- Email: [email protected]
Potential relationships among myocardial stiffness, the measured level of myocardial backscatter (“image brightness”), and the magnitude of the systematic variation of backscatter (cyclic variation) over the heart cycle
Potential Relationships Among Myocardial Stiffness, the Measured Level of Myocardial Backscatter (“Image Brightness”), and the Magnitude of the Systematic Variation of Backscatter (Cyclic Variation) Over the Heart Cycle Mark R. Holland, PhD, Kirk D. Wallace, PhD, and James G. Miller, PhD, St Louis, Missouri
Background: In a number of recently published studies comparing measurements from patients with those from control subjects, a decreased magnitude of the systematic variation of backscattered energy over the heart cycle (cyclic variation) is accompanied by an increased level of overall myocardial backscatter (calibrated myocardial image brightness) when measured at a specific phase of the heart cycle (eg, end systole or end diastole). The goal of this study was to investigate whether this observation is consistent with predictions based on a model of the mechanisms of cyclic variation incorporating changes in relative intracellular and extracellular acoustic impedance over the heart cycle. Methods: A previously described 3-component Maxwell-type model of muscle mechanics representing cardiac cell mechanical behavior was utilized to predict the systematic variation in the relative acoustic impedance differences between intracellular and extracellular elastic properties over the heart cycle and hence the observed magnitude of cyclic variation and overall myocardial scattering level. Predictions were obtained for a series of specific values of relative intracellular and extracellular acoustic impedance.
Perhaps one of the most successful approaches to
clinical ultrasonic tissue characterization has been the measurement of the systematic variation of backscattered energy from the myocardium over the heart cycle (ie, cyclic variation of backscatter). This measurement was first reported by Madaras et al1 in
From Washington University. Supported in part by National Institutes of Health R37 HL40302. Reprint requests: Mark R. Holland, PhD, Department of Physics, Campus Box 1105, Washington University, One Brookings Dr, St Louis, MO 63130 (E-mail: [email protected]). 0894-7317/$30.00 Copyright 2004 by the American Society of Echocardiography. doi:10.1016/j.echo.2004.06.004
Results: Results indicate that the predicted magnitude of cyclic variation can be directly related to the overall myocardial backscatter level. For example, specific changes in the acoustic impedance (stiffness properties) of the extracellular matrix without any change in the intracellular acoustic impedance result in predicted values of ⴚ43.5 dB, ⴚ38.5 dB, and ⴚ33.5 dB for end-diastolic myocardial backscatter levels with corresponding values of 5.0 dB, 2.5 dB, and 1.3 dB for the predicted magnitude of cyclic variation, respectively. Conclusion: This study suggests that observed decreases in the magnitude of cyclic variation with concomitant increases in the measured overall myocardial backscatter level are consistent with predictions from a model based on the relative acoustic impedance differences between intracellular and extracellular elastic properties over the heart cycle. These results suggest that ultrasonic backscatter measurements may provide a noninvasive approach for assessing some relationships among myocardial stiffness, degree of fibrosis, and contractile performance. (J Am Soc Echocardiogr 2004;17:1131-7.)
1983 and has been successfully applied to characterize a wide spectrum of specific cardiac pathologies. Comprehensive reviews citing specific studies that demonstrate how this approach has been applied to characterize ischemia and infarction; dilated cardiomyopathy; hearts of patients with diabetes; and hypertension and hypertrophy, among other pathologies, can be found in the published literature.2-4 In addition to reporting measurements of the cyclic variation of backscatter, some published studies also report the myocardial backscatter level relative to a reference at a specific time during the heart cycle (eg, end diastole) as an estimate of the overall backscattering level (“brightness”) of the
1131
1132 Holland, Wallace, Miller
Figure 1 Conceptual drawing of 3-component Maxwelltype model of muscle mechanics representing cardiac cell mechanical behavior utilized to predict systematic variation in relative acoustic impedance differences between intracellular and extracellular elastic properties over heart cycle.17,18
myocardium. For example, in several recently published studies comparing measurements from patients with those from control subjects, both the magnitude of the cyclic variation of backscatter and estimates of the overall backscatter level are reported.5-16 In several of these studies, the magnitude of cyclic variation was decreased and the apparent level of overall myocardial backscatter (ie, calibrated myocardial image brightness at a specific phase of the heart cycle) was increased when measurements of patients were compared with those from the control subjects.5,6,9,11-16 The goal of this study was to investigate whether the observed relationships between the level of myocardial backscatter and the magnitude of cyclic variation are consistent with predictions based on a model of the mechanisms of cyclic variation incorporating changes in relative intracellular and extracellular acoustic impedance over the heart cycle. Our approach was to employ a previously described 3-component Maxwell-type model of myocardial mechanics17,18 to predict the systematic variation in the relative acoustic impedance differences between intracellular and extracellular elastic properties over the heart cycle and hence the observed magnitude of cyclic variation and overall myocardial scattering level. Relationship Between the Measured Ultrasonic Backscatter and Intrinsic Myocardial Properties During the Heart Cycle The specific mechanisms responsible for the observed systematic variation of backscattered energy over the heart cycle remain unspecified. Both the intrinsic material properties (eg, elasticity, density) as well as geometrical properties of scatterers within the myocardium can affect the measured level of
Journal of the American Society of Echocardiography November 2004
backscattered ultrasonic energy. These contributions have been incorporated into specific models proposed to explain the observed ultrasonic backscatter.19,20 In models originally proposed by our laboratory, the relationship between myocardial intracellular and extracellular properties, and ultrasonic backscatter, is explicitly addressed.17,18,20 In these models, it is hypothesized that the observed level of myocardial backscatter is related, in part, to the relative acoustic impedance difference between the intracellular (myocyte) and extracellular components of myocardium. The larger the relative acoustic impedance difference between the intracellular and extracellular components, the greater the level of backscatter. In a model first proposed by Wickline et al,17,18 contributions to the observed cyclic variation of backscattered energy are attributed, in part, to a systematic variation in the relative acoustic impedance differences between intracellular and extracellular elastic properties. Because differences in acoustic impedance are determined partly by differences in elastic moduli, changes in local elastic moduli resulting from the non-Hookian (ie, a nonlinear stress–strain relationship) behavior of myocardial elastic properties may alter the degree of local acoustic impedance mismatch over the heart cycle resulting in corresponding changes in backscatter. Figure 1 depicts the 3-component Maxwell-type model of muscle mechanics used. In this model, the intracellular contractile element shortens during systole and stretches the intracellular series– elastic element. This series– elastic element exhibits a nonHookian elastic behavior with elongation (ie, the elastic modulus [Ese] increases with elongation) leading to an increased intracellular stiffness and, hence, increased acoustic impedance during contraction. Thus, the intracellular impedance becomes closer in value to the relatively larger impedance of the stiffer extracellular impedance during systole. This results in a reduction in the acoustic impedance mismatch during systole and hence a reduced degree of backscatter. The relative changes in the intracellular and extracellular impedance over the heart cycle, and thus the level backscatter, are illustrated graphically in Figure 2, in which ⌬ZD represents the impedance difference at end diastole and ⌬ZS represents the impedance difference at end systole. Clinical Measurements of Myocardial Backscatter and the Characterization of Cyclic Variation Measurements of the cyclic variation of backscattered energy from specific myocardial regions are typically obtained by placing a region-of-interest in the midmyocardium of 2-dimensional or M-mode integrated backscatter images and adjusting its posi-
Journal of the American Society of Echocardiography Volume 17 Number 11
tion over the heart cycle so that approximately the same region of myocardium is investigated. The average backscatter value within the region-of-interest as a function of time is determined, yielding a plot of the mean ultrasonic backscatter over the heart cycle. A representative result of this data plot is illustrated in Figure 3 for two heart cycles. The cyclic variation of backscatter data can be characterized in terms of its magnitude and its normalized time delay relative to the length of the systolic interval.21-24 Estimates of the “absolute” level of backscattered energy from the myocardium at a specific time during the heart cycle (eg, at end diastole) must be obtained relative to a reference in which the backscatter (or reflection) properties are well characterized.25,26 Absolute myocardial backscatter measurements are readily obtained for excised myocardial specimens in a water bath where a well-characterized reference medium can be employed (eg, a polished stainless-steel plate or a well-characterized tissue mimicking phantom) but pose a much greater challenge in the clinical setting with human subjects. For clinical measurements, researchers have sometimes used the backscatter from blood in the left ventricular chamber27,28 or the bright pericardial echoes29 to serve as the reference. Ideally it would be preferable to characterize the backscatter from the myocardium in terms of its intrinsic backscatter properties (ie, the backscatter coefficient) but this would require detailed compensation of the measured backscattered signals for the effects of attenuation and diffraction (beam volume) not readily obtainable in the clinical setting.25,26,30
Holland, Wallace, Miller 1133
Figure 2 Graphical illustration showing relative changes in intracellular and extracellular impedance over heart cycle and thus level backscatter. ⌬ZD, Impedance difference at end diastole; ⌬ZS, impedance difference at end systole.
