Diastolic Ventricular Function in Children: A Doppler Echocardiographic Study Establishing Normal Values and Predictors of Increased Ventricular End-Diastolic Pressure

Diastolic Ventricular Function in Children: A Doppler Echocardiographic Study Establishing Normal Values and Predictors of Increased Ventricular End-Diastolic Pressure PATRICK KENT

R.

w. O'LEARY, M.D., KRITVIKROM DURONGPISITKUL, M.D.,* TIMOTHY M. CORDES, M.D.,t BAILEY, PH.D., DONALD J. HAGLER, M.D.,

A. JAMIL TAJIK,

• Objective: To extend noninvasive assessment. of diastolic cardiac function into the pediatric age-group. • Design: This study was divided into two phases, the first of which was designed to provide an age-appropriate set of normal diastolic Doppler echocardiographic data for children and adolescents and the second of which was to determine whether these Doppler techniques could be used to identify children with increased ventricular end-diastolic pressure (EDP). • Material and Methods: Complete echocardiographic studies focusing on Doppler variables of diastolic ventricular function were performed on 223 normal children. Values observed were analyzed for dependence on age, heart rate, and gender. Results from the normal group were then compared with Doppler values observed in a group of 24 children with catheterization-substantiated increases in ventricular EDP. • Results: Normal values for the Doppler factors studied vary with both age and heart rate. The variables that

B. SEWARD,

M.D.

most confidently distinguished children with increased EDP from normal subjects were the ratio of and the difference between the durations of pulmonary vein atrial reversal and the mitral A wave. A ratio of 1.2 or more or a difference of 29 ms or more identified those children with increased EDP with sensitivities of 88 and 90% and specificities of 86 and 86 %, respectively. • Conclusion: Use of the normal data and the Doppler techniques described in this study will allow confident assessment of diastolic function in children as well as in adults. Mayo Clin Proc 1998;73:616-628 A = atrial (component of mitral inflow Doppler signal); E = early (diastolic component of mitral inflow Doppler signal); EDP = end-diastolic pressure; IVRT = isovolumic relaxation time; PVAR = pulmonary vein atrial reversal; TVI = time velocity integral

T

he importance of diastolic ventricular performance has become increasingly apparent in recent years. In fact, in some acquired cardiac disease states, diastolic dysfunction precedes the onset of impaired systolic performance. 1,2 Studies in adult patients with various cardiac disorders have been able to correlate the degree of diastolic dysfunction with symptoms and prognosis."? Ventricular diastolic performance is a key determinant of cardiac function in several types of pediatric cardiac disease as well.v" Most pediatric investigators, however, have focused primarily on systolic ventricular function

when assessing cardiac performance. This trend has occurred for several reasons. First, until recently, the only reliable method for assessment of diastolic function available to pediatric cardiologists was invasive-namely, hemodynamic cardiac catheterization performed to measure ventricular end-diastolic pressure (EDP). Second, although Doppler echocardiography has been central in the understanding of diastolic function and dysfunction in adults, 19 normal diastolic Doppler data have not been available in all pediatric age-groups. Several investigators have reported normal mitral valve or tricuspid valve velocities and flow pattems.P'" but these studies either have dealt with one specific age-group or have not included many of the variables now considered essential for the complete assessment of diastolic performance in adults (such as pulmonary venous flow variables). With use of these modem Doppler factors in adult patients, investigators have even reported noninvasive approaches to estimating left ventricular EDP.26.27 Ventricular EDP can be altered by loading conditions. Thus, EDP, by itself, does not completely describe ventricular diastolic function." Nevertheless, this invasively

From the Section of Pediatric Cardiology (P.w.a., K.D., T.M.C., D.J.H., A.J.T., J.B.S.), Division of Cardiovascular Diseases and Internal Medicine (P.w.a., D.J.H., A.J.T., J.B.S.), and Section of Biostatistics (K.R.B.), Mayo Clinic Rochester, Rochester, Minnesota. *Current address: Bangkok, Thailand. tCurrent address: Riley Hospital/Indiana University Medical Center, Indianapolis, Indiana. This study was supported in part by the Mayo Foundation. Address reprint requests to Dr. P. W. O'Leary, Section of Pediatric Cardiology, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905. Mayo Clin Proc 1998;73:616-628

M.D., AND JAMES

616

© 1998 Mayo Foundation for Medical Education and Research

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Mayo Clin Proc, July 1998, Vol 73

obtained value has frequently been used as the only indicator of diastolic performance in both adults and children. Several recent studies in adult patients'":" have suggested that one of the most important noninvasive descriptors of left ventricular EDP is the relationship of the duration of the forward and reverse flows caused by atrial contraction. Atrial forward flow is usually represented by the duration of the mitral atrial filling wave (A wave). Reverse flow is described by the flow reversal in the pulmonary vein after atrial contraction. A strong association between increased ventricular EDP and the duration of flow reversal exceeding that of forward flow was observed in these studies. To date, this relationship has not been investigated in children. The initial phase of this study was undertaken to provide a complete set of normal diastolic Doppler data for the left ventricle in children and adolescents. The goal of the second phase was to determine whether the techniques of noninvasive assessment of diastolic function could be used to identify children with increased ventricular EDP. SUBJECTS AND METHODS

