- Email: [email protected]
Usefulness of pulsed tissue Doppler imaging for evaluating systolic and diastolic left ventricular function in patients with AL (primary) amyloidosis
Usefulness of Pulsed Tissue Doppler Imaging for Evaluating Systolic and Diastolic Left Ventricular Function in Patients With AL (Primary) Amyloidosis Jun Koyama,
MD, PhD,
Patricia A. Ray-Sequin, BS, Ravin Davidoff, Rodney H. Falk, MD
MBBCh,
and
To clarify whether pulsed tissue Doppler imaging at multiple left ventricular LV sites could help to explain the mechanism of congestive heart failure (CHF) in patients with primary amyloidosis, we examined 86 consecutive patients with primary amyloidosis confirmed by biopsy (group I, 31 patients without cardiac involvement; group II, 31 patients with evidence of heart involvement but no CHF; and group III, 24 patients with heart involvement, clinical CHF, and normal fractional shortening >28%). Peak early diastolic myocardial velocities in group II were significantly lower than those in group I, and the values in group III were also significantly lower than those in group II at most sites. In contrast to diastolic
abnormalities, peak systolic wall motion velocities in group III were significantly lower than those in group II, but there were no significant differences between groups I and II. Thus, cardiac amyloidosis is characterized by an initial impairment in early cardiac relaxation, whereas CHF is associated with an impairment of peak systolic wall motion velocities, most prominently seen in the longitudinal axis. This systolic dysfunction can be detected by pulsed tissue Doppler imaging, even when ejection fraction is in the normal range. 䊚2002 by Excerpta Medica, Inc. (Am J Cardiol 2002;89:1067–1071)
ardiac amyloidosis is associated with increased left ventricular (LV) wall thickness, normal or C decreased LV cavity size, and congestive heart failure
stomach (n ⫽ 5), nerve (n ⫽ 3), colon (n ⫽ 2), lung (n ⫽ 2), tongue (n ⫽ 2), and others (n ⫽ 8). AL amyloidosis was confirmed by the finding of a monoclonal protein in the serum or urine and/or a monoclonal population of plasma cells in the bone marrow when evaluated by immunohistochemistry.10 Patients with familial (n ⫽ 4), secondary (n ⫽ 2), and senile (n ⫽ 3) cardiac amyloidosis were excluded as were patients with a history of systemic hypertension or significant valvular heart disease, which may have caused LV hypertrophy. Patients with atrial fibrillation were also excluded because of the high beat-tobeat variability of the TDI velocities. Cardiac involvement was defined as the mean value of LV thickness (half of the sum of the thickness of ventricular septum and posterior walls) ⬎12 mm. The diagnosis of CHF was made by 1 of the investigators (RHF) who obtained a detailed history and examined each patient, but who had no knowledge of the results of TDI. Clinical CHF was defined as the existence of dyspnea on exertion, associated with orthopnea, paroxysmal nocturnal dyspnea, or a chest x-ray appearance of heart failure and/or the finding of elevated jugular venous pressure with peripheral edema. Sixty-five patients had evidence of cardiac involvement, of whom 34 had clinical CHF (CHF group). Ten patients in the CHF group had a fractional shortening below the lower limit of normal (⬍28%),21 and these were considered to have advanced amyloid heart disease and excluded from further analysis. The 31 patients who had cardiac involvement without CHF were defined as the “no-CHF” group. Thirty-one patients had no echocardiographic features of cardiac amyloid-
(CHF) with normal or mildly reduced LV ejection fraction.1–10 The initial manifestation of CHF in cardiac amyloidosis has been attributed to diastolic dysfunction, followed late in the disease by deterioration of systolic function.7,11–15 Pulsed tissue Doppler imaging (TDI) at the mitral annulus is a well-established method to estimate regional myocardial velocities,16 –20 and it may be a more sensitive indicator of cardiac function than standard measurements. However, there are few data evaluating the clinical value of TDI in cardiac amyloidosis. Such is the purpose of this study.
METHODS
Patient group: The study group consisted of 86 consecutive patients with AL (primary) amyloidosis. The diagnosis of amyloidosis was made by biopsy of an involved organ, which demonstrated the typical Congo-red birefringence when viewed under polarized light. The following organs underwent biopsy; kidney (n ⫽ 54), heart (n ⫽ 13), liver (n ⫽ 6),
From the Section of Cardiology, Boston University Medical Center, Boston, Massachusetts. This study was supported in part by a research grant from the Japan Health Sciences Foundation, by General Clinical Research Center, Grant M01RR00533 from the National Institutes of Health, Bethesda, Maryland, and by the Sue Sellors Finley Amyloid Fund. Manuscript received December 20, 2001; revised manuscript received and accepted January 26, 2002. Address for reprints: Rodney H. Falk, MD, Boston Medical Center, Section of Cardiology, 88 East Newton Street, Boston, Massachusetts 02118. E-mail: [email protected]. ©2002 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 89 May 1, 2002
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FIGURE 1. Position of the sample volumes in each cross-sectional view. ANT ⴝ anterior wall; 2CH ⴝ apical 2-chamber view; 4CH ⴝ apical 4-chamber view; INF ⴝ inferior wall; IVS ⴝ interventricular septum; LAT ⴝ lateral wall; PLAX ⴝ parasternal long-axis view; PW ⴝ posterior wall.