Figure 3 Illustration depicting cyclic variation of backscattered energy over two heart cycles.
METHODS A computer simulation utilizing the 3-component Maxwell-type model was implemented to describe the systematic variation in the relative acoustic impedance differences between intracellular and extracellular elastic properties over the heart cycle and, hence, predict both the observed magnitude of cyclic variation and overall myocardial scattering level. Predictions were obtained for a series of specific values of relative intracellular and extracellular acoustic impedance. In this implementation, the predicted backscatter from the myocardium at a specific time during the heart cycle was obtained as follows. Standard treatments are well known (eg, Morse and Ingard31) for scattering from an object small compared with the wavelength of the interrogating ultrasonic field and differing by only modest amounts in mechanical properties (compressibility and density) from the surrounding medium. Under these conditions the scattered ultrasonic field can be expressed as the sum of two terms, a term in the difference in compressibility (a monopole term that is
independent of angle) and term in the difference in density (a dipole term with a characteristic angular dependence). Both of these terms contribute to the scattering observed at 180 degrees (ie, backscatter). An approximate but highly accurate transformation can be carried out17 that shows that the scattered field can alternatively be written as the sum of a term related to the difference in characteristic impedance with a backward facing cardioid shape and a term in the difference in velocity with a forward facing cardioid shape. For scattering at 180 degrees (backscatter), the forward facing cardioid term is zero and hence the only contribution is from the impedance difference. For the case of backscatter, the backscattered power therefore takes on the relatively simple form expressed in equation 1: Backscatter ⬀
共Z e ⫺ Z i兲 2 共Z e ⫹ Z i兲 2
(1)
where Ze represents the extracellular acoustic impedance and Zi represents the intracellular acoustic impedance.
Journal of the American Society of Echocardiography November 2004
1134 Holland, Wallace, Miller
ues of the extracellular acoustic impedance were always kept equal, ie, ZeD ⫽ ZeS.) The result was a series of predicted magnitudes of cyclic variation and corresponding backscattered levels (characterized in terms of the end-diastolic backscatter level) for each impedance set chosen.
RESULTS
Figure 4 A, Family of curves depicting predicted relationships between values of magnitude of cyclic variation and corresponding end-diastolic backscatter level. Each curve represents results obtained for specific choice of intracellular end-systolic and end-diastolic impedance over same range of extracellular impedance values. B, Graphic illustration showing representative cyclic variation plots corresponding to end-diastolic myocardial backscatter levels and magnitude of cyclic variation of points A, B, and C on middle curve of panel A. The relationship between acoustic impedance and the inherent elastic properties can be expressed as: Z ⫽ pc ⫽
冑 䡠 共elastic stiffness moduli兲,
(2)
where is the mass density and c is the velocity of sound. In implementing the computer simulation, we specified the diastolic and systolic acoustic impedance (elastic properties) for the extracellular and intracellular components of the model using values in the range of 1.5 ⫻ 105 rayls. We chose to produce a series of predictions where we kept the difference between systolic and diastolic intracellular acoustic impedance the same (ie, ZiD ⫺ ZiS ⫽ constant) while we systematically increased the extracellular acoustic impedance. (The systolic and diastolic val-
Results of the computer simulation indicate that the predicted magnitude of cyclic variation is directly related to the overall myocardial backscatter level. Figure 4,A, illustrates a family of curves depicting the predicted relationships between the values of the magnitude of cyclic variation and the corresponding end-diastolic backscatter level. Each curve represents the results obtained for a specific choice of intracellular end-systolic and end-diastolic impedance (ZiS, ZiD) over the same range of extracellular impedance values. In each case, the predicted magnitude of cyclic variation decreases as the predicted end-diastolic backscatter level increases. As an example, for the middle curve in Figure 4, A, specific changes in the acoustic impedance (elastic properties) of the extracellular matrix without any change in the difference between systolic and diastolic intracellular acoustic impedance result in predicted values of ⫺43.5 dB, ⫺38.5 dB, and ⫺33.5 dB for end-diastolic myocardial backscatter levels with corresponding values of 5.0 dB, 2.5 dB, and 1.3 dB for the predicted magnitude of cyclic variation, respectively. These specific values are labeled as points A, B, and C on the middle curve of Figure 4, A. Representative cyclic variation plots corresponding to the enddiastolic myocardial backscatter levels and magnitude of cyclic variation of points A, B, and C in Figure 4,A, are illustrated in Figure 4,B, which graphically illustrates the predicted reduction in the magnitude of cyclic variation as the enddiastolic myocardial backscatter level increases.
