- Email: [email protected]
Should we be evaluating the ventricle or the myocardium? Advances in tissue characterization
FEIGENBAUM LECTURE 2003
Should We Be Evaluating the Ventricle or the Myocardium? Advances in Tissue Characterization Thomas H. Marwick, MBBS, PhD, Brisbane, Australia
The assessment of left ventricular (LV) dysfunction
has become the most frequent indication for echocardiography, a growth that has been driven by the epidemic of heart failure. The value of echocardiography for assessing LV dysfunction is unquestionable, the quantification of both LV systolic and diastolic dysfunction being a reliable indicator of mortality.1,2 Nonetheless, whereas the ejection fraction and diastolic assessment are important clinical parameters, they are highly dependent on loading and may produce abnormal results under unusual loading conditions. Moreover, in a number of situations where the LV is evaluated, although the overall function is an important finding, the referring clinician is really requesting an assessment of the nature of the underlying myocardial tissue (Table 1). Indeed, in some situations (eg, among family members of patients with a cardiomyopathy) questions arise about the presence of pathology despite the presence of normal ventricular function. Traditionally, it has been difficult to obtain this information because of the lack of sufficiently sensitive parameters, but a number of new developments have shown such success in this area that the clinical application of tools to assess the myocardium in routine practice appears finally to be a realistic proposition.
TECHNIQUES FOR MYOCARDIAL CHARACTERIZATION The first available techniques for characterizing the myocardium were on the basis of analysis of myocardial backscatter, caused by the scattering of ultrasound from small structures. The 2 aspects of this signal that are measured include cyclic variation, which appears to reflect the crossover of the myocardial contractile apparatus, even in the absence of From the University of Queensland, Brisbane, Australia. Reprint requests: Thomas H. Marwick, MBBS, PhD, University of Queensland, Department of Medicine, Princess Alexandra Hospital, Ipswich Rd, Brisbane, Qld 4012, Australia. (E-mail: [email protected]). J Am Soc Echocardiogr 2004;17:168-72. 0894-7317/$30.00 Copyright 2004 by the American Society of Echocardiography. doi:10.1067/j.echo.2003.10.021
168
Table 1 Relevance of myocardial characterization in common clinical scenarios Presentation
Dyspnea Postinfarction Regurgitant valve lesions
Postheart transplant Patients at risk of LVD (families with cardiomyopathy, anthacyclines, diabetes)
Findings
Systolic/diastolic function Nature of underlying tissue Overall LV function Myocardial viability Overall LV function Is the myocardium running out of reserve? Overall LV function Evidence of rejection Overall LV function Preclinical myocardial disease
LV, Left ventricular; LVD, left ventricular dysfunction.
apparent movement, and absolute levels of backscatter, usually calibrated to adjacent areas of either very high or very low density (respectively, the pericardium and the ventricular chamber) that correspond to the reflectivity of the tissue (Figure 1). Although these techniques have successfully been used to identify myocardial viability,3,4 and characterize hypertrophic myocardium, hypertrophic cardiomyopathy,5 infiltrations in amyloid heart disease, and thrombi,6 this technique remains technically very challenging, both because of a poor signal-to-noise ratio and an anisotropy leading to differences in the waveforms depending on which part of the heart is being interrogated and from which angle. Doppler tissue approaches have been shown to provide analogous information to myocardial backscatter. A wide range of techniques may be used, ranging from pulsed wave tissue Doppler, color tissue Doppler with offline analysis of displacement of velocity gradient, myocardial strain rate, and strain techniques. For both tissue velocity (Figure 2) and strain rate (Figure 3) techniques, a range of parameters can be measured, and this has led to a good deal of confusion in their clinical application. As matters currently stand, the measurement of peak systolic and diastolic tissue velocities appear to be the most robust techniques with high levels of observer concordance, but they do have the disadvantage of being susceptible to tethering by adjacent
Journal of the American Society of Echocardiography Volume 17 Number 2
Marwick 169
Figure 1 Tissue characterization from integrated backscatter (IB). Top, Cyclic variation (CV) from midseptum; apical images are not commonly used because of influence of anisotropy. Bottom, Measurement of calibrated IB (CIB) from comparison of posterior wall and pericardium.
Figure 3 Strain rate (SR) and strain measurements. Magnitude parameters include peak systolic SR, peak early diastolic SR, peak systolic strain, end-systolic strain, maximum strain, and postsystolic thickening (maximum strain after AVC [line]– end-systolic strain). Timing parameters (which may be less subject to error from angulation) include time to relaxation, contraction, and peak SR. AVC, Aortic valve closure; PSS, peak systolic strain; PK, peak.
correspond to the degree of myocardial fibrosis,9,10 which is a unifying feature in the characterization of abnormal myocardium. Figure 2 Measurement techniques with Doppler tissue. Data can be acquired with pulsed wave (PW), color (giving velocity waveforms), tissue tracking (displacement), or velocity gradient. Most commonly measured parameters are peak systolic (S) and early diastolic (E) velocities. A, Late diastolic velocity.