FIGURE 2. Measurements of pulsed TDI. Am ⴝ peak late diastolic wall motion velocity; ECG ⴝ electrocardiogram; Em ⴝ peak early diastolic wall motion velocity; PCG ⴝ phonocardiogram; Sm ⴝ peak systolic wall motion velocity.
osis and these patients were defined as the “noncardiac amyloid” group. The protocol was approved by the institutional review board, and written informed consent was obtained from each patient before ultrasound examination. Ultrasound examination: All ultrasound examinations were performed with a commercially available echocardiographic machine (Sonos 5500, HewlettPackard, Andover, Massachusetts) with simultaneous recording of phonocardiography. The thickness of the interventricular septum and LV posterior wall, and the LV end-diastolic and endsystolic diameters were determined from the M-mode at the level of chordae, and LV fractional shortening was calculated. LV end-diastolic and end-systolic volumes and ejection fraction were measured by the biplane (from apical 2- and 4-chamber views) modified Simpson method. Pulsed Doppler echocardiography of transmitral, pulmonary venous, and LV outflow tract flow velocities were performed, positioning a sample volume at the level of the mitral tips, the right upper pulmonary vein 1 cm below the ostium, and just below the aortic valve, respectively, in the apical 4-chamber view, and were recorded on VHS videotape at a speed of 100 mm/s. TDI was performed using harmonic imaging (S4 1068 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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probe, 1.8/3.6 MHz), and the gate length of regions of interest was set at 0.17 cm. Sample volumes were placed on the basal and midposterior walls in the parasternal long-axis view, and on the basal interventricular septum, basal lateral, basal inferior, and basal anterior walls in apical 2- and 4-chamber views (Figure 1). Measurements: The off-line analyses of transmitral flow, pulmonary venous flow, LV outflow tract flow, and TDI velocities were performed using computerized planimetry (Color Cine view, TomTec Imaging Systems, Colorado). Five or more consecutive beats were measured and averaged for each measurement. The peak velocities of early and late filling waves, early/late filling ratio of peak velocities, and deceleration time of early filling waves were measured from transmitral flow velocities, and the peak velocities of systolic, diastolic, and atrial contractile waves, and diastolic/systolic ratio of peak velocities were also measured from the pulmonary venous flow velocities. Isovolumic contraction time was measured as the time interval between the R wave and the onset of LV outflow, and isovolumic relaxation time was measured as the time interval between the second heart sound and the onset of transmitral flow. LV ejection time was measured as the duration of LV outflow velocity profile. Peak systolic wall motion velocities, peak early diastolic wall motion velocities, and peak late diastolic wall motion velocities were measured with TDI (Figure 2). All data of the ultrasound examination were analyzed by 1 investigator (JK) who was unaware of the patients’ clinical status. Statistics: All data are expressed as mean ⫾ SD. Statistical analyses were performed with a commercially available software program (Stat View 5.0, SAS Institute Inc., Cary, North Carolina). Differences among 3 groups were assessed with the chi-square test for categorical variables. Comparisons among groups were made using 1-way factorial analysis of variance, followed by the Scheffe´ test. A difference was considered significant when the p value was ⬍0.05.
RESULTS
Patient characteristics: Clinical characteristics and 2-dimensional echocardiographic measurements are MAY 1, 2002
TABLE 1 Patient Characteristics
Groups Age (yrs) Men/women Heart rate (beats/min) Mean LV thickness (mm) LV end-diastolic diameter (mm) LV end-systolic diameter (mm) Fractional shortening (%) Left atrial diameter (mm) LV end-diastolic volume (ml) LV end-systolic volume (ml) Ejection fraction (%)
CHF (FS ⬎28%)
Noncardiac Amyloid (n ⫽ 31)
⫺ (n ⫽ 31)
⫹ (n ⫽ 24)
58 ⫾ 10 16/15 71 ⫾ 12 10 ⫾ 1 47 ⫾ 6 28 ⫾ 5 39 ⫾ 10 38 ⫾ 5 89 ⫾ 29 31 ⫾ 16 67 ⫾ 9
61 ⫾ 11 20/11 71 ⫾ 12 14 ⫾ 2* 44 ⫾ 8 27 ⫾ 7 39 ⫾ 9 38 ⫾ 6 88 ⫾ 26 28 ⫾ 12 69 ⫾ 7
63 ⫾ 9 14/10 77 ⫾ 12 16 ⫾ 3*† 44 ⫾ 8 28 ⫾ 6 36 ⫾ 7 40 ⫾ 9 84 ⫾ 31 29 ⫾ 15 66 ⫾ 7
*p ⬍0.0001 versus noncardiac amyloid; †p ⬍0.0001 versus no CHF (by the Scheffe´ test). Values are expressed as mean ⫾ SD. FS ⫽ fractional shortening.