DISCUSSION The results of these computer simulations show that the predicted values of the magnitude of cyclic variation decrease as the predicted values of the end-diastolic backscatter level increase. This prediction is consistent with the clinical measurements reported in a number of recent studies.5,6,9,11-16 The behavior of our predicted results can be understood by considering the relative values of and changes in the intracellular and extracellular impedance. A choice of specific values for the extracellular and intracellular acoustic impedance over the heart cy-
Journal of the American Society of Echocardiography Volume 17 Number 11
cle will give rise to a predicted magnitude of cyclic variation power proportional to the square of the ratio of the diastolic to systolic impedance differences (⌬ZD/⌬ZS from Figure 2) and a predicted end-diastolic backscatter power value proportional to (⌬ZD2). If the extracellular acoustic impedance is increased but the intracellular acoustic impedance remains the same, the ratio of the impedance differences will decrease and the end-diastolic impedance difference will increase resulting in a decrease in the predicted magnitude of cyclic variation with an increase in the predicted end-diastolic backscatter level, respectively. The results of these specific simulations were obtained by keeping the difference between systolic and diastolic intracellular acoustic impedance the same while systematically increasing the extracellular acoustic impedance. However, this does not represent the only way to achieve the observed relationship between the overall level of myocardial backscatter and the magnitude of cyclic variation. One could, for example, generate a similar predicted relationship by keeping the extracellular acoustic impedance values constant while systematically decreasing the values of systolic and diastolic intracellular acoustic impedance. Our model cannot distinguish between these different scenarios; nonetheless, our results seem to suggest the overall level of myocardial backscatter and the magnitude of cyclic variation are intimately linked. Utilizing a 3-component Maxwell-type model of cardiac muscle mechanics to predict the nature of cyclic variation represents only one aspect of the potential contributions to the observed behavior of myocardial backscatter over the heart cycle. Other sources such as changes in scatterer (myocytes and other potential scattering sources) size and number density as well as geometric orientation over the heart cycle may also contribute significantly to the observed cyclic variation of backscattered energy. Glueck et al32 demonstrated that superfused stimulated frog gastrocnemius preparations manifested changes in backscatter from the relaxed to the tetanized state. Wear et al33 reported that isotonic but not isometric contractions induced altered backscatter in stimulated superfused papillary muscle preparations. The model proposed by Rose et al20 permits changes in geometry as a source of cyclic variation, since the backscatter coefficients depend on shape and orientation of the principal scattering unit, which can change across the heart cycle as myofibers contract (by shortening and thickening) and also alter their principal orientations. The effects of myocardial fiber orientation can be readily observed and quantified in echocardiographic images of human beings34 and may play a significant role in the observed echocardiographic view-dependence of cyclic variation measurements.21,35-38
Holland, Wallace, Miller 1135
Although there are several studies that report a decrease in the magnitude of cyclic variation with a concomitant increase in the measured level of overall myocardial backscatter when measurements of patients are compared with those from the control subjects5,6,9,11-16 there are other studies that do not appear to demonstrate this trend.7,8,10 In these studies, the magnitude of cyclic variation is reported to decrease with no significant difference in the measured level of overall myocardial backscatter. One potential explanation of these observations may be related to the difficulty in obtaining measurements of the absolute level of backscatter from the myocardium. As discussed above, measurements of the absolute level of backscatter require the identification and utilization of a well-characterized reference. This is often a significant challenge in the clinical setting. Measurements that exhibit no significant difference in the measured level of overall myocardial backscatter when measurements of patients are compared with those from control subjects may reflect the difficulty in obtaining measurements. Furthermore, there may be specific circumstances in which the magnitude of cyclic variation could be altered without an associated change in the overall end-diastolic backscatter level. This could occur, for example, where there is a change in regional contractile function such as that associated with the reported transmural heterogeneity of cyclic variation.39 In this case, transmural variations in contractile function could result in increased regional intracellular impedance during systole but leave the intracellular acoustic impedance during diastole unaffected. This might result in changes in the observed transmural magnitude of cyclic variation with no corresponding change in the observed end-diastolic backscatter level. Conclusion The results of this study suggest that observed decreases in the magnitude of cyclic variation with concomitant increases in the measured overall myocardial backscatter level are consistent with predictions from a model based on the relative acoustic impedance differences between intracellular and extracellular elastic properties over the heart cycle. Because specific cardiac pathologies can potentially alter the composition of intracellular and extracellular structural components, the results presented suggest that ultrasonic backscatter measurements may provide a noninvasive approach for assessing some relationships among stiffness properties, degree of fibrosis, and contractile performance. The authors gratefully acknowledge the seminal contributions of Lewis J. Thomas III, PhD, and Samuel A. Wickline, MD, in the development of the 3-component Maxwelltype model of muscle mechanics to predict the systematic
1136 Holland, Wallace, Miller
variation in the relative acoustic impedance differences over the heart cycle.
REFERENCES 1. Madaras EI, Barzilai B, Perez JE, Sobel BE, Miller JG. Changes in myocardial backscatter throughout the cardiac cycle. Ultrason Imaging 1983;5:229-39. 2. Perez JE, Holland MR, Barzailai B, Handley SM, Vandenberg BF, Miller JG, et al. Ultrasonic characterization of cardiovascular tissue. In: Skorton DJ, Seelbert HR, Wolf GL, Brundage BH, editors. Cardiac imaging–a companion to Braunwald’s heart disease. Vol 1. 2nd ed. Philadelphia: WB Saunders Co; 1996. p. 606-22. 3. Di Bello V, Pedrinelli R, Talini E, Giorgi D, Bertini A, Dell’Omo G, et al. Ultrasonic myocardial tissue characterization: a methodological review. Ital Heart J 2001;2:333-43. 4. Miller JG, Perez JE, Wickline SA, Baldwin SL, Barzilai B, Davila-Roman V, et al. Backscatter imaging and myocardial tissue characterization. Proc IEEE Ultrason Symp 1998; 98CH36102:1373-83. 5. Di Bello V, Giorgi D, Talini E, Dell’ Omo G, Palagi C, Romano MF, et al. Incremental value of ultrasonic tissue characterization (backscatter) in the evaluation of left ventricular myocardial structure and mechanics in essential arterial hypertension. Circulation 2003;107:74-80. 6. Yuda S, Short L, Leano R, Marwick TH. Myocardial abnormalities in hypertensive patients with normal and abnormal left ventricular filling: a study of ultrasound tissue characterization and strain. Clin Sci (Colch) 2002;103:283-93. 7. Maceira AM, Barba J, Beloqui O, Diez J. Ultrasonic backscatter and diastolic function in hypertensive patients. Hypertension 2002;40:239-43. 8. Maceira AM, Barba J, Varo N, Beloqui O, Diez J. Ultrasonic backscatter and serum marker of cardiac fibrosis in hypertensives. Hypertension 2002;39:923-8. 9. Di Bello V, Pedrinelli R, Bertini A, Giorgi D, Talini E, Dell’Omo G, et al. Cyclic variation of the myocardial integrated backscatter signal in hypertensive cardiopathy: a preliminary study. Coron Artery Dis 2001;12:267-75. 10. Di Bello V, Pedrinelli R, Giorgi D, Bertini A, Talini E, Dell’Omo G, et al. Ultrasonic myocardial textural parameters and midwall left ventricular mechanics in essential arterial hypertension. J Hum Hypertens 2000;14:9-16. 11. Di Bello V, Panichi V, Pedrinelli R, Giorgi D, Bianchi M, Bertini A, et al. Ultrasonic videodensitometric analysis of myocardium in end-stage renal disease treated with haemodialysis. Nephrol Dial Transplant 1999;14:2184-91. 12. Di Bello V, Pedrinelli R, Bianchi M, Giorgi D, Bertini A, Valenti G, et al. Ultrasonic myocardial texture in hypertensive mild-to-moderate left ventricular hypertrophy: a videodensitometric study. Am J Hypertens 1998;11:155-64. 13. Di Bello V, Pedrinelli R, Giorgi D, Bertini A, Talarico L, Caputo MT, et al. Ultrasonic videodensitometric analysis of two different models of left ventricular hypertrophy: athlete’s heart and hypertension. Hypertension 1997;29:937-44. 14. Zoni A, Regolisti G, Aschieri D, Borghetti A. Myocardial ultrasonic tissue characterization in patients with different types of left ventricular hypertrophy: a videodensitometric approach. J Am Soc Echocardiogr 1997;10:74-82. 15. Di Bello V, Giampietro O, Matteucci E, Talarico L, Giorgi D, Bertini A, et al. Ultrasonic videodensitometric analysis in type 1 diabetic myocardium. Coron Artery Dis 1996;7:895-901.
