Pediatr Cardiol 23:378±387, 2002 DOI: 10.1007/s00246-002-1506-4

Original Articles Heart Rate Is the Major Determinant of Diastolic Filling Pattern During Growth: A Radionuclide Ventriculography Assessment G. Arsos,1 E. Moralidis,1 N. Karatzas,1 I. Iakovou,1 S. Georga,1 D. Koliouskas,2 G. Langazalis,1 C. Karakatsanis1

1 Department of Nuclear Medicine, Aristotle University Medical School, Hippokration Hospital, Thessaloniki, Greece

1 2 Department of Pediatric Oncology, Hippokration Hospital, Thessaloniki, Greece

Abstract. Left ventricular diastolic ®lling is a fundamental constituent of cardiac performance. Diastolic function in both adults and children can be routinely assessed by radionuclide ventriculography (RNV). It has previously been shown that factors such as heart rate (HR) and age can signi®cantly modify diastolic performance in adults, thus limiting the clinical applicability of RNV diastolic indices. The aim of this study was to investigate various factors that may a€ect diastolic function in childhood. Seventy-nine children, aged 40 days to 15 years, were enrolled in the study; their HR ranged from 45 to 160 beats per minute (bpm). All had intact cardiac function and were submitted to baseline RNV prior to chemotherapy initiation for malignancies. Using stepwise linear regression analysis, HR was identi®ed as the major factor a€ecting RNV diastolic indices during growth. Applying univariate regression models, diastolic indices were corrected for a referrence HR of 100 bpm; this substantially reduced variability of RNV diastolic indices along age increments, allowing for the establishment of reference ranges. In conclusion, HR was shown to be the major determinant of RNV diastolic indices during growth. Adjustment for this variable alone can o€er reference ranges for the assessment of left ventricular ®lling in childhood.

complex process, re¯ecting the interaction of a variety of factors, such as myocardial relaxation, passive mechanical properties of the myocardium, loading conditions, and uniformity of activation and inactivation [4, 12, 19]. The pattern of left ventricular ®lling can be noninvasively assessed by equilibrium radionuclide ventriculography (RNV); Doppler echocardiography (D-echo), and magnetic resonance imaging [1, 10, 24]. Currently, semiquantitative diastolic function indices are used for clinical purposes, but their wide application may be limited by inherent methodological problems. The role of diastolic function is less well recognized in pediatric populations [26]. Limited data exist on diastolic ®lling pattern in infants and children from D-echo ¯ow velocity measurements at the mitral ori®ce [6, 15, 17, 28]. No normal ranges for RNV diastolic indices have been reported for clinical use in pediatrics, despite the fact that this technique has been applied in children [25, 30]. In this retrospective study the diastolic ®lling pattern is assessed by RNV in a pediatric population with intact heart function. In particular, the importance of some potentially in¯uencing factors, such as age, heart rate (HR), body size, heart size, and systolic function, is investigated.

Key words: Heart rate Ð Diastolic ®lling Ð Radionuclide ventriculography

Patients and Methods Population Recruitment

Diastolic ®lling plays a signi®cant role in global cardiac performance [20, 31]. Left ventricular ®lling is a Correspondence to: G. Arsos at Zaka 19, Panorama, 552 36 Thessaloniki, Greece

The population studied consisted of 79 children (49 boys, 30 girls) referred for baseline RNV study before initiation of potentially cardiotoxic chemotherapy. Their ages ranged from 40 days to 15 years (mean 7.0 ‹ 4.5 years) and their HR ranged from 45 to 160 beats per minute (bpm) (mean 101.8 ‹ 25.4 bpm). The underlying disease was acute lymphocytic leukemia in 36 cases, lymphoma in 14, sarcomas in 10, Wilms' tumor in 9, and other less common

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the heart cycle to the lowest TAC point, with ®lling time (FT) being the rest of the R-R interval. Peak ®lling rate (PFR) was de®ned as the peak of the ®rst derivative curve at the ®rst half of diastole and it was expressed in both end diastolic volumes per second (EDV/ sec) and stroke volumes per second (SV/sec). The interval from the lowest TAC point to the time when PFR occurred was de®ned as time to peak ®lling rate (TPF). The late positive de¯ection of the ®rst derivative curve was attributed to the atrial contraction, and from the corresponding TAC de¯ection the atrial component to diastolic ®lling (A/V) was measured and expressed as percentage of SV. The ®rst third ®lling fraction (1/3FF) was designated as the percentage of left ventricular ®lling during the ®rst third of FT. All these parameters for diastolic function assessment have been previously described [1, 16]. EDV and ESV (and hence SV) were calculated using a previously validated count ratio-based method [22].