TABLE 2 Doppler Flow Data
Groups Transmitral flow-peak E velocity (m/s) Transmitral flow-peak A velocity (m/s) Transmitral flow E/A Deceleration time of transmitral flow (m/s) Pulmonary venous flow peak S velocity (m/s) Pulmonary venous flow peak D velocity (m/s) Pulmonary venous flow peak A velocity (m/s) Pulmonary venous flow D/S Isovolumic contraction time (m/s) Isovolumic relaxation time (m/s) Ejection time (m/s)
CHF (FS ⬎28%)
Noncardiac Amyloid (n ⫽ 31)
⫺ (n ⫽ 31)
⫹ (n ⫽ 24)
0.74 ⫾ 0.19
0.77 ⫾ 0.28
0.84 ⫾ 0.28
0.75 ⫾0.15
0.87 ⫾ 0.24
0.67 ⫾ 0.25†
1.01 ⫾ 0.25 180 ⫾ 54
0.91 ⫾ 0.33 160 ⫾ 69
1.53 ⫾ 1.10† 134 ⫾ 44*
0.60 ⫾ 0.15
0.56 ⫾ 0.16
0.46 ⫾ 0.14*
0.45 ⫾ 0.13
0.42 ⫾ 0.11
0.49 ⫾ 0.15
0.32 ⫾ 0.12
0.33 ⫾ 0.19
0.27 ⫾ 0.08
0.79 ⫾ 0.38 83 ⫾ 21
0.84 ⫾ 0.44 82 ⫾ 20
1.26 ⫾ 0.81 87 ⫾ 24
75 ⫾ 19
79 ⫾ 23
75 ⫾ 27
300 ⫾ 30
290 ⫾ 39
264 ⫾ 29‡
*p ⬍0.05 versus noncardiac amyloid; †p ⬍0.05 versus no CHF; ‡p ⬍0.01 versus noncardiac amyloid (by the Scheffe´ test). Values are expressed as mean ⫾ SD. Abbreviation as in Table 1.
listed in Table 1. The mean value of LV thickness was significantly different among the 3 groups, but there were no differences in fractional shortening and LV ejection fraction. Doppler measurements: Indexes of transmitral flow, pulmonary venous flow, and Doppler time intervals are listed in Table 2. The transmitral E-wave velocity did not differ significantly among the patient groups. The transmitral A-wave velocity and E-wave deceleration time in the group with CHF were significantly lower than in the other 2 groups. Similar differences were seen in the measurements of pulmonary venous flow. The peak velocity of the systolic wave of the pulmonary venous flow did not differ among groups. There was a trend to higher
diastolic/systolic ratios of pulmonary venous flow in the group with CHF, but this did not reach statistical significance. With regard to time intervals, there was no difference in isovolumic contraction or relaxation time among groups, but the ejection time was shorter in the group with CHF. Tissue Doppler measurements: Figure 3 shows peak systolic wall motion velocities, peak early diastolic wall motion velocities, and peak late diastolic wall motion velocities, respectively, at the various walls. There was a relative difference in velocities at these sites, which was preserved in each group. Peak systolic wall motion velocities did not differ between the noncardiac amyloid and no-CHF groups (Figure 3A). In contrast to the lack of difference in fractional shortening, patients with CHF had significantly reduced systolic components of TDI. Diastolic abnormalities are well recognized in cardiac amyloidosis, and were reflected by a decreased early diastolic wall motion velocity wave when patients with evidence of cardiac amyloid were compared with those with no evidence (Figure 3B). The pattern of peak late diastolic wall motion velocities was similar to that of peak systolic wall motion velocities (Figure 3C), with no significant difference between the noncardiac amyloid and no-CHF groups, but a significant difference at almost all sites in the CHF group.
