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Tissue Doppler imaging enables the identification of diastolic dysfunction of pseudonormal pattern in Chagas' disease
Tissue Doppler Imaging Enables the Identification of Diastolic Dysfunction of Pseudonormal Pattern in Chagas’ Disease Márcio Vinícius Lins Barros, MD, Manoel Otávio da Costa Rocha, MD, PhD, Antonio Luiz Pinho Ribeiro, MD, PhD, and Fernando Santana Machado, MD, Belo Horizonte, Minas Gerais, Brazil
The Doppler pseudonormal pattern of left ventricular (LV) diastolic function filling, characterized by apparent normal transmitral flow velocities, indicates advanced diastolic dysfunction with abnormal relaxation and compliance. Left ventricular diastolic dysfunction has been shown to occur in the early stages of the outcome of Chagas cardiopathy, and its identification may potentially contribute to the management of those patients. The aim of this study was to evaluate the usefulness of tissue Doppler imaging (TDI) in identifying LV diastolic dysfunction in patients with Chagas’ disease with pseudonormal transmitral flow. For this purpose, 89 patients with Chagas’ disease (48 men) who had no other pathology and showed normal (n = 79) or pseudonormal (n = 10) patterns of diastolic function by pulsed wave Doppler were submitted to TDI. A significant LV systolic impairment in terms of the dimensions (P = .00001), ejection fraction (P = .000001), and wall motion score (P = .000002) was observed in patients with diastolic dysfunction when compared with the
group with normal LV diastolic function. Tissue Doppler imaging enabled the recognition of a pseudonormal type of transmitral flow velocity with high statistical significance through early (P = .000008) and late (P = .0003) expansion waves. The sensitivity and specificity in detecting LV diastolic dysfunction with TDI in the septal, anterior, inferior, posterior, and lateral walls were 90% and 87.3%, 87.3% and 90%, 87.3% and 90%, 84.8% and 90%, and 84.8 and 90%, respectively. In conclusion, TDI enabled the differentiation of patients with Chagas’ disease with normal LV diastolic function and those with the pathologic LV pseudonormal pattern with high statistical significance. Moreover, this article shows the potential in demonstrating the occurrence of major alterations in the LV performance of patients with Chagas’ disease with LV diastolic dysfunction, as well as the occurrence of signs of an increased LV filling pressure in those patients. (J Am Soc Echocardiogr 2001;14:353-9.)
INTRODUCTION Chagas’ disease is an infection caused by the protozoan Trypanosoma cruzi. The number of infected people in countries in Latin America is estimated to be about 18 million, resulting in great social and economic impact.1 Heart involvement in Chagas’ disease is the major mechanism responsible for the high From Ecoar, Noninvasive Diagnostic Medicine; and the Department of Medicine and Post-Graduation Course in Tropical Medicine, Faculty of Medicine/UFMG (Federal University of Minas Gerais); Belo Horizonte, MG, Brazil. Partially financed by CNPq and PRPq. Reprint requests: Dr Márcio Vinícius Lins Barros, Av. Contorno 6760, Santo Antônio, 30110-110 Belo Horizonte, MG, Brazil (E-mail: [email protected]). Copyright © 2001 by the American Society of Echocardiography. 0894-7317/2001/$35.00 + 0 27/1/111155 doi:10.1067/mje.2001.111155
morbidity and mortality rates in this population. Diastolic dysfunction has been demonstrated to occur even during the early stages of this disease.2 The analysis of transmitral flow by pulsed wave Doppler (PWD) has been used widely for the evaluation of left ventricular (LV) diastolic function. However, the great range of factors that may affect ventricular filling, especially those determining an increase in the diastolic pressure, may impose difficulties in the recognition of the abnormal filling pattern called pseudonormalization. This advanced degree of diastolic impairment frequently requires special maneuvers or other methods to unmask the underlying ventricular disfunction.3 Tissue Doppler imaging (TDI), a new technique recently incorporated in echocardiographic studies, enables the direct quantitative measurement of contraction and relaxation velocities of the cardiac mus353
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Table 1 Echocardiographic parameters in 89 patients with Chagas’ disease with normal (group 1) and altered (group 2) left ventricular diastolic function Group 1
LVDD (mm) LVSD (mm) LA (mm) EF (%) WMS
51.0 34.3 34.4 60.7 1.2
± ± ± ± ±
4.4 4.9 2.3 6.6 0.4
Group 2
63.0 47.4 42.9 37.9 2.1
± ± ± ± ±
7.4 10.4 4.3 7.2 0.3
Table 2 Diastolic function parameters in 89 patients with Chagas’ disease with normal (group 1) and altered (group 2) left ventricular diastolic function
P
Variable
.00001 .0003 .000001 .000001 .000002
E (cm/s) A (cm/s) E/A IVRT (ms) DT (ms) S (cm/s) D (cm/s) Ar (cm/s) Ad (ms)
LVDD, Left ventricular end-diastolic diameter; LVSD, left ventricular endsystolic diameter; LA, left atrial diameter; EF, left ventricular ejection fraction; WMS, wall motion score.
cle. Its usefulness has been demonstrated in the assessment of ventricular diastolic function, including the evaluation of cases that are difficult to interpret solely on the basis of the usual indexes obtained by conventional PWD.4 The aim of this study was to use TDI and PWD to compare patients with Chagas’ disease with normal LV diastolic function and those with a pseudonormal type of LV filling.