segments and translation caused by myocardial and extracardiac motion. In contrast, the strain techniques produce more uniform measurements throughout the myocardium, relatively independent of translation and tethering, and lacking the base-toapex gradient that is witnessed with velocity assessment.7,8 This site specificity of strain techniques is probably less important for the evaluation of generalized LV problems, as opposed to regional problems such as coronary artery disease. Experimental studies have shown the similarity between myocardial backscatter and strain measurements in experimental models, and indeed separate studies have shown that both tissue velocity and backscatter
CLINICAL SCENARIOS INVOLVING TISSUE CHARACTERIZATION Myocardial Viability The most common situation where the assessment of ventricular function is insufficient on its own, without an understanding of myocardial behavior, is the assessment of myocardial viability. A number of studies have emphasized the very high prevalence of viable myocardium after infarction.11 The clinical detection of this tissue remains an important challenge, especially in patients with LV impairment, where revascularization may restore function and thereby improve prognosis.12,13 Although a number of imaging approaches are used for the assessment of myocardial viability, the assessment of myocardial contractile reserve is recognized to be a highly specific signal for viability, although it is limited by subjectivity. Simple tissue velocity measurements in
170 Marwick
Journal of the American Society of Echocardiography February 2004
Figure 4 Demonstration of augmentation of contraction with dobutamine. Color anatomic M-mode images show strain rate (SR) from apex to base of lateral wall throughout cardiac cycle. There is area of reduced thickening in midlateral wall at rest (A, green, circled) that improves with low-dose dobutamine (D, yellow, circled). Same midlateral segment shows positive values (ie, lengthening) of both SR and strain at rest (B and C) and negative values (ie, shortening) at low-dose (D and E).
this situation are susceptible to tethering by adjacent segments.14 However, the use of strain and strain rate imaging may facilitate the detection of this tissue on the basis of resting characteristics including postsystolic thickening,15 and particularly on the basis of increased strain rate (Figure 4), and the resolution of delayed contraction and relaxation with dobutamine.16 Indeed, strain rate imaging has been shown to be more effective for this purpose than tissue velocity assessment.16 Preclinical Detection of Myocardial Disease It has been apparent for a number of years that the families of patients with idiopathic dilated cardiomyopathy are at risk of the development of this disease.17 Indeed, biopsy studies have shown histologic changes of hypertrophy, apoptosis, and immunohistochemical markers in apparently healthy relatives of patients with cardiomyopathies. With the development of treatments to prevent and delay the onset of heart failure, the detection of these preclinical manifestations has become more important. Although some of this work has been performed with myocardial backscatter (eg, the identification of cardiac effects from systemic sclerosis and subclinical hyperthyroidism),18,19 as discussed earlier, this is not amenable to wide application. However, myocardial velocity gradients are a more robust measure that has been shown to be effective for the detection of patients with preclinical disease such as Friedreich’s ataxia, the parameters providing the most discrimination being obtained in early diastole.20 Indeed, analysis of myocardial velocity gradients has shown abnormalities in proportion to the degree of genotypic disturbance for patients with preclinical disease. A simpler approach of examin-
ing peak systolic and diastolic velocities has been shown to identify subclinical right ventricular dysfunction for patients with cystic fibrosis.21 Patients with diabetes are an important group of individuals with subclinical myocardial dysfunction. These patients are more likely to have heart failure develop, and their outcome with heart failure is worse than that of patients without diabetes.22 However, the presence of a distinct diabetic cardiac muscle disease has been suggested but unproven for many years, largely because of the high prevalence of other causes of LV dysfunction in patients with diabetes, including coronary disease, hypertension, and LV hypertrophy. However, several recent studies have documented the presence of abnormal myocardial filling patterns and diastolic myocardial velocities when these other diseases are taken into account.23-26 Moreover, disturbances of backscatter, strain, and strain rate are analogous for patients with diabetes to those with hypertension, and the combination of both appears to be summative.25 The mechanisms and therapy of this condition are likely to be active areas of research. LV Hypertrophy Although the development of LV hypertrophy is most widely associated with myocardial dysfunction, other phenomena occur in the hypertrophic ventricle including LV fibrosis, abnormal coronary flow reserve, and sometimes coronary artery disease. Doppler tissue parameters have been shown to be normal in individuals with athletic LV hypertrophy, in contrast with those with hypertrophic cardiomyopathy or hypertension, where tissue velocities and velocity gradients are reduced.27,28 Moreover, the relatives of patients with hypertro-
Journal of the American Society of Echocardiography Volume 17 Number 2
Marwick 171
Table 2 Doppler tissue criteria for diagnosis of transplant rejection Sm tSm Sm/tSm Em tEm Em/tEm
Changes
Sensitivity (%)
Specificity (%)
⬎10% Reduction ⬎10% Increment ⬎10% Reduction ⬎10% Reduction ⬎10% Increment ⬎10% Reduction
88 83 87 92 93 92
94 94 96 92 95 94
Em, Peak myocardial diastolic velocity; Sm, peak myocardial systolic velocity; tEm, time to peak myocardial systolic velocity; tSm, time to peak myocarcial systolic velocity.
