The Systolic to Diastolic Duration Ratio in Children with Hypoplastic Left Heart Syndrome: A Novel Doppler Index of Right Ventricular Function

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1 The Systolic to Diastolic Duration Ratio in Children with Hypoplastic Left Heart Syndrome: A Novel Doppler Index of Right Ventricular Function Mark K. Friedberg, MD, and Norman H. Silverman, MD, DSc (Med), FAHA, FACC, FASE, Stanford, California Background: Right ventricular (RV) function is an important determinant of clinical status in children with hypoplastic left heart syndrome (HLHS). However, assessment of RV function remains challenging because of its complex morphology. We investigated the S/D duration ratio in children with HLHS as a novel index of global RV function. Methods: We measured systolic (S) and diastolic (D) duration using tricuspid regurgitation duration from Doppler flow, to calculate the S/D ratio in 33 children with HLHS and 33 control subjects matched for age and sex. We compared the S/D ratio between patients with HLHS and control subjects, between patients with HLHS and normal and abnormal RV function, and between patients with HLHS at different stages of palliation. We further correlated the S/D ratio with catheterization data. Results: Patients and control subjects were well matched for age ( vs years, not significant) sex, and heart rate (cycle length vs milliseconds, not significant). Patients with HLHS had a significantly higher S/D ratio than control subjects ( vs , P <.0001). The S/D ratio became increasingly elevated in HLHS at higher heart rates, but not in control subjects. The S/D ratio was significantly higher in patients with HLHS and decreased RV function as compared with patients with HLHS and normal RV function ( vs , P.006), and significantly increased in patients with Norwood stage 1 versus patients with Norwood stages 2 and 3 HLHS (2.16 vs 1.4 and 1.32, respectively, P <.01 and P <.001, respectively). The S/D ratio did not correlate with catheterization-derived RV end-d pressure or cardiac index. Conclusions: Patients with HLHS have an increased S/D ratio as a result of a shortened D and prolonged S. Measurement of the S/D duration ratio using Doppler flow is a novel method to augment assessment of global RV function in HLHS. (J Am Soc Echocardiogr 2007;20: ) Children born with hypoplastic left heart syndrome (HLHS) are palliated by using the morphologic right ventricle (RV) as the systemic pumping chamber, rendering the RV vulnerable to functional compromise. 1 A portion of patients with HLHS will develop clinically significant RV dysfunction, a particularly worrisome situation in the setting of a partial or total cavopulmonary connection and some of these patients will experience morbidity that requires further intervention or heart transplantation. 2-5 Therefore, noninvasive assessment of RV From the Division of Pediatric Cardiology, Department of Pediatrics, Lucille Packard Children s Hospital and Stanford University. Dr Friedberg is a Glaser Pediatric Research Network fellow. Reprint requests: Norman H. Silverman, MD, DSc (Med), FAHA, FACC, FASE, Division of Pediatric Cardiology, 750 Welch Rd, Suite 305, Palo Alto, CA, ( norm.silverman@stanford.edu) /$32.00 Copyright 2007 by the American Society of Echocardiography. doi: /j.echo function is important in the treatment of patients with HLHS. However, despite existing methods, echocardiographic assessment of RV function remains challenging because of its complex geometry and additional echocardiographic methods to evaluate RV function are needed. We previously found 6,7 that the systolic (S) to diastolic (D) duration (S/D) ratio was abnormally increased in patients with dilated cardiomyopathy, and was an indicator of 8 global cardiac function in these patients. We now hypothesized that children with a systemic RV as a result of HLHS have an elevated S/D ratio. Therefore, the objective of this study was to investigate the S/D ratio in children with HLHS. METHODS Study Population After approval from the institutional review board, we retrospectively reviewed echocardiograms and catheter- 749