METHODS From January 1998 through April 1999, 89 patients with Chagas’ disease (41 women, 48 men) were selected with a prospective collection of data and were separated into 2 groups according to the pattern of LV diastolic filling as assessed by PWD. Group 1 consisted of 79 persons with a normal filling pattern, and group 2 comprised 10 persons with a pseudonormal filling pattern. The research project was examined and approved by the Committee of Research Ethics of the Federal University of Minas Gerais. All patients were selected after being screened with standardized clinical and physical examinations, electrocardiography, chest radiography, laboratory tests (complete blood cell count, creatinine, urea, glycemia, potassium, sodium, thyrotropin, and serum examinations for T. cruzi ), and Doppler echocardiography. We defined patients with Chagas’ disease as those persons whose serum tested positive for T. cruzi in at least 2 of the 3 different techniques available (reaction to indirect immunofluorescence, indirect hemagglutination, and enzyme-linked immunosorbent assay). Persons with the following were excluded: systemic arterial hypertension, coronary artery disease, rheumatic diseases, diabetes mellitus or glucose intolerance, thyroid dysfunction, kidney failure, chronic obstructive pulmonary disease, hydroelectrolytic disorders, or significant anemia and pregnancy. All patients were submitted to a complete Doppler echo-
Group 1
72.8 51.8 1.4 90.2 183.3 46.8 49.3 32.2 101.5
± ± ± ± ± ± ± ± ±
8.7 9.1 0.3 6.1 17.1 5.3 5.4 16.4 14.2
Group 2
74.2 44.0 1.9 93.0 195.4 37.8 57.0 41.9 134.3
± ± ± ± ± ± ± ± ±
16.8 16.0 0.2 10.5 37.3 5.4 4.1 2.6 6.1
P
.94 .05 .22 .24 .09 .0006 .0004 .0001 .00004
E, Peak early transmitral flow wave velocity; A, atrial contraction velocity; E/A, E/A ratio index; IVRT, isovolumic relaxation time; DT, early filling deceleration time; S, pulmonary venous systolic flow wave; D, pulmonary venous diastolic flow wave; Ar, pulmonary atrial reversal flow wave; Ad, duration of pulmonary atrial reversal flow wave.
cardiographic study with a commercially available ultrasonographic system equipped with TDI capabilities (ATL HDI 5000, Bothell,Wash).The following echocardiographic parameters were assessed: LV end-systolic and end-diastolic diameters, left atrial diameter, wall motion score, and LV ejection fraction through Simpson’s method. Pulsed wave Doppler recordings of transmitral flow were acquired from the apical 4-chamber view, with the Doppler sample volume placed at the level of the mitral valve leaflet tips for measuring peak early (E) wave and atrial contraction (A) wave velocities and early filling deceleration time (DT). Isovolumic relaxation time (IVRT) was measured by placing the Doppler sample volume at the LV outflow tract.The assessment of pulmonary venous flow was recorded by placing the sample volume 1 cm into the right upper pulmonary vein and measuring the peak systolic wave, diastolic wave, and atrial reversal wave velocities.To identify the pseudonormal LV filling pattern, we used the published criteria accepted by the Canadian Consensus on Diastolic Function.3 Tissue Doppler imaging was obtained by using the apical window at apical 4-chamber, apical 2-chamber, and long apical views for evaluating the septal, lateral, inferior, anterior, and posterior walls.The sample volume was placed at the basal portion of the referred walls to determine the longitudinal expansion velocities, which were obtained by measuring the initial (e´) and final (a´) diastolic velocities and the ratio between them from 3 averaged consecutive beats. The clinical and the echocardiographic data were analyzed with the statistic packages Epiinfo version 6 (Centers for Disease Control and Prevention–CDC, Atlanta, Ga), MINITAB version 11 (State College, Pa), and Analyse-IT version 1.50 for Windows (Analyse-IT Software, Ltd, Leeds, UK). In all tests, the alpha level was .05. The qualitative vari-
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Table 3 TDI early filling wave (e´) analysis in different walls of the left ventricle in 89 patients with Chagas’ disease with normal (group 1) and altered (group 2) left ventricular diastolic function Wall
Septal Lateral Anterior Posterior Inferior
Group 1 (cm/s)
14.1 16.5 16.5 15.3 14.5
± ± ± ± ±
2.8 3.7 3.2 4.0 3.9
Group 2 (cm/s)
8.9 10.6 9.9 7.9 7.9
± ± ± ± ±
1.5 3.2 2.4 3.6 3.0
Table 4 Tissue Doppler imaging late filling wave (a´) in different walls of the left ventricle in 89 patients with Chagas’ disease with normal (group 1) and altered (group 2) left ventricular diastolic function
P
Wall
.000008 .00016 .000006 .00004 .0003
Septal Lateral Anterior Posterior Inferior
ables of the two groups were compared with the chisquare test. The quantitative variables were described through mean and SD, and the two groups were compared with the Student t test. For each e´-wave TDI index, a receiver operating characteristic (ROC) curve was constructed, which plotted the sensitivity (true-positive rate) against 1-specificity (false-positive rate).
RESULTS The echocardiographic data are summarized in Table 1. Chamber dimensions and LV systolic parameters were significantly abnormal in patients with Chagas’ disease with LV diastolic dysfunction compared with those in patients with normal LV diastolic function. The analysis of the transmitral flow velocities data in both groups is displayed in Table 2. No significant statistical differences were found regarding the early and atrial contraction peak velocities, early and atrial peak velocities (E/A) ratio, IVRT, and DT. Tables 3 and 4 show the TDI data derived from the myocardium longitudinal expansion velocities in the several walls of the left ventricle through early (e´) and late (a´) filling waves. In all segments analyzed, the TDI E/A ratios were higher in group 1 than in group 2. A significant statistical difference was clearly seen among the various parameters in all walls assessed. Table 5 displays the results of the ROC curve for the e´-wave measurements, which were obtained to assess regional diastolic function in different walls of the left ventricle.The area under the curve is a measure of the discriminatory power of the variable tested (TDI index) to predict the outcome—in this case, the pseudonormal filling pattern.The larger the area under the ROC curve, the better the variable is at predicting group membership. Numerically, it ranges from 0 to 1, with 0 being indiscriminative and 1 being perfectly discriminative. The results demonstrate a reasonable accuracy of the e´ wave for this
Group 1 (cm/s)
Group 2 (cm/s)
7.6 7.9 7.6 7.5 7.1
6.0 6.3 6.1 5.3 4.9
± ± ± ± ±
1.6 1.7 1.2 2.0 1.6
± ± ± ± ±
1.1 1.5 1.1 1.3 1.3
P
.0003 .007 .0004 .0002 .0008
Table 5 Sensitivity and specificity of tissue Doppler imaging early filling wave (e´) by receiver operating characteristic curves in patients with Chagas’ disease with normal and abnormal left ventricular diastolic function Wall
Septal Lateral Anterior Posterior Inferior
Area*
Cuttoff point e´
Sensitivity (%)
Specificity (%)
0.932 0.866 0.937 0.897 0.903
11 13 12 10 9
89 84.8 87.3 84.8 87.3
87.3 90 90 90 90
*Area numeric values range from 0 to 1, with 0 being indiscriminative and 1 being perfectly discriminative.
purpose in all the walls evaluated, with sensitivity ranging from 84.8% to 90% and specificity ranging from 87.3% to 90%. Figure 1 shows PWD images of a patient with a pseudonormal pattern of transmitral flow velocity at rest and during Valsalva’s maneuver (A and B), and the pulmonary vein flow of the same patient (C) shows signs of elevated LV filling pressures.The TDI assessment of the basal portion of the septum (Figure 2) clearly shows a low-velocity early filling wave and an altered ratio between the early and late waves, implying the presence of an abnormal ventricular relaxation. Figure 3 illustrates the ROC curve from the early filling wave in the septal wall obtained with TDI, which indicates that this index accurately discriminates a pseudonormal filling pattern in this group of patients with Chagas’ disease.