DISCUSSION
In our study, 86 consecutively examined patients with AL amyloidosis and a normal LV fractional shortening were divided into 3 groups according to the existence of CHF and echocardiographic cardiac involvement. Although LV diastolic dysfunction was confirmed by Doppler echocardiography, it was shown more easily with TDI than standard Doppler echocardiography. TDI data indicate that peak early diastolic wall motion velocity is decreased in most walls before the onset of CHF and that it decreases further once CHF occurs. Patients in this study were selected to include only those with a normal fractional shortening to investigate whether this was an accurate reflection of normal systolic function, and 10 patients were excluded because of a reduced fractional shortening (⬍28%). Fractional shortening is a measure of the change in ventricular short-axis dimension, whereas TDI can measure long-axis contraction. No difference in fractional shortening could be
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initially characterized by an impairment in early regional myocardial relaxation, but that the presence of CHF is associated with impairment of longitudinal LV contraction even when fractional shortening is normal. Longitudinal contractile dysfunction has been described in a variety of cardiac conditions,19,22 and our data suggest that it may be a previously unrecognized contributory feature to heart failure in amyloidosis. As expected, patients with CHF had significant abnormalities in transmitral and pulmonary venous flow.13–15 However, despite the presence of myocardial infiltration, the group of patients without CHF could not be distinguished from the noncardiac amyloid group by these indexes. Despite the similarities in transmitral and pulmonary venous flow between the noncardiac amyloid and no-CHF groups, TDI clearly showed a significant difference, suggesting that TDI is not only capable of detecting longitudinal systolic dysfunction, but is also more sensitive than Doppler flow measurements for detecting diastolic abnormalities. The finding that systolic wall motion velocities were only seen in the presence of CHF, whereas diastolic abnormalities were seen in the presence of asymptomatic amyloid infiltration of the left ventricle suggests that CHF in cardiac amyloidosis is not, as previously believed, primarily a diastolic abnormality, but that longitudinal systolic dysfunction may be a prerequisite.
FIGURE 3. A, Sm at various walls. The values of Sm at basal PW, IVS, Lat, and Inf in the group with CHF were significantly lower than those in the noncardiac amyloid (circles) and/or noCHF (squares) groups. *p <0.05 versus noncardiac amyloid; †p <0.05 versus no-CHF; ‡p <0.01 versus noncardiac amyloid. B, Em at various walls. The values of Em at basal PW, IVS, Lat, and Ant in the no-CHF group were significantly lower than those in the noncardiac amyloid group, and those values at almost all sites in the group with CHF were significantly lower than those in the noncardiac amyloid group. *p <0.05 versus noncardiac amyloid; †p <0.01 versus noncardiac amyloid; ‡p <0.001 versus noncardiac amyloid; §p <0.0001 versus noncardiac amyloid, 㥋p <0.05 versus no-CHF. C, Am at various walls. The values of Am at IVS, and Inf in the CHF group (fractional shortening [FS]>28%, triangles) were significantly lower than those in both the noncardiac amyloid and no-CHF groups. *p <0.05 versus noncardiac amyloid; †p <0.0001 versus noncardiac amyloid; ‡p <0.05 versus no-CHF; §p <0.01 versus no-CHF. Abbreviations as in Figures 1 and 2.