Normal Subjects All study subjects were volunteers with no history of cardiopulmonary disease. They were recruited from a local elementary and high school. We attempted to obtain similar numbers of boys and girls from each grade level. This study was reviewed and approved by the Mayo Institutional Review Board and the school board before subject enrollment. Written informed consent was obtained from each subject's parents or guardians, and verbal consent was also obtained from the subjects themselves at the time of echocardiographic examination. Before enrollment, each subject and the parents or guardians completed a health status questionnaire. In addition, height, weight, and blood pressure were measured at the time of the echocardiographic study. Examinations were performed in spaces provided at each of the schools, to minimize the amount of time students spent away from the classroom. Students with a history of appreciable heart murmur, congenital heart disease, or substantial pulmonary disease (including asthma) were excluded from the study. Subjects who were found to have previously unknown abnormalities during the examination were also excluded, and their families were notified so that appropriate follow-up evaluation and treatment could be arranged. Echocardiographic Examinations Complete two-dimensional and Doppler echocardiographic studies were performed on all the normal subjects by using an Acuson XPIO diagnostic cardiac ultrasound system (Acuson Corp., Mountain View, California).

Diastolic Ventricular Function in Children

617

Doppler flow signals analyzed in this study were obtained by using the methods identical to those described by the Canadian consensus panel on measurement and reporting of diastolic dysfunction by echocardiography." Signals analyzed included pulsed-wave Doppler recordings at the tips of the mitral valve leaflets and in the proximal right lower pulmonary vein. Left ventricular isovolumic relaxation time (IVRT) was determined by using continuouswave Doppler recording in the left ventricular outflow tract to measure the interval between aortic closure and mitral opening. The transducer was positioned at the cardiac apex for all these measurements.

Signal Measurement All echocardiograms were recorded on 3/4 -inch U-matic videotape for subsequent review and analysis. Measurement of the Doppler signals was performed with use of an off-line analysis system (Nova MicroSonics ImageVue DCR System, Mahwah, New Jersey). At a minimum, three measurements of each value were made and averaged for data analysis. The mitral valve inflow signal was divided into early (E wave) and atrial (A wave) components at the point where the mid-diastolic flow velocity curve changed from a negative to a positive slope ("the E at A velocity"). If no change in slope occurred or if the E at A velocity occurred at a velocity greater than one-half the peak E velocity, the signal was considered to be fused. Similarly, a division in the pulmonary vein forward flow signal was made at the point where the flow velocity curve changed slope. Systolic flows occurred before the slope change, and diastolic flows occurred after. Mitral A wave duration included the interval from the E at A velocity to cessation of forward flow. The duration of pulmonary vein atrial reversal (PVAR) was measured from the onset to the cessation of reversed flow occurring after the P wave on the simultaneously recorded, single-lead surface electrocardiogram. The variables measured are diagrammatically shown in Figure I. In addition to these standard measurements, the relative durations of the atrial flows (forward and reversed) were assessed by an alternative method that allowed assessment of patients with fusion of the mitral inflow signal. 33 This approach involved determination of the interval from the end of mitral forward flow to the R wave on the surface electrocardiogram (end A to R wave interval). Then the interval from the end of atrial reversal in the pulmonary vein to the R wave was measured (end PVAR to R interval) (Fig. 2). The end A to R wave interval was then subtracted from the end PVAR to R interval (end PVAR to R interval minus end A to R interval). A positive value indicated that the duration of reversed flow (PVAR) exceeded the dura-

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Diastolic Ventricular Function in Children

Mayo Clin Proc, Jul y 1998, Vol 73

e

ECG ECG Velocity

E

MV

MV

I

Velocity

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o

o

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PV L..-_--'-_ _---.:.._ _----ll----7

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Fig. 1. Diagram depicting typical mitral valve (M V) and pulmonary vein (PV) Doppler flow tracings. Standard measurements used to assess diastolic function are shown. A = atrial filling wave; A-d = duration of atrial filling wave; D = pulmonary vein diastolic flow wave; DT = mitral deceleration time; aTVl = time velocity integral of pulmonary vein diastolic flow wave; E = early filling wave; ECG = electrocardiogram; PVAR = pulmonary vein atrial reversal flow wave; PVAR-d = duration of PVAR flow; S = pulmonary vein systolic flow wave; sTVI = time velocity integral of pulmonary vein systolic flow wave.