DISCUSSION Chronic Chagas’ cardiomyopathy represents a serious myocarditis that usually determines multiple areas of focal fibrosis throughout the entire myocardium. This heart damage is histologically expressed
356 Barros et al
A
B
C Figure 1 Pulsed wave Doppler image of transmitral flow at rest (A) and during (B) Valsalva’s maneuver, showing a typical response of pseudonormal pattern. Pulmonary vein flow (C) shows a reversed A wave with high velocity (46 cm/s) and prolonged duration (130 ms), associated with a ratio S/D <1. E, Initial diastolic wave; A, final diastolic wave; S/D, pulmonary vein systolic flow to diastolic flow velocities ratio.
by a predominantly intrafascicular collagenous neoformation caused by the inflammatory process and replacement of myocells. Possible mechanisms for the myocardial damage are the continuous destruc-
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tion of myocells and the development of a nonuniform myocell hypertrophy. These result in major alterations of the cardiac fiber architecture and heavy damage to the microcirculation and excitoconductor system of the myocardium, culminating in progressive impairment of the organ and consequent heart failure.5 Assessment of LV filling provides an important contribution to our understanding of the severity of the physiologic damage caused by a cardiopathy. Many reports of diastolic function studies have identified LV filling as a cause of signs and symptoms in patients with no systolic dysfunction.6,7 The development of LV diastolic dysfunction carries a negative prognosis in the outcome of patients with several pathologic heart conditions, and sometimes the proper assessment of the LV filling physiology may represent one of the most important aspects of the global clinical decision-making and therapy strategy. Left ventricular diastolic dysfunction may be present in even the early stages of Chagas’ disease.2,8 In general terms, ventricular filling can be divided into two components: an active component, which is closely related to ventricular relaxation and predominates in the initial phases of the diastole (during the isovolumic relaxation and rapid filling), and a passive component, related to ventricular compliance and predominating in the last two thirds of diastole (during the period of diastasis and atrial contraction).9 Chagas’ cardiopathy may lead to impairment of both phases of LV filling. Initially, it alters ventricular relaxation and progressively causes disorders related to the compliance of the chamber.The mechanisms involved may result from alterations affecting different components of the heart, not only the myocardial fibers, but also the support system, interstice, excitoconductor system, autonomic nervous system, and vascular integrity.5,10 Even in a focal and less intense involvement of those structural components of the heart, impairment of LV filling may denote major damage of the left ventricle.2 Diastolic function parameters have been studied thoroughly already by PWD echocardiography with the use of transmitral and pulmonary venous flow dynamics.Those rates have proved useful in the evaluation of several physiologic parameters related to the diastolic function, such as relaxation, compliance, and ventricular filling pressure.11,12 The pulsed Doppler technique that is used to evaluate LV diastolic function through the assessment of transmitral flow presents a peculiar pattern, in which similar values may be found between subjects with normal filling patterns and those with major alterations of ventricular filling, represented by the pseudonormal type of filling. In subjects with a nor-
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Figure 2 Tissue Doppler image at basal septum of the same patient in Figure 1, demonstrating a low-velocity early expansion wave (e) associated with an inverted ratio between e and a waves. E, Inital diastolic wave; A, final diastolic wave.
mal pattern, the rapid-filling phase predominates over the late-filling phase (atrial contraction), resulting in an E/A ratio >1 and normal values for IVRT. Alterations in the ventricular relaxation (stage 1) slow the rapid-filling phase and, consequently, increase the participation of atrial contraction.As the diastolic dysfunction progresses, ventricular diastolic pressure increases; this results in an increase in preload and atrial pressure so that proper diastolic filling can be reestablished. These events determine an early opening of the mitral valve, which is accompanied by a decrease in the IVRT, an increase in the rapid-filling velocity as shown by the E wave, and a decrease in DT caused by rapid equalization between the pressures of the two chambers. Finally, a decrease in the A wave results from difficulties in emptying at the end of diastole because of a noncomplacent ventricle. During this phase, the mitral flow pattern may be similar to the one found in subjects with a normal pattern, characterizing pseudonormalization (stage 2). As the diastolic damage worsens, E-wave velocity increases progressively, and the A-wave velocity, IVRT, and DT decrease, characterizing a pattern called restrictive (stage 3). In such processes, pronounced alterations can be observed in the ventricular relaxation and compliance, which are associated with the increase in ventricular filling, the significant increase in atrial pressures, and, frequently, the contractile failure of that chamber.3,11-13 The analysis of the pulmonary venous flow and the use of maneuvers that decrease venous return14-16 are fundamental for the proper recognition of the pseudonormal flow pattern. However, it is not always possible to analyze all the components of the
Barros et al 357
Figure 3 Early-filling wave (e´ ) receiver operating characteristic curve plot (septal tissue Doppler imaging) in patients with Chagas’ disease with and without pseudonormal filling pattern. The number next to each label refers to cutoff value.