Fig. 1. RNV time±activity curve with its ®rst derivative (lower curve). Open rectangles represent actual measurements. 1/3FF, ®rst third ®lling fraction; ET, emptying time; FT, ®lling time; PFR, peak ®lling rate; TPF, time to peak ®lling rate.

types of tumors in 10. Their cardiac performance was judged intact on the basis of history, physical examination, electrocardiography, and echocardiographic evaluation, as needed. No febrile patients were included and time was given to crying children to calm down. Cases with neural crest tumors were not enrolled to exclude potential chronic catecholamine in¯uence. Height (H) and body weight (W) were measured in all cases and the body surface area (BSA) was calculated according to the Dubois and Dubois' formula [9]: BSA = H0.725 W0.425 71.84.

Radionuclide Ventriculography The in vivo labeling technique was used to label autologous red blood cells with 99mTcO4 . The administered pertechnetate activity dose was escalated according to the European Association of Nuclear Medicine Pediatric Task Group schedule [27]. Acquisition was performed at rest in the supine position. The gamma detector, equipped with a general-purpose parallel hole collimator, was positioned at best septal view and the photopeak of the gamma camera was set at 140 keV with a 20% window. R-R interval was divided in 24 frames and a dynamic ®ltration mode acquisition was 2 used, with rejection of R-R intervals out with ‹10% of the mean interval. Typically, 5000 kcounts per study were acquired. Tail frames were appropriately corrected for loss of counts due to R-R variation. Using a second derivative edge detection technique regions of interest (ROIs) were automatically generated for each of the 24 frames. These ROIs were subsequently manually corrected where obvious errors were noted. A background ROI was drawn at the inferolateral edge of the left ventricle. The background-substracted time±activity curve (TAC) was generated and it was approximated by a fourth-order Fourier transformation. The ®rst derivative of the latter, representing the rate of left ventricular volume changes, was supplementary used for accurate measurement of both the timing of diastolic events and the diastolic parameters (Fig. 1). Ejection fraction (EF) was calculated in the usual manner. Ejection time (ET) was designated as the period from the start of

Statistics Descriptive statistics are presented as mean ‹1 standard deviation (SD). Normal curve plots were ®tted over data histograms for normal distribution assessment. The explanatory power of each individual variable on diastolic parameters was sequentially assessed by forward stepwise regression analysis. Dependence of various diastolic indices on HR was modeled by univariate regression analysis and the best ®tting linear or polynomial equation was selected using statistical criteria. The goodness of ®t of the regression equations to the data was assessed by Pearson's correlation coecient (r). The nonparametric Kruskall±Wallis test was used for comparisons of more than two independent groups followed by Dunnett's C-test for pairwise comparisons between groups. Statistical signi®cance was accepted for p values <0.05.

Results The late TAC de¯ection, allowing atrial kick identi®cation and A/V assessment, was detectable in 50 cases. The rest of diastolic indices were easily measured in all cases, even in the presence of high HR. A negative correlation between age and HR was found (HR = 0.27 age2±7.54 age + 134, r = ±0.61, p < 0.0001). HR declined with increasing age and the rate of change was progressively decelerated (Fig. 2). No appreciable change was noted beyond the age of 14 years. Time variables, diastolic indices, and ejection fraction values of the entire population are listed in Table 1. HR, EF, PFR (EDV/sec), PFR (SV/sec), TPF, TPF/FT, A/V, and the 1/3FF values were normally distributed. The e€ect of age, EF, HR, EDV, SV, and BSA on diastolic ®lling indices, investigated by forward stepwise regression analysis, was as follows: PFR (EDV/sec) was signi®cantly a€ected by only HR (adjusted r2 = 0.519). PFR (SV/sec) was also signi®cantly a€ected by HR (adjusted r2 = 0.569), the addition of EF in the model being of minimal importance (adjusted r2 = 0.597). TPF was signi®cantly a€ected by only HR (adjusted r2 = 0.291), as was

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Fig. 2. Relation between age and heart rate (HR).