demonstrated among the 3 groups studied. The peak systolic wall motion velocities measured by TDI showed no significant difference between the noncardiac amyloid and no-CHF groups. However, in contrast to preserved fractional shortening, clinical evidence of CHF was associated with reduced values of longitudinal ventricular contraction at all sites measured. These results suggest that cardiac amyloidosis is 1070 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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1. Swanton RH, Brooksby IAB, Davies MJ, Coltart DJ, Jenkins BS, Webb-Peploe MM. Systolic and diastolic ventricular function in cardiac amyloidosis. Am J Cardiol 1977;39:658 –664. 2. Child JS, Krivokapich J, Abbasi AS. Increased right ventricular wall thickness on echocardiography in amyloid infiltrative cardiomyopathy. Am J Cardiol 1979; 44:1391–1395. 3. Siqueira-Filho AG, Cunha CLP, Tajik AJ, Seward JB, Schattenberg TT, Giuliani ER. M-mode and two-dimensional echocardiographic features in cardiac amyloidosis. Circulation 1981;63:188 –196. 4. St John Sutton MG, Reichek N, Kastor JA, Giuliani ER. Computerized M-mode echocardiographic analysis of left ventricular dysfunction in cardiac amyloid. Circulation 1982;66:790 –799. 5. Roberts WC, Waller BF. Cardiac amyloidosis causing cardiac dysfunction: analysis of 54 necropsy patients. Am J Cardiol 1983;52:137–146. 6. Falk RH, Rubinow A, Cohen AS. Cardiac arrhythmias in systemic amyloidosis: correlation with echocardiographic abnormalities. J Am Coll Cardiol 1984; 3:107–113. 7. Cueto-Garcia L, Reeder GS, Kyle RA, Wood DL, Seward JB, Naessens J, Offord KP, Greipp PR, Edwards WD, Tajik AJ. Echocardiographic findings in systemic amyloidosis: spectrum of cardiac involvement and relation to survival. J Am Coll Cardiol 1985;6:737–743. 8. Falk RH, Plehn JF, Deering T, Schick EC, Boinay P, Rubinow A, Skinner M, Cohen AS. Sensitivity and specificity of the echocardiographic features of cardiac amyloidosis. Am J Cardiol 1987;59:418 –422. 9. Plehn JF, Friedman BJ. Diastolic dysfunction in amyloid heart disease: restrictive cardiomyopathy or not? J Am Coll Cardiol 1989;13:54 –56. 10. Falk RH, Comenzo RL, Skinner M. The systemic amyloidosis. N Engl J Med 1997;337:898 –909. 11. Benotti JR, Grossman W, Cohn PF. Clinical profile of restrictive cardiomyopathy. Circulation 1980;61:1206 –1212. 12. Tyberg TI, Goodyer AVN, Hurst VW III, Alexander J, Langou RA. Left ventricular filling in differentiating restrictive amyloid cardiomyopathy and constrictive pericarditis. Am J Cardiol 1981:791–796. 13. Klein AL, Hatle LK, Burstow DJ, Seward JB, Kyle RA, Bailey KR, Luscher TF, Gertz MA, Tajik AJ. Doppler characterization of left ventricular diastolic function in cardiac amyloidosis. J Am Coll Cardiol 1989;13:1017–1026. 14. Klein AL, Hatle LK, Taliercio CP, Taylor CL, Kyle RA, Bailey KR, Seward JB, Tajik AJ. Serial Doppler echocardiographic follow-up of left ventricular diastolic function in cardiac amyloidosis. J Am Coll Cardiol 1990;16:1135–1141.
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15. Klein AL, Hatle LK, Taliercio CP, Oh KJ, Kyle RA, Gertz MA, Bailey KR, Seward JB, Tajik AJ. Prognostic significance of Doppler measures of diastolic function in cardiac amyloidosis. Circulation 1991;83:808 –816. 16. Garcia MJ, Rodriguez L, Ares M, Griffin BP, Thomas JD, Klein AL. Differentiation of constrictive pericarditis from restrictive cardiomyopathy: assessment of left ventricular diastolic velocities in longitudinal axis by Doppler tissue imaging. J Am Coll Cardiol 1996;27:108 –114. 17. Oki T, Tabata T, Yamada H, Abe M, Onose Y, Wakatsuki T, Fujinaga H, Sakabe K, Ikata J, Nishikado A, Iuchi A, Ito S. Right and left ventricular wall motion velocities as diagnostic indicators of constrictive pericarditis. Am J Cardiol 1998;81:465–470. 18. Oki T, Mishiro Y, Yamada H, Onose Y, Matsuoka M, Wakatsuki T, Tabata T, Ito S. Detection of left ventricular regional relaxation abnormalities and
asynchrony in patients with hypertrophic cardiomyopathy with the use of tissue Doppler imaging. Am Heart J 2000;139:497–502. 19. 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 –36. 20. Oki T, Tabata T, Yamada H, Wakatsuki T, Shinohara H, Nishikado A, Iuchi A, Fukuda N, Ito S. Clinical application of pulsed Doppler tissue imaging for assessing abnormal left ventricular relaxation. Am J Cardiol 1997;79:921–928. 21. Gardin JM, Henry WL, Savage DD, Ware JH, Burn C, Borer JS. Echocardiographic measurements in normal subjects: evaluation of an adult population without clinically apparent heart disease. J Clin Ultrasound 1979;7:439 –447. 22. Jones CJH, Raposo L, Gibson DG. Functional importance of the long axis dynamics of the human left ventricle. Br Heart J 1990;63:215–220.
