had no significant effect on longitudinal strain, circumferential strain, or SR. There were no differences in speckle-tracking echocardiographic parameters between the neonates who were or were not ventilated. Angiotensin-converting enzyme inhibitors had no effect on strain parameters in the pre-BCPA, pre-Fontan, and post-Fontan groups. Conventional 2D Echocardiographic Parameters Two-dimensional echocardiography showed that EDAi was significantly increased at the pre-BCPA stage compared with the pre-Fontan stage (P = .003) but not the pre-Norwood stage, while indexed RV end-systolic area did not vary among stages (Table 3). Global ventricular systolic functional indices such as FAC and myocardial performance index were unchanged among the four stages. Indexed tricuspid annular plane systolic excursion was significantly higher at the pre-Norwood stage compared with the other three stages and also higher at the pre-BCPA stage compared with the pre-Fontan and post-Fontan stages (P < .0001). Both Doppler tissue imaging S0 velocity (P = .0003) and IVA (P < .0001) were significantly higher at the pre-Norwood stage compared with the three other stages, and both were also higher at pre-BCPA stage compared with the pre-Fontan and post-Fontan stages. The presence of moderate or greater atrioventricular valve regurgitation was found in 13% of all patients. Speckle-Tracking Echocardiographic Parameters Strain. There was a significant difference in longitudinal strain among the four groups (P = .004) because of the pre-Norwood stage’s showing greater longitudinal strain than the pre-BCPA stage (Figure 1). There was no significant variation in circumferential strain among the four stages. The ratio of longitudinal to circumferential ratio decreased significantly from the pre-Norwood to the preBCPA stage (P = .02) (Table 4). SR. We found a significant variation among the four stages for both longitudinal (P < .0001) and circumferential (P = .0002) SR (Figure 1). Post hoc testing revealed that longitudinal SR was significantly greater at the pre-Norwood stage than at the three other stages, while circumferential SR was significantly greater at the pre-Norwood stage compared with the pre-BCPA and pre-Fontan stages but not significantly different from the post-Fontan stage. In the circumferential dimension, there was a trend for SR to increase at the post-Fontan stage, although this was not statistically significant (Table 4). We repeated the longitudinal SR comparisons by excluding neonates who received inotropes and still found significantly increased longitudinal SRs at the neonatal stage compared with the three other stages (P < .001). PSSi. There were significant variations in longitudinal (P = .003) and circumferential (P = .002) PSSi among the groups (Figure 2). Post hoc
Tham et al 317
Journal of the American Society of Echocardiography Volume 27 Number 3
Table 2 Demographic and clinical characteristics of patients Variable
Pre-Norwood
Pre-BCPA
Pre-Fontan
Post-Fontan
Age at echocardiography BSA (cm2) SaO2 (%) SBP (mm Hg) Inotropes Diuretics ACE inhibitors b-blockers
3.0 6 3.5 d 0.21 6 0.03 88 6 6 62 6 10 54% 0 0 0
5.3 6 2.1 mo 0.30 6 0.05 77 6 4 87 6 15 0 52% 68% 5%
3.5 6 1.0 y 0.63 6 0.15 81 6 6 97 6 11 0 24% 75% 25%
3.7 6 1.2 y 0.63 6 0.09 86 6 6 107 6 21 0 67% 60% 7%
ACE, Angiotensin-converting enzyme; BSA, body surface area; SaO2, oxygen saturation; SBP, systolic blood pressure. Data are expressed as mean 6 SD or as percentages.