Table 1. Time variables, diastolic indices, and ejection fraction

HR (bpm) R-R (msec) ET (msec) ET/R-R (%) FT (msec) FT/R-R (%) FT/ET TPF (msec) TPF/FT (%) PFR (EDV/sec) PFR (SV/sec) 1/3FF (%SV) A/V (%SV) EF (%)

Mean ‹ SD

Range

101.8 628.2 263.7 42.6 373.7 57.5 1.4 131.3 37.0 4.8 7.7 36.3 16.7 63.5

45±160 375±1333 126±451 28.7±56.0 171±950 44.0±71.3 0.8±2.5 43±289 14.7±56.0 2.3±8.2 3.5±14.6 7.9±69.2 0.6±51.4 52.3±83.2

‹ ‹ ‹ ‹ ‹ ‹ ‹ ‹ ‹ ‹ ‹ ‹ ‹ ‹

25.4 169.5 52.2 6.4 142.0 6.4 0.4 39.6 9.8 1.6 2.9 13.4 11.2 6.3

1/3FF(SV), the ®lling fraction during the ®rst third of diastole; A/ V, atrial contribution to left ventricular ®lling; EF, ejection fraction; ET, ejection time; FT, ®lling time; HR, heart rate; n, number of patients, PFR (EDV/sec), peak ®lling rate in end diastolic volumes per second; PFR (SV/sec), peak ®lling rate in stroke volumes per second; R-R, cardiac cycle length; TPF, time to peak ®lling rate. For the variable A/V, n = 50.

TPF/F (adjusted r2 = 0.270). HR was the only signi®cant predictor for 1/3FF (adjusted r2 = 0.525). Finally, A/V was signi®cantly a€ected by HR (adjusted r2 = 0.607), with the incorporation of EF in the model adding little (adjusted r2= 0.666). In all cases, age, EDV, SV and BSA were excluded because they did not ful®ll the entry criterion (F < 0.05). 3 These results show that HR is the only variable with considerable explanatory power for the variability of diastolic parameters, with the EF having

minimal additional impact on some diastolic indices and the rest of variables having no impact. Therefore, simple regression models, linear or polynomial, were further employed for detailed investigation of the dependence of diastolic ®lling pattern on HR. The choice of the regression equation in each case was based on both scatter plots of data and selection of the best ®t model. The results of regression analysis between HR and various time and diastolic parameters are presented in Table 2. Signi®cant correlations were found between HR and all the investigated depended variables. As HR increased, ET duration decreased linearly but its relative contribution to the entire cardiac cycle (ET/R-R) increased up to a HR limit of about 140 bpm (Figs. 3a and 4a). On the contrary, FT decreased both in absolute units and as a fraction of the cardiac cycle (FT/R-R) to a HR limit of 140 bpm (Figs. 3c and 4c). The ratio FT/ET also decreased with increasing HR up to 140 bpm (Fig 5a). TPF linearly decreased as HR increased. However, it increased in relation to FT up to a HR of 140 bpm; namely, PFR was achieved later during the ®lling period in higher HR (Figs. 6a and 6c). A weak negative correlation was noted between EF and HR. PFR expressed in either EDV/sec or SV/sec correlated positively with HR (Figs. 7a and 7c). However, the percentage of stroke volume entering the left ventricle during the early ®lling period was diminished in high HR , demonstrated by the strong negative correlation between 1/3FF and HR. Finally, the atrial contribution to ventricular ®lling was augmented with increasing HR (Figs. 8a and 8c). In order to reduce the dependence of various parameters on HR, corrected values were calculated for an arbitrary HR value of 100 bpm. The 100-bpm reference value was selected because it is both very close to the mean HR of the population studied (101.8 bpm) and an easy number for calculations. Corrected values were calculated as follows. If the dependent variable regresses linearly on HR (independent variable), the relationship between a given value P of the dependent variable and the corresponding HR value is described as follows: P ˆ aHR ‡ b

…1†

For the reference heart rate value (HRc) and the corresponding, corrected value of the dependent parameter (Pc), Eq. (1) can be rewritten as Pc ˆ aHRc ‡ b

…2†

Substracting Eq. (2) from Eq. (1) results in Pc ˆ P

a…HR

HRc †

…3†

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Table 2. Regression equations of time variables, diastolic indices, and ejection fraction vs heart rate