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MD, PhD,
Patricia A. Ray-Sequin, BS, Ravin Davidoff, Rodney H. Falk, MD
MBBCh,
and
To clarify whether pulsed tissue Doppler imaging at multiple left ventricular LV sites could help to explain the mechanism of congestive heart failure (CHF) in patients with primary amyloidosis, we examined 86 consecutive patients with primary amyloidosis confirmed by biopsy (group I, 31 patients without cardiac involvement; group II, 31 patients with evidence of heart involvement but no CHF; and group III, 24 patients with heart involvement, clinical CHF, and normal fractional shortening >28%). Peak early diastolic myocardial velocities in group II were significantly lower than those in group I, and the values in group III were also significantly lower than those in group II at most sites. In contrast to diastolic
abnormalities, peak systolic wall motion velocities in group III were significantly lower than those in group II, but there were no significant differences between groups I and II. Thus, cardiac amyloidosis is characterized by an initial impairment in early cardiac relaxation, whereas CHF is associated with an impairment of peak systolic wall motion velocities, most prominently seen in the longitudinal axis. This systolic dysfunction can be detected by pulsed tissue Doppler imaging, even when ejection fraction is in the normal range. 䊚2002 by Excerpta Medica, Inc. (Am J Cardiol 2002;89:1067–1071)
ardiac amyloidosis is associated with increased left ventricular (LV) wall thickness, normal or C decreased LV cavity size, and congestive heart failure
stomach (n ⫽ 5), nerve (n ⫽ 3), colon (n ⫽ 2), lung (n ⫽ 2), tongue (n ⫽ 2), and others (n ⫽ 8). AL amyloidosis was confirmed by the finding of a monoclonal protein in the serum or urine and/or a monoclonal population of plasma cells in the bone marrow when evaluated by immunohistochemistry.10 Patients with familial (n ⫽ 4), secondary (n ⫽ 2), and senile (n ⫽ 3) cardiac amyloidosis were excluded as were patients with a history of systemic hypertension or significant valvular heart disease, which may have caused LV hypertrophy. Patients with atrial fibrillation were also excluded because of the high beat-tobeat variability of the TDI velocities. Cardiac involvement was defined as the mean value of LV thickness (half of the sum of the thickness of ventricular septum and posterior walls) ⬎12 mm. The diagnosis of CHF was made by 1 of the investigators (RHF) who obtained a detailed history and examined each patient, but who had no knowledge of the results of TDI. Clinical CHF was defined as the existence of dyspnea on exertion, associated with orthopnea, paroxysmal nocturnal dyspnea, or a chest x-ray appearance of heart failure and/or the finding of elevated jugular venous pressure with peripheral edema. Sixty-five patients had evidence of cardiac involvement, of whom 34 had clinical CHF (CHF group). Ten patients in the CHF group had a fractional shortening below the lower limit of normal (⬍28%),21 and these were considered to have advanced amyloid heart disease and excluded from further analysis. The 31 patients who had cardiac involvement without CHF were defined as the “no-CHF” group. Thirty-one patients had no echocardiographic features of cardiac amyloid-
(CHF) with normal or mildly reduced LV ejection fraction.1–10 The initial manifestation of CHF in cardiac amyloidosis has been attributed to diastolic dysfunction, followed late in the disease by deterioration of systolic function.7,11–15 Pulsed tissue Doppler imaging (TDI) at the mitral annulus is a well-established method to estimate regional myocardial velocities,16 –20 and it may be a more sensitive indicator of cardiac function than standard measurements. However, there are few data evaluating the clinical value of TDI in cardiac amyloidosis. Such is the purpose of this study.
METHODS
Patient group: The study group consisted of 86 consecutive patients with AL (primary) amyloidosis. The diagnosis of amyloidosis was made by biopsy of an involved organ, which demonstrated the typical Congo-red birefringence when viewed under polarized light. The following organs underwent biopsy; kidney (n ⫽ 54), heart (n ⫽ 13), liver (n ⫽ 6),
From the Section of Cardiology, Boston University Medical Center, Boston, Massachusetts. This study was supported in part by a research grant from the Japan Health Sciences Foundation, by General Clinical Research Center, Grant M01RR00533 from the National Institutes of Health, Bethesda, Maryland, and by the Sue Sellors Finley Amyloid Fund. Manuscript received December 20, 2001; revised manuscript received and accepted January 26, 2002. Address for reprints: Rodney H. Falk, MD, Boston Medical Center, Section of Cardiology, 88 East Newton Street, Boston, Massachusetts 02118. E-mail: [email protected]. ©2002 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 89 May 1, 2002
0002-9149/02/$–see front matter PII S0002-9149(02)02277-4
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FIGURE 1. Position of the sample volumes in each cross-sectional view. ANT ⴝ anterior wall; 2CH ⴝ apical 2-chamber view; 4CH ⴝ apical 4-chamber view; INF ⴝ inferior wall; IVS ⴝ interventricular septum; LAT ⴝ lateral wall; PLAX ⴝ parasternal long-axis view; PW ⴝ posterior wall.
FIGURE 2. Measurements of pulsed TDI. Am ⴝ peak late diastolic wall motion velocity; ECG ⴝ electrocardiogram; Em ⴝ peak early diastolic wall motion velocity; PCG ⴝ phonocardiogram; Sm ⴝ peak systolic wall motion velocity.