Fig. 2. Diagramdemonstrating alternative technique for calculating the difference betweenpulmonary vein atrial reversal (PVAR) flow wave and atrial (A ) filling wave durations. Time "zero" is arbitrarily assigned to peak of R wave on electrocardiogram (ECG). If atrial flow ends before time zero, the interval is assigned a negative value. If flow continues past R wave, the interval is given a positive value. The End A to R interval is subtracted from the End PVAR to R interval to derive the difference in duration. D = pulmonary vein diastolic flow wave; E = early filling wave; MV = mitral valve flow tracing; PV = pulmonary vein flow tracing; S =pulmonary vein systolic flow wave.

tion of forward flow. Negative values indicated dominance of the forward flow (A wave) duration.

statistical software (SAS version 6.11 [SAS Institute Inc.] and S-PLUS version 3.4, release 1 [MathSoft Inc.]). Replications were analyzed for consistency, and gross internal discrepancies were assessed for accuracy. Thereafter, the mean s of the three replicate values were used as the basic data for analysis. Only nine normal subjects younger than 5 years of age were studied (two subjects who were 4 years old and seven who were 3 years old). These subjects were pooled into a single group for statistical analyses based on age. This "pooled" group will be referred to as the 4-yearold group. For display of these data , box plots of each variable , stratified by age in years, were plotted against age. These box plots show estimated medians, quartiles, and 95% confidence interval s for each year of age. To establish normal ranges and to determine significant correlates of each variable, we used simple and multiple linear regres sion. Age, gender, and RR interval (heart rate) were the primary independent variables. Univariate and bivariate regressions of each Doppler variable on age and RR interval were used to determine the individual and independent

Pediatric Patients With Increased EDP We retrospectively identified all pediatric patients (younger than 21 years of age) who had catheterizationconfirmed ventricular EDP of 18 mm Hg or more and had Doppler echocardiography performed after 1991. The echocardiograms were obtained shortly before or after the catheterization. The clinical histories, echocardiograms, and catheterizations of these patients were reviewed. For those patients who fulfilled entry criteria, videotape recordings of their echocardiographic study were analyzed and remeasured by using the foregoing protocol that was described for the normal subjects.

Statistical Analysis Clinical, demographic, and echocardiographic data from both the normal volunteers and the patients with increased EDP were entered into a common electronic database and analyzed by using commercially available

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Diastolic Ventricular Function in Children

Mayo Clin Proc, July 1998, Vol 73

effects of age and heart rate on the diastolic Doppler determinations. The estimated associations (simple and partial) between the independent variables and the Doppler measurements were classified into one of four categories: (1) nonsignificant, (2) significant but "weak" (R 2 < 0.10), (3) "moderate" (0.10 < R 2 < 0.20), or (4) "strong" (R2 > 0.20). In other words, an independent variable with a weak association accounted for less than 10% of the observed variation in the Doppler measurement. Independent variables with moderate or strong associations accounted for between 10 and 20% or more than 20% of the observed variation, respectively. Clinical significance was considered limited to the "strong" and "moderate" categories, in which the standard deviation of prediction was improved by at least 10% by inclusion of the variable. Because gender rarely showed a statistically significant association and never had a clinically significant effect on the Doppler variables in this group of normal children, attention was focused on age- and heart rate-specific normal ranges. Normal 90% ranges, stratified by age or heart rate (RR interval), were determined as follows. Simple linear regression models with age and RR interval were used to determine the mean relationships. For determination of whether the widths of prediction intervals should vary, the absolute residuals from each fit were regressed against the independent variable. The raw residuals were then rescaled by dividing by the model-based predicted mean absolute residual. The resulting scaled residuals were pooled, and nonparametric estimates of the upper and lower 5th percentiles were determined. Finally, the normal upper and lower limits were calculated by adding these to the mean function. This procedure ensures that changes in mean and scale are allowed for and that the observed proportion of subjects outside the prediction bands (in each direction) equals the theoretical proportion of 5%. Data from patients with increased EDP and data from the normal subjects were compared by using the unpaired Student t test. Variables found to be significantly different between the two groups were further examined by estimating their receiver-operator characteristic curves and determining points on each curve associated with high sensitivity and specificity for predicting the presence of increased EDP. RESULTS

Normal Children Of 226 children who were enrolled in the study and who underwent echocardiographic examination, 3 were excluded from subsequent analysis because of the detection of cardiac abnormalities during the examination. Of these three children, one had asymptomatic dilated cardiomyopathy with an ejection fraction of 35%, one had a bicuspid

4

5

6

7

8

9

619

10 11 12 13 14 15 16 17 18

Age of children (yr)

Fig. 3. Age distribution of normal children in study. Histogram displays number of normal children enrolled by year of age. Subjects younger than 5 years of age were pooled into the 4-yearold group (see Statistical Analysis).

aortic valve without stenosis, and one had mild mitral regurgitation without prolapse. The final normal study group consisted of III male and 112 female subjects. Their mean age was 10.6 years (median age, 10; range, 3 to 18). The age distribution of the normal children is outlined in Figure 3. The body size and vital signs of these children were normal, as summarized in Table 1. All subjects were in sinus rhythm during the evaluation.