ET (msec) ET/R-R (%) FT (msec) FT/R-R (%) FT/ET TPF (msec) TPF/FT (%) PFR (EDV/sec) PFR (SV/sec) 1/3FF(SV) A/V/(%SV) EF (%)

r

P

Regression equation

)0.77 0.70 )0.95 )0.63 )0.72 )0.55 0.55 0.72 0.76 )0.76 0.78 )0.36

<0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 0.001 <0.0001 <0.0001 0.0001 <0.0001 0.001

ET = )1.59 HR + 425.76 ET/R-R = )0.0024 HR2+ 0.67 HR -0.84 FT = 0.066 HR2 ) 18.95 HR + 1576.25 FT/R-R = 0.0022 HR2 ) 0.63 HR + 97.42 FT/ET = 0.00018 HR2 ) 0.049 HR + 4.35 TPF = )0.85 HR + 218.33 TPF/FT = )0.00230 HR2 + 0.69 HR - 7.83 PFR(EDV/sec)=0.046 HR )0.11 PFR(SV/sec)=0.087 HR )1.08 1/3FF(%SV)=0.004 HR2 ) 1.25 HR + 118.43 A/V=0.34 HR )17.29 EF = )0.089 HR + 72.62

Abbreviations as in Table 1. For the variable A/V, n = 50.

Fig. 3. Relations between (a) emptying time (ET) and HR, (b) emtying time corrected at 100 bpm (cET) and HR, (c) ®lling time (FT) and HR and (d) ®lling time corrected at 100 bpm (cFT) and HR.

For the second-degree polynomial regression equations, it can be similarly shown that Pc ˆ P

a…HR

HRc †

b…HR2

HR2c †

…4†

Regression analysis between corrected values of all diastolic parameters and HR showed no

signi®cant correlation (Figs. 3b, 3d, 4b, 4d, 5b, 6b, 6d, 7b, 7d, 8b, and 8d). Similarly, when regression analysis was applied between age and HRcorrected values of all the parameters studied, no signi®cant correlation was found. Additionally, no signi®cant correlations were found between the cEF

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Fig. 4. Relations between (a) emptying time/R-R as percentage [ET/R-R (%)] and HR, (b) emptying time/R-R as percentage, corrected at 100 bpm [cET]/R-R(%)]and HR, (c) ®lling time/R-R as percentage [FT/R-R(%)] and HR, and (d) ®lling time/R-R as percentage corrected at 100 bpm [cFT/R-R(%)] and HR.

and the corrected values of all the parameters investigated. The entire study population was arbitrarily divided into three consecutive groups according to age in ascending order. The ®rst group consisted of 29 individuals aged less than 5 years, the second group comprised 27 individuals with an age range of 5 years to less than 10 years, and the third group included 23 individuals aged 10 years or older. The somatometric data, time parameters, and RNV diastolic function indices are listed in Table 3 and the results of pair comparisons between the groups are also presented. A statistically signi®cant di€erence in both time parameters and diastolic indices between these age groups was found (Table 3). The values of the corrected diastolic indices at a HR of 100 bpm for all the age groups are presented in Table 4. Because no signi®cant di€erence was found in any diastolic parameter between the corrected values of the age groups, a fourth group including the entire study population (all patients) was formed. Mean values ‹ standard deviation of all diastolic parameters for this group are also presented in Table 4. Discussion These data demonstrate that the diastolic ®lling pattern changes in normal hearts throughout human

development (Table 3). Moreover, the multiple regression analysis results demonstrate that the major determinant of left ventricular ®lling pattern in intact hearts during somatic growth is HR, with the rest of variables studied o€ering no or minimal explanatory power. When adjusting the RNV diastolic indices for HR alone, no signi®cant variation is observed during human development (Table 4).

Population The population studied represents the entire spectrum of infancy and adolescence. It has been previously shown that in normal adult hearts diastolic function deteriorates with advancing age [5, 29]. It is highly unlikely that in the age range studied degenerative processes might modify myocardial performance. Heart rate has been recognized as a signi®cant factor a€ecting the left ventricular ®lling pattern in adults [1, 8, 14, 18]. During human development HR gradually declines to the much lower adult levels (Fig. 2). However, during growth somatic changes also take place regarding entire body (BSA) and cardiac chamber volumes (EDV and ESV). Heart chamber volume changes are known to regulate/ interact with cardiac performance in health and disease [30].