phic cardiomyopathy, even in the absence of phenotypic expression, demonstrate abnormal myocardial contractile behavior that can be identified by tissue Doppler.29 Finally, the use of tissue velocity may help us understand the development of symptoms for patients with hypertension. These individuals, even before diastolic dysfunction develops, demonstrate abnormal strain and strain rate along with reduced cyclic variation, implying the development of LV contractile impairment. These changes precede the development of overt LV hypertrophy or changes in the magnitude of myocardial backscatter, suggesting that these functional changes correspond to abnormal contraction rather than fibrosis.30 Identification of Transplant Rejection The performance of sequential biopsies for patients undergoing heart transplant is a potential cause of significant morbidity and, rarely, mortality. Various techniques have been examined to identify this process noninvasively, and tissue velocity imaging appears to be both effective and highly feasible. In large studies31,32 both the combination of systolic and diastolic tissue velocity, and absolute velocities and timing parameters, have demonstrated high levels of accuracy in the recognition of rejection (Table 2). These techniques are particularly useful if the patient is able to act as their own control in the course of routine follow up. Moreover, these data suggest that these tissue velocities may also be used in the recognition of transplant coronary disease. Myocardial Dysfunction with Regurgitant Valve Pathology The morbidity from regurgitant valve lesions is related to the volume load to which the ventricle is exposed. Although there is some enthusiasm for earlier intervention on regurgitant valve lesions on the basis of the degree of regurgitation,33 a repair is not always possible and in this situation, a more conservative approach to surgical timing is on the basis of assessment of the ventricular response to volume loading, including an assessment of the LV contractile reserve with exercise.34 However, the
accurate measurement of LV volumes after exercise remains technically challenging, and long-axis tissue velocity corresponds to contractile reserve, and is easier to perform.35 Indeed, long-axis tissue velocity at rest appears to reflect contractile reserve in both aortic and mitral regurgitation.35,36 Conclusions Our approach to LV impairment in the past has been dependent on the assessment of LV regional and global performance. Although these measurements remain prognostically very useful, they are insensitive markers of LV impairment that are highly dependent on loading conditions. As our practice moves progressively to preempt the occurrence of overt LV dysfunction, sensitive tools for the detection of abnormal myocardium are likely to be of clinical value. The experience in a number of diseases indicates that myocardial tissue characterization using tissue velocity, strain, and strain rate may provide these tools. The next phases of this research will be to identify clinically robust parameters to guide therapy and then examine the impact of the combination of these markers and therapeutic alterations on outcome. REFERENCES 1. Volpi A, De Vita C, Franzosi MG, Geraci E, Maggioni AP, Mauri F, et al. Determinants of 6 month mortality in survivors of myocardial infarction after thrombolysis: results of the GISSI-2 database. Circulation 1994;88:416-29. 2. Xie GY, Berk MR, Smith MD, Gurley JC, DeMaria AN. Prognostic value of Doppler transmitral flow patterns in patients with congestive heart failure. J Am Coll Cardiol 1994; 24:132-9. 3. Milunski MR, Mohr GA, Wear KA, Sobel BE, Miller JG, Wickline SA. Early identification with ultrasonic integrated backscatter of viable but stunned myocardium in dogs. J Am Coll Cardiol 1989;14:462-71. 4. Milunski MR, Mohr GA, Perez JE, Vered Z, Wear KA, Gessler CJ, et al. Ultrasonic tissue characterization with integrated backscatter: acute myocardial ischemia, reperfusion, and stunned myocardium in patients. Circulation 1989;80:491503. 5. Lattanzi F, Di Bello V, Picano E, Caputo MT, Talarico L, Di Muro C, et al. Normal ultrasonic myocardial reflectivity in athletes with increased left ventricular mass: a tissue characterization study. Circulation 1992;85:1828-34. 6. Perez JE, Miller JG, Holland MR, Wickline SA, Waggoner AD, Barzilai B, et al. Ultrasonic tissue characterization: integrated backscatter imaging for detecting myocardial structural properties and on-line quantitation of cardiac function. Am J Card Imaging 1994;8:106-12. 7. Edvardsen T, Gerber BL, Garot J, Bluemke DA, Lima JA, Smiseth OA. Quantitative assessment of intrinsic regional myocardial deformation by Doppler strain rate echocardiography in humans: validation against three-dimensional tagged magnetic resonance imaging. Circulation 2002;106:50-6. 8. Urheim S, Edvardsen T, Torp H, Angelsen B, Smiseth OA. Myocardial strain by Doppler echocardiography: validation of
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9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