Journal of the American Society of Echocardiography November 2004
16. Pacileo G, Limongelli G, Verrengia M, Gimeno J, Di Salvo G, Calabro R. Backscatter evaluation of myocardial functional and textural findings in children with right ventricular pressure and/or volume overload. Am J Cardiol 2004;93:594-7. 17. Wickline SA, Thomas LJ III, Miller JG, Sobel BE, Perez JE. A relationship between ultrasonic integrated backscatter and myocardial contractile function. J Clin Invest 1985;76:215160. 18. Wickline SA, Thomas LJ III, Miller JG, Sobel BE, Perez JE. The dependence of myocardial ultrasonic integrated backscatter on contractile performance. Circulation 1985;72:183-92. 19. Kumar KN, Mottley JG. Quantitative modeling of the anisotropy of ultrasonic backscatter from canine myocardium. IEEE Trans Ultrason Ferroelect Freq Contr 1994;41:441-50. 20. Rose JH, Kaufmann MR, Wickline SA, Hall CS, Miller JG. A proposed microscopic elastic wave theory for ultrasonic backscatter from myocardial tissue. J Acoust Soc Am 1995;97: 656-68. 21. Finch-Johnston AE, Gussak HM, Mobley J, Holland MR, Petrovic O, Perez JE, et al. Cyclic variation of integrated backscatter: dependence of time delay on the echocardiographic view used and the myocardial segment analyzed. J Am Soc Echocardiogr 2000;13:9-17. 22. Finch-Johnston AE, Gussak HM, Mobley J, Holland MR, Petrovic O, Perez JE, et al. Dependence of “apparent” magnitude on the time delay of cyclic variation of myocardial backscatter. Ultrasound Med Biol 1999;25:759-62. 23. Mohr GA, Vered Z, Barzilai B, Perez JE, Sobel BE, Miller JG. Automated determination of the magnitude and time delay (“phase”) of the cardiac cycle dependent variation of myocardial ultrasonic integrated backscatter. Ultrason Imaging 1989;11:245-59. 24. Mobley J, Banta CE, Gussak HM, Perez JE, Miller JG. Clinical tissue characterization: online determination of magnitude and time delay myocardial backscatter. Video J Echocardiogr 1995;5:40-8. 25. O’Donnell M, Miller JG. Quantitative broadband ultrasonic backscatter: an approach to non-destructive evaluation in acoustically inhomogeneous materials. J Appl Physics 1981; 52:1056-65. 26. Miller JG, Perez JE, Mottley JG, Madaras EI, Johnston PH, Blodgett ED, et al. Myocardial tissue characterization: an approach based on quantitative backscatter and attenuation. Proc IEEE Ultrason Symp Atlanta 1983;83CH1947-1:78293. 27. Naito J, Masuyama T, Mano T, Yamamoto K, Doi Y, Kondo H, et al. Validation of transthoracic myocardial ultrasonic tissue characterization: comparison of transthoracic and openchest measurements of integrated backscatter. Ultrasound Med Biol 1995;21:33-40. 28. Naito J, Masuyama T, Mano T, Kondo H, Yamamoto K, Nagano R, et al. Ultrasonic myocardial tissue characterization in patients with dilated cardiomyopathy: value in noninvasive assessment of myocardial fibrosis. Am Heart J 1996;131:11521. 29. Di Bello V, Talarico L, Picano E, Di Muro C, Landini L, Paterni M, et al. Increased echodensity of myocardial wall in the diabetic heart: an ultrasound tissue characterization study. J Am Coll Cardiol 1995;25:1408-15. 30. Wear KA, Milunski MR, Wickline SA, Perez JE, Sobel BE, Miller JG. Differentiation between acutely ischemic myocardium and zones of completed infarction in dogs on the basis of
Journal of the American Society of Echocardiography Volume 17 Number 11
31. 32.
33.
34.
35.
frequency-dependent backscatter. J Acoust Soc Am 1989;85: 2634-41. Morse PM, Ingard KU. Theoretical acoustics. Princeton (NJ): Princeton University Press; 1968. Glueck RM, Mottley JG, Sobel BE, Miller JG, Perez JE. Changes in ultrasonic attenuation and backscatter of muscle with state of contraction. Ultrasound Med Biol 1985;11:60510. Wear KA, Shoup TA, Popp RL. Ultrasonic characterization of canine myocardium contraction. IEEE Trans Ultrason Ferroelect Freq Contr 1986;UFFC-33:347-53. Holland MR, Wilkenshoff UM, Finch-Johnston AE, Handley SM, Perez JE, Miller JG. Effects of myocardial fiber orientation in echocardiography: quantitative measurements and computer simulation of the regional dependence of backscattered ultrasound in the parasternal short-axis view. J Am Soc Echocardiogr 1998;11:929-37. Vandenberg BF, Stuhlmuller JE, Rath L, Kerber RE, Collins SM, Melton HE, et al. Diagnosis of recent myocardial infarc-
Holland, Wallace, Miller 1137
36.
37.
38.
39.
tion with quantitative backscatter imaging: preliminary studies. J Am Soc Echocardiogr 1991;4:10-8. Vandenberg BF, Rath L, Shoup TA, Kerber RE, Collins SM, Skorton DJ. Cyclic variation of ultrasound backscatter in normal myocardium is view dependent: clinical studies with a real-time backscatter imaging system. J Am Soc Echocardiogr 1989;2:308-14. Lange A, Moran CM, Palka P, Fenn LN, Sutherland GR, McDicken WN. The variation of integrated backscatter in human hearts in differing ultrasonic transthoracic views. J Am Soc Echocardiogr 1995;8:830-8. Bouki KP, Lange A, Palka P, Moran CM, Fenn LN, Wright RA, et al. Regional variations of ultrasonic integrated backscatter in normal and myopathic left ventricles–a new multiview approach. Eur Heart J 1996;17:1747-55. Bombardini T, Galli R, Paterni M, Pingitore A, Pierangeli A, Picano E. A videodensitometric study of transmural heterogeneity of cyclic echo amplitude variation in human myocardium. Am J Cardiol 1996;78:212-6.