pulmonary venous flow correctly by means of transthoracic echocardiography nor by maneuvers such as Valsalva’s because of several factors that may affect the processing of the study and the results obtained (eg, an uncooperative patient, a restricted acoustic window, the technical expertise of the examiner). Tissue Doppler imaging has proved to be very promising for evaluating ventricular relaxation in several pathologic conditions.17-20 This method uses a “filter” to eliminate the signal coming from blood flow and to study the Doppler standard of expansion and contraction velocities of the cardiac muscle, characterized by high amplitudes and low velocities. Therefore, the characteristics of the motion of myocardial walls throughout the cardiac cycle can be analyzed quantitatively, enabling a more accurate analysis of the behavior of the myocardium.21,22 Furthermore, the expansion waves from the ventricular walls assessed by TDI are less influenced by load alterations, and they primarily relate to ventricular relaxation. In addition, a good correlation exists between the initial diastolic peak velocity and the ventricular relaxation measurements obtained through invasive methods at the catheterization laboratory.23,24 This study demonstrates the utility of TDI in discriminating pseudonormal types of transmitral flow patterns in patients with Chagas’ disease and no other evident cardiopathy. All indexes analyzed showed a significant statistical difference in all walls evaluated when compared with those of patients with Chagas’ disease and no evidence of diastolic dysfunction. In previous studies performed by our
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group, we demonstrated, for the first time, alterations in the contractility and relaxation of myocardial longitudinal fibers by using TDI in chronic Chagas’ cardiopathy in its many forms.8,25 This method has shown regional alterations in patients with Chagas’ disease when both systolic and diastolic functions are evaluated, demonstrating the precocity of the abnormalities caused by this pathology, even in asymptomatic patients. Moreover, we also observed in this study that the presence of more intense alterations in ventricular filling were always accompanied by impairment of the contractile function. In chronic Chagas’ disease, alterations in relaxation and compliance may be related to the degree of fibrosis resulting from the myocarditis, and therefore the presence of LV diastolic dysfunction with signs of increased ventricular filling pressures may have a prognostic importance. Among the limitations of this study, it is important to mention the noninvasive nature of the methods applied in this study to evaluate the LV diastolic function, together with the fact that the indexes assessed in these series of patients have never been validated in other studies.3,11-13,26 The measurements obtained by TDI are not related exclusively to the expansion of the myocardial fibers because they may also be influenced by the translational movement of the heart, though those effects were minimized by the use of the longitudinal axis for the analyses and measurements done at the cardiac base. Moreover, our main goal for the assessed data was not to obtain absolute values of the velocity of expansion of the myocardium, but to draw parallels between the two groups and to determine the correlation of the data to the transmitral flow velocities obtained by PWD. In conclusion, TDI enabled the differentiation of patients with Chagas’ disease with normal LV diastolic function and those with the pathologic pattern of pseudonormal diastolic function. The study also demonstrated the potential of TDI to show the occurrence of major alterations in the LV performance of patients with Chagas’ disease with LV diastolic dysfunction as well as the occurrence of signs of an increased LV filling pressure in those patients. Therefore the results observed in this series may be useful in the clinical risk stratification of this special group of patients with Chagas’ disease.
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REFERENCES 18. 1. World Health Organization Expert Committee. Chagas’ disease. In: World Organization Technical Report Series 697. Geneva: WHO; 1984. p. 50-5. 2. Cunha C. Estudo Doppler ecocardiográfico evolutivo da
função ventricular na forma indeterminada da doença de Chagas. Tese. Curitiba (Brasil): Universidade Federal do Paraná; 1997. Rakowski H, Appleton C, Chan KL, et al. Canadian consensus recommendations for the measurement and reporting of diastolic dysfunction by echocardiography. J Am Soc Echocardiogr 1996;9:736-60. Farias CA, Rodriquez L, Garcia MJ, Sun JP, Klein AL, Thomas JD. Assessment of diastolic function by tissue Doppler echocardiography: comparison with standard transmitral and pulmonary venous flow. J Am Soc Echocardiogr 1999;12:609-17. Bogliolo L. As causas anatômicas da insuficiência cardíaca na cardiopatia (miocardite) chagásica crônica, estudadas comparativamente com as causas anatômicas da insuficiência cardíaca noutras patologias. Parte 2. Arq Bras Cardiol 1976;29:479-83. Brutsaert DL, Sys SU, Gillebert TC. Diastolic failure: pathophysiology and therapeutic implications. J Am Coll Cardiol 1993;22:318-25. Rihal CS, Nishimura RA, Hatle LK, Bailey KR, Tajik AJ. Systolic and diastolic dysfunction in patients with clinical diagnosis of dilated cardiomyopathy: relation to symptoms and prognosis. Circulation 1994;90:2772-9. Barros MVL, Rocha MOC, Ribeiro ALP, Bittencourt R, Procópio R, Machado FS. Doppler Tissular e função diastólica na doença de Chagas. Rev Soc Bras Med Trop 1999;32 (Suppl ll):90-1. Nishimura RA, Abel MD, Hatle LK. Assessment of diastolic function of the heart: background and current applications of Doppler echocardiography. Part I: Physiologic and pathophysiologic features. Mayo Clin Proc 1989;64:71-81. Andrade ZA. Patologia da doença de Chagas. In: Brener Z, Andrade ZA, Barral-Neto M, editors. Trypanosoma Cruzi e doença de Chagas. Rio de Janeiro: Guanabara Koogan; 2000. p. 201-31. Appleton CP, Hatle LK. The natural history of left ventricular filling abnormalities: assessment by 2-dimensional and Doppler echocardiography. Echocardiography 1992;9:437-57. Grodecki PV, Klein AL. Pitfalls in the echo-Doppler assessment of diastolic dysfunction. Echocardiography 1993;10:213-34. Nishimura RA, Abel MD, Hatle LK. Assessment of diastolic function of the heart: background and current applications of Doppler echocardiography. Part II: Clinical studies. Mayo Clin Proc 1989;64:181-204. Jensen JL, Williams BJB, Johnson BL, Johnson BL, Miller LK, Ginter TL. Feasibility of obtaining pulmonary venous flow velocity in cardiac patients using transthoracic pulsed wave Doppler technique. J Am Soc Echocardiogr 1997;10:60-6. Dumesnil JG, Gaudreault G, Honos GN, et al. Use of Valsalva maneuver to unmask left ventricular diastolic function abnormalities by Doppler echocardiography in patients with coronary artery disease or systemic hypertension. Am J Cardiol 1991;68:515-9. Nishimura RA, Tajik AJ. The Valsalva maneuver and response revisited. Mayo Clin Proc 1986;61:211-7. Cardin N, Longo S, Ferreira T, Pereira T, Gouveia D, Pereira A, et al. Tissue Doppler echocardiography in the assessment of regional diastolic function in hypertrophic cardiomyopathy [abstract]. Eur Heart J 1996;17:2233. Garcia MJ, Rodriques L, Ares M, Griffin BP, Thomas JD, Klein AL. Differentiation of constrictive pericarditis from restrictive cardiomyopathy: assessment of left ventricular diastolic velocities in the longitudinal axis by Doppler tissue imaging. J Am Coll Cardiol 1996;27:108-14.