Doppler Flow Values in Normal Children The Doppler values observed in normal children are summarized in Tables 2, 3, and 4. The data were separated into three broad age categories: 3 to 8 years, 9 to 12 years, and 13 to 18 years. Fused mitral inflow Doppler signals were noted in 14,7, and none of the children in these three Table I.-Normal Volunteers (N = 223*): Descriptive Variables and Vital Signst Factor

Mean

SD

Range

Age (yr) Height (em) Weight (kg) BSA (rrr') BP(mmHg) Systolic Diastolic Mean Heart rate (beats/min)

10.6 145 42.9 1.3

3.9 22 19.4 0.4

3-18 94-190 13-137 0.6-2.6

106 64 78 79

13 9 9 13

76-142 40-90 53-104 50-113

*Of 226 children enrolled in the study, 3 were excluded because of detection of cardiac abnormalities during the examination. tBP = arterial blood pressure; BSA = body surface area; SD = standard deviation.

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Diastolic Ventricular Function in Children

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Table 2.-Normal Doppler Data (N = 223): Mitral Valve Flow Variables and Left Ventricular Isovolumic Relaxation Time, Stratified by Age-Group* 3-8 yr (N = 75) Factor E velocity (cm/s) E TVI (em) A velocity (cm/s) A TVI (em) A duration (ms) E at A velocity (cm/s) E to A velocity ratio E to A TVI ratio Deceleration time (ms) End mitral A to R wave interval (ms) LV IVRT (ms)

9-12 yr (N = 72)

13-17 yr (N = 76)

Mean

1 SD

Mean

1 SD

Mean

1 SD

92

14 2.6

15 2.9 9 1.0 21 5 0.6 1.5 19

88 14.0 39 3.7 141 12 2.3 4.2 172

14 2.9 8

15 10

27 74

12.0 42 3.7 136 16 2.4 3.7 145

22 7 0.7 2.0 18

86 12.3 41 3.7 142 14 2.2 3.7 157

34 62

16 10

29 67

11 1.1

1.1

22 4 0.6 1.7

22 19 13

*A = atrial filling wave; E = early filling wave; IVRT = isovolumic relaxation time; LV = left ventricular; SD = standard deviation; TVI = time velocity integral. these three variables, the clinical differences attributable to gender were extremely minor. Therefore, gender was ignored in the subsequent determination of normal values. We recognized that use of this approach creates a small possibility for a type I error, in light of the large number of variables considered in this study. Age and Hearl Rale.-Mean RR interval increased progressively by 20 ms per year of age from 630 ms at age 3 years to 920 ms at age 18 years, and this relationship accounted for approximately a third of the overall variability in RR interval. Because of this strong association and because of the importance of the RR interval in determining many of the Doppler variables, separation of the contributions of age and RR interval to the echocardiographic

age-groups, respectively. Analyses requiring measurement of separate E or A wave variables were not performed in patients with fused signals.

Influence of Gender, Age, and Heart Rate on Normal Values Gender.-Gender had no influence on most of the variables studied. Boys, however, had a slightly larger mitral E wave time velocity integral (TVI) (13.3 ± 3.0 em versus 12.3 ± 2.7 ern; P = 0.02) and pulmonary vein diastolic TVI (10.5 ± 3.0 cm versus 9.6 ± 2.7 em; P = 0.04) as well as a lower ratio of pulmonary vein systolic TVI to diastolic TVI (1.1 ± 0.3 versus 1.3 ± 0.4; P = 0.007) than were observed in girls. Despite the statistical significance demonstrated in

Table 3.-Normal Doppler Data (N = 223): Pulmonary Vein Flow Variables* 3-8 yr (N = 75)

9-12 yr (N = 72)

13-17 yr (N = 76)

Factor

Mean

I SD

Mean

1 SD

Mean

1 SD

Systolic velocity (cm/s) Systolic TVI (em) Diastolic velocity (cm/s) Diastolic TVI (em) Ratio of systolic to diastolic velocity Ratio of systolic to diastolic TVI Atrial reversal velocity (cm/s) Atrial reversal duration (ms) Atrial reversal TVI (em)

46 11.1 59 8.8

9 2.3 8 1.8

45 11.5 54 9.2

9 2.2 9 2.5

41 10.8 59 12.I

10 2.8 11 3.1

0.8

0.2

0.8

0.2

0.7

0.2

1.3

0.3

1.3

0.4

0.9

0.3

21

4

21

5

21

7

130 1.7

20 0.5

125 1.6

20 0.6

140 2.0

28 0.9

*SD = standard deviation; TVI = time velocity integral.