Background: In a number of recently published studies comparing measurements from patients with those from control subjects, a decreased magnitude of the systematic variation of backscattered energy over the heart cycle (cyclic variation) is accompanied by an increased level of overall myocardial backscatter (calibrated myocardial image brightness) when measured at a specific phase of the heart cycle (eg, end systole or end diastole). The goal of this study was to investigate whether this observation is consistent with predictions based on a model of the mechanisms of cyclic variation incorporating changes in relative intracellular and extracellular acoustic impedance over the heart cycle. Methods: A previously described 3-component Maxwell-type model of muscle mechanics representing cardiac cell mechanical behavior was utilized to predict the systematic variation in the relative acoustic impedance differences between intracellular and extracellular elastic properties over the heart cycle and hence the observed magnitude of cyclic variation and overall myocardial scattering level. Predictions were obtained for a series of specific values of relative intracellular and extracellular acoustic impedance.
Perhaps one of the most successful approaches to
clinical ultrasonic tissue characterization has been the measurement of the systematic variation of backscattered energy from the myocardium over the heart cycle (ie, cyclic variation of backscatter). This measurement was first reported by Madaras et al1 in
From Washington University. Supported in part by National Institutes of Health R37 HL40302. Reprint requests: Mark R. Holland, PhD, Department of Physics, Campus Box 1105, Washington University, One Brookings Dr, St Louis, MO 63130 (E-mail: [email protected]). 0894-7317/$30.00 Copyright 2004 by the American Society of Echocardiography. doi:10.1016/j.echo.2004.06.004
Results: Results indicate that the predicted magnitude of cyclic variation can be directly related to the overall myocardial backscatter level. For example, specific changes in the acoustic impedance (stiffness properties) of the extracellular matrix without any change in the intracellular acoustic impedance result in predicted values of ⴚ43.5 dB, ⴚ38.5 dB, and ⴚ33.5 dB for end-diastolic myocardial backscatter levels with corresponding values of 5.0 dB, 2.5 dB, and 1.3 dB for the predicted magnitude of cyclic variation, respectively. Conclusion: This study suggests that observed decreases in the magnitude of cyclic variation with concomitant increases in the measured overall myocardial backscatter level are consistent with predictions from a model based on the relative acoustic impedance differences between intracellular and extracellular elastic properties over the heart cycle. These results suggest that ultrasonic backscatter measurements may provide a noninvasive approach for assessing some relationships among myocardial stiffness, degree of fibrosis, and contractile performance. (J Am Soc Echocardiogr 2004;17:1131-7.)
1983 and has been successfully applied to characterize a wide spectrum of specific cardiac pathologies. Comprehensive reviews citing specific studies that demonstrate how this approach has been applied to characterize ischemia and infarction; dilated cardiomyopathy; hearts of patients with diabetes; and hypertension and hypertrophy, among other pathologies, can be found in the published literature.2-4 In addition to reporting measurements of the cyclic variation of backscatter, some published studies also report the myocardial backscatter level relative to a reference at a specific time during the heart cycle (eg, end diastole) as an estimate of the overall backscattering level (“brightness”) of the
1131
1132 Holland, Wallace, Miller
Figure 1 Conceptual drawing of 3-component Maxwelltype model of muscle mechanics representing cardiac cell mechanical behavior utilized to predict systematic variation in relative acoustic impedance differences between intracellular and extracellular elastic properties over heart cycle.17,18
myocardium. For example, in several recently published studies comparing measurements from patients with those from control subjects, both the magnitude of the cyclic variation of backscatter and estimates of the overall backscatter level are reported.5-16 In several of these studies, the magnitude of cyclic variation was decreased and the apparent level of overall myocardial backscatter (ie, calibrated myocardial image brightness at a specific phase of the heart cycle) was increased when measurements of patients were compared with those from the control subjects.5,6,9,11-16 The goal of this study was to investigate whether the observed relationships between the level of myocardial backscatter and the magnitude of cyclic variation are consistent with predictions based on a model of the mechanisms of cyclic variation incorporating changes in relative intracellular and extracellular acoustic impedance over the heart cycle. Our approach was to employ a previously described 3-component Maxwell-type model of myocardial mechanics17,18 to predict the systematic variation in the relative acoustic impedance differences between intracellular and extracellular elastic properties over the heart cycle and hence the observed magnitude of cyclic variation and overall myocardial scattering level. Relationship Between the Measured Ultrasonic Backscatter and Intrinsic Myocardial Properties During the Heart Cycle The specific mechanisms responsible for the observed systematic variation of backscattered energy over the heart cycle remain unspecified. Both the intrinsic material properties (eg, elasticity, density) as well as geometrical properties of scatterers within the myocardium can affect the measured level of
Journal of the American Society of Echocardiography November 2004
backscattered ultrasonic energy. These contributions have been incorporated into specific models proposed to explain the observed ultrasonic backscatter.19,20 In models originally proposed by our laboratory, the relationship between myocardial intracellular and extracellular properties, and ultrasonic backscatter, is explicitly addressed.17,18,20 In these models, it is hypothesized that the observed level of myocardial backscatter is related, in part, to the relative acoustic impedance difference between the intracellular (myocyte) and extracellular components of myocardium. The larger the relative acoustic impedance difference between the intracellular and extracellular components, the greater the level of backscatter. In a model first proposed by Wickline et al,17,18 contributions to the observed cyclic variation of backscattered energy are attributed, in part, to a systematic variation in the relative acoustic impedance differences between intracellular and extracellular elastic properties. Because differences in acoustic impedance are determined partly by differences in elastic moduli, changes in local elastic moduli resulting from the non-Hookian (ie, a nonlinear stress–strain relationship) behavior of myocardial elastic properties may alter the degree of local acoustic impedance mismatch over the heart cycle resulting in corresponding changes in backscatter. Figure 1 depicts the 3-component Maxwell-type model of muscle mechanics used. In this model, the intracellular contractile element shortens during systole and stretches the intracellular series– elastic element. This series– elastic element exhibits a nonHookian elastic behavior with elongation (ie, the elastic modulus [Ese] increases with elongation) leading to an increased intracellular stiffness and, hence, increased acoustic impedance during contraction. Thus, the intracellular impedance becomes closer in value to the relatively larger impedance of the stiffer extracellular impedance during systole. This results in a reduction in the acoustic impedance mismatch during systole and hence a reduced degree of backscatter. The relative changes in the intracellular and extracellular impedance over the heart cycle, and thus the level backscatter, are illustrated graphically in Figure 2, in which ⌬ZD represents the impedance difference at end diastole and ⌬ZS represents the impedance difference at end systole. Clinical Measurements of Myocardial Backscatter and the Characterization of Cyclic Variation Measurements of the cyclic variation of backscattered energy from specific myocardial regions are typically obtained by placing a region-of-interest in the midmyocardium of 2-dimensional or M-mode integrated backscatter images and adjusting its posi-
Journal of the American Society of Echocardiography Volume 17 Number 11
tion over the heart cycle so that approximately the same region of myocardium is investigated. The average backscatter value within the region-of-interest as a function of time is determined, yielding a plot of the mean ultrasonic backscatter over the heart cycle. A representative result of this data plot is illustrated in Figure 3 for two heart cycles. The cyclic variation of backscatter data can be characterized in terms of its magnitude and its normalized time delay relative to the length of the systolic interval.21-24 Estimates of the “absolute” level of backscattered energy from the myocardium at a specific time during the heart cycle (eg, at end diastole) must be obtained relative to a reference in which the backscatter (or reflection) properties are well characterized.25,26 Absolute myocardial backscatter measurements are readily obtained for excised myocardial specimens in a water bath where a well-characterized reference medium can be employed (eg, a polished stainless-steel plate or a well-characterized tissue mimicking phantom) but pose a much greater challenge in the clinical setting with human subjects. For clinical measurements, researchers have sometimes used the backscatter from blood in the left ventricular chamber27,28 or the bright pericardial echoes29 to serve as the reference. Ideally it would be preferable to characterize the backscatter from the myocardium in terms of its intrinsic backscatter properties (ie, the backscatter coefficient) but this would require detailed compensation of the measured backscattered signals for the effects of attenuation and diffraction (beam volume) not readily obtainable in the clinical setting.25,26,30
Holland, Wallace, Miller 1133
Figure 2 Graphical illustration showing relative changes in intracellular and extracellular impedance over heart cycle and thus level backscatter. ⌬ZD, Impedance difference at end diastole; ⌬ZS, impedance difference at end systole.