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19. Zamorano J, Wallbridge DR, Ge J, Drozd J, Nesser J, Erbel R. Assessment of cardiac physiology by tissue Doppler echocardiography. Eur Heart J 1997;18:330-9. 20. Garcia-Fernandez MA, Zamorano J, Azevedo J. Doppler tissue imaging in ischemic heart disease. In: Doppler tissue imaging echocardiography. Madrid: McGraw-Hill; 1998. p. 63-87. 21. Izaaz K, Thompson A, Ethevenot G, Gloez GL, Brembilla B, Pernot C. Doppler echocardiography measurement of low velocity motion of the left ventricular posterior wall. Am J Cardiol 1989;64:66-75. 22. Pai RG, Kanwaljit S. Amplitudes, durations and timings of apically directed left ventricular myocardial velocities. 1. Their normal pattern and coupling to ventricular filling and ejection. J Am Soc Echocardiogr 1998;11:112-8.
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23. Oki T, Tabata T, Yamada H, et al. Clinical application of pulsed Doppler tissue imaging for assessing abnormal left ventricular relaxation. Am J Cardiol 1997;79:921-8. 24. Sohn DW, Chai IH, Lee DJ, Kim HC, Kim HS, Oh BHl, et al. Assessment of mitral annular velocity by Doppler tissue imaging in the evaluation of left ventricular diastolic function. J Am Coll Cardiol 1997;30:474-80. 25. Barros MVL, Ribeiro ALP, Rocha MOC, Silva MG, Bittencourt RJ, Machado FS. Tissue Doppler echocardiography discloses early systolic ventricular dysfunction in Chagas’ disease [abstract]. Eur J Echocardiography 1999;Dec(Suppl):43. 26. Appleton CP, Hatle L, Popp RL. Relation of transmitral flow velocity patterns to left ventricular diastolic function; new insights from a combined hemodynamic and Doppler echocardiography study. J Am Coll Cardiol 1988;12:426-40.
The Doppler pseudonormal pattern of left ventricular (LV) diastolic function filling, characterized by apparent normal transmitral flow velocities, indicates advanced diastolic dysfunction with abnormal relaxation and compliance. Left ventricular diastolic dysfunction has been shown to occur in the early stages of the outcome of Chagas cardiopathy, and its identification may potentially contribute to the management of those patients. The aim of this study was to evaluate the usefulness of tissue Doppler imaging (TDI) in identifying LV diastolic dysfunction in patients with Chagas’ disease with pseudonormal transmitral flow. For this purpose, 89 patients with Chagas’ disease (48 men) who had no other pathology and showed normal (n = 79) or pseudonormal (n = 10) patterns of diastolic function by pulsed wave Doppler were submitted to TDI. A significant LV systolic impairment in terms of the dimensions (P = .00001), ejection fraction (P = .000001), and wall motion score (P = .000002) was observed in patients with diastolic dysfunction when compared with the
group with normal LV diastolic function. Tissue Doppler imaging enabled the recognition of a pseudonormal type of transmitral flow velocity with high statistical significance through early (P = .000008) and late (P = .0003) expansion waves. The sensitivity and specificity in detecting LV diastolic dysfunction with TDI in the septal, anterior, inferior, posterior, and lateral walls were 90% and 87.3%, 87.3% and 90%, 87.3% and 90%, 84.8% and 90%, and 84.8 and 90%, respectively. In conclusion, TDI enabled the differentiation of patients with Chagas’ disease with normal LV diastolic function and those with the pathologic LV pseudonormal pattern with high statistical significance. Moreover, this article shows the potential in demonstrating the occurrence of major alterations in the LV performance of patients with Chagas’ disease with LV diastolic dysfunction, as well as the occurrence of signs of an increased LV filling pressure in those patients. (J Am Soc Echocardiogr 2001;14:353-9.)
INTRODUCTION Chagas’ disease is an infection caused by the protozoan Trypanosoma cruzi. The number of infected people in countries in Latin America is estimated to be about 18 million, resulting in great social and economic impact.1 Heart involvement in Chagas’ disease is the major mechanism responsible for the high From Ecoar, Noninvasive Diagnostic Medicine; and the Department of Medicine and Post-Graduation Course in Tropical Medicine, Faculty of Medicine/UFMG (Federal University of Minas Gerais); Belo Horizonte, MG, Brazil. Partially financed by CNPq and PRPq. Reprint requests: Dr Márcio Vinícius Lins Barros, Av. Contorno 6760, Santo Antônio, 30110-110 Belo Horizonte, MG, Brazil (E-mail: [email protected]). Copyright © 2001 by the American Society of Echocardiography. 0894-7317/2001/$35.00 + 0 27/1/111155 doi:10.1067/mje.2001.111155
morbidity and mortality rates in this population. Diastolic dysfunction has been demonstrated to occur even during the early stages of this disease.2 The analysis of transmitral flow by pulsed wave Doppler (PWD) has been used widely for the evaluation of left ventricular (LV) diastolic function. However, the great range of factors that may affect ventricular filling, especially those determining an increase in the diastolic pressure, may impose difficulties in the recognition of the abnormal filling pattern called pseudonormalization. This advanced degree of diastolic impairment frequently requires special maneuvers or other methods to unmask the underlying ventricular disfunction.3 Tissue Doppler imaging (TDI), a new technique recently incorporated in echocardiographic studies, enables the direct quantitative measurement of contraction and relaxation velocities of the cardiac mus353
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354 Barros et al
Table 1 Echocardiographic parameters in 89 patients with Chagas’ disease with normal (group 1) and altered (group 2) left ventricular diastolic function Group 1
LVDD (mm) LVSD (mm) LA (mm) EF (%) WMS
51.0 34.3 34.4 60.7 1.2
± ± ± ± ±
4.4 4.9 2.3 6.6 0.4
Group 2
63.0 47.4 42.9 37.9 2.1
± ± ± ± ±
7.4 10.4 4.3 7.2 0.3
Table 2 Diastolic function parameters in 89 patients with Chagas’ disease with normal (group 1) and altered (group 2) left ventricular diastolic function
P
Variable
.00001 .0003 .000001 .000001 .000002
E (cm/s) A (cm/s) E/A IVRT (ms) DT (ms) S (cm/s) D (cm/s) Ar (cm/s) Ad (ms)
LVDD, Left ventricular end-diastolic diameter; LVSD, left ventricular endsystolic diameter; LA, left atrial diameter; EF, left ventricular ejection fraction; WMS, wall motion score.
cle. Its usefulness has been demonstrated in the assessment of ventricular diastolic function, including the evaluation of cases that are difficult to interpret solely on the basis of the usual indexes obtained by conventional PWD.4 The aim of this study was to use TDI and PWD to compare patients with Chagas’ disease with normal LV diastolic function and those with a pseudonormal type of LV filling.