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seems to continuously decrease with increasing HR, a diastole-sparing e€ect may be observed at HR values higher than 140 bpm, at which FT changes level o€ (Figs. 3c and 4c). Diastolic Function Parameters

Fig. 5. Relations between (a) ®lling time/emtying time (FT/ET) and HR, and (b) ®lling time/emptying time corrected at 100 bpm (cFT/ET) and HR.

Regression Analysis Potentially in¯uencing factors were included in the statistical model in order to assess their impact on diastolic function. Univariate regression analysis showed that heart rate posseses a considerable predictive power for PFR (EDV/sec), PFR (SV/sec), TPF, TPF/FT, 1/ 3FF, and A/V changes during development. Given the heart rate e€ect, EF minimally a€ects PFR (SV/sec) and A/V. No diastolic function parameter was signi®cantly in¯uenced by age, EDV, SV, and BSA. Time Indices HR changes have a substantial e€ect on the partition of cardiac cycle. Increasing HR diminishes FT more than ET, and thus the FT/ET ratio also decreases (Figs. 3a, 3c, and 5a). Consequently, the ET occupies a higher proportion of the cardiac cycle with increasing HR, thus limiting the left ventricular ®lling time (Figs. 4a and 4c). Interestingly, although ET

PFR (expressed in either EDV/sec or SV/sec) increases with increasing HR (Figs. 7a and 7c). Similar ®ndings for early ®lling have been reported using Decho and RNV [8, 14]. However, the dependence of PFR on HR is not easily explained. A complicating factor is that neither EDV nor SV remain unchanged with increasing HR. Indeed, He et al. [14] showed that EDV and SV decreased to 74% and 86% of the baseline value, respectively, when HR increased from 52 bpm to 102 bpm. Thus, the positive correlation between PFR and HR may to a certain extent be attributed to measurement unit changes. Decreasing the magnitude of the measurement unit (EDV or SV) numerically increases the result (PFR value). Moreover, increased variability of EDV with age in a pediatric population has been described [2]. Therefore, it is not surprising that even after correction for HR, PFR (either in EDV/sec or SV/sec) continues to show considerable random variation about the regression line (Figs. 7b and 7d). The ®rst third ®lling fraction decreases as HR increases (Fig. 8a), in contrast to the positive PFR± HR relationship (Figs. 7a and 7c). This di€erence is particularly striking because both 1/3FF and PFR are considered to parallel diastolic function changes. TPF, in absolute units, was found to diminish with increasing HR; however, when expressed as a fraction of the FT, it increases, indicating that PFR is achieved later during the shortened diastole. This may explain why PFR and 1/3FF are not unidirectionally correlated to HR. Finally, the atrial component of left ventricular ®lling is augmented in high HR (Fig. 8c), which is consistent with previously published adulthood data [14]. Corrected Diastolic Indices The results in Table 3 show that time variables and diastolic indices change during growth. We proved that when these parameters are corrected for a reference HR (100 bpm in our case) no signi®cant variation is observed along the age increments in either cardiac cycle intervals or diastolic indices, and uniform descriptive statistics can be formulated covering the entire range from early infancy to adolescence (Table 4). This indicates the minimal e€ect of the variables studied, apart from HR, on the

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Fig. 6. Relations between (a) time to peak ®lling (TPF) and HR (b) time to peak ®lling corrected at 100 bpm (cTPF) and HR, (c) time to peak ®lling/R-R as percentage [TPF/FT(%)] and HR, and (d) time to peak ®lling/FT as percentage corrected at 100 bpm [cTPF/FT(%)] and HR.

Fig. 7. Relations between (a) peak ®lling rate in EDV/sec and [PFR(EDV/sec)] and HR, (b) peak ®lling rate in EDV/second corrected at 100 bpm [cPFR(EDV/sec)] and HR, (c) peak ®lling rate in SV/second [PFR(SV/sec)] and HR, and (d) peak ®lling rate in SV/second corrected at 100 bpm [cPFR(SV/sec)] and HR.

diastolic ®lling pattern. Correction power is considerable; for example, the mean A/V (25.6%) of the age group 1 (mean HR, 121.1 bpm) is 2.43 times

higher than that of age group 3 (mean A/V, 10.5%; mean HR, 80.7 bpm). After correction for a HR of 100 bpm, the A/V ratio of the two age groups be-

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Fig. 8. Relations between (a) ®rst third ®lling fraction as percentage of SV [1/3FF(%SV)] and HR, (b) ®rst third ®lling fraction as percentage of SV corrected at HR 100 bpm [c1/3FF(%SV)] and HR, (c) atrial contribution (as percentage of SV) to ventricular ®lling [A/V(%)] and HR, and (d) atrial contribution (as percentage of SV) to ventricular ®lling corrected at 100 bpm [cA/V(%)] and HR. Table 3. Age, size variables, time variables, diastolic indices, and ejection fraction in three age groups

Agea BSA (m2)a EDV (ml)a ESV (ml)a HR (bpm)a ET (msec)b ET/R-R (%)c FT (msec)d FT/R-R (%)d TPF (msec)d TPF/FT (%)b PFR (EDV/sec)d PFR (SV/sec)d 1/3FF (%SV)b A/V (%SV)d EF (%)d

Age group 1 (n = 29)

Age group 2 (n = 27)

Age group 3 (n = 23)

P value

2.5 0.60 28.3 11.2 121.1 232 45.7 278 54.3 109 38.5 5.96 9.93 30.4 25.6 60.7

6.7 0.95 53.1 18.8 99.0 265 42.0 386 58.5 148 40.5 4.51 7.10 34.7 15.4 64.3

12.9 ‹ 1.8 1.49 ‹ 0.21 109.4 ‹ 33.6 36.8 ‹ 13.5 80.7 ‹ 15.2 303 ‹ 40.2 39.5 ‹ 5.8 481 ‹ 150.1 60.5 ‹ 5.8 140 ‹ 31 30.9 ‹ 7.3 3.74 ‹0.99 5.72 ‹ 1.66 45.4 ‹ 11.8 10.5 ‹ 5.9 66.1 ‹ 6.2

<0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.005 <0.001 <0.005 <0.001 <0.005 <0.001 <0.001 <0.001 <0.005 <0.005

‹ ‹ ‹ ‹ ‹ ‹ ‹ ‹ ‹ ‹ ‹ ‹ ‹ ‹ ‹ ‹

1.3 0.16 11.3 4.7 20.3 39 5.3 61 5.3 27 8.8 1.39 2.59 10.9 12.0 5.7

‹ ‹ ‹ ‹ ‹ ‹ ‹ ‹ ‹ ‹ ‹ ‹ ‹ ‹ ‹ ‹

1.4 0.17 20.8 8.1 21.7 52 6.6 130 6.5 46 10.7 1.58 2.49 13.3 10.3 5.9

Abbreviations as in Table 1. Values of variables are expressed as mean ‹SD. BSA, body surface area. For the variable A/V, n = 14, 20, and 16 for groups 1, 2, and 3, respectively. a Statistically signi®cant di€erence for all pair comparisons between groups. b Statistically signi®cant di€erence in comparing groups 1 vs 3 and 2 vs 3. c Statistically signi®cant di€erence in comparing groups 1 vs 3. d Statistically signi®cant di€erence in comparing groups 1 vs 2 and 1 vs 3.

comes 0.92 (15.9 vs 17.2%). By adjusting RNV diastolic indices to a reference HR, global reference values from infancy to adolescence can be established.

Diastolic dysfunction may be an early ®nding of chemotherapy cardiotoxicity and radionuclide ventriculography is a reliable method for left ventricular ®lling assessment. Therefore, a potential clinical value

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Table 4. Time variables, diastolic indices, and ejection fraction in three age groups after correction for HR = 100 bpm according to regression equations

cET (msec) cET/R-R(%) cFT(msec) cFT/R-R(%) cTPF(msec) cTPF/FT (%) cPFR(EDV/sec) cPFR(SV/sec) c1/3FF cA/V CEF

Age group 1 (n = 29)

Age group 2 (n = 27)

Age group 3 (n = 23)

P value

All patients (n = 79)

265 43.7 343 56.4 127 38.4 4.99 8.10 35.8 15.9 62.6

263 43.2 350 57.3 147 41.8 4.55 7.19 31.9 15.9 64.2

272 44.6 331 55.5 124 36.7 4.63 7.40 33.5 17.2 64.3

ns ns ns ns ns ns ns ns ns ns ns

267 ‹ 33 43.8 ‹ 4.5 342 ‹ 44 56.5 ‹ 4.6 133 ‹ 33 38.0 ‹ 8.2 4.74 ‹ 1.13 7.58 ‹ 1.89 33.8 ‹ 8.7 16.3 ‹ 7.0 63.6 ‹ 5.8

‹ ‹ ‹ ‹ ‹ ‹ ‹ ‹ ‹ ‹ ‹

24 5.0 28 5.1 25 8.4 1.32 2.41 9.4 8.5 5.5

‹ 44 ‹ 4.5 ‹ 52 ‹ 4.5 ‹ 41 ‹ 8.7 ‹ 1.06 ‹ 1.49 ‹ 9.6 ‹ 7.1 ‹ 6.4

‹ 29 ‹ 4.0 ‹ 50 ‹ 4.0 ‹ 27 ‹ 5.9 ‹ 0.92 ‹ 1.43 ‹ 6.1 ‹ 5.9 ‹ 5.7

Abbreviations as in Table 1. Pre®x c denotes corrected. Values of variables are expressed as mean ‹SD. For the variable cA/V, n = 14, 20, 16, and 50 for groups 1, 2, 3, and all patients, respectively. ns, not signi®cant.

of HR-adjusted diastolic indices could be a more accurate monitoring of children receiving anthracyclines [7, 11, 15, 21, 23]. Other Studies The e€ect of HR on left ventricular ®lling in adults has been addressed using both D-echo and RNV [3, 13, 14, 18]. Normal adult populations do not usually have a wide resting HR range to reliably investigate its e€ect on diastolic indices. As a consequence, in most of the previous publications high HR was achieved with exercise or pacing. Therefore, other interfering factors (e.g., increased contractile status, changing loading conditions, and altered conduction sequence) were not necessarily excluded. However, a substantial dependence of diastolic ®lling pattern on HR has been demonstrated, but these observations cannot be extrapolated in younger populations. Potential factors that may modulate the diastolic ®lling pattern during human development have been investigated by Doppler ¯ow velocity measurements [6, 15, 17, 28]. Heart rate was found to be a signi®cant determinant of some echocardiographic diastolic ®lling indices in children in some but not all of these reports [6, 28]. Moreover, age, BSA, and the stroke volume crossing the mitral valve have also been implicated as important variables that regulate left ventricular ®lling in infants, children, and adolescents [6, 15, 17, 28]. In addition, normal Doppler echocardiographic ranges during growth have been reported [6, 28]. However, Doppler maximal blood ¯ow velocity measurements cannot be directly compared to RNV volume change calculations at diastole. Apparently, not all factors a€ecting the Doppler ¯ow measurements can modify the RNV volume change pattern. Thus, identi®cation of consistencies and in-

consistencies with existing reports is not feasible. Finally, echocardiogaphic examination is not technically adequate in a percentage of individuals, reliable assessment necessitates experienced operators, and accurate measurement of diastolic indices is achieved by averaging a few cardiac cycles. This is in contrast to RNV, which minimally depends on both the patients' body habitus and the operator's experience, whereas the diastolic ®lling pattern is assessed by averaging several hundred cardiac cycles. 4 Conclusion This study demonstrates that the diastolic ®lling pattern in intact young hearts signi®cantly changes during development. HR was found to be the major determinant of diastolic function, EF was of minimal importance, and other variables (age, BSA, EDV, and SV) were not important. By adjusting for HR alone, reference values of RNV diastolic indices during growth may be established. Thus, the correction of diastolic indices at a reference HR may allow for improved, age-independent RNV assessment of the left ventricular ®lling pattern in pediatric populations. References 1. Arrighi JA, Soufer R (1995) Left ventricular diastolic function: physiology, methods of assessment, and clinical signi®cance. J Nucl Cardiol 6:525±543 2. Arsos G, Moralidis E, Iakovou I, et al (2001) Left ventricular volumes variability during human growth (Abs). J Nucl Cardiol 8:S102 3. Bianco JA, Filiberti AW, Baker SP, et al (1985) Ejection fraction and heart rate correlate with diastolic peak ®lling rate at rest and during exercise. Chest 88:107±113

Arsos et al.: Heart Rate Is the Major Determinant of Diastolic Filling Patern

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