osis and these patients were defined as the “noncardiac amyloid” group. The protocol was approved by the institutional review board, and written informed consent was obtained from each patient before ultrasound examination. Ultrasound examination: All ultrasound examinations were performed with a commercially available echocardiographic machine (Sonos 5500, HewlettPackard, Andover, Massachusetts) with simultaneous recording of phonocardiography. The thickness of the interventricular septum and LV posterior wall, and the LV end-diastolic and endsystolic diameters were determined from the M-mode at the level of chordae, and LV fractional shortening was calculated. LV end-diastolic and end-systolic volumes and ejection fraction were measured by the biplane (from apical 2- and 4-chamber views) modified Simpson method. Pulsed Doppler echocardiography of transmitral, pulmonary venous, and LV outflow tract flow velocities were performed, positioning a sample volume at the level of the mitral tips, the right upper pulmonary vein 1 cm below the ostium, and just below the aortic valve, respectively, in the apical 4-chamber view, and were recorded on VHS videotape at a speed of 100 mm/s. TDI was performed using harmonic imaging (S4 1068 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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probe, 1.8/3.6 MHz), and the gate length of regions of interest was set at 0.17 cm. Sample volumes were placed on the basal and midposterior walls in the parasternal long-axis view, and on the basal interventricular septum, basal lateral, basal inferior, and basal anterior walls in apical 2- and 4-chamber views (Figure 1). Measurements: The off-line analyses of transmitral flow, pulmonary venous flow, LV outflow tract flow, and TDI velocities were performed using computerized planimetry (Color Cine view, TomTec Imaging Systems, Colorado). Five or more consecutive beats were measured and averaged for each measurement. The peak velocities of early and late filling waves, early/late filling ratio of peak velocities, and deceleration time of early filling waves were measured from transmitral flow velocities, and the peak velocities of systolic, diastolic, and atrial contractile waves, and diastolic/systolic ratio of peak velocities were also measured from the pulmonary venous flow velocities. Isovolumic contraction time was measured as the time interval between the R wave and the onset of LV outflow, and isovolumic relaxation time was measured as the time interval between the second heart sound and the onset of transmitral flow. LV ejection time was measured as the duration of LV outflow velocity profile. Peak systolic wall motion velocities, peak early diastolic wall motion velocities, and peak late diastolic wall motion velocities were measured with TDI (Figure 2). All data of the ultrasound examination were analyzed by 1 investigator (JK) who was unaware of the patients’ clinical status. Statistics: All data are expressed as mean ⫾ SD. Statistical analyses were performed with a commercially available software program (Stat View 5.0, SAS Institute Inc., Cary, North Carolina). Differences among 3 groups were assessed with the chi-square test for categorical variables. Comparisons among groups were made using 1-way factorial analysis of variance, followed by the Scheffe´ test. A difference was considered significant when the p value was ⬍0.05.
RESULTS
Patient characteristics: Clinical characteristics and 2-dimensional echocardiographic measurements are MAY 1, 2002
TABLE 1 Patient Characteristics
Groups Age (yrs) Men/women Heart rate (beats/min) Mean LV thickness (mm) LV end-diastolic diameter (mm) LV end-systolic diameter (mm) Fractional shortening (%) Left atrial diameter (mm) LV end-diastolic volume (ml) LV end-systolic volume (ml) Ejection fraction (%)
CHF (FS ⬎28%)
Noncardiac Amyloid (n ⫽ 31)
⫺ (n ⫽ 31)
⫹ (n ⫽ 24)
58 ⫾ 10 16/15 71 ⫾ 12 10 ⫾ 1 47 ⫾ 6 28 ⫾ 5 39 ⫾ 10 38 ⫾ 5 89 ⫾ 29 31 ⫾ 16 67 ⫾ 9
61 ⫾ 11 20/11 71 ⫾ 12 14 ⫾ 2* 44 ⫾ 8 27 ⫾ 7 39 ⫾ 9 38 ⫾ 6 88 ⫾ 26 28 ⫾ 12 69 ⫾ 7
63 ⫾ 9 14/10 77 ⫾ 12 16 ⫾ 3*† 44 ⫾ 8 28 ⫾ 6 36 ⫾ 7 40 ⫾ 9 84 ⫾ 31 29 ⫾ 15 66 ⫾ 7
*p ⬍0.0001 versus noncardiac amyloid; †p ⬍0.0001 versus no CHF (by the Scheffe´ test). Values are expressed as mean ⫾ SD. FS ⫽ fractional shortening.