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Mayo Clin Proc, July 1998, Vol 73

Diastolic Ventricular Function in Children

621

Table 4.-Normal Doppler Data (N = 223): Comparisons of the Pulmonary Vein Atrial Reversal to the Mitral Valve Atrial Wave* 9-12 yr

3-8 yr (N =75) Factor Ratio data PVAR/MV A reversal duration PVAR/MV A reversal TVI Difference data PVAR duration - MV A duration (ms) Alternative method for calculating "PV AR duration - MV A duration" (ms)

(N

13-17yr (N =76)

=72)

Mean

ISD

Mean

1 SD

Mean

ISD

0.96 0.52

0.19 0.25

0.88 0.46

0.16 0.22

0.98 0.60

0.23 0.43

-8

26

-17

24

-6

33

16

20

4

27

-1

32

*A =atrial wave; MV = mitral valve; PVAR =pulmonary vein atrial reversal; SD =standard deviation; TVI = time velocity integral.

variables was acknowledged to be difficult. The results, however, can be described by defining which of the two variables is more strongly associated and whether the effect of age is independent of, or accounted for by, the effect of RR interval-indeed, in some cases, whether the effect of age is even in the same direction before and after controlling for RR interval. Results are presented first in terms of the effects of age and RR interval separately and then in terms of the independent effect of age after controlling for RR interval. Age and RR interval effects and interactions are summarized in Table 5. Analysis for Effect of Age Without Controlling for RR Interval.-Increasing age was strongly associated with increasing values of mitral deceleration time (Fig. 4) and pulmonary vein diastolic TVI (R2 > 0.20). Moderate positive associations (0.10 < R2 < 0.20) were observed between age and IVRT (Fig. 5) and E wave TVL Weak: (clinically insignificant; R2 < 0.10) positive associations were seen between age and the end A wave to R wave interval, ratio of E to A wave TVI, PVAR duration, and TVL No strong negative associations with age were noted. Pulmonary vein systolic to diastolic TVI ratio did decrease with increasing age (Fig. 6). This negative association was of moderate strength (0.10 < R 2 < 0.20). Weak: negative age associations were observed for A wave velocity, E at A velocity, pulmonary vein systolic velocity, the ratio of pulmonary vein systolic to diastolic TVI, and the ratio of PVAR TVI to mitral A wave TVI (R2 < 0.10). Analysis for Effect of Heart Rate (RR Interval) Without Controlling for Age.-Increasing RR interval (decreasing heart rate) was strongly associated (R2 > 0.20) with increasing values of mitral deceleration time (Fig. 7), mitral E wave TVI, the ratios of E to A wave velocity and TVI (Fig. 8 and 9), and pulmonary vein diastolic TVL In other words, as the heart rates of the study subjects increased, the observed values decreased. Moderate positive

associations (0.10 < R2 < 0.20) were seen between RR interval and IVRT (Fig. 10) and PVAR duration. Weak: positive associations (clinically insignificant; R2 < 0.10) were observed for mitral E wave velocity, mitral A wave duration, pulmonary vein systolic TVI, and PVAR TVL RR interval demonstrated no strong negative associations. Moderate negative associations (0.10 < R2 < 0.20) were noted with mitral A wave velocity, mitral E at A velocity, and the ratio of PVAR TVI to mitral A wave TVL In other words, as the heart rate increased, these values also tended to increase. Weak, clinically insignificant, negative associations between RR interval and mitral A wave TVI and the ratio of pulmonary vein systolic to diastolic TVI were observed (R 2 < 0.10). Bivariate Analysis for Independent Effects of Age and RR Interval (Heart Rate).-When these analyses were repeated during control of variations in RR interval, age was found to have no influence on the values ofE wave TVI, E at A velocity, PVAR duration and TVI, the ratio of pulmonary vein systolic to diastolic TVI, and the ratio of PVAR TVI to mitral A wave TVI (see bivariate partial associations in Table 5). In fact, all the independent effects of age were weak:. Strong independent positive associations (R2 > 0.20) were noted between RR interval and mitral E wave TVI as well as between RR interval and E to A ratios (both velocity and TVI). In other words, increasing heart rate was associated with decreasing Doppler values. A moderate positive association with RR interval was seen for PVAR duration. No strong negative associations were noted. Moderate negative associations were observed between RR interval and mitral A wave velocity, E at A velocity, and the ratio of PVAR TVI to mitral A waveTVL The effect of age and RR interval on mitral flow velocities was unique. In most cases, age and RR interval influenced the Doppler variable in a similar manner. Although

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Diastolic Ventricular Function in Children

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Table 5.-Influences of Age and Heart Rate on Diastolic Doppler Variables in Children*

Variable Mitral E velocity Mitral A velocity End A to R interval Duration of A wave Mitral deceleration time Mitral E wave TVI Mitral A wave TVI Mitral E at A velocity Mitral E to A ratio (velocity) Mitral E to A ratio (TVI) LV IVRT PV systolic peak velocity PV diastolic peak velocity Peak PVAR velocity PVAR duration PV systolic TVI PV diastolic TVI PVAR TVI PV systolic to diastolic ratio (velocity) PV systolic to diastolic ratio (TVI) Ratio of PVAR to mitral A wave duration Ratio of PVAR to mitral A wave TVI

Univariate associationst Age RR

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*A = atrial; E = early; IVRT = isovolumic relaxation time; LV = left ventricular; PV = pulmonary vein; PVAR = pulmonary vein atrial reversal; RR = RR interval; TVI = time velocity integral; - = no effect; i = weak association (R 2 < 0.10); ii = moderate association (0.10 < R2 < 0.20); iii = strong association (R2 > 0.20). tUnivariate associationscolumn demonstratesthe association between age or heart rate (RR interval) and each dependent variable without accounting for other influences. Bivariate partial associations column demonstrates the effect of age or heart rate on each dependent variable after controlling for the influence of the other independent variable (age or heart rate). Upward arrowsindicate positive associations between age or RR interval and the measured variable; downward arrows indicate negative associations. The number of arrows shown increases as the degree of association increases.