Table 3 Traditional 2D echocardiographic parameters at each surgical stage Variable 2
2
EDAi (cm /m ) ESAi (cm2/m2) FAC (%) MPI IVA (cm/sec2) S0 velocity (cm/sec) TAPSEi (cm/m2) More than moderate TR
Pre-Norwood
Pre-BCPA
Pre-Fontan
Post-Fontan
P
27 6 6.7 18 6 5.8 36 6 8 0.47 6 0.12 2.3 6 1.2* 6.6 6 2.1* 4.1 6 0.88* 8%
32 6 9.5* 20 6 9.3 39 6 13 0.46 6 0.13 1.3 6 0.8†a 3.6 6 0.7† 2.3 6 0.37†a 16%
26 6 6.5 17 6 4.0 33 6 4 0.49 6 0.12 0.49 6 0.12†b 4.5 6 1.3† 1.5 6 0.34†b 24%
22 6 5.8 15 6 5.0 34 6 9 0.45 6 0.18 0.45 6 0.18†b 3.9 6 1.7† 1.1 6 0.35†b 6%
.003 NS NS NS
Insights into the Evolution of Myocardial Dysfunction in the Functionally Single Right Ventricle between Staged Palliations Using Speckle-Tracking Echocardiography Edythe B. Tham, MBBS, Jeffery F. Smallhorn, MBBS, Sachie Kaneko, MD, Sabira Valiani, MD, Kimberley A. Myers, MD, Timothy M. Colen, MBBS, Shelby Kutty, MD, and Nee S. Khoo, MBChB, Edmonton and Calgary, Alberta, Canada; Omaha, Nebraska
Background: The long-term prognosis of hypoplastic left heart syndrome is limited by progressive right ventricular dysfunction. The aim of this study was to determine the trends in single right ventricular systolic function between staged palliative surgeries using speckle-tracking and conventional echocardiography. Methods: There were 76 patients with functionally single right ventricles at the (1) pre-Norwood (n = 26), (2) pre–bidirectional cavopulmonary anastomosis (BCPA; n = 19), (3) pre-Fontan (n = 16), and (4) postFontan (n = 15) stages, compared with 30 controls of similar ages. Speckle-tracking-derived longitudinal and circumferential strain and strain rate, postsystolic strain index, and mechanical dyssynchrony index were compared with conventional measures of ventricular function. Differences between stages were analyzed using analysis of variance (P < .05). Results: Strain rate was highest at the pre-Norwood stage and decreased at the other stages (longitudinal P < .0001, circumferential P = .0002), as opposed to controls, in whom strain rate was maintained. Longitudinal strain was significantly decreased at the pre-BCPA stage compared with the pre-Norwood stage (P = .004), but circumferential strain was maintained, resulting in a corresponding decrease in the ratio of longitudinal to circumferential strain, which failed to resemble that of controls. Longitudinal (P = .003) and circumferential (P = .002) postsystolic strain indices were greatest at the pre-BCPA stage. Conclusions: A decline in contractility occurred at the pre-BCPA stage. Although there was evidence of adaptation of the single right ventricle, this failed to resemble the normal left ventricle and may be insufficient to handle the chronic volume load or insult from previous surgery. These findings suggest an intrinsic inability of the single right ventricular myocardium to fully adapt to chronic systemic pressures. (J Am Soc Echocardiogr 2014;27:314-22.) Keywords: Speckle-tracking imaging, Single ventricle, Ventricular function, Strain, Echocardiography
Advances in surgical techniques and perioperative care over the past decade have been associated with improved early and long-term survival of patients with hypoplastic left heart syndrome (HLHS).1,2 Even patients with less favorable hemodynamics than those outlined by the original selection criteria are now undergoing the Fontan procedure.3 However, single right ventricular (RV) function may deteriorate over time.4-6 Understanding the mechanisms of myocardial dysfunction may allow the early optimization of medical management.4 Risk factors for long-term outcomes include tricuspid From the Stollery Children’s Hospital, Edmonton, Alberta, Canada (E.B.T., J.F.S., S.K., S.V., T.M.C., N.S.K.); Alberta Children’s Hospital, Calgary, Alberta, Canada (K.A.M.); and University of Nebraska College of Medicine/Children’s Hospital and Medical Center, Omaha, Nebraska (S.K.). Reprint requests: Edythe B. Tham, MBBS, Stollery Children’s Hospital, Division of Pediatric Cardiology, 4C2.28 WMC HSC, 8440-112 Street, Edmonton, AB T6G 2B7, Canada (E-mail: [email protected]). 0894-7317/$36.00 Copyright 2014 by the American Society of Echocardiography. http://dx.doi.org/10.1016/j.echo.2013.11.012
314
regurgitation, unfavorable ventricular morphology, diastolic dysfunction, and afterload mismatch.7 Other postulated mechanisms include impaired coronary flow reserve and mechanical dyssynchrony.8-12 Serial assessment of ventricular function is important in the longterm care of these patients.13,14 However, there is no widely accepted technique by which to quantify single RV function, because of the right ventricle’s complex asymmetric geometry.4 Conventional echocardiographic indices of ventricular function are largely qualitative, while quantitative methods are limited by their load dependency and geometric assumptions. Systolic function as assessed by cardiac magnetic resonance imaging is reliable and accurate, but it provides only a global index of ventricular function, and it does not assess the complex contraction mechanics in the single right ventricle.15-17 Speckle-tracking echocardiography measuring ventricular function using strain and contractility from strain rate (SR) are angle-independent and reproducible methods of quantifying ventricular deformation.18 Furthermore, as shown in our previous longitudinal study of HLHS between the pre-Norwood and pre–bidirectional cavopulmonary anastomosis (BCPA) stages, these methods enable the assessment of both longitudinal and circumferential contractility,
Journal of the American Society of Echocardiography Volume 27 Number 3
Abbreviations
BCPA = Bidirectional cavopulmonary anastomosis
EDAi = Indexed right ventricular end-diastolic area FAC = Fractional area change HLHS = Hypoplastic left heart syndrome
Tham et al 315
providing important insights into the adaptive changes that occur within the single right ventricle when facing systemic pressures.18 The aim of this study was to gain insight into the evolution of systolic dysfunction in functionally single right ventricles between the stages of palliative surgery using speckletracking echocardiography.