TABLE 2 Doppler Flow Data
Groups Transmitral flow-peak E velocity (m/s) Transmitral flow-peak A velocity (m/s) Transmitral flow E/A Deceleration time of transmitral flow (m/s) Pulmonary venous flow peak S velocity (m/s) Pulmonary venous flow peak D velocity (m/s) Pulmonary venous flow peak A velocity (m/s) Pulmonary venous flow D/S Isovolumic contraction time (m/s) Isovolumic relaxation time (m/s) Ejection time (m/s)
CHF (FS ⬎28%)
Noncardiac Amyloid (n ⫽ 31)
⫺ (n ⫽ 31)
⫹ (n ⫽ 24)
0.74 ⫾ 0.19
0.77 ⫾ 0.28
0.84 ⫾ 0.28
0.75 ⫾0.15
0.87 ⫾ 0.24
0.67 ⫾ 0.25†
1.01 ⫾ 0.25 180 ⫾ 54
0.91 ⫾ 0.33 160 ⫾ 69
1.53 ⫾ 1.10† 134 ⫾ 44*
0.60 ⫾ 0.15
0.56 ⫾ 0.16
0.46 ⫾ 0.14*
0.45 ⫾ 0.13
0.42 ⫾ 0.11
0.49 ⫾ 0.15
0.32 ⫾ 0.12
0.33 ⫾ 0.19
0.27 ⫾ 0.08
0.79 ⫾ 0.38 83 ⫾ 21
0.84 ⫾ 0.44 82 ⫾ 20
1.26 ⫾ 0.81 87 ⫾ 24
75 ⫾ 19
79 ⫾ 23
75 ⫾ 27
300 ⫾ 30
290 ⫾ 39
264 ⫾ 29‡
*p ⬍0.05 versus noncardiac amyloid; †p ⬍0.05 versus no CHF; ‡p ⬍0.01 versus noncardiac amyloid (by the Scheffe´ test). Values are expressed as mean ⫾ SD. Abbreviation as in Table 1.
listed in Table 1. The mean value of LV thickness was significantly different among the 3 groups, but there were no differences in fractional shortening and LV ejection fraction. Doppler measurements: Indexes of transmitral flow, pulmonary venous flow, and Doppler time intervals are listed in Table 2. The transmitral E-wave velocity did not differ significantly among the patient groups. The transmitral A-wave velocity and E-wave deceleration time in the group with CHF were significantly lower than in the other 2 groups. Similar differences were seen in the measurements of pulmonary venous flow. The peak velocity of the systolic wave of the pulmonary venous flow did not differ among groups. There was a trend to higher
diastolic/systolic ratios of pulmonary venous flow in the group with CHF, but this did not reach statistical significance. With regard to time intervals, there was no difference in isovolumic contraction or relaxation time among groups, but the ejection time was shorter in the group with CHF. Tissue Doppler measurements: Figure 3 shows peak systolic wall motion velocities, peak early diastolic wall motion velocities, and peak late diastolic wall motion velocities, respectively, at the various walls. There was a relative difference in velocities at these sites, which was preserved in each group. Peak systolic wall motion velocities did not differ between the noncardiac amyloid and no-CHF groups (Figure 3A). In contrast to the lack of difference in fractional shortening, patients with CHF had significantly reduced systolic components of TDI. Diastolic abnormalities are well recognized in cardiac amyloidosis, and were reflected by a decreased early diastolic wall motion velocity wave when patients with evidence of cardiac amyloid were compared with those with no evidence (Figure 3B). The pattern of peak late diastolic wall motion velocities was similar to that of peak systolic wall motion velocities (Figure 3C), with no significant difference between the noncardiac amyloid and no-CHF groups, but a significant difference at almost all sites in the CHF group.
DISCUSSION
In our study, 86 consecutively examined patients with AL amyloidosis and a normal LV fractional shortening were divided into 3 groups according to the existence of CHF and echocardiographic cardiac involvement. Although LV diastolic dysfunction was confirmed by Doppler echocardiography, it was shown more easily with TDI than standard Doppler echocardiography. TDI data indicate that peak early diastolic wall motion velocity is decreased in most walls before the onset of CHF and that it decreases further once CHF occurs. Patients in this study were selected to include only those with a normal fractional shortening to investigate whether this was an accurate reflection of normal systolic function, and 10 patients were excluded because of a reduced fractional shortening (⬍28%). Fractional shortening is a measure of the change in ventricular short-axis dimension, whereas TDI can measure long-axis contraction. No difference in fractional shortening could be
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initially characterized by an impairment in early regional myocardial relaxation, but that the presence of CHF is associated with impairment of longitudinal LV contraction even when fractional shortening is normal. Longitudinal contractile dysfunction has been described in a variety of cardiac conditions,19,22 and our data suggest that it may be a previously unrecognized contributory feature to heart failure in amyloidosis. As expected, patients with CHF had significant abnormalities in transmitral and pulmonary venous flow.13–15 However, despite the presence of myocardial infiltration, the group of patients without CHF could not be distinguished from the noncardiac amyloid group by these indexes. Despite the similarities in transmitral and pulmonary venous flow between the noncardiac amyloid and no-CHF groups, TDI clearly showed a significant difference, suggesting that TDI is not only capable of detecting longitudinal systolic dysfunction, but is also more sensitive than Doppler flow measurements for detecting diastolic abnormalities. The finding that systolic wall motion velocities were only seen in the presence of CHF, whereas diastolic abnormalities were seen in the presