Normal values of left ventricular systolic and diastolic function derived from signal-averaged acoustic quantification waveforms: a multicenter study

Normal Values of Left Ventricular Systolic and Diastolic Function Derived from Signal-averaged Acoustic Quantification Waveforms: A Multicenter Study Kirk T. Spencer, MD, Victor Mor-Avi, PhD, Jim Kirkpatrick, MD, John Gorcsan III, MD, Thomas R. Kimball, MD, Mark J. Monaghan, PhD, Julio E. Perez, MD, Lynn Weinert, BS, James Bednarz, RDCS, Kathy Edelman, RDCS, Betty Glascock, RDCS, Jane Hancock, MD, Chris Baumann, RDCS, and Roberto M. Lang, MD, Chicago, Illinois; Pittsburgh, Pennsylvania; Cincinnati, Ohio; London, United Kingdom; and St Louis, Missouri

Automated border-detection techniques such as acoustic quantification have proven accurate and useful for quantifying left ventricular (LV) function. We acquired LV acoustic quantification waveforms from the parasternal short-axis window in 140 healthy patients in the age range of 16 to 78 years. Signal-averaged waveforms were analyzed for parameters of systolic and diastolic performance. The average fractional area change was 54 ⴞ 12%, and there were no significant changes in LV systolic function in the age range studied. There were signif-

Assessment of left ventricular (LV) systolic and

diastolic performance composes 2 of the most common reasons for echocardiography. Despite the availability of several quantitative techniques, assessment of ventricular performance in most clinical echocardiographic laboratories is qualitative or, at best, semiquantitative. Automated border-detection techniques such as acoustic quantification (AQ) have proven accurate and useful for quantifying LV function.1-10 However, the routine use of AQ from an apical 4-chamber view to determine LV ejection fraction has limitations. These limitations include lateral attenuation of endocardial backscatter signals and difficulty separating LV from left atrial cavities throughout the cardiac cycle. Although relatively simple to master, performing AQ from the apical

From the University of Chicago, Chicago, Illinois; University of Pittsburgh, Pittsburgh, Pennsylvania (J.G., K.E.); Children’s Hospital, Cincinnati, Ohio (T.R.K., B.G.); King’s College Hospital, London, United Kingdom (M.J.M., J.H.); and Washington University, St Louis, Missouri (J.E.P., C.B.). Reprint requests: Kirk T. Spencer, MD, Section of Cardiology, University of Chicago, Medical Center, 584l S Maryland Ave, MC5084, Chicago, IL 60637 (E-mail: kspencer@medicine. bsd.uchicago.edu). Copyright 2003 by the American Society of Echocardiography. 0894-7317/2003/$30.00 ⫹ 0 doi:10.1067/j.echo.2003.09.002

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icant changes in diastolic parameters with aging. The percentage of contribution to total LV filling occurring during atrial filling nearly tripled during the 6 decades studied, from 13% in the youngest cohort to 36% in the eighth decade of life. This study provides normal reference values for systolic and diastolic parameters of LV function determined from signal-averaged acoustic quantification waveforms acquired from the parasternal short-axis view in adult and adolescent patients over a wide age range. (J Am Soc Echocardiogr 2003;16:1244-51.)

views requires attention to several technical considerations.11 We have noted that AQ of the LV from the parasternal window can often be acquired more quickly than from the apical 4- or 2-chamber views. The short-axis LV area waveforms are more stable and reproducible compared with LV volume waveforms derived from the apical views. Moreover, adequate short-axis views can be obtained in the vast majority of patients from the parasternal window independent of body habitus. Imaging from this view also eliminates several of the technical considerations, making it potentially easier for inexperienced users. However, when evaluating LV systolic function, clinicians are accustomed to interpreting LV ejection fraction, not fractional area change. Part of the shortcoming to using area waveforms is that normal values of LV area data have never been established in a large group of patients over a wide age range. Likewise, although AQ has shown potential for evaluating LV diastolic performance, its use has been partially limited by the lack of established normal values of diastolic AQ area parameters. We, therefore, sought to establish normal values of LV systolic and diastolic function calculated from LV area waveforms acquired from the parasternal short-axis window in adult and adolescent patients.

Journal of the American Society of Echocardiography Volume 16 Number 12

Figure 1 Individual data points for left ventricular shortaxis area measurements. Age is in years.

Spencer et al 1245

Figure 2 Individual data points for left ventricular systolic function parameters. Age is in years. EDA, End-diastolic area.

METHODS In all, 140 patients (64 male and 76 female, age 16-78 years) were enrolled at 6 participating centers. Control subjects and patients referred for echocardiography who met the following criteria were included: no clinical history of cardiovascular disease; normal sinus rhythm; absence of left bundle branch block; normal blood pressure; absence of wallmotion abnormality on 2-dimensional echocardiographic screening; no more than trivial aortic insufficiency or mild mitral, tricuspid, or pulmonic regurgitation; normal LV mass; and ejection fraction ⬎50% calculated from manual tracings of end-systolic and end-diastolic frames using the method of disks in the apical 4-chamber view. Using a commercially available system (Sonos 5500, Philips Medical, Andover, Mass), images were obtained from the parasternal short-axis window at the midpapil-

lary level. The automated border-detection system was activated and optimized as previously described by adjusting the overall gain and time gain compensation.11 Lateral gain was used to minimize dropout tangential to the ultrasound beam. An area of interest was drawn around the LV cavity taking care to exclude the right ventricular cavity. The LV area waveform was displayed and visual confirmation of a consistent, stable waveform was made. Between 30 and 45 seconds of LV area versus time data were acquired to magneto-optical disk during quiet respiration without breath holding. All LV area waveforms were analyzed offline using custom software. The continuous LV area waveform data were signal averaged to form a single composite waveform. From this signal-averaged waveform the first derivative of the LV area was computed. Software automatically

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1246 Spencer et al

Table 1 Normal values of left ventricular area grouped by decade Decade of life Area

2

3

4

5

6

7

8

Overall

N EDA (cm2) EEA (cm2) ERFA (cm2)

12 11 ⫾ 3 5.2 ⫾ 1.7 10 ⫾ 3

28 11 ⫾ 2 4.7 ⫾ 1.8 9.9 ⫾ 2.4

26 11 ⫾ 3 4.8 ⫾ 2.2 9.4 ⫾ 2.7

23 12 ⫾ 3 5.7 ⫾ 2.4 10 ⫾ 3

17 11 ⫾ 3 4.8 ⫾ 2.2 9.5 ⫾ 2.5

18 11 ⫾ 3 5.7 ⫾ 2.2 9.7 ⫾ 2.6

16 10 ⫾ 3 4.9 ⫾ 2.0 8.2 ⫾ 2.7

140 11 ⫾ 3 5.0 ⫾ 2.1 9.6 ⫾ 2.7

EDA, End-diastolic area; EEA, end-ejection area; ERFA, end-rapid filling area The second decade includes 16- to 19-year-old patients.

Table 2 Normal values of left ventricular systolic function grouped by decade Decade of life Systolic

2

3

4

5

6

7

8

Overall

FAC (%) PER (cm2/s) PER/EDA

52 ⫾ 9 30 ⫾ 13 2.8 ⫾ 0.6

57 ⫾ 10 33 ⫾ 9 3.1 ⫾ 0.7

55 ⫾ 10 30 ⫾ 9 2.9 ⫾ 0.6

53 ⫾ 15 33 ⫾ 10 2.8 ⫾ 0.9

57 ⫾ 13 30 ⫾ 8 2.8 ⫾ 0.7

51 ⫾ 14 30 ⫾ 10 2.6 ⫾ 0.7

53 ⫾ 12 30 ⫾ 9 2.9 ⫾ 0.5

54 ⫾ 12 31 ⫾ 10 2.9 ⫾ 0.7

EDA, End-diastolic area; FAC, fractional area change; PER, peak ejection rate. The second decade includes 16- to 19-year-old patients.

identified the different phases of the cardiac cycle using morphologic criteria of the area and derivative curves. The end-diastolic, end-ejection, and end-passive filling areas were then determined. Parameters of LV systolic performance included fractional area change calculated as: (end-diastolic area ⫺ end-ejection area)/end-diastolic area. Peak ejection rate was determined as the maximum value of the LV area derivative waveform during ejection. This index was normalized by dividing its value by the LV end-diastolic area. Diastolic parameters included the passive filling percentage, which was computed as the total amount of ventricular filling that occurred during passive filling, and the atrial filling fraction, which was calculated as the percentage of total cardiac LV filling that occurred during atrial contraction. Additional parameters included the peak passive filling rate and the peak atrial filling rate derived from the LV area first derivative curve, and the ratio of these slopes. The values of the slopes were normalized by dividing by the LV end-diastolic area. The first third fractional filling was computed as the proportion of total ventricular filling occurring within the first third of diastole. Variables were expressed as mean ⫾ SD and grouped by decade for tabulation. Regression analysis against age was performed for each variable in all patients and correlation coefficients determined. A P value of less than .05 was considered statistically significant.

RESULTS In all, 148 patients were studied and data were adequate to analyze in 140 (95%) of them. The LV short-axis area data for all patients are presented in Figure 1 and average values by decade are shown in

Table 1. LV size remained stable from the latter portion of the second through the eighth decade of life with no statistically significant association with age. The average values for parameters of systolic LV performance are detailed in Table 2. The average fractional area change was 54 ⫾ 12%. Values for fractional area change and peak ejection rate remained stable during the age range studied (Figure 2). The average values by decade for diastolic parameters derived from the short-axis LV AQ area waveform are shown in Table 3. On average for the entire group, the peak passive LV filling rate was more rapid than the peak atrial filling rate by a factor of 2.5 to 1. For the entire population, 77% of the LV short-axis expansion occurred during early diastolic filling and 21% during atrial contraction. When evaluated as continuous variables over age, several moderate correlations appeared (Table 4). The peak atrial filling rate increased with age, which, together with a reduction in the peak passive filling rate, led to a significant reduction in the ratio of peak passive to peak atrial filling over time (Figure 3). In the youngest patients, this ratio was as high as 3.8 to 1 whereas, by the eighth decade of life, the rates of passive and atrial filling equalized resulting in an average ratio of 1.0 ⫾ 0.5. Likewise, there is a moderate correlation for the percent of passive filling that declines with age, and a corresponding increase in the atrial filling percentage with aging (Figure 4). Composite LV AQ curves were generated by averaging the area- and time-normalized curves from all patients within each decade (Figure 5). These composite waveforms reveal the age-related changes that occur in all LV parameters. The increasing

Journal of the American Society of Echocardiography Volume 16 Number 12

Figure 3 Individual data points with regression lines for left ventricular diastolic filling rates. Age is in years. EDA, End-diastolic area.

contribution of atrial contraction to LV filling and increase in atrial filling rate that occur with advancing age are easily apparent. The preservation of the systolic portion of the waveforms is also demonstrated. The values of AQ parameters for male and female patients are shown in Table 5. The LV sizes at all phases of the cardiac cycle were larger for male patients. When indexed for body surface area, these differences were eliminated. The only systolic parameter that differed was the peak ejection rate, which was larger in male patients. However, when adjusted for the larger end-diastolic areas of men and adolescent boys, this difference was no longer significant. Likewise, after adjusting for end-diastolic area, there were no significant differences in parameters of LV diastolic function between the sexes.

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Figure 4 Individual data points with regression lines for left ventricular diastolic function parameters. Age is in years. F1/3FF, First third fractional filling.

DISCUSSION AQ has been used during the last decade for the evaluation of LV systolic and diastolic performance.1-10 AQ has typically been acquired from the apical 4-chamber view in volume mode to calculate LV ejection fraction, a parameter with which physicians have great familiarity. However, routine clinical use of this technique from the apical views has been limited by a number of factors. Additional time is required to set up, optimize, and acquire LV AQ volume waveforms from the apical acoustic window. In addition, there are several technical considerations that can affect the quantitative data if not carefully addressed.11 These technical consider-

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Table 3 Normal values of left ventricular diastolic function grouped by decade Decade of life Diastolic 2

PRFR (cm /s) PRFR/EDA PAFR (cm2/s) PAFR/EDA PRFR/PAFR F1/3FF (%) RF (%) AF (%)

2

3

4

5

6

7

8

Overall

42 ⫾ 16 3.8 ⫾ 1.0 13 ⫾ 6 1.2 ⫾ 0.7 3.8 ⫾ 2.1 74 ⫾ 13 86 ⫾ 7 12 ⫾ 7

45 ⫾ 13 4.3 ⫾ 1.1 15 ⫾ 7 1.4 ⫾ 0.7 3.5 ⫾ 1.9 72 ⫾ 11 85 ⫾ 7 13 ⫾ 7

38 ⫾ 11 3.7 ⫾ 1.1 18 ⫾ 9 1.7 ⫾ 0.7 2.5 ⫾ 1.3 68 ⫾ 11 80 ⫾ 7 19 ⫾ 7

43 ⫾ 18 3.6 ⫾ 1.1 21 ⫾ 8 1.8 ⫾ 0.7 2.4 ⫾ 1.4 68 ⫾ 14 77 ⫾ 9 22 ⫾ 9

44 ⫾ 15 4.2 ⫾ 1.4 21 ⫾ 9 2.0 ⫾ 0.9 2.2 ⫾ 0.9 66 ⫾ 11 75 ⫾ 7 23 ⫾ 7

34 ⫾ 13 3.1 ⫾ 1.1 22 ⫾ 10 2.0 ⫾ 1.1 1.8 ⫾ 1.0 60 ⫾ 12 72 ⫾ 11 27 ⫾ 10

27 ⫾ 10 2.9 ⫾ 1.3 29 ⫾ 12 3.1 ⫾ 1.4 1.0 ⫾ 0.5 48 ⫾ 17 63 ⫾ 9 36 ⫾ 10

40 ⫾ 15 3.7 ⫾ 1.2 19 ⫾ 10 1.8 ⫾ 1.0 2.5 ⫾ 1.6 66 ⫾ 14 77 ⫾ 11 21 ⫾ 11

AF, Atrial filling; EDA, end-diastolic area; F1/3FF, first third fractional filling; PAFR, peak atrial filling rate; PRFR, peak rapid filling rate; RF, rapid filling. The second decade includes 16- to 19-year-old patients.

Table 4 Correlation coefficients for all acoustic quantification parameters regressed against age All subjects Variable

R

P

EDA (cm2) EEA (cm2) ERFA (cm2) FAC (%) PER (cm2/s) PER/EDA PRFR (cm2/s) PRFR/EDA PAFR (cm2/s) PAFR/EDA PRFR/PAFR F1/3FF (%) RF (%) AF (%)

– – – – – – ⫺0.28 ⫺0.30 0.44 0.44 ⫺0.49 ⫺0.48 ⫺0.64 0.64

NS NS NS NS NS NS ⬍.001 ⬍.001 ⬍.001 ⬍.001 ⬍.001 ⬍.001 ⬍.001 ⬍.001

AF, Atrial filling; EDA, end-diastolic area; EEA, end-ejection area; ERFA, end-rapid filling area; F1/3FF, first third fractional filling; FAC, fractional area change; NS, not significant; PAFR, peak atrial filling rate; PER, peak ejection rate; PRFR, peak rapid filling rate; RF, rapid filling.

ations include foreshortening of the LV cavity and contamination of the LV volume waveform from the right ventricular or left atrial cavities. Lastly, adequate visualization of the entire endocardium is required to insure accurate automated tracking of the borders, which can be problematic in the apex and the lateral segments. AQ from the parasternal short-axis view is easier to optimize for adequate automated border tracking for many reasons. Image quality is generally better from this window, resulting in improved endocardial definition and, consequently, enhanced automated border tracking. In addition, there are fewer technical considerations than from the apical views, making LV short-axis AQ not only quicker to perform but also more reliable. Previous publications have demonstrated that the interobserver variability AQ data is lower for the short-axis than the apical 4-chamber view.5,12 However, broad clinical implementation of short-axis AQ requires having a data set

Figure 5 Composite left ventricular (LV) area waveforms by decade. These curves are time- and area-normalized to demonstrate morphologic rather than quantitative differences. Arrow, Differences in atrial filling component between decades of life; y axis, 0% to 100% of total LV area; x axis, 0% to 100% of cardiac cycle duration.

of normal values. Although established for children,13,14 this data set is not available for adults. Normal Values for AQ Assessment of Systolic Function Part of the limitation in using short-axis AQ is the unfamiliarity with fractional area change as a measure of LV performance. Several prior studies have shown that fractional area change correlates well with radionuclide-7,8 and angiographic-determined15 ejection fraction. LV short-axis AQ has also been validated in animal and human studies.16,17 Similar to all parameters that assess LV performance in a single tomographic plane, fractional area change is most accurate if ventricular performance in the imaging plane is representative of overall ventricular performance. This technique may prove less useful for patients with regional wall-motion abnormalities or abnormal septal motion. The average value of 54% for fractional area change of the LV in the parasternal short-axis view

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Table 5 Normal values for female and male patients Variable

Female

Male

P

N Age (y) EDA (cm2) EEA (cm2) ERFA (cm2) EDA/BSA EEA/BSA ERFA/BSA FAC (%) PER (cm2/s) PER/EDA PRFR (cm2/s) PRFR/EDA PAFR (cm2/s) PAFR/EDA PRFR/PAFR F1/3FF (%) RF (%) AF (%)

76 45 ⫾ 18 10 ⫾ 2 4.7 ⫾ 1.8 9.0 ⫾ 2.8 6.1 ⫾ 1.4 2.8 ⫾ 1.1 5.4 ⫾ 1.3 55 ⫾ 11 29 ⫾ 8 2.8 ⫾ 0.7 36 ⫾ 11 3.6 ⫾ 1.1 19 ⫾ 9 1.9 ⫾ 0.9 2.5 ⫾ 1.6 64 ⫾ 15 78 ⫾ 11 21 ⫾ 11

64 40 ⫾ 17 12 ⫾ 3 5.5 ⫾ 2.3 10 ⫾ 3 6.0 ⫾ 1.6 2.8 ⫾ 1.2 5.3 ⫾ 1.5 54 ⫾ 12 34 ⫾ 10 2.9 ⫾ 0.7 43 ⫾ 17 3.8 ⫾ 1.4 20 ⫾ 10 1.8 ⫾ 1.0 2.6 ⫾ 1.5 68 ⫾ 13 77 ⫾ 10 21 ⫾ 10

NS .001 .023 .002 NS NS NS NS .002 NS .002 NS NS NS NS NS NS NS

AF, Atrial filling; BSA, body surface area; EDA, end-diastolic area; EEA, end-ejection area; ERFA, end-rapid filling area; F1/3FF, first third fractional filling; FAC, fractional area change; NS, not significant; PAFR, peak atrial filling rate; PER, peak ejection rate; PRFR, peak rapid filling rate; RF, rapid filling.

in this article is similar to that previously reported in a group of 60 patients of 55.6%.6 In that study, the peak ejection rate was reported as 44 cm2/s, which is higher than that recorded in our study of 31 cm2/s. This likely reflects the fact that the prior study used AQ derivative curves derived from single cardiac cycles as opposed to the signal-averaged waveforms we used in this study. We have previously shown that there is significant noise in AQ waveforms. This noise is accentuated in the derivative curves leading to significant overestimations.18 Chandra et al19 demonstrated a reduction in peak ejection rate values after filtering the 2-dimensional AQ data to remove noise. When the systolic parameters were evaluated over a wide range of ages, no significant change in fractional area change or peak ejection rate was noted. Although changes in systolic parameters have been noted in childhood, prior echocardiographic studies measuring ejection phase indices of LV performance in adult patients have either shown no change20-24 or a small increase25,26 in fractional shortening with age. One of the largest echocardiographic studies involving 464 clinically healthy adults revealed a slight increase in fractional shortening with age, but the relationship was quite weak, with an R value of 0.11.27 LV ejection fraction at rest, determined by radionuclide methods, has also been shown to be unchanged with aging in adults.28-31

Normal Values for AQ Assessment of Diastolic Function Assessment of LV diastolic function from AQ waveforms has not been commonly used in clinical practice. Most prior studies have used offline analysis of AQ waveforms from single cardiac cycles that are often distorted by noise. Improved AQ waveforms have become available using signal averaging.32 The acquisition of data from the short-axis rather than from the apical view further enhances waveform reliability. The combined use of signal averaging and short-axis acquisition results in sufficient morphologic detail of the diastolic waveform to allow automated and rapid quantification. Analysis of the diastolic portion of the LV shortaxis AQ waveforms demonstrated that on average in adult and adolescent patients, 77% of LV filling occurs during passive filling and 21% occurs during atrial contraction. These values are similar to 2 prior studies that used AQ in smaller groups of 19 and 21 patients, in which it was reported that 78% and 74% of short-axis expansion occurred during passive filling, respectively.5,33 A third study reported an average passive filling fraction of 57%.4 This lower value can be partially explained by the older population studied (mean age 52 years compared with 44 years in the current study). Peak rates of passive and atrial filling in this study of 40 and 19 cm2/s, respectively, are lower than those reported in several prior AQ studies in which small groups of healthy patients (19-42 patients) were evaluated.2,4,33 This undoubtedly represents the fact that these prior studies did not use signalaveraged AQ waveforms. The derivative waveforms computed from individual (nonaveraged) area curves show significant noise and variability, which could lead to erroneous estimates of ventricular filling rates. We believe that the lower values in the current study are more representative of true values, because they were obtained in a large cohort using signal-averaged, less noisy waveforms. This conclusion is supported by the fact that prior comparisons of AQ peak filling rates, determined from individual beats with radionuclide data, have shown AQ overestimation.5 The ratio of peak passive to peak atrial filling in this study was 2.5, which is higher than previously reported values. A study of 42 patients with a similar mean age reported a ratio of 2.0. Another study reported a ratio of 1.8, however, the older age (52 years) in that study may account for some of the difference. The higher peak passive to atrial filling rate ratio in this study likely represents the use of low-noise, signal-averaged AQ waveforms. As the peak atrial filling rate typically is smaller, the signalto-noise ratio for this measurement is higher, leading to greater overestimation of this parameter.

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When diastolic parameters were evaluated over the age range of 16 to 78 years, most of the indexes had a statistically significant correlation with age. The strongest correlations were noted for increasing peak atrial filling rate and atrial filling fraction with increasing age. The percentage of contribution to total LV filling occurring during atrial filling nearly tripled during the 6 decades studied, from 13% in the youngest cohort to 36% in the eighth decade of life. Strong negative correlations with age were observed for the first third fractional filling and passive filling fraction. As both the peak passive filling rate and peak atrial filling rate varied with age but in opposite directions, the ratio of these 2 variables accentuated the age-related change in ventricular diastolic performance. The peak passive to peak atrial filling ratio varied in a linear fashion from 3.8 to 1.0 during a 60-year age range. These agerelated changes in diastolic performance have been well documented in multiple prior studies using Doppler echocardiography, radionuclide angiography, and magnetic resonance imaging.34-39

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8.

9.

10.

11.

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13.

Conclusion This study provides normal reference values for systolic and diastolic parameters of LV function determined from signal-averaged AQ waveforms acquired from the parasternal short-axis view in adult and adolescent patients over a wide age range. Establishing these normal values should allow this technique to be more widely used in the clinical setting.

14. 15.

16.

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