a new method to quantify regional myocardial function. Circulation 2000;102:1158-64. Shan K, Bick RJ, Poindexter BJ, Shimoni S, Letsou GV, Reardon MJ, et al. Relation of tissue Doppler derived myocardial velocities to myocardial structure and beta-adrenergic receptor density in humans. J Am Coll Cardiol 2000;36: 891-6. Picano E, Pelosi G, Marzilli M, Lattanzi F, Benassi A, Landini L, et al. In vivo quantitative ultrasonic evaluation of myocardial fibrosis in humans. Circulation 1990;81:58-64. Coletta A, Thackray S, Nikitin N, Cleland JG. Clinical trials update: highlights of the scientific sessions of the American College of Cardiology 2002; LIFE, DANAMI 2, MADIT-2, MIRACLE-ICD, OVERTURE, OCTAVE, ENABLE 1 and 2, CHRISTMAS, AFFIRM, RACE, WIZARD, AZACS, REMATCH, BNP trial and HARDBALL. Eur J Heart Fail 2002;4:381-8. Meluzin J, Cerny J, Frelich MS, Stetka F, Spinarova L, Popelova J, et al. Prognostic value of the amount of dysfunctional but viable myocardium in revascularized patients with coronary artery disease and left ventricular dysfunction. J Am Coll Cardiol 1998;32:912-20. Allman KC, Shaw LJ, Hachamovitch R, Udelson JE. Myocardial viability testing and impact of revascularization on prognosis in patients with coronary artery disease and left ventricular dysfunction: a meta-analysis. J Am Coll Cardiol 2002;39: 1151-8. Cain P, Khoury V, Short L, Marwick TH. Usefulness of quantitative echocardiographic techniques to predict recovery of regional and global left ventricular function after acute myocardial infarction. Am J Cardiol 2003;91:391-6. Jamal F, Szilard M, Kukulski T, Liu XK, D’hooge J, Bijnens B, et al. Changes in systolic and postsystolic wall thickening during acute coronary occlusion and reperfusion in closedchest pigs: implications for the assessment of regional myocardial function. J Am Soc Echocardiogr 2001;14:691-7. Hoffmann R, Altiok E, Nowak B, Heussen N, Kuhl H, Kaiser HJ, et al. Strain rate measurement by Doppler echocardiography allows improved assessment of myocardial viability inpatients with depressed left ventricular function. J Am Coll Cardiol 2002;39:443-9. McKenna CJ, Sugrue DD, Kwon HM, Sangiorgi G, Carlson PJ, Mahon N, et al. Histopathologic changes in asymptomatic relatives of patients with idiopathic dilated cardiomyopathy. Am J Cardiol 1999;83:281-3 A6. Ferri C, Di Bello V, Martini A, Giorgi D, Storino FA, Bianchi M, et al. Heart involvement in systemic sclerosis: an ultrasonic tissue characterization study. Ann Rheum Dis 1998;57:296-302. Monzani F, Di Bello V, Caraccio N, Bertini A, Giorgi D, Giusti C, et al. Effect of levothyroxine on cardiac function and structure in subclinical hypothyroidism: a double blind, placebo-controlled study. J Clin Endocrinol Metab 2001;86:1110-5. Dutka DP, Donnelly JE, Palka P, Lange A, Nunez DJ, Nihoyannopoulos P. Echocardiographic characterization of cardiomyopathy in Friedreich’s ataxia with tissue Doppler echocardiographically derived myocardial velocity gradients. Circulation 2000;102:1276-82. Ionescu AA, Ionescu AA, Payne N, Obieta-Fresnedo I, Fraser AG, Shale DJ. Subclinical right ventricular dysfunction in cystic fibrosis: a study using tissue Doppler echocardiography. Am J Respir Crit Care Med 2001;163:1212-8. Tang WH, Young JB. Cardiomyopathy and heart failure in diabetes. Endocrinol Metab Clin North Am 2001;30:1031-46.
Journal of the American Society of Echocardiography February 2004
23. Poirier P, Bogaty P, Garneau C, Marois L, Dumesnil JG. Diastolic dysfunction in normotensive men with well-controlled type 2 diabetes: importance of maneuvers in echocardiographic screening for preclinical diabetic cardiomyopathy. Diabetes Care 2001;24:5-10. 24. Zabalgoitia M, Ismaeil MF, Anderson L, Maklady FA. Prevalence of diastolic dysfunction in normotensive, asymptomatic patients with well-controlled type 2 diabetes mellitus. Am J Cardiol 2001;87:320-3. 25. Fang ZY, Yuda S, Anderson V, Short L, Case C, Marwick TH. Echocardiographic detection of early diabetic myocardial disease. J Am Coll Cardiol 2003;41:611-7. 26. Hansen A, Johansson BL, Wahren J, von Bibra H. C-peptide exerts beneficial effects on myocardial blood flow and function in patients with type 1 diabetes. Diabetes 2002;51:3077-82. 27. Palka P, Lange A, Fleming RM, Donnelly JE, Dutka DP, Starkey IR, et al. Differences in myocardial velocity gradient measured throughout the cardiac cycle in patients with hypertrophic cardiomyopathy, athletes and patients with left ventricular hypertrophy due to hypertension. J Am Coll Cardiol 1997;30:760-8. 28. Vinereanu D, Florescu N, Sculthorpe N, Tweddel AC, Stephens MR, Fraser AG. Differentiation between pathologic and physiologic left ventricular hypertrophy by tissue Doppler assessment of long-axis function in patients with hypertrophic cardiomyopathy or systemic hypertension and in athletes. Am J Cardiol 2001;88:53-8. 29. Nagueh SF, Bachinski LL, Meyer D, Hill R, Zoghbi WA, Tam JW, et al. Tissue Doppler imaging consistently detects myocardial abnormalities in patients with hypertrophic cardiomyopathy and provides a novel means for an early diagnosis before and independently of hypertrophy. Circulation 2001; 104:128-30. 30. 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. 31. Mankad S, Murali S, Kormos RL, Mandarino WA, Gorcsan J III. Evaluation of the potential role of color-coded tissue Doppler echocardiography in the detection of allograft rejection in heart transplant recipients. Am Heart J 1999;138:721-30. 32. Dandel M, Hummel M, Muller J, Wellnhofer E, Meyer R, Solowjowa N, et al. Reliability of tissue Doppler wall motion monitoring after heart transplantation for replacement of invasive routine screenings by optimally timed cardiac biopsies and catheterizations. Circulation 2001;104:I184-91. 33. Enriquez-Sarano M, Tajik AJ, Schaff HV, Orszulak TA, McGoon MD, bailey KR, et al. Echocardiographic prediction of left ventricular function after correction of mitral regurgitation: results and clinical implications [see comments]. J Am Coll Cardiol 1994;24:1536-43. 34. Leung DY, Griffin BP, Stewart WJ, Cosgrove DM, Thomas JD, Marwick TH. Left ventricular function after valve repair for chronic mitral regurgitation: predictive value of preoperative assessment of contractile reserve by exercise echocardiography. J Am Coll Cardiol 1996;28:1198-205. 35. Haluska BA, Short L, Marwick TH. Relationship of ventricular longitudinal function to contractile reserve in patients with mitral regurgitation. Am Heart J 2003;146:183-8. 36. Vinereanu D, Ionescu AA, Fraser AG. Assessment of left ventricular long axis contraction can detect early myocardial dysfunction in asymptomatic patients with severe aortic regurgitation. Heart 2001;85:30-6.