2 750 Friedberg and Silverman June 2007 velocity wave) and relaxation (end of S velocity wave to beginning of early D velocity wave) intervals divided by the ejection period (S velocity wave interval), measured in the same cardiac cycle. Figure 1 Representative Doppler tracing obtained from apical 4-chamber view from patient with hypoplastic left heart syndrome. Duration of systole is measured from duration of tricuspid regurgitation (TR) (white bar, S). Interval between end of TR flow to onset of regurgitant flow in subsequent cardiac cycle demarcates duration of diastole (white bar, D). ization data from children with HLHS, who we identified from the pediatric echocardiography database between the years 2003 to HLHS was defined as a left ventricle inadequate to support systemic circulation, requiring a Norwood type procedure as palliation in the neonatal period. Patients were excluded if there was inadequate tricuspid regurgitation (TR) to determine the S/D ratio. Control subjects consisted of healthy children, matched for age and sex, who were undergoing echocardiography for a murmur and in whom the echocardiogram finding was normal. Echocardiography Echocardiography was performed with an ultrasound system (Sequoia, Acuson-Siemens, Mountain View, Calif) using probes with frequencies appropriate for patient size. Images were obtained with a simultaneous electrocardiogram tracing on the ultrasound display. Doppler flow signals of TR were acquired from the apical 4-chamber view by continuous wave Doppler. S was measured as the duration of TR. D was measured as the interval from the end of the TR jet to the onset of the subsequent TR jet (Figure 1). Measurements were made offline from digitally stored images using commercially available software (KinetDx, Acuson-Siemens) from 3 cardiac cycles and the results averaged. RV function was described using visual assessment by a senior pediatric echocardiographer according to the clinical standards used in our laboratory as normal, mildly decreased, moderately decreased, or poor. In addition, the RV fractional area change was calculated as the RV area traced from the apical 4-chamber view equivalent in D minus the RV area traced from the apical 4-chamber view equivalent in S divided by the RV area traced from the apical 4-chamber view equivalent in D (fractional area change percent RV area (D) RV area (S) /RV area (D) 100). 9 Tissue Doppler was used to calculate the tissue velocity derived Tei index, calculated as the sum of the isovolumic contraction (end of late D velocity wave to beginning of S Catheterization Catheterization data were retrospectively recorded if the catheterization was performed within a 60-day period from the echocardiogram. The RV end-d pressure was recorded using standard techniques with fluid-filled catheters. The cardiac index was calculated using the Fick method. Statistics Statistical analysis used commercially available software (Sigmastat, Jandel Scientific, San Rafael, Calif; and Graphpad, InStat, San Diego, Calif). The primary outcome was the S/D ratio. S duration is expressed as a decimal fraction of the cardiac cycle (S/S D). Heart rate is expressed as the electrocardiographic R-R interval in milliseconds or beats/ min. Continuous variables were compared by the nonpaired Student t test or 1-way analysis of variance for multiple comparisons and results displayed as the mean SD. When the variance significantly differed between two groups, the Welch correction was applied. Post hoc testing for multiple comparisons was performed with the Tukey Kramer test. Correlation between heart rate and the S/D ratio was assessed by scatter plots and linear regression. All P values are 2-sided and were considered significant at the less than.05 level. RESULTS Of 41 patients with HLHS eligible for the study, 8 had TR inadequate for analysis because of its trivial nature, leaving 33 for inclusion. Their demographics and clinical characteristics and those of the 33 control subjects are presented in Table 1. Patients and control subjects were well matched for age ( vs years, respectively, not significant) and sex, and had similar heart rates (R-R interval vs milliseconds, respectively, not significant) (Table 1). All control subjects had normal cardiac function. In all, 25 children with HLHS had normal RV function, 4 had mildly reduced function, 1 had moderately reduced function, and 2 had poor RV function. Patients with HLHS and abnormal function by visual assessment had a lower fractional area of change than HLHS with normal function by visual assessment (31 10 vs %, respectively, P.01). The S/D ratio of patients with HLHS was significantly higher that that of control subjects ( [range ] vs [range ], P.0001) (Figure 2, A). This elevated ratio resulted from a higher S fraction of the cardiac cycle in patients with HLHS