echocardiographic parameters, were recruited from the Stollery Children’s Hospital and the University of Nebraska. Because the pre-Fontan and post-Fontan stages were of the same age, we divided the controls into only three age groups of similar ages to patients with single right ventricles. All controls had no histories of cardiac pathology or respiratory disease and no family histories of cardiomyopathy. They had normal results on physical examination, 12-lead electrocardiography, and echocardiography. The parents of all subjects enrolled gave informed consent to participate in the study, which was approved by the health research ethics boards of both institutions.
METHODS
Echocardiographic Protocol All echocardiographic studies were performed using a Vivid 7 ultrasound machine (GE Medical Systems, Milwaukee, WI) with electrocardiographic and respiratory gating and stored on an offline EchoPAC (version 7.1) system (GE Medical Systems) for later analysis. A standard anatomic evaluation and functional examination were performed only by technicians or physicians experienced with our institution’s detailed single-ventricle functional protocol. All preBCPA patients were sedated for their studies, most receiving chloral hydrate (60–80 mg/kg); three studies were performed during general anesthesia in association with other procedures.
IVA = Isovolumic acceleration MDI = Mechanical dyssynchrony index
Study Subjects Since 2007, we have embarked index on a prospective, longitudinal study of ventricular function in RV = Right ventricular patients with HLHS and its SR = Strain rate variants (i.e., functionally single 2D = Two-dimensional right ventricle) at the Stollery Children’s Hospital, University of Alberta. This cross-sectional study was performed in patients selected from our study population at four different stages of surgical palliation, and thus each patient was only included once. PSSi = Postsystolic strain
Clinical Variables Demographic and clinical data collected included age, body surface area, oxygen saturation, blood pressure, and medications at the time of echocardiography. Note was made if patients were sedated at the time of the study. At the pre-Norwood stage, mechanical ventilation, blood pH and lactate, antenatal diagnosis, and modified inotrope score were recorded.19 The use of angiotensin-converting enzyme inhibitors was noted. Subjects Patients with functionally single right ventricles presenting to the Stollery Children’s Hospital were included. Patients were studied at a single time point at one of four possible surgical stages: the (1) pre-Norwood (pre–surgical intervention), (2) pre-BCPA, (3) preFontan, and (4) post-Fontan stages. These were chosen to represent different volume-loading conditions. Echocardiography was performed shortly after diagnosis at the pre-Norwood stage and at the time of presurgical assessment at the pre-BCPA or pre-Fontan stage. If the post-Fontan echocardiographic assessment was close to the time of discharge, it was performed once chest tubes were removed and there were no pleural effusions. All patients with the intent to proceed to the next stage of surgery were included whether they subsequently underwent the surgical procedure or not (i.e., an ‘‘intentionto-treat’’ approach). The type of Fontan procedure performed (lateral tunnel or extracardiac conduit) and the presence of a fenestration were recorded, as well as the time frame between the Fontan procedure and post-Fontan echocardiography. Exclusion criteria were arrhythmias, pacemakers, and inability to cooperate for an adequate functional echocardiographic study. Patients who did not undergo stage I procedures under cardiopulmonary bypass were excluded. Control Population Healthy volunteers between day 1 of life to 3.5 years of age, to represent the normal maturational changes for speckle-tracking
Two-Dimensional Echocardiography. Traditional parameters for the assessment of ventricular systolic function applicable to the single right ventricle were measured as described in previous studies.4,15,20 These included (1) tricuspid annular plane systolic excursion of the RV free wall indexed to body surface area, a measure of longitudinal systolic function; (2) Doppler tissue imaging assessment of tricuspid annular velocity to determine S0 velocity and myocardial performance index; (3) isovolumic acceleration (IVA) from color tissue Doppler; (4) indexed RV enddiastolic area (EDAi) and systole, from the apical ‘‘four-chamber’’ view, as surrogates for ventricular volumes, as we have previously shown a good correlation