Should We Be Evaluating the Ventricle or the Myocardium? Advances in Tissue Characterization Thomas H. Marwick, MBBS, PhD, Brisbane, Australia
The assessment of left ventricular (LV) dysfunction
has become the most frequent indication for echocardiography, a growth that has been driven by the epidemic of heart failure. The value of echocardiography for assessing LV dysfunction is unquestionable, the quantification of both LV systolic and diastolic dysfunction being a reliable indicator of mortality.1,2 Nonetheless, whereas the ejection fraction and diastolic assessment are important clinical parameters, they are highly dependent on loading and may produce abnormal results under unusual loading conditions. Moreover, in a number of situations where the LV is evaluated, although the overall function is an important finding, the referring clinician is really requesting an assessment of the nature of the underlying myocardial tissue (Table 1). Indeed, in some situations (eg, among family members of patients with a cardiomyopathy) questions arise about the presence of pathology despite the presence of normal ventricular function. Traditionally, it has been difficult to obtain this information because of the lack of sufficiently sensitive parameters, but a number of new developments have shown such success in this area that the clinical application of tools to assess the myocardium in routine practice appears finally to be a realistic proposition.
TECHNIQUES FOR MYOCARDIAL CHARACTERIZATION The first available techniques for characterizing the myocardium were on the basis of analysis of myocardial backscatter, caused by the scattering of ultrasound from small structures. The 2 aspects of this signal that are measured include cyclic variation, which appears to reflect the crossover of the myocardial contractile apparatus, even in the absence of From the University of Queensland, Brisbane, Australia. Reprint requests: Thomas H. Marwick, MBBS, PhD, University of Queensland, Department of Medicine, Princess Alexandra Hospital, Ipswich Rd, Brisbane, Qld 4012, Australia. (E-mail: [email protected]). J Am Soc Echocardiogr 2004;17:168-72. 0894-7317/$30.00 Copyright 2004 by the American Society of Echocardiography. doi:10.1067/j.echo.2003.10.021
168
Table 1 Relevance of myocardial characterization in common clinical scenarios Presentation
Dyspnea Postinfarction Regurgitant valve lesions
Postheart transplant Patients at risk of LVD (families with cardiomyopathy, anthacyclines, diabetes)
Findings
Systolic/diastolic function Nature of underlying tissue Overall LV function Myocardial viability Overall LV function Is the myocardium running out of reserve? Overall LV function Evidence of rejection Overall LV function Preclinical myocardial disease
LV, Left ventricular; LVD, left ventricular dysfunction.
apparent movement, and absolute levels of backscatter, usually calibrated to adjacent areas of either very high or very low density (respectively, the pericardium and the ventricular chamber) that correspond to the reflectivity of the tissue (Figure 1). Although these techniques have successfully been used to identify myocardial viability,3,4 and characterize hypertrophic myocardium, hypertrophic cardiomyopathy,5 infiltrations in amyloid heart disease, and thrombi,6 this technique remains technically very challenging, both because of a poor signal-to-noise ratio and an anisotropy leading to differences in the waveforms depending on which part of the heart is being interrogated and from which angle. Doppler tissue approaches have been shown to provide analogous information to myocardial backscatter. A wide range of techniques may be used, ranging from pulsed wave tissue Doppler, color tissue Doppler with offline analysis of displacement of velocity gradient, myocardial strain rate, and strain techniques. For both tissue velocity (Figure 2) and strain rate (Figure 3) techniques, a range of parameters can be measured, and this has led to a good deal of confusion in their clinical application. As matters currently stand, the measurement of peak systolic and diastolic tissue velocities appear to be the most robust techniques with high levels of observer concordance, but they do have the disadvantage of being susceptible to tethering by adjacent
Journal of the American Society of Echocardiography Volume 17 Number 2
Marwick 169
Figure 1 Tissue characterization from integrated backscatter (IB). Top, Cyclic variation (CV) from midseptum; apical images are not commonly used because of influence of anisotropy. Bottom, Measurement of calibrated IB (CIB) from comparison of posterior wall and pericardium.
Figure 3 Strain rate (SR) and strain measurements. Magnitude parameters include peak systolic SR, peak early diastolic SR, peak systolic strain, end-systolic strain, maximum strain, and postsystolic thickening (maximum strain after AVC [line]– end-systolic strain). Timing parameters (which may be less subject to error from angulation) include time to relaxation, contraction, and peak SR. AVC, Aortic valve closure; PSS, peak systolic strain; PK, peak.
correspond to the degree of myocardial fibrosis,9,10 which is a unifying feature in the characterization of abnormal myocardium. Figure 2 Measurement techniques with Doppler tissue. Data can be acquired with pulsed wave (PW), color (giving velocity waveforms), tissue tracking (displacement), or velocity gradient. Most commonly measured parameters are peak systolic (S) and early diastolic (E) velocities. A, Late diastolic velocity.