METHODS From January 1998 through April 1999, 89 patients with Chagas’ disease (41 women, 48 men) were selected with a prospective collection of data and were separated into 2 groups according to the pattern of LV diastolic filling as assessed by PWD. Group 1 consisted of 79 persons with a normal filling pattern, and group 2 comprised 10 persons with a pseudonormal filling pattern. The research project was examined and approved by the Committee of Research Ethics of the Federal University of Minas Gerais. All patients were selected after being screened with standardized clinical and physical examinations, electrocardiography, chest radiography, laboratory tests (complete blood cell count, creatinine, urea, glycemia, potassium, sodium, thyrotropin, and serum examinations for T. cruzi ), and Doppler echocardiography. We defined patients with Chagas’ disease as those persons whose serum tested positive for T. cruzi in at least 2 of the 3 different techniques available (reaction to indirect immunofluorescence, indirect hemagglutination, and enzyme-linked immunosorbent assay). Persons with the following were excluded: systemic arterial hypertension, coronary artery disease, rheumatic diseases, diabetes mellitus or glucose intolerance, thyroid dysfunction, kidney failure, chronic obstructive pulmonary disease, hydroelectrolytic disorders, or significant anemia and pregnancy. All patients were submitted to a complete Doppler echo-
Group 1
72.8 51.8 1.4 90.2 183.3 46.8 49.3 32.2 101.5
± ± ± ± ± ± ± ± ±
8.7 9.1 0.3 6.1 17.1 5.3 5.4 16.4 14.2
Group 2
74.2 44.0 1.9 93.0 195.4 37.8 57.0 41.9 134.3
± ± ± ± ± ± ± ± ±
16.8 16.0 0.2 10.5 37.3 5.4 4.1 2.6 6.1
P
.94 .05 .22 .24 .09 .0006 .0004 .0001 .00004
E, Peak early transmitral flow wave velocity; A, atrial contraction velocity; E/A, E/A ratio index; IVRT, isovolumic relaxation time; DT, early filling deceleration time; S, pulmonary venous systolic flow wave; D, pulmonary venous diastolic flow wave; Ar, pulmonary atrial reversal flow wave; Ad, duration of pulmonary atrial reversal flow wave.
cardiographic study with a commercially available ultrasonographic system equipped with TDI capabilities (ATL HDI 5000, Bothell,Wash).The following echocardiographic parameters were assessed: LV end-systolic and end-diastolic diameters, left atrial diameter, wall motion score, and LV ejection fraction through Simpson’s method. Pulsed wave Doppler recordings of transmitral flow were acquired from the apical 4-chamber view, with the Doppler sample volume placed at the level of the mitral valve leaflet tips for measuring peak early (E) wave and atrial contraction (A) wave velocities and early filling deceleration time (DT). Isovolumic relaxation time (IVRT) was measured by placing the Doppler sample volume at the LV outflow tract.The assessment of pulmonary venous flow was recorded by placing the sample volume 1 cm into the right upper pulmonary vein and measuring the peak systolic wave, diastolic wave, and atrial reversal wave velocities.To identify the pseudonormal LV filling pattern, we used the published criteria accepted by the Canadian Consensus on Diastolic Function.3 Tissue Doppler imaging was obtained by using the apical window at apical 4-chamber, apical 2-chamber, and long apical views for evaluating the septal, lateral, inferior, anterior, and posterior walls.The sample volume was placed at the basal portion of the referred walls to determine the longitudinal expansion velocities, which were obtained by measuring the initial (e´) and final (a´) diastolic velocities and the ratio between them from 3 averaged consecutive beats. The clinical and the echocardiographic data were analyzed with the statistic packages Epiinfo version 6 (Centers for Disease Control and Prevention–CDC, Atlanta, Ga), MINITAB version 11 (State College, Pa), and Analyse-IT version 1.50 for Windows (Analyse-IT Software, Ltd, Leeds, UK). In all tests, the alpha level was .05. The qualitative vari-
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Barros et al 355
Table 3 TDI early filling wave (e´) analysis in different walls of the left ventricle in 89 patients with Chagas’ disease with normal (group 1) and altered (group 2) left ventricular diastolic function Wall
Septal Lateral Anterior Posterior Inferior
Group 1 (cm/s)
14.1 16.5 16.5 15.3 14.5
± ± ± ± ±
2.8 3.7 3.2 4.0 3.9
Group 2 (cm/s)
8.9 10.6 9.9 7.9 7.9
± ± ± ± ±
1.5 3.2 2.4 3.6 3.0
Table 4 Tissue Doppler imaging late filling wave (a´) in different walls of the left ventricle in 89 patients with Chagas’ disease with normal (group 1) and altered (group 2) left ventricular diastolic function
P
Wall
.000008 .00016 .000006 .00004 .0003
Septal Lateral Anterior Posterior Inferior
ables of the two groups were compared with the chisquare test. The quantitative variables were described through mean and SD, and the two groups were compared with the Student t test. For each e´-wave TDI index, a receiver operating characteristic (ROC) curve was constructed, which plotted the sensitivity (true-positive rate) against 1-specificity (false-positive rate).