univariate assessment showed concordant effects of age and RR interval, however, bivariate analysis revealed that the independent influences of age and RR interval on mitral flow variables were actually discordant (Table 5). For mitral E to A ratios (velocity and TVI), the dominant influence was RR interval; increasing RR interval (decreasing heart rate) was strongly associated with increasing values for these ratios (Fig. 8 and 9). The independent

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Fig. 4. Association of age and mitral deceleration time. Solid line = predicted mean, as determined by linear regression. Dashed lines = 90% confidence limits for overall group. Boxes = values ranging from the 25th to the 75th percentile for each agegroup, by years. Line within each box = median value for that age-group. Vertical lines extending from each box = 95% confidence intervals for that specific age-group. Subjects younger than 5 years of age were pooled into the 4-year-old category (see Statistical Analysis). effect of increasing age was actually a decrease in the value of the ratios. This effect was a weakly negative association and was masked by the dominant influence of heart rate when age was analyzed without adjustment for RR interval. The independent influences of age and RR interval were also discordant for mitral E velocity, A velocity, and TVI, but these differences were less dramatic. Because heart rate had the dominant influence on mitral flow variables, use of heart rate-stratified normal values to interpret these signals would be most appropriate (Fig. 7, 8, and 9). For other variables, simple age-stratified normal ranges may be sufficient (Tables 2, 3, and 4 and Fig. 4, 5, 6, and 11).

Relationship of PVAR to Mitral A Wave in Normal Children Of the 223 normal subjects, 19 (8.5%) had no atrial reversal flow detected in the pulmonary vein. These subjects were excluded from the following analysis to avoid skewing the comparison values by their inclusion, although absence of reversal is clearly within the range of normal. Moreover, subjects with an unmeasurable A wave (fused mitral inflow signals) were excluded from this initial analysis, which used durations measured directly from the Doppler flow-velocity signal. Thus, 162 subjects had both PV AR and measurable mitral A waves. Observed ratios and differences are shown in Table 4. Gender had no significant influence on these ratios. The effects of age and heart rate have already been discussed. The essentially flat

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Mayo Clin Proc, July 1998, Vol 73

120 "T"--

Diastolic Ventricular Function in Children

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Fig. 5. Association of age and left ventricular isovolumic relaxation time (LV IVRT). See legend for Figure 4 for design and other explanations.

Fig. 6. Association of age and ratio of pulmonary vein (PV) systolic time velocity integral (TV!) to diastolic TVI. See legend for Figure 4 for design and other explanations.

relationship between age, as well as heart rate, and the ratio of the durations of PVAR and the mitral A wave is shown in Figures 11 and 12. An alternative technique for determining the difference between the duration of the PVAR and the mitral A wave with use of the end PVAR to R wave and end A to R intervals was possible in 181 of the normal volunteers (Fig. 2). This method demonstrated a mean difference of 6.7 ms between the PVAR and the A wave (PVAR being slightly longer). The standard deviation was 27 ms. These values were not significantly different from those derived by measuring the flow durations directly from the spectral Doppler tracing. The directly measured value for the difference between PVAR and the A wave was -10 ± 28 ms (A wave being slightly longer than the PVAR; N = 162).

Pediatric Patients With Increased Ventricular EDP The entry criteria for this portion of the study were fulfilled by 24 children (age younger than 21 years, catheterization-documented ventricular EDP of 18 mm Hg or more, and a cardiac Doppler examination near the time of catheterization). The mean age of this group was 10.6 ± 5.3 years. The mean ventricular EDP was 22.5 ± 4.9 mm Hg (range, 18 to 39). The primary cardiac diagnoses in these 24 patients were defects of the conotruncus (in 9), aortic or subaortic stenosis (in 5), hypertrophic or restrictive cardiomyopathy (in 5), univentricular heart of left ventricular type (in 3), ventricular septal defect and coarctation of the aorta (in 1), and atrioventricular septal defect (in 1). No significant differences were found in age, height, weight, body surface area, heart rate, mean

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For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

624

Diastolic Ventricular Function in Children

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Doppler Flow Variables in Children With Increased EDP Most mitral and pulmonary vein Doppler flow variables observed in patients with increased ventricular EDP were similar to those described in the normal subjects. Variables noted to be significantly different between these patients and the nonnal subjects are summarized in Table 6. The variables that best distinguished one group from the other were as follows: the ratio of PVAR duration to mitral A wave duration, the difference of these durations, and the ratio of the PVAR TVI to the mitral A wave TVI. The