segments and translation caused by myocardial and extracardiac motion. In contrast, the strain techniques produce more uniform measurements throughout the myocardium, relatively independent of translation and tethering, and lacking the base-toapex gradient that is witnessed with velocity assessment.7,8 This site specificity of strain techniques is probably less important for the evaluation of generalized LV problems, as opposed to regional problems such as coronary artery disease. Experimental studies have shown the similarity between myocardial backscatter and strain measurements in experimental models, and indeed separate studies have shown that both tissue velocity and backscatter
CLINICAL SCENARIOS INVOLVING TISSUE CHARACTERIZATION Myocardial Viability The most common situation where the assessment of ventricular function is insufficient on its own, without an understanding of myocardial behavior, is the assessment of myocardial viability. A number of studies have emphasized the very high prevalence of viable myocardium after infarction.11 The clinical detection of this tissue remains an important challenge, especially in patients with LV impairment, where revascularization may restore function and thereby improve prognosis.12,13 Although a number of imaging approaches are used for the assessment of myocardial viability, the assessment of myocardial contractile reserve is recognized to be a highly specific signal for viability, although it is limited by subjectivity. Simple tissue velocity measurements in
170 Marwick
Journal of the American Society of Echocardiography February 2004
Figure 4 Demonstration of augmentation of contraction with dobutamine. Color anatomic M-mode images show strain rate (SR) from apex to base of lateral wall throughout cardiac cycle. There is area of reduced thickening in midlateral wall at rest (A, green, circled) that improves with low-dose dobutamine (D, yellow, circled). Same midlateral segment shows positive values (ie, lengthening) of both SR and strain at rest (B and C) and negative values (ie, shortening) at low-dose (D and E).
this situation are susceptible to tethering by adjacent segments.14 However, the use of strain and strain rate imaging may facilitate the detection of this tissue on the basis of resting characteristics including postsystolic thickening,15 and particularly on the basis of increased strain rate (Figure 4), and the resolution of delayed contraction and relaxation with dobutamine.16 Indeed, strain rate imaging has been shown to be more effective for this purpose than tissue velocity assessment.16 Preclinical Detection of Myocardial Disease It has been apparent for a number of years that the families of patients with idiopathic dilated cardiomyopathy are at risk of the development of this disease.17 Indeed, biopsy studies have shown histologic changes of hypertrophy, apoptosis, and immunohistochemical markers in apparently healthy relatives of patients with cardiomyopathies. With the development of treatments to prevent and delay the onset of heart failure, the detection of these preclinical manifestations has become more important. Although some of this work has been performed with myocardial backscatter (eg, the identification of cardiac effects from systemic sclerosis and subclinical hyperthyroidism),18,19 as discussed earlier, this is not amenable to wide application. However, myocardial velocity gradients are a more robust measure that has been shown to be effective for the detection of patients with preclinical disease such as Friedreich’s ataxia, the parameters providing the most discrimination being obtained in early diastole.20 Indeed, analysis of myocardial velocity gradients has shown abnormalities in proportion to the degree of genotypic disturbance for patients with preclinical disease. A simpler approach of examin-
ing peak systolic and diastolic velocities has been shown to identify subclinical right ventricular dysfunction for patients with cystic fibrosis.21 Patients with diabetes are an important group of individuals with subclinical myocardial dysfunction. These patients are more likely to have heart failure develop, and their outcome with heart failure is worse than that of patients without diabetes.22 However, the presence of a distinct diabetic cardiac muscle disease has been suggested but unproven for many years, largely because of the high prevalence of other causes of LV dysfunction in patients with diabetes, including coronary disease, hypertension, and LV hypertrophy. However, several recent studies have documented the presence of abnormal myocardial filling patterns and diastolic myocardial velocities when these other diseases are taken into account.23-26 Moreover, disturbances of backscatter, strain, and strain rate are analogous for patients with diabetes to those with hypertension, and the combination of both appears to be summative.25 The mechanisms and therapy of this condition are likely to be active areas of research. LV Hypertrophy Although the development of LV hypertrophy is most widely associated with myocardial dysfunction, other phenomena occur in the hypertrophic ventricle including LV fibrosis, abnormal coronary flow reserve, and sometimes coronary artery disease. Doppler tissue parameters have been shown to be normal in individuals with athletic LV hypertrophy, in contrast with those with hypertrophic cardiomyopathy or hypertension, where tissue velocities and velocity gradients are reduced.27,28 Moreover, the relatives of patients with hypertro-
Journal of the American Society of Echocardiography Volume 17 Number 2
Marwick 171
Table 2 Doppler tissue criteria for diagnosis of transplant rejection Sm tSm Sm/tSm Em tEm Em/tEm
Changes
Sensitivity (%)
Specificity (%)
⬎10% Reduction ⬎10% Increment ⬎10% Reduction ⬎10% Reduction ⬎10% Increment ⬎10% Reduction
88 83 87 92 93 92
94 94 96 92 95 94
Em, Peak myocardial diastolic velocity; Sm, peak myocardial systolic velocity; tEm, time to peak myocardial systolic velocity; tSm, time to peak myocarcial systolic velocity.