RESULTS The echocardiographic data are summarized in Table 1. Chamber dimensions and LV systolic parameters were significantly abnormal in patients with Chagas’ disease with LV diastolic dysfunction compared with those in patients with normal LV diastolic function. The analysis of the transmitral flow velocities data in both groups is displayed in Table 2. No significant statistical differences were found regarding the early and atrial contraction peak velocities, early and atrial peak velocities (E/A) ratio, IVRT, and DT. Tables 3 and 4 show the TDI data derived from the myocardium longitudinal expansion velocities in the several walls of the left ventricle through early (e´) and late (a´) filling waves. In all segments analyzed, the TDI E/A ratios were higher in group 1 than in group 2. A significant statistical difference was clearly seen among the various parameters in all walls assessed. Table 5 displays the results of the ROC curve for the e´-wave measurements, which were obtained to assess regional diastolic function in different walls of the left ventricle.The area under the curve is a measure of the discriminatory power of the variable tested (TDI index) to predict the outcome—in this case, the pseudonormal filling pattern.The larger the area under the ROC curve, the better the variable is at predicting group membership. Numerically, it ranges from 0 to 1, with 0 being indiscriminative and 1 being perfectly discriminative. The results demonstrate a reasonable accuracy of the e´ wave for this
Group 1 (cm/s)
Group 2 (cm/s)
7.6 7.9 7.6 7.5 7.1
6.0 6.3 6.1 5.3 4.9
± ± ± ± ±
1.6 1.7 1.2 2.0 1.6
± ± ± ± ±
1.1 1.5 1.1 1.3 1.3
P
.0003 .007 .0004 .0002 .0008
Table 5 Sensitivity and specificity of tissue Doppler imaging early filling wave (e´) by receiver operating characteristic curves in patients with Chagas’ disease with normal and abnormal left ventricular diastolic function Wall
Septal Lateral Anterior Posterior Inferior
Area*
Cuttoff point e´
Sensitivity (%)
Specificity (%)
0.932 0.866 0.937 0.897 0.903
11 13 12 10 9
89 84.8 87.3 84.8 87.3
87.3 90 90 90 90
*Area numeric values range from 0 to 1, with 0 being indiscriminative and 1 being perfectly discriminative.
purpose in all the walls evaluated, with sensitivity ranging from 84.8% to 90% and specificity ranging from 87.3% to 90%. Figure 1 shows PWD images of a patient with a pseudonormal pattern of transmitral flow velocity at rest and during Valsalva’s maneuver (A and B), and the pulmonary vein flow of the same patient (C) shows signs of elevated LV filling pressures.The TDI assessment of the basal portion of the septum (Figure 2) clearly shows a low-velocity early filling wave and an altered ratio between the early and late waves, implying the presence of an abnormal ventricular relaxation. Figure 3 illustrates the ROC curve from the early filling wave in the septal wall obtained with TDI, which indicates that this index accurately discriminates a pseudonormal filling pattern in this group of patients with Chagas’ disease.
DISCUSSION Chronic Chagas’ cardiomyopathy represents a serious myocarditis that usually determines multiple areas of focal fibrosis throughout the entire myocardium. This heart damage is histologically expressed
356 Barros et al
A
B
C Figure 1 Pulsed wave Doppler image of transmitral flow at rest (A) and during (B) Valsalva’s maneuver, showing a typical response of pseudonormal pattern. Pulmonary vein flow (C) shows a reversed A wave with high velocity (46 cm/s) and prolonged duration (130 ms), associated with a ratio S/D <1. E, Initial diastolic wave; A, final diastolic wave; S/D, pulmonary vein systolic flow to diastolic flow velocities ratio.
by a predominantly intrafascicular collagenous neoformation caused by the inflammatory process and replacement of myocells. Possible mechanisms for the myocardial damage are the continuous destruc-
Journal of the American Society of Echocardiography May 2001
tion of myocells and the development of a nonuniform myocell hypertrophy. These result in major alterations of the cardiac fiber architecture and heavy damage to the microcirculation and excitoconductor system of the myocardium, culminating in progressive impairment of the organ and consequent heart failure.5 Assessment of LV filling provides an important contribution to our understanding of the severity of the physiologic damage caused by a cardiopathy. Many reports of diastolic function studies have identified LV filling as a cause of signs and symptoms in patients with no systolic dysfunction.6,7 The development of LV diastolic dysfunction carries a negative prognosis in the outcome of patients with several pathologic heart conditions, and sometimes the proper assessment of the LV filling physiology may represent one of the most important aspects of the global clinical decision-making and therapy strategy. Left ventricular diastolic dysfunction may be present in even the early stages of Chagas’ disease.2,8 In general terms, ventricular filling can be divided into two components: an active component, which is closely related to ventricular relaxation and predominates in the initial phases of the diastole (during the isovolumic relaxation and rapid filling), and a passive component, related to ventricular compliance and predominating in the last two thirds of diastole (during the period of diastasis and atrial contraction).9 Chagas’ cardiopathy may lead to impairment of both phases of LV filling. Initially, it alters ventricular relaxation and progressively causes disorders related to the compliance of the chamber.The mechanisms involved may result from alterations affecting different components of the heart, not only the myocardial fibers, but also the support system, interstice, excitoconductor system, autonomic nervous system, and vascular integrity.5,10 Even in a focal and less intense involvement of those structural components of the heart, impairment of LV filling may denote major damage of the left ventricle.2 Diastolic function parameters have been studied thoroughly already by PWD echocardiography with the use of transmitral and pulmonary venous flow dynamics.Those rates have proved useful in the evaluation of several physiologic parameters related to the diastolic function, such as relaxation, compliance, and ventricular filling pressure.11,12 The pulsed Doppler technique that is used to evaluate LV diastolic function through the assessment of transmitral flow presents a peculiar pattern, in which similar values may be found between subjects with normal filling patterns and those with major alterations of ventricular filling, represented by the pseudonormal type of filling. In subjects with a nor-
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Figure 2 Tissue Doppler image at basal septum of the same patient in Figure 1, demonstrating a low-velocity early expansion wave (e) associated with an inverted ratio between e and a waves. E, Inital diastolic wave; A, final diastolic wave.