3 Volume 20 Number 6 Friedberg and Silverman 751 Table 1 Demographics and characteristics of 33 children with hypoplastic left heart syndrome and 33 control subjects matched for age and sex HLHS Control P Age, y (median, range) (0.5, ) (0.6, ).92 Male Female R-R interval, ms (median, range) (488, ) (515, ) NS Stage of palliation Norwood (stage 1) (%) 17 (51) Partial cavopulmonary connection (stage 2) (%) 9 (27) Total cavopulmonary connection (stage 3) (%) 7 (21) Ventricular function (median, range) FAC (%): (45, 18-71) FS% 38 5 (38, ) Visual assessment Normal Mildly reduced 4 Moderately reduced 1 Poor 2 Catheterization RVEDP, mm Hg (median, range) (9, 5-17) Cardiac index, L/min/m 2 (median, range) (3.45, ) FAC, Fractional area of change; FS, fractional shortening; HLHS, hypoplastic left heart syndrome; NS, not significant; RVEDP, right ventricular end-diastolic pressure. versus control subjects ( [range ] vs [range ], P.0001) (Figure 2, B). Table 2 presents data from echocardiography and catheterization from the group of patients with HLHS who had decreased RV function. The S/D ratio was significantly higher in patients with HLHS and decreased RV function as compared with patients with HLHS who had normal RV function ( vs , P.001) (Figure 3). The S fraction of the cardiac cycle was weakly correlated to heart rate in the patients with HLHS (r 0.45, P.01), but not in control subjects (r 0.29, P.12). Figure 4 depicts the S/D ratio plotted against the R-R interval in patients with HLHS and control subjects. At higher heart rates (lower cycle lengths), the S/D ratio increased dramatically in the patients with HLHS as opposed to control subjects where there was no significant change in the S/D ratio with change in heart rate. Twelve patients had Doppler tissue imaging (DTI) of the tricuspid annulus available for calculation of the tissue velocity derived Tei index. The DTI Tei index was in an abnormally high, but narrow range ( ), whereas the S/D ratio varied more widely between 0.8 and 2.8 (Figure 5). The two indexes were not significantly correlated (r 0.5, P.11). Two patients with HLHS and decreased RV function had a DTI Tei index available. These two patients had a DTI Tei of 0.47 and 0.49 and a S/D ratio of 2.08 and 2.38, respectively. Further analysis of the S/D ratio by stage of palliation showed significant differences between the groups. Patients who were post-norwood stage 1 had a significantly higher S/D ratio than those who were poststage 2 or 3 (2.16 vs 1.4 and 1.32, respectively, P.01 and P.001, respectively) (Figure 6). When each subgroup was compared individually against control subjects, the S/D ratio of the patients in Norwood stages 1, 2, and 3 were all higher than that of control subjects (2.16, 1.4, and 1.32 vs 0.81, P.001, P.001, and P.05, respectively). Fourteen patients had cardiac catheterization within 60 days of echocardiography (mean SD 16 14, median 13, range 0-42 days). These patients were clinically stable in the time interval between echocardiography and cardiac catheterization. There was no correlation between the S/D ratio and the RV end-d pressure (r 0.04, P.8), cardiac index (r 0.8, P.7), pulmonary vascular resistance (r 0.29, P.38), or systemic vascular resistance (r 0.56, P.056) as measured at cardiac catheterization. DISCUSSION Patients with HLHS are susceptible to RV dysfunction because of the RV being the systemic pumping chamber and exposed to systemic level resistance, volume overload from atrioventricular regurgitation or an elevated pulmonary to systemic blood flow ratio (Qp/Qs), detrimental effects of cardiopulmonary bypass, ventriculotomy (if a RV to pulmonary artery conduit had been placed as part of the initial palliation), and possible aortic arch obstruction. 1-3,6,13,14 Some of these fac - tors change significantly between the different stages of palliation. For example, the Qp/Qs ratio decreases between the first and second stages of

4 752 Friedberg and Silverman June 2007 Figure 2 Box plots of systolic (S) to diastolic (D) duration ratio (A) and S duration expressed as fraction of cardiac cycle (B) in 33 children with hypoplastic left heart syndrome (HLHS) and 33 healthy control subjects matched for age and sex. palliation. Echocardiography is the primary method to assess RV function in HLHS, yet assessment of RV function remains challenging because of its complex morphology. 6 In practice, qualitative visual assess - ment of RV function is commonly used as the primary method to evaluate RV function, even though quantitative measures add valuable information. 7,15,16 In this study, we demonstrate that - pa tients with HLHS have an abnormally high S/D ratio because of a shortened D and relatively lengthened S and that this geometric-independent index provides a simple and widely available echocardiographic method to augment assessment of RV function in HLHS. Heart rate is a major determinant of D and S duration and at resting heart rates, S constitutes about 40% of the cardiac cycle in healthy children. 8,17,18 In contrast, patients with HLHS have an increased S/D ratio as a result of a reversal in the relative durations of S and D, despite having similar heart rates to control subjects, indicating that the D shortening and increased S/D ratio results from intrinsic abnormalities of the palliated systemic RV. This abnormal reversal of the S/D ratio is important as D dysfunction and decreased D filling compromise coronary perfusion and may further worsen ventricular function The elevated S/D ratio is disproportionately accentuated at higher heart rates in patients with HLHS as compared with control subjects. This abnormal response may contribute to the hemodynamic intolerance that patients with a functionally single ventricle have to arrhythmia and tachycardia and may also contribute to their abnormal exercise capability. 