phic cardiomyopathy, even in the absence of phenotypic expression, demonstrate abnormal myocardial contractile behavior that can be identified by tissue Doppler.29 Finally, the use of tissue velocity may help us understand the development of symptoms for patients with hypertension. These individuals, even before diastolic dysfunction develops, demonstrate abnormal strain and strain rate along with reduced cyclic variation, implying the development of LV contractile impairment. These changes precede the development of overt LV hypertrophy or changes in the magnitude of myocardial backscatter, suggesting that these functional changes correspond to abnormal contraction rather than fibrosis.30 Identification of Transplant Rejection The performance of sequential biopsies for patients undergoing heart transplant is a potential cause of significant morbidity and, rarely, mortality. Various techniques have been examined to identify this process noninvasively, and tissue velocity imaging appears to be both effective and highly feasible. In large studies31,32 both the combination of systolic and diastolic tissue velocity, and absolute velocities and timing parameters, have demonstrated high levels of accuracy in the recognition of rejection (Table 2). These techniques are particularly useful if the patient is able to act as their own control in the course of routine follow up. Moreover, these data suggest that these tissue velocities may also be used in the recognition of transplant coronary disease. Myocardial Dysfunction with Regurgitant Valve Pathology The morbidity from regurgitant valve lesions is related to the volume load to which the ventricle is exposed. Although there is some enthusiasm for earlier intervention on regurgitant valve lesions on the basis of the degree of regurgitation,33 a repair is not always possible and in this situation, a more conservative approach to surgical timing is on the basis of assessment of the ventricular response to volume loading, including an assessment of the LV contractile reserve with exercise.34 However, the
accurate measurement of LV volumes after exercise remains technically challenging, and long-axis tissue velocity corresponds to contractile reserve, and is easier to perform.35 Indeed, long-axis tissue velocity at rest appears to reflect contractile reserve in both aortic and mitral regurgitation.35,36 Conclusions Our approach to LV impairment in the past has been dependent on the assessment of LV regional and global performance. Although these measurements remain prognostically very useful, they are insensitive markers of LV impairment that are highly dependent on loading conditions. As our practice moves progressively to preempt the occurrence of overt LV dysfunction, sensitive tools for the detection of abnormal myocardium are likely to be of clinical value. The experience in a number of diseases indicates that myocardial tissue characterization using tissue velocity, strain, and strain rate may provide these tools. The next phases of this research will be to identify clinically robust parameters to guide therapy and then examine the impact of the combination of these markers and therapeutic alterations on outcome. REFERENCES 1. Volpi A, De Vita C, Franzosi MG, Geraci E, Maggioni AP, Mauri F, et al. Determinants of 6 month mortality in survivors of myocardial infarction after thrombolysis: results of the GISSI-2 database. Circulation 1994;88:416-29. 2. Xie GY, Berk MR, Smith MD, Gurley JC, DeMaria AN. Prognostic value of Doppler transmitral flow patterns in patients with congestive heart failure. J Am Coll Cardiol 1994; 24:132-9. 3. Milunski MR, Mohr GA, Wear KA, Sobel BE, Miller JG, Wickline SA. Early identification with ultrasonic integrated backscatter of viable but stunned myocardium in dogs. J Am Coll Cardiol 1989;14:462-71. 4. Milunski MR, Mohr GA, Perez JE, Vered Z, Wear KA, Gessler CJ, et al. Ultrasonic tissue characterization with integrated backscatter: acute myocardial ischemia, reperfusion, and stunned myocardium in patients. Circulation 1989;80:491503. 5. Lattanzi F, Di Bello V, Picano E, Caputo MT, Talarico L, Di Muro C, et al. Normal ultrasonic myocardial reflectivity in athletes with increased left ventricular mass: a tissue characterization study. Circulation 1992;85:1828-34. 6. Perez JE, Miller JG, Holland MR, Wickline SA, Waggoner AD, Barzilai B, et al. Ultrasonic tissue characterization: integrated backscatter imaging for detecting myocardial structural properties and on-line quantitation of cardiac function. Am J Card Imaging 1994;8:106-12. 7. Edvardsen T, Gerber BL, Garot J, Bluemke DA, Lima JA, Smiseth OA. Quantitative assessment of intrinsic regional myocardial deformation by Doppler strain rate echocardiography in humans: validation against three-dimensional tagged magnetic resonance imaging. Circulation 2002;106:50-6. 8. Urheim S, Edvardsen T, Torp H, Angelsen B, Smiseth OA. Myocardial strain by Doppler echocardiography: validation of
172 Marwick
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