mal pattern, the rapid-filling phase predominates over the late-filling phase (atrial contraction), resulting in an E/A ratio >1 and normal values for IVRT. Alterations in the ventricular relaxation (stage 1) slow the rapid-filling phase and, consequently, increase the participation of atrial contraction.As the diastolic dysfunction progresses, ventricular diastolic pressure increases; this results in an increase in preload and atrial pressure so that proper diastolic filling can be reestablished. These events determine an early opening of the mitral valve, which is accompanied by a decrease in the IVRT, an increase in the rapid-filling velocity as shown by the E wave, and a decrease in DT caused by rapid equalization between the pressures of the two chambers. Finally, a decrease in the A wave results from difficulties in emptying at the end of diastole because of a noncomplacent ventricle. During this phase, the mitral flow pattern may be similar to the one found in subjects with a normal pattern, characterizing pseudonormalization (stage 2). As the diastolic damage worsens, E-wave velocity increases progressively, and the A-wave velocity, IVRT, and DT decrease, characterizing a pattern called restrictive (stage 3). In such processes, pronounced alterations can be observed in the ventricular relaxation and compliance, which are associated with the increase in ventricular filling, the significant increase in atrial pressures, and, frequently, the contractile failure of that chamber.3,11-13 The analysis of the pulmonary venous flow and the use of maneuvers that decrease venous return14-16 are fundamental for the proper recognition of the pseudonormal flow pattern. However, it is not always possible to analyze all the components of the
Barros et al 357
Figure 3 Early-filling wave (e´ ) receiver operating characteristic curve plot (septal tissue Doppler imaging) in patients with Chagas’ disease with and without pseudonormal filling pattern. The number next to each label refers to cutoff value.
pulmonary venous flow correctly by means of transthoracic echocardiography nor by maneuvers such as Valsalva’s because of several factors that may affect the processing of the study and the results obtained (eg, an uncooperative patient, a restricted acoustic window, the technical expertise of the examiner). Tissue Doppler imaging has proved to be very promising for evaluating ventricular relaxation in several pathologic conditions.17-20 This method uses a “filter” to eliminate the signal coming from blood flow and to study the Doppler standard of expansion and contraction velocities of the cardiac muscle, characterized by high amplitudes and low velocities. Therefore, the characteristics of the motion of myocardial walls throughout the cardiac cycle can be analyzed quantitatively, enabling a more accurate analysis of the behavior of the myocardium.21,22 Furthermore, the expansion waves from the ventricular walls assessed by TDI are less influenced by load alterations, and they primarily relate to ventricular relaxation. In addition, a good correlation exists between the initial diastolic peak velocity and the ventricular relaxation measurements obtained through invasive methods at the catheterization laboratory.23,24 This study demonstrates the utility of TDI in discriminating pseudonormal types of transmitral flow patterns in patients with Chagas’ disease and no other evident cardiopathy. All indexes analyzed showed a significant statistical difference in all walls evaluated when compared with those of patients with Chagas’ disease and no evidence of diastolic dysfunction. In previous studies performed by our
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358 Barros et al
group, we demonstrated, for the first time, alterations in the contractility and relaxation of myocardial longitudinal fibers by using TDI in chronic Chagas’ cardiopathy in its many forms.8,25 This method has shown regional alterations in patients with Chagas’ disease when both systolic and diastolic functions are evaluated, demonstrating the precocity of the abnormalities caused by this pathology, even in asymptomatic patients. Moreover, we also observed in this study that the presence of more intense alterations in ventricular filling were always accompanied by impairment of the contractile function. In chronic Chagas’ disease, alterations in relaxation and compliance may be related to the degree of fibrosis resulting from the myocarditis, and therefore the presence of LV diastolic dysfunction with signs of increased ventricular filling pressures may have a prognostic importance. Among the limitations of this study, it is important to mention the noninvasive nature of the methods applied in this study to evaluate the LV diastolic function, together with the fact that the indexes assessed in these series of patients have never been validated in other studies.3,11-13,26 The measurements obtained by TDI are not related exclusively to the expansion of the myocardial fibers because they may also be influenced by the translational movement of the heart, though those effects were minimized by the use of the longitudinal axis for the analyses and measurements done at the cardiac base. Moreover, our main goal for the assessed data was not to obtain absolute values of the velocity of expansion of the myocardium, but to draw parallels between the two groups and to determine the correlation of the data to the transmitral flow velocities obtained by PWD. In conclusion, TDI enabled the differentiation of patients with Chagas’ disease with normal LV diastolic function and those with the pathologic pattern of pseudonormal diastolic function. The study also demonstrated the potential of TDI to show the occurrence of major alterations in the LV performance of patients with Chagas’ disease with LV diastolic dysfunction as well as the occurrence of signs of an increased LV filling pressure in those patients. Therefore the results observed in this series may be useful in the clinical risk stratification of this special group of patients with Chagas’ disease.
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19. Zamorano J, Wallbridge DR, Ge J, Drozd J, Nesser J, Erbel R. Assessment of cardiac physiology by tissue Doppler echocardiography. Eur Heart J 1997;18:330-9. 20. Garcia-Fernandez MA, Zamorano J, Azevedo J. Doppler tissue imaging in ischemic heart disease. In: Doppler tissue imaging echocardiography. Madrid: McGraw-Hill; 1998. p. 63-87. 21. Izaaz K, Thompson A, Ethevenot G, Gloez GL, Brembilla B, Pernot C. Doppler echocardiography measurement of low velocity motion of the left ventricular posterior wall. Am J Cardiol 1989;64:66-75. 22. Pai RG, Kanwaljit S. Amplitudes, durations and timings of apically directed left ventricular myocardial velocities. 1. Their normal pattern and coupling to ventricular filling and ejection. J Am Soc Echocardiogr 1998;11:112-8.
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23. Oki T, Tabata T, Yamada H, et al. Clinical application of pulsed Doppler tissue imaging for assessing abnormal left ventricular relaxation. Am J Cardiol 1997;79:921-8. 24. Sohn DW, Chai IH, Lee DJ, Kim HC, Kim HS, Oh BHl, et al. Assessment of mitral annular velocity by Doppler tissue imaging in the evaluation of left ventricular diastolic function. J Am Coll Cardiol 1997;30:474-80. 25. Barros MVL, Ribeiro ALP, Rocha MOC, Silva MG, Bittencourt RJ, Machado FS. Tissue Doppler echocardiography discloses early systolic ventricular dysfunction in Chagas’ disease [abstract]. Eur J Echocardiography 1999;Dec(Suppl):43. 26. Appleton CP, Hatle L, Popp RL. Relation of transmitral flow velocity patterns to left ventricular diastolic function; new insights from a combined hemodynamic and Doppler echocardiography study. J Am Coll Cardiol 1988;12:426-40.