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values that most accurately separated normal subjects from patients with increased EDP for each of these variables are shown in Table 7 and Figures 13 and 14. Although the other variables found in Table 6 showed statistically significant differences between the normal and the patient groups, these variables demonstrated enough clinical overlap that they could not be used for accurate identification of the presence of increased EDP in individual cases. Twenty of the normal control group had prolonged atrial reversal durations with use of the criteria outlined in Table 7. No statistically significant differences were found in age, heart rate, blood pressure, body size, or gender between these children and either the other normal control subjects or the patients with increased EDP. DISCUSSION In recent years, the understanding of diastole and our ability to assess diastolic ventricular performance have progressed rapidly. Much of this increased awareness has come from investigations involving Doppler echocardiography. Application of these principles to cardiac disease in children has been difficult because age-appropriate normal values were not available. The Doppler data obtained from the normal children in the current study provide the necessary foundation for useful investigation of pediatric diastolic function and dysfunction. In fact, the second phase of the current study demonstrates that it is already possible, given age-appropriate normal data, to apply the principles of adult diastology to children. This initial analysis of pediatric diastolic function focused on Doppler variables that might be used to predict the presence of increased ventricular EDP. Ventricular EDP has been used for many years as a crude indicator of

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Mayo Clin Proc, J uly 1998, Vol 73

Diastolic Ventricular Function in Children

clinical pediatric cardiology made it a logical target for inve stigation. Traditional anal ysis of isol ated mitral valve flow pattern s, such as E to A ratio and deceleration time , did not provide sensitive or specific markers for increased EDP in this study or in previous reports.v -" In fact , patients who demonstrate "pseudonorrnalization" have been found to have completely normal mitral flow veloc ity curves, despite the presence of moderate diastolic dys function and an increased left atri al pressure.P-" Analys is of pulmonary venous flow determinants in isolation has similar limitations. An appropriate and more powerful method of diastolic assessment uses both the mitral and the pulmonary venous flow patterns. This type of comparison was first proposed by Ros svoll and Harle. " In a group of 45 adults, they found a strong association between left ventricular EDP of more than 15 mm Hg and a duration of PV AR that exceeded the duration of the mitral A wave. Subsequent studies, also in adults, have supported this ob servation.27.30.31 Because these atrial flows are generated at the end of diastole, they may be altered in conditions in which the EDP is increased. This study revealed that prolongation of PV AR duration was also associated with increased ventricular EDP in

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Table 6.-Diastolic Doppler Variables With Significant Differences Between Normal Children and Pat ients With Increased Left Ventricular End-Diastolic Pressure* Normal (N = 223) Variables

N

Mean

SD

High LVEDP (N = 24) N Mean SD

MV E at A velocity (cm/s) MV A velocity (cm/s) End MV A to R interval (ms)'] MV A TVI(cm) P vein systolic TVI (em) PVAR velocity (cm/s) PVAR duration (ms) PVAR TVI (em) Ratio: MV E velocity to A velocity Ratio: MV E TVI to A TVI Ratio: PVAR to MV A durations Ratio: PVAR TVI to MV A TVI Difference: PVAR and MV A durations (ms) Difference: PVAR and MV A durations (ms r]

144 208 214 209 215 171 169 169

14.3 40.5 29.7 3.71 11.2 21.2 131.7 1.77

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15 17 16 17 15 18 18 15

23.2 52.2 -2.6 4.76 8.8 24.7 166.3 2.56

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0.0001 0.0003 0.0004 0.0283 0.0070 0.0477 0.0000 0.0013

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*A =atrial; E =early filling wave; LVEDP =left ventricular end-diastolic pressure; MV =mitral valve; P =pulmonary; PVAR =pulmonary vein atrial reversal; SD = standard deviation; TVI = time velocity integral. t A negative value indicates that the mitral forward flow stops before the peak R wave. tAltemative method of determining the difference (see text).

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626

Diastolic Ventricular Function in Children

Mayo Clin Proc, July 1998, Vol 73

Table 7.-Clinical Indicators of Increased End-Diastolic Pressure, Including Sensitivities and Specificities* Doppler variable

Maximal "normal" value

Sensitivity (%)

Specificity (%)

1.2

88

86

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90

86

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88 92

Ratio of PVAR to MV A duration Difference between PVAR and MV A duration Alternative method for calculating the difference between PVAR and MV A duration Ratio of PVAR TVI to MV A TVI

*A = atrial;

MV = mitral valve; PVAR = pulmonary vein atrial reversal; TVI = time velocity integral.

children. This relationship was most predictive when the reversal duration was examined relative to the duration of the mitral A wave. Some normal children, however, will have PVAR that is slightly longer than the mitral A wave (see Table 4). Therefore, the simple criterion (atrial reversal duration greater than mitral A wave) that was proposed by Rossvoll and Harle" cannot be directly applied to children. For appropriate application of this concept to children, the more specific criteria outlined in Table 7 for the ratio of and difference between atrial reversal to mitral A wave durations should be used. They provide meaningful benchmarks that can be used in pediatric populations with acceptable levels of sensitivity and specificity.