between these two-dimensional (2D) measures and magnetic resonance imaging–derived volumes18; and (5) calculated 2D fractional area change (FAC). The presence of tricuspid regurgitation was classified subjectively as none, mild, moderate, or severe. Speckle-Tracking Echocardiography. Two-dimensional grayscale images captured at the equivalent apical ‘‘four-chamber’’ (longitudinal) and basal short-axis (circumferential) planes optimized for higher frame rate (115 6 33 Hz) were analyzed by a single observer. Speckle-tracking imaging measured global longitudinal and circumferential strain and SR. The ratio of longitudinal to circumferential strain was calculated to determine their relative contribution to contraction. The postsystolic strain index (PSSi) was calculated as [(peak strain peak systolic strain)/peak strain] and expressed as a percentage. Mechanical dyssynchrony in the longitudinal and circumferential dimensions was measured as the standard deviation of segmental time to peak strain. Measurements were made in the single right ventricle in the study patients and the normal left ventricles of controls. We previously reported low interobserver variability, a small 1.96 within-subject standard deviation, and high intraclass correlation coefficients for all the reported parameters, indicating good repeatability of these novel parameters in an anatomically similar cohort of patients with single right ventricles using the same equipment and analytic software.18 Because of the importance of accurate timing of these parameters, we noted the heart rate at the time of our
316 Tham et al
Journal of the American Society of Echocardiography March 2014
Table 1 Types of single ventricular morphology Stage
HLHS
Critical AS
Heterotaxy/AVSD
Other*
Pre-Norwood Pre-BCPA Pre-Fontan Post-Fontan
85% 79% 94% 60%
4% 0% 0% 20%
11% 21% 0% 20%
0% 0% 6% 0%
AS, Aortic stenosis; AVSD, atrioventricular septal defect. *Double-outlet right ventricle plus hypoplastic left ventricle.
M-mode calculation of aortic valve closure, and at the strain image, and chose comparative images that had heart rate variability of 620 beats/min, noting that heart rate variation of 620 beats/min accounted for 69-msec error. Statistical Analysis Results are expressed as mean 6 SD. Differences between the stages for each parameter were analyzed using one-way analysis of variance with Tukey-Kramer or Dunn’s post hoc comparison test within groups (P < .05) using GraphPad Prism version 5.04 (GraphPad Software, San Diego, CA). The differences among the three control groups were analyzed in the same fashion to determine maturational trends. Differences between neonates who received ventilation or inotropes and patients who received angiotensin-converting enzyme inhibitors were compared with those without, using unpaired t tests. Pearson’s correlation coefficients were used to determine associations between speckle-tracking and 2D echocardiographic parameters. Although previous studies have used the normal left ventricle in a biventricular circulation as a control population for the single right ventricle, this is not a valid comparison, because of the different fiber architecture and orientation in the RV and left ventricular myocardium, so direct comparisons with controls at each stage were not evaluated.
RESULTS Subjects A total of 76 subjects formed the study group: (1) 26 at the pre-Norwood stage (3.0 6 3.5 days), (2) 19 at the pre-BCPA stage (5.3 6 2.1 months), (3) 16 at the pre-Fontan stage (3.5 6 1.0 year), and (4) 15 at the post-Fontan stage (3.7 6 1.2 years). Echocardiography was performed a mean of 4 6 9 months after the Fontan procedure. All patients had HLHS or its variants, as shown in Table 1. Thirty controls, with 10 in each group, were of similar ages to our patient group: (1) neonates (4 6 3.2 days), (2) 5.8 6 2.9 months, and (3) 3.8 6 0.7 years. Demographic data and clinical characteristics are displayed in Table 2. Clinical Data All neonates were in stable condition at the time of the study, with normal mean blood pH (7.4 6 0.1) and lactate (1.6 6 0.7 mmol/L). In the pre-Norwood group, 88% had prenatal diagnoses, 58% were ventilated (mostly because of apnea secondary to prostaglandin E1 infusion), and 54% received inotropes (milrinone or dobutamine), with a mean inotrope score of 3.7 6 3.6. Oxygen saturation varied significantly among the groups (P < .0001), as expected, with higher saturations at the pre-Norwood stage compared with the pre-BCPA and pre-Fontan stages and greater saturations at the post-Fontan stage