Figure 3 Illustration depicting cyclic variation of backscattered energy over two heart cycles.
METHODS A computer simulation utilizing the 3-component Maxwell-type model was implemented to describe the systematic variation in the relative acoustic impedance differences between intracellular and extracellular elastic properties over the heart cycle and, hence, predict both the observed magnitude of cyclic variation and overall myocardial scattering level. Predictions were obtained for a series of specific values of relative intracellular and extracellular acoustic impedance. In this implementation, the predicted backscatter from the myocardium at a specific time during the heart cycle was obtained as follows. Standard treatments are well known (eg, Morse and Ingard31) for scattering from an object small compared with the wavelength of the interrogating ultrasonic field and differing by only modest amounts in mechanical properties (compressibility and density) from the surrounding medium. Under these conditions the scattered ultrasonic field can be expressed as the sum of two terms, a term in the difference in compressibility (a monopole term that is
independent of angle) and term in the difference in density (a dipole term with a characteristic angular dependence). Both of these terms contribute to the scattering observed at 180 degrees (ie, backscatter). An approximate but highly accurate transformation can be carried out17 that shows that the scattered field can alternatively be written as the sum of a term related to the difference in characteristic impedance with a backward facing cardioid shape and a term in the difference in velocity with a forward facing cardioid shape. For scattering at 180 degrees (backscatter), the forward facing cardioid term is zero and hence the only contribution is from the impedance difference. For the case of backscatter, the backscattered power therefore takes on the relatively simple form expressed in equation 1: Backscatter ⬀
共Z e ⫺ Z i兲 2 共Z e ⫹ Z i兲 2
(1)
where Ze represents the extracellular acoustic impedance and Zi represents the intracellular acoustic impedance.
Journal of the American Society of Echocardiography November 2004
1134 Holland, Wallace, Miller
ues of the extracellular acoustic impedance were always kept equal, ie, ZeD ⫽ ZeS.) The result was a series of predicted magnitudes of cyclic variation and corresponding backscattered levels (characterized in terms of the end-diastolic backscatter level) for each impedance set chosen.
RESULTS
Figure 4 A, Family of curves depicting predicted relationships between values of magnitude of cyclic variation and corresponding end-diastolic backscatter level. Each curve represents results obtained for specific choice of intracellular end-systolic and end-diastolic impedance over same range of extracellular impedance values. B, Graphic illustration showing representative cyclic variation plots corresponding to end-diastolic myocardial backscatter levels and magnitude of cyclic variation of points A, B, and C on middle curve of panel A. The relationship between acoustic impedance and the inherent elastic properties can be expressed as: Z ⫽ pc ⫽
冑 䡠 共elastic stiffness moduli兲,
(2)
where is the mass density and c is the velocity of sound. In implementing the computer simulation, we specified the diastolic and systolic acoustic impedance (elastic properties) for the extracellular and intracellular components of the model using values in the range of 1.5 ⫻ 105 rayls. We chose to produce a series of predictions where we kept the difference between systolic and diastolic intracellular acoustic impedance the same (ie, ZiD ⫺ ZiS ⫽ constant) while we systematically increased the extracellular acoustic impedance. (The systolic and diastolic val-
Results of the computer simulation indicate that the predicted magnitude of cyclic variation is directly related to the overall myocardial backscatter level. Figure 4,A, illustrates a family of curves depicting the predicted relationships between the values of the magnitude of cyclic variation and the corresponding end-diastolic backscatter level. Each curve represents the results obtained for a specific choice of intracellular end-systolic and end-diastolic impedance (ZiS, ZiD) over the same range of extracellular impedance values. In each case, the predicted magnitude of cyclic variation decreases as the predicted end-diastolic backscatter level increases. As an example, for the middle curve in Figure 4, A, specific changes in the acoustic impedance (elastic properties) of the extracellular matrix without any change in the difference between systolic and diastolic intracellular acoustic impedance result in predicted values of ⫺43.5 dB, ⫺38.5 dB, and ⫺33.5 dB for end-diastolic myocardial backscatter levels with corresponding values of 5.0 dB, 2.5 dB, and 1.3 dB for the predicted magnitude of cyclic variation, respectively. These specific values are labeled as points A, B, and C on the middle curve of Figure 4, A. Representative cyclic variation plots corresponding to the enddiastolic myocardial backscatter levels and magnitude of cyclic variation of points A, B, and C in Figure 4,A, are illustrated in Figure 4,B, which graphically illustrates the predicted reduction in the magnitude of cyclic variation as the enddiastolic myocardial backscatter level increases.