a new method to quantify regional myocardial function. Circulation 2000;102:1158-64. Shan K, Bick RJ, Poindexter BJ, Shimoni S, Letsou GV, Reardon MJ, et al. Relation of tissue Doppler derived myocardial velocities to myocardial structure and beta-adrenergic receptor density in humans. J Am Coll Cardiol 2000;36: 891-6. Picano E, Pelosi G, Marzilli M, Lattanzi F, Benassi A, Landini L, et al. In vivo quantitative ultrasonic evaluation of myocardial fibrosis in humans. Circulation 1990;81:58-64. Coletta A, Thackray S, Nikitin N, Cleland JG. Clinical trials update: highlights of the scientific sessions of the American College of Cardiology 2002; LIFE, DANAMI 2, MADIT-2, MIRACLE-ICD, OVERTURE, OCTAVE, ENABLE 1 and 2, CHRISTMAS, AFFIRM, RACE, WIZARD, AZACS, REMATCH, BNP trial and HARDBALL. Eur J Heart Fail 2002;4:381-8. Meluzin J, Cerny J, Frelich MS, Stetka F, Spinarova L, Popelova J, et al. Prognostic value of the amount of dysfunctional but viable myocardium in revascularized patients with coronary artery disease and left ventricular dysfunction. J Am Coll Cardiol 1998;32:912-20. Allman KC, Shaw LJ, Hachamovitch R, Udelson JE. Myocardial viability testing and impact of revascularization on prognosis in patients with coronary artery disease and left ventricular dysfunction: a meta-analysis. J Am Coll Cardiol 2002;39: 1151-8. Cain P, Khoury V, Short L, Marwick TH. Usefulness of quantitative echocardiographic techniques to predict recovery of regional and global left ventricular function after acute myocardial infarction. Am J Cardiol 2003;91:391-6. Jamal F, Szilard M, Kukulski T, Liu XK, D’hooge J, Bijnens B, et al. Changes in systolic and postsystolic wall thickening during acute coronary occlusion and reperfusion in closedchest pigs: implications for the assessment of regional myocardial function. J Am Soc Echocardiogr 2001;14:691-7. Hoffmann R, Altiok E, Nowak B, Heussen N, Kuhl H, Kaiser HJ, et al. Strain rate measurement by Doppler echocardiography allows improved assessment of myocardial viability inpatients with depressed left ventricular function. J Am Coll Cardiol 2002;39:443-9. McKenna CJ, Sugrue DD, Kwon HM, Sangiorgi G, Carlson PJ, Mahon N, et al. Histopathologic changes in asymptomatic relatives of patients with idiopathic dilated cardiomyopathy. Am J Cardiol 1999;83:281-3 A6. Ferri C, Di Bello V, Martini A, Giorgi D, Storino FA, Bianchi M, et al. Heart involvement in systemic sclerosis: an ultrasonic tissue characterization study. Ann Rheum Dis 1998;57:296-302. Monzani F, Di Bello V, Caraccio N, Bertini A, Giorgi D, Giusti C, et al. Effect of levothyroxine on cardiac function and structure in subclinical hypothyroidism: a double blind, placebo-controlled study. J Clin Endocrinol Metab 2001;86:1110-5. Dutka DP, Donnelly JE, Palka P, Lange A, Nunez DJ, Nihoyannopoulos P. Echocardiographic characterization of cardiomyopathy in Friedreich’s ataxia with tissue Doppler echocardiographically derived myocardial velocity gradients. Circulation 2000;102:1276-82. Ionescu AA, Ionescu AA, Payne N, Obieta-Fresnedo I, Fraser AG, Shale DJ. Subclinical right ventricular dysfunction in cystic fibrosis: a study using tissue Doppler echocardiography. Am J Respir Crit Care Med 2001;163:1212-8. Tang WH, Young JB. Cardiomyopathy and heart failure in diabetes. Endocrinol Metab Clin North Am 2001;30:1031-46.
Journal of the American Society of Echocardiography February 2004
23. Poirier P, Bogaty P, Garneau C, Marois L, Dumesnil JG. Diastolic dysfunction in normotensive men with well-controlled type 2 diabetes: importance of maneuvers in echocardiographic screening for preclinical diabetic cardiomyopathy. Diabetes Care 2001;24:5-10. 24. Zabalgoitia M, Ismaeil MF, Anderson L, Maklady FA. Prevalence of diastolic dysfunction in normotensive, asymptomatic patients with well-controlled type 2 diabetes mellitus. Am J Cardiol 2001;87:320-3. 25. Fang ZY, Yuda S, Anderson V, Short L, Case C, Marwick TH. Echocardiographic detection of early diabetic myocardial disease. J Am Coll Cardiol 2003;41:611-7. 26. Hansen A, Johansson BL, Wahren J, von Bibra H. C-peptide exerts beneficial effects on myocardial blood flow and function in patients with type 1 diabetes. Diabetes 2002;51:3077-82. 27. Palka P, Lange A, Fleming RM, Donnelly JE, Dutka DP, Starkey IR, et al. Differences in myocardial velocity gradient measured throughout the cardiac cycle in patients with hypertrophic cardiomyopathy, athletes and patients with left ventricular hypertrophy due to hypertension. J Am Coll Cardiol 1997;30:760-8. 28. Vinereanu D, Florescu N, Sculthorpe N, Tweddel AC, Stephens MR, Fraser AG. Differentiation between pathologic and physiologic left ventricular hypertrophy by tissue Doppler assessment of long-axis function in patients with hypertrophic cardiomyopathy or systemic hypertension and in athletes. Am J Cardiol 2001;88:53-8. 29. Nagueh SF, Bachinski LL, Meyer D, Hill R, Zoghbi WA, Tam JW, et al. Tissue Doppler imaging consistently detects myocardial abnormalities in patients with hypertrophic cardiomyopathy and provides a novel means for an early diagnosis before and independently of hypertrophy. Circulation 2001; 104:128-30. 30. 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. 31. Mankad S, Murali S, Kormos RL, Mandarino WA, Gorcsan J III. Evaluation of the potential role of color-coded tissue Doppler echocardiography in the detection of allograft rejection in heart transplant recipients. Am Heart J 1999;138:721-30. 32. Dandel M, Hummel M, Muller J, Wellnhofer E, Meyer R, Solowjowa N, et al. Reliability of tissue Doppler wall motion monitoring after heart transplantation for replacement of invasive routine screenings by optimally timed cardiac biopsies and catheterizations. Circulation 2001;104:I184-91. 33. Enriquez-Sarano M, Tajik AJ, Schaff HV, Orszulak TA, McGoon MD, bailey KR, et al. Echocardiographic prediction of left ventricular function after correction of mitral regurgitation: results and clinical implications [see comments]. J Am Coll Cardiol 1994;24:1536-43. 34. Leung DY, Griffin BP, Stewart WJ, Cosgrove DM, Thomas JD, Marwick TH. Left ventricular function after valve repair for chronic mitral regurgitation: predictive value of preoperative assessment of contractile reserve by exercise echocardiography. J Am Coll Cardiol 1996;28:1198-205. 35. Haluska BA, Short L, Marwick TH. Relationship of ventricular longitudinal function to contractile reserve in patients with mitral regurgitation. Am Heart J 2003;146:183-8. 36. Vinereanu D, Ionescu AA, Fraser AG. Assessment of left ventricular long axis contraction can detect early myocardial dysfunction in asymptomatic patients with severe aortic regurgitation. Heart 2001;85:30-6.