compared with the pre-BCPA and pre-Fontan stages. In the pre-BCPA group, all patients had undergone previous Norwood procedures with Sano shunts under cardiopulmonary bypass. In the post-Fontan group, 94% were fenestrated, 11 (73%) received extracardiac conduits, three (20%) underwent lateral tunnel Fontan procedures, and one (7%) had a Kawashima procedure. Effect of Medical Interventions Neonates receiving inotropes had increased longitudinal SRs compared with those who did not receive inotropes (1.9 6 0.52%/sec vs 1.5 6 0.19%/sec, P = .01). Inotropes had no significant effect on longitudinal strain, circumferential strain, or SR. There were no differences in speckle-tracking echocardiographic parameters between the neonates who were or were not ventilated. Angiotensin-converting enzyme inhibitors had no effect on strain parameters in the pre-BCPA, pre-Fontan, and post-Fontan groups. Conventional 2D Echocardiographic Parameters Two-dimensional echocardiography showed that EDAi was significantly increased at the pre-BCPA stage compared with the pre-Fontan stage (P = .003) but not the pre-Norwood stage, while indexed RV end-systolic area did not vary among stages (Table 3). Global ventricular systolic functional indices such as FAC and myocardial performance index were unchanged among the four stages. Indexed tricuspid annular plane systolic excursion was significantly higher at the pre-Norwood stage compared with the other three stages and also higher at the pre-BCPA stage compared with the pre-Fontan and post-Fontan stages (P < .0001). Both Doppler tissue imaging S0 velocity (P = .0003) and IVA (P < .0001) were significantly higher at the pre-Norwood stage compared with the three other stages, and both were also higher at pre-BCPA stage compared with the pre-Fontan and post-Fontan stages. The presence of moderate or greater atrioventricular valve regurgitation was found in 13% of all patients. Speckle-Tracking Echocardiographic Parameters Strain. There was a significant difference in longitudinal strain among the four groups (P = .004) because of the pre-Norwood stage’s showing greater longitudinal strain than the pre-BCPA stage (Figure 1). There was no significant variation in circumferential strain among the four stages. The ratio of longitudinal to circumferential ratio decreased significantly from the pre-Norwood to the preBCPA stage (P = .02) (Table 4). SR. We found a significant variation among the four stages for both longitudinal (P < .0001) and circumferential (P = .0002) SR (Figure 1). Post hoc testing revealed that longitudinal SR was significantly greater at the pre-Norwood stage than at the three other stages, while circumferential SR was significantly greater at the pre-Norwood stage compared with the pre-BCPA and pre-Fontan stages but not significantly different from the post-Fontan stage. In the circumferential dimension, there was a trend for SR to increase at the post-Fontan stage, although this was not statistically significant (Table 4). We repeated the longitudinal SR comparisons by excluding neonates who received inotropes and still found significantly increased longitudinal SRs at the neonatal stage compared with the three other stages (P < .001). PSSi. There were significant variations in longitudinal (P = .003) and circumferential (P = .002) PSSi among the groups (Figure 2). Post hoc
Tham et al 317
Journal of the American Society of Echocardiography Volume 27 Number 3
Table 2 Demographic and clinical characteristics of patients Variable
Pre-Norwood
Pre-BCPA
Pre-Fontan
Post-Fontan
Age at echocardiography BSA (cm2) SaO2 (%) SBP (mm Hg) Inotropes Diuretics ACE inhibitors b-blockers
3.0 6 3.5 d 0.21 6 0.03 88 6 6 62 6 10 54% 0 0 0
5.3 6 2.1 mo 0.30 6 0.05 77 6 4 87 6 15 0 52% 68% 5%
3.5 6 1.0 y 0.63 6 0.15 81 6 6 97 6 11 0 24% 75% 25%
3.7 6 1.2 y 0.63 6 0.09 86 6 6 107 6 21 0 67% 60% 7%
ACE, Angiotensin-converting enzyme; BSA, body surface area; SaO2, oxygen saturation; SBP, systolic blood pressure. Data are expressed as mean 6 SD or as percentages.
Table 3 Traditional 2D echocardiographic parameters at each surgical stage Variable 2
2
EDAi (cm /m ) ESAi (cm2/m2) FAC (%) MPI IVA (cm/sec2) S0 velocity (cm/sec) TAPSEi (cm/m2) More than moderate TR
Pre-Norwood
Pre-BCPA
Pre-Fontan
Post-Fontan
P
27 6 6.7 18 6 5.8 36 6 8 0.47 6 0.12 2.3 6 1.2* 6.6 6 2.1* 4.1 6 0.88* 8%
32 6 9.5* 20 6 9.3 39 6 13 0.46 6 0.13 1.3 6 0.8†a 3.6 6 0.7† 2.3 6 0.37†a 16%
26 6 6.5 17 6 4.0 33 6 4 0.49 6 0.12 0.49 6 0.12†b 4.5 6 1.3† 1.5 6 0.34†b 24%
22 6 5.8 15 6 5.0 34 6 9 0.45 6 0.18 0.45 6 0.18†b 3.9 6 1.7† 1.1 6 0.35†b 6%
.003 NS NS NS