DISCUSSION The results of these computer simulations show that the predicted values of the magnitude of cyclic variation decrease as the predicted values of the end-diastolic backscatter level increase. This prediction is consistent with the clinical measurements reported in a number of recent studies.5,6,9,11-16 The behavior of our predicted results can be understood by considering the relative values of and changes in the intracellular and extracellular impedance. A choice of specific values for the extracellular and intracellular acoustic impedance over the heart cy-
Journal of the American Society of Echocardiography Volume 17 Number 11
cle will give rise to a predicted magnitude of cyclic variation power proportional to the square of the ratio of the diastolic to systolic impedance differences (⌬ZD/⌬ZS from Figure 2) and a predicted end-diastolic backscatter power value proportional to (⌬ZD2). If the extracellular acoustic impedance is increased but the intracellular acoustic impedance remains the same, the ratio of the impedance differences will decrease and the end-diastolic impedance difference will increase resulting in a decrease in the predicted magnitude of cyclic variation with an increase in the predicted end-diastolic backscatter level, respectively. The results of these specific simulations were obtained by keeping the difference between systolic and diastolic intracellular acoustic impedance the same while systematically increasing the extracellular acoustic impedance. However, this does not represent the only way to achieve the observed relationship between the overall level of myocardial backscatter and the magnitude of cyclic variation. One could, for example, generate a similar predicted relationship by keeping the extracellular acoustic impedance values constant while systematically decreasing the values of systolic and diastolic intracellular acoustic impedance. Our model cannot distinguish between these different scenarios; nonetheless, our results seem to suggest the overall level of myocardial backscatter and the magnitude of cyclic variation are intimately linked. Utilizing a 3-component Maxwell-type model of cardiac muscle mechanics to predict the nature of cyclic variation represents only one aspect of the potential contributions to the observed behavior of myocardial backscatter over the heart cycle. Other sources such as changes in scatterer (myocytes and other potential scattering sources) size and number density as well as geometric orientation over the heart cycle may also contribute significantly to the observed cyclic variation of backscattered energy. Glueck et al32 demonstrated that superfused stimulated frog gastrocnemius preparations manifested changes in backscatter from the relaxed to the tetanized state. Wear et al33 reported that isotonic but not isometric contractions induced altered backscatter in stimulated superfused papillary muscle preparations. The model proposed by Rose et al20 permits changes in geometry as a source of cyclic variation, since the backscatter coefficients depend on shape and orientation of the principal scattering unit, which can change across the heart cycle as myofibers contract (by shortening and thickening) and also alter their principal orientations. The effects of myocardial fiber orientation can be readily observed and quantified in echocardiographic images of human beings34 and may play a significant role in the observed echocardiographic view-dependence of cyclic variation measurements.21,35-38
Holland, Wallace, Miller 1135
Although there are several studies that report a decrease in the magnitude of cyclic variation with a concomitant increase in the measured level of overall myocardial backscatter when measurements of patients are compared with those from the control subjects5,6,9,11-16 there are other studies that do not appear to demonstrate this trend.7,8,10 In these studies, the magnitude of cyclic variation is reported to decrease with no significant difference in the measured level of overall myocardial backscatter. One potential explanation of these observations may be related to the difficulty in obtaining measurements of the absolute level of backscatter from the myocardium. As discussed above, measurements of the absolute level of backscatter require the identification and utilization of a well-characterized reference. This is often a significant challenge in the clinical setting. Measurements that exhibit no significant difference in the measured level of overall myocardial backscatter when measurements of patients are compared with those from control subjects may reflect the difficulty in obtaining measurements. Furthermore, there may be specific circumstances in which the magnitude of cyclic variation could be altered without an associated change in the overall end-diastolic backscatter level. This could occur, for example, where there is a change in regional contractile function such as that associated with the reported transmural heterogeneity of cyclic variation.39 In this case, transmural variations in contractile function could result in increased regional intracellular impedance during systole but leave the intracellular acoustic impedance during diastole unaffected. This might result in changes in the observed transmural magnitude of cyclic variation with no corresponding change in the observed end-diastolic backscatter level. Conclusion The results of this study suggest that observed decreases in the magnitude of cyclic variation with concomitant increases in the measured overall myocardial backscatter level are consistent with predictions from a model based on the relative acoustic impedance differences between intracellular and extracellular elastic properties over the heart cycle. Because specific cardiac pathologies can potentially alter the composition of intracellular and extracellular structural components, the results presented suggest that ultrasonic backscatter measurements may provide a noninvasive approach for assessing some relationships among stiffness properties, degree of fibrosis, and contractile performance. The authors gratefully acknowledge the seminal contributions of Lewis J. Thomas III, PhD, and Samuel A. Wickline, MD, in the development of the 3-component Maxwelltype model of muscle mechanics to predict the systematic
1136 Holland, Wallace, Miller
variation in the relative acoustic impedance differences over the heart cycle.
REFERENCES 1. Madaras EI, Barzilai B, Perez JE, Sobel BE, Miller JG. Changes in myocardial backscatter throughout the cardiac cycle. Ultrason Imaging 1983;5:229-39. 2. Perez JE, Holland MR, Barzailai B, Handley SM, Vandenberg BF, Miller JG, et al. Ultrasonic characterization of cardiovascular tissue. In: Skorton DJ, Seelbert HR, Wolf GL, Brundage BH, editors. Cardiac imaging–a companion to Braunwald’s heart disease. Vol 1. 2nd ed. Philadelphia: WB Saunders Co; 1996. p. 606-22. 3. Di Bello V, Pedrinelli R, Talini E, Giorgi D, Bertini A, Dell’Omo G, et al. Ultrasonic myocardial tissue characterization: a methodological review. Ital Heart J 2001;2:333-43. 4. Miller JG, Perez JE, Wickline SA, Baldwin SL, Barzilai B, Davila-Roman V, et al. Backscatter imaging and myocardial tissue characterization. Proc IEEE Ultrason Symp 1998; 98CH36102:1373-83. 5. Di Bello V, Giorgi D, Talini E, Dell’ Omo G, Palagi C, Romano MF, et al. Incremental value of ultrasonic tissue characterization (backscatter) in the evaluation of left ventricular myocardial structure and mechanics in essential arterial hypertension. Circulation 2003;107:74-80. 6. Yuda S, Short L, Leano R, Marwick TH. Myocardial abnormalities in hypertensive patients with normal and abnormal left ventricular filling: a study of ultrasound tissue characterization and strain. Clin Sci (Colch) 2002;103:283-93. 7. Maceira AM, Barba J, Beloqui O, Diez J. Ultrasonic backscatter and diastolic function in hypertensive patients. Hypertension 2002;40:239-43. 8. Maceira AM, Barba J, Varo N, Beloqui O, Diez J. Ultrasonic backscatter and serum marker of cardiac fibrosis in hypertensives. Hypertension 2002;39:923-8. 9. Di Bello V, Pedrinelli R, Bertini A, Giorgi D, Talini E, Dell’Omo G, et al. Cyclic variation of the myocardial integrated backscatter signal in hypertensive cardiopathy: a preliminary study. Coron Artery Dis 2001;12:267-75. 10. Di Bello V, Pedrinelli R, Giorgi D, Bertini A, Talini E, Dell’Omo G, et al. Ultrasonic myocardial textural parameters and midwall left ventricular mechanics in essential arterial hypertension. J Hum Hypertens 2000;14:9-16. 11. Di Bello V, Panichi V, Pedrinelli R, Giorgi D, Bianchi M, Bertini A, et al. Ultrasonic videodensitometric analysis of myocardium in end-stage renal disease treated with haemodialysis. Nephrol Dial Transplant 1999;14:2184-91. 12. Di Bello V, Pedrinelli R, Bianchi M, Giorgi D, Bertini A, Valenti G, et al. Ultrasonic myocardial texture in hypertensive mild-to-moderate left ventricular hypertrophy: a videodensitometric study. Am J Hypertens 1998;11:155-64. 13. Di Bello V, Pedrinelli R, Giorgi D, Bertini A, Talarico L, Caputo MT, et al. Ultrasonic videodensitometric analysis of two different models of left ventricular hypertrophy: athlete’s heart and hypertension. Hypertension 1997;29:937-44. 14. Zoni A, Regolisti G, Aschieri D, Borghetti A. Myocardial ultrasonic tissue characterization in patients with different types of left ventricular hypertrophy: a videodensitometric approach. J Am Soc Echocardiogr 1997;10:74-82. 15. Di Bello V, Giampietro O, Matteucci E, Talarico L, Giorgi D, Bertini A, et al. Ultrasonic videodensitometric analysis in type 1 diabetic myocardium. Coron Artery Dis 1996;7:895-901.