13 Patients with HLHS and abnormal ventricular function by visual assessment had a higher S/D ratio than patients with HLHS with normal function. We have previously found that the S/D ratio is abnormally high in children with dilated cardiomyopathy, suggesting that an abnormal S/D ratio is a generic index of global cardiac dysfunction, rather than a disease-specific index. 8 The S/D ratio may be affected by factors other than heart rate such as vascular resistance, medications affecting vascular resistance, and loading conditions. In our study, the correlation between the S/D ratio and systemic vascular resistance just failed to reach statistical significance, possibly because of the small number of patients who had catheterization data. There was no correlation between the S/D ratio and the pulmonary vascular resistance. There was a substantial difference between patients with HLHS who were post-norwood stage 1 than those who were post-norwood stages 2 and 3. In Norwood stage 1, the ventricle handles an increased volume load as a result of an increased pulmonary blood flow to systemic blood flow ratio (Qp/Qs). Stages 2 and 3 of the Norwood palliation reduce the volume load on the RV. Therefore, the differences between the post-norwood stage 1 group and the other groups may be the result of different loading conditions rather than differences in RV contractility. However, the S/D ratio of these groups was still significantly higher than that of control subjects, reflecting, in our opinion, decreased RV function. Differences in calcium handling resulting from differences in myocardial maturation also affects ventricular contractility and may have influenced the differences in the S/D ratio between patients with Norwood stage 1 who are neonates and the older 23 patients with stages 2 and 3. The S/D ratio, as a global index, probably reflects both ventricular loading and contractility and the functional end result of the different factors affecting RV function.

5 Volume 20 Number 6 Friedberg and Silverman 753 Table 2 Echocardiographic and catheterization characteristics of children with hypoplastic left heart syndrome defined by visual assessment of having abnormal ventricular function RV function visual assessment Palliation stage Echocardiographic FAC Invasive RVEDP Invasive cardiac index S/D ratio 1 Poor Poor Moderately reduced 3 40 NA NA Mildly reduced 1 50 NA NA Mildly reduced 1 27 NA NA Mildly reduced Mildly reduced D, Diastolic; FAC, fractional area of change; NA, not applicable; RV, right ventricular; RVEDP, RV end-diastolic pressure; S, systolic. Figure 3 Box and whisker plots of systolic (S) to diastolic (D) duration ratio in healthy control subjects and children with hypoplastic left heart syndrome (HLHS) with normal versus abnormal right ventricular (RV) function by visual assessment. ANOVA, Analysis of variance. The S/D ratio differs from S time intervals such as the pre-ejection/ejection time ratio, in that the S/D ratio includes the entire duration of S and D, rather than subsets of these intervals and accentuates the 17,24 effect of D dysfunction on global function. The S/D ratio is also different from the Tei index, which is similar in concept to S time intervals, but uses the ratio of isovolumic contraction and relaxation duration to ejection duration. In contrast to the 10,12,25 Tei index, the S/D ratio measures isovolumic duration plus ejection time divided by isovolumic relaxation duration plus inflow duration. Thus, the S/D ratio reflects the relative contribution of S and D to the cardiac cycle and the related effects of S and D to each other. In patients with HLHS, S, as defined by the TR duration, is prolonged at the expense of a shortened D, a phenomenon of cardiac dysfunction not completely accounted for by the Tei index, as the only D phase incorporated into the Tei index is isovolumic relaxation. In our study, the DTI Tei index spanned a narrower range than the S/D ratio Figure 4 Relation between heart rate (expressed as R-R interval) and systolic (S) to diastolic (D) duration ratio in 33 children with hypoplastic left heart syndrome (solid squares) and 33 healthy control subjects matched for age and sex (open circles). over the patient population. This may suggest that the S/D ratio can discriminate between patients with HLHS and abnormal ventricular function as opposed to those with normal ventricular function better than the DTI Tei index does. This warrants