STUDY LIMITATIONS

Although the information presented in this study is more extensive than the data in earlier reports, it does not include infants and neonates. Therefore, we cannot confidently extend these methods to those age-groups as yet. Although the evaluation of the relative durations of atrial reversal and forward flow provided the most sensitive and specific marker for increased EDP, approximately 10% of normal patients will have "abnormally" long reversal durations when the criteria outlined in this study are used. Unfortunately, no significant differences were noted between these children and the other normal control subjects. Therefore, we cannot speculate about why they should have had prolonged PVAR. We hypothesize that the presence of both

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Fig. 13. Detecting elevated end-diastolic pressure (EDP) with use of ratio of pulmonary vein atrial reversal (PVAR) to mitral valve (MV) atrial filling wave (A) duration. Ratios observed in normal children are depicted by box plot at left. Plot on right describes data from children with EDP of 18 mm Hg or more. Long, solid horizontal line = separation point between the two groups (cutpoint ratio = 1.2), with a sensitivity of 88% and a specificity of 86%. Brackets = 95% confidence limits for each box plot. Boxes = 75% of each group. Line in center of each box = median for the group; shaded area around line =95% confidence interval for median value.

Normal children

High EDP

Fig. 14. Detecting elevated end-diastolic pressure (EDP) with use of difference between pulmonary vein atrial reversal (PVAR) and mitral valve (MV) atrial filling wave (A) duration. Differences observed in normal children are shown by box plot at left. Plot on right describes data from children with EDP of 18 mm Hg or more. Long, solid horizontal line = separation cutpoint (29 ms) between the two groups, with a sensitivity of 90% and a specificity of 86%. Brackets = 95% confidence limits for each box plot. Boxes = 75% of each group. Line in center of each box = median for the group; shaded area around line = 95% confidence interval for median value.

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Diastolic Ventricular Function in Children

Mayo Clin Proc, July 1998, Vol 73

prolonged atrial reversal and cardiac abnormalities may provide better positive predictive value than use of the Doppler criteria in isolation; however, further investigation will be necessary to determine whether this is true. The abnormal group described herein was studied retrospectively. Therefore, the data obtained were not as complete as one would have desired. For example, only four patients in the group with increased EDP had direct measurements of left atrial pressure; as a result, we could not analyze the effect of left atrial pressure on Doppler flow variables. Although the difference between the durations of the A wave and the PVAR can be determined in patients with fusion of the mitral inflow Doppler signal, these assessments require that the patient be in a regular sinus rhythm. These findings may be more difficult to apply to patients in other rhythms. Moreover, this report describes factors and analyses specifically focused on the left ventricle. Further investigation will be needed before we can confidently assess the diastolic performance of the right ventricle or complex ventricles with mixed morphologic features. In addition, new techniques of diastolic analysis, such as color M-mode examination of flow propagation." were not examined and may offer important additional insights into diastolic function. Finally, the normal data described herein were obtained in a group with a relatively homogeneous ethnic background. Therefore, we are unable to comment on the effects, if any, that ethnicity may have on these diastolic variables. CONCLUSION Diastole has often been the forgotten portion of the cardiac cycle, especially in pediatric patients. Recent advances in the understanding of heart failure and its causes point out that diastolic performance and the effect of diastolic dysfunction can no longer be ignored. Doppler echocardiography has provided many insights into diastole and disturbances of diastolic function in adults. The Doppler echocardiographic data obtained in children in this study allow the same type of analyses to be applied to the pediatric patient. Clearly, one cannot interpret the mitral inflow pattern in isolation and expect to obtain an accurate understanding of left ventricular diastolic performance. Use of the normal data and the Doppler techniques described in this study should allow the concepts of diastology to extend into pediatric practice. Broader application of these techniques will provide a more complete understanding of diastolic function and dysfunction in childhood. ACKNOWLEDGMENT We gratefully recognize the essential technical assistance of Barbara E. Walsh, R.D.C.S., and Eileen Nemec,

627

R.D.C.S. We also appreciate the statistical support provided by Christine M. Boos and Lynn H. Urban. We thank the staff and students of St. John's Elementary School and Lourdes High School, Rochester, Minnesota, without whom this study would not have been possible.

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TEXT BITES FROM OTHER JOURNALS The risk for colorectal cancer was decreased among women currently receiving postmenopausal hormone therapy, but the apparent reduction substantially diminished upon cessation of therapy. Hormone use was inversely associated with large colorectal adenomas but not small ones. -Ann Intern Med 1998;128:705-712 Current smoking was associated with a nearly sixfold increase in risk for a postoperative pulmonary complication. Reduction in smoking within 1 month of surgery was not associated with a decreased risk of postoperative pulmonary complications. -Chest 1998;113:883-889 Reduction in the useful field of view increases crash risk in older drivers. Given the relatively high prevalence of visual processing impairment among the elderly, visual dysfunction and eye disease deserve further examination as causes of motor vehicle crashes and injury. -lAMA 1998;279:1083-/088 Treatment of ventilator-dependent premature infants with dexamethasone at two weeks of age is more hazardous and no more beneficial than treatment at four weeks of age. -N EnglJ Med 1998;338:1112-1118

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