Journal of the American Society of Echocardiography November 2004
16. Pacileo G, Limongelli G, Verrengia M, Gimeno J, Di Salvo G, Calabro R. Backscatter evaluation of myocardial functional and textural findings in children with right ventricular pressure and/or volume overload. Am J Cardiol 2004;93:594-7. 17. Wickline SA, Thomas LJ III, Miller JG, Sobel BE, Perez JE. A relationship between ultrasonic integrated backscatter and myocardial contractile function. J Clin Invest 1985;76:215160. 18. Wickline SA, Thomas LJ III, Miller JG, Sobel BE, Perez JE. The dependence of myocardial ultrasonic integrated backscatter on contractile performance. Circulation 1985;72:183-92. 19. Kumar KN, Mottley JG. Quantitative modeling of the anisotropy of ultrasonic backscatter from canine myocardium. IEEE Trans Ultrason Ferroelect Freq Contr 1994;41:441-50. 20. Rose JH, Kaufmann MR, Wickline SA, Hall CS, Miller JG. A proposed microscopic elastic wave theory for ultrasonic backscatter from myocardial tissue. J Acoust Soc Am 1995;97: 656-68. 21. Finch-Johnston AE, Gussak HM, Mobley J, Holland MR, Petrovic O, Perez JE, et al. Cyclic variation of integrated backscatter: dependence of time delay on the echocardiographic view used and the myocardial segment analyzed. J Am Soc Echocardiogr 2000;13:9-17. 22. Finch-Johnston AE, Gussak HM, Mobley J, Holland MR, Petrovic O, Perez JE, et al. Dependence of “apparent” magnitude on the time delay of cyclic variation of myocardial backscatter. Ultrasound Med Biol 1999;25:759-62. 23. Mohr GA, Vered Z, Barzilai B, Perez JE, Sobel BE, Miller JG. Automated determination of the magnitude and time delay (“phase”) of the cardiac cycle dependent variation of myocardial ultrasonic integrated backscatter. Ultrason Imaging 1989;11:245-59. 24. Mobley J, Banta CE, Gussak HM, Perez JE, Miller JG. Clinical tissue characterization: online determination of magnitude and time delay myocardial backscatter. Video J Echocardiogr 1995;5:40-8. 25. O’Donnell M, Miller JG. Quantitative broadband ultrasonic backscatter: an approach to non-destructive evaluation in acoustically inhomogeneous materials. J Appl Physics 1981; 52:1056-65. 26. Miller JG, Perez JE, Mottley JG, Madaras EI, Johnston PH, Blodgett ED, et al. Myocardial tissue characterization: an approach based on quantitative backscatter and attenuation. Proc IEEE Ultrason Symp Atlanta 1983;83CH1947-1:78293. 27. Naito J, Masuyama T, Mano T, Yamamoto K, Doi Y, Kondo H, et al. Validation of transthoracic myocardial ultrasonic tissue characterization: comparison of transthoracic and openchest measurements of integrated backscatter. Ultrasound Med Biol 1995;21:33-40. 28. Naito J, Masuyama T, Mano T, Kondo H, Yamamoto K, Nagano R, et al. Ultrasonic myocardial tissue characterization in patients with dilated cardiomyopathy: value in noninvasive assessment of myocardial fibrosis. Am Heart J 1996;131:11521. 29. Di Bello V, Talarico L, Picano E, Di Muro C, Landini L, Paterni M, et al. Increased echodensity of myocardial wall in the diabetic heart: an ultrasound tissue characterization study. J Am Coll Cardiol 1995;25:1408-15. 30. Wear KA, Milunski MR, Wickline SA, Perez JE, Sobel BE, Miller JG. Differentiation between acutely ischemic myocardium and zones of completed infarction in dogs on the basis of
Journal of the American Society of Echocardiography Volume 17 Number 11
31. 32.
33.
34.
35.
frequency-dependent backscatter. J Acoust Soc Am 1989;85: 2634-41. Morse PM, Ingard KU. Theoretical acoustics. Princeton (NJ): Princeton University Press; 1968. Glueck RM, Mottley JG, Sobel BE, Miller JG, Perez JE. Changes in ultrasonic attenuation and backscatter of muscle with state of contraction. Ultrasound Med Biol 1985;11:60510. Wear KA, Shoup TA, Popp RL. Ultrasonic characterization of canine myocardium contraction. IEEE Trans Ultrason Ferroelect Freq Contr 1986;UFFC-33:347-53. Holland MR, Wilkenshoff UM, Finch-Johnston AE, Handley SM, Perez JE, Miller JG. Effects of myocardial fiber orientation in echocardiography: quantitative measurements and computer simulation of the regional dependence of backscattered ultrasound in the parasternal short-axis view. J Am Soc Echocardiogr 1998;11:929-37. Vandenberg BF, Stuhlmuller JE, Rath L, Kerber RE, Collins SM, Melton HE, et al. Diagnosis of recent myocardial infarc-
Holland, Wallace, Miller 1137
36.
37.
38.
39.
tion with quantitative backscatter imaging: preliminary studies. J Am Soc Echocardiogr 1991;4:10-8. Vandenberg BF, Rath L, Shoup TA, Kerber RE, Collins SM, Skorton DJ. Cyclic variation of ultrasound backscatter in normal myocardium is view dependent: clinical studies with a real-time backscatter imaging system. J Am Soc Echocardiogr 1989;2:308-14. Lange A, Moran CM, Palka P, Fenn LN, Sutherland GR, McDicken WN. The variation of integrated backscatter in human hearts in differing ultrasonic transthoracic views. J Am Soc Echocardiogr 1995;8:830-8. Bouki KP, Lange A, Palka P, Moran CM, Fenn LN, Wright RA, et al. Regional variations of ultrasonic integrated backscatter in normal and myopathic left ventricles–a new multiview approach. Eur Heart J 1996;17:1747-55. Bombardini T, Galli R, Paterni M, Pingitore A, Pierangeli A, Picano E. A videodensitometric study of transmural heterogeneity of cyclic echo amplitude variation in human myocardium. Am J Cardiol 1996;78:212-6.