further investigation, as our study population was too small to definitively evaluate this point. In practice, we believe it is prudent to use a variety of complimentary methods to assess RV function because of the complexity of the problem and the specific pitfalls of each individual method. This study and the S/D ratio method have a number of limitations. The study was retrospective. Echocardiography was not simultaneous with catheterization and catheterization data were not available for all patients. Patients with HLHS may not have adequate TR and this was a reason to exclude 20% of the prospective candidates for this study. On the other hand, if a TR jet is present, even if suboptimal in quality, it is usually possible to discern the onset and termination of the envelope, allowing measurement of the TR duration. Measurement of S

6 754 Friedberg and Silverman June 2007 with dilated cardiomyopathy. Therefore, an elevated S/D ratio is likely the result of abnormal cardiac function rather than a specific disease process. Measurement of the S/D ratio is easily achieved using Doppler flow and provides a novel method to augment current assessment of RV function in patients with HLHS. The S/D ratio should be further investigated in other disease states where the RV is susceptible to functional compromise. REFERENCES Figure 5 Scatter plot depicting relation between systolic (S) to diastolic (D) duration ratio and tissue Doppler derived Tei index in children with hypoplastic left heart syndrome. Figure 6 Box and whisker plots of systolic (S) to diastolic (D) duration ratio in healthy control subjects and children with hypoplastic left heart syndrome (HLHS) post-norwood stages 1, 2, and 3. duration by TR flow includes the isovolumic period and duration of ventricular contraction, but not the electromechanical delay. In addition, regurgitant flow may end before tricuspid valve closure, potentially leading to underestimating of the S duration. However, these factors are probably not substantial and for practical purposes the duration of TR adequately approximates the duration of S. Summary In summary, patients with HLHS have an increased S/D ratio as a result of shortening of D and prolongation of S, a finding previously observed in patients 1. Altmann K, Printz BF, Solowiejczky DE, Gersony WM, Quaegebeur J, Apfel HD. Two-dimensional echocardiographic assessment of right ventricular function as a predictor of outcome in hypoplastic left heart syndrome. Am J Cardiol 2000; 86: Murdison KA, Baffa JM, Farrell PE Jr, Chang AC, Barber G, Norwood WI, et al. Hypoplastic left heart syndrome: outcome after initial reconstruction and before modified Fontan procedure. Circulation 1990;82:IV Forbess JM, Cook N, Serraf A, Burke RP, Mayer JE Jr, Jonas RA. An institutional experience with second- and third-stage palliative procedures for hypoplastic left heart syndrome: the impact of the bidirectional cavopulmonary shunt. J Am Coll Cardiol 1997;29: Mitchell ME, Ittenbach RF, Gaynor JW, Wernovsky G, Nicolson S, Spray TL. Intermediate outcomes after the Fontan procedure in the current era. J Thorac Cardiovasc Surg 2006; 131: Gentles TL, Gauvreau K, Mayer JE Jr, Fishberger SB, Burnett J, Colan SD, et al. Functional outcome after the Fontan operation: factors influencing late morbidity. J Thorac Cardiovasc Surg 1997;114: Mahle WT, Coon PD, Wernovsky G, Rychik J. Quantitative echocardiographic assessment of the performance of the functionally single right ventricle after the Fontan operation. Cardiol Young 2001;11: Friedberg MK, Rosenthal DN. New developments in echocardiographic methods to assess right ventricular function in congenital heart disease. Curr Opin Cardiol 2005;20: Friedberg MK, Silverman NH. Cardiac ventricular diastolic and systolic duration in children with heart failure secondary to idiopathic dilated cardiomyopathy. Am J Cardiol 2006;97: Kimball TR, Witt SA, Khoury PR, Daniels SR. Automated echocardiographic analysis of systemic ventricular performance in hypoplastic left heart syndrome. J Am Soc Echocardiogr 1996;9: Tei C. New non-invasive index for combined systolic and diastolic ventricular function. J Cardiol 1995;26: Abd El Rahman MY, Abdul-Khaliq H, Vogel M, Alexi- Meskischvili V, Gutberlet M, Hetzer R, et al. Value of the new Doppler-derived myocardial performance index for the evaluation of right and left ventricular function following repair of tetralogy of Fallot. Pediatr Cardiol 2002;23: Yasuoka K, Harada K, Toyono M, Tamura M, Yamamoto F. Tei index determined by tissue Doppler imaging in patients with pulmonary regurgitation after repair of tetralogy of Fallot. Pediatr Cardiol 2004;25: Giannico S, Hammad F, Amodeo A, Michielon G, Drago F, Turchetta A, et al. Clinical outcome of 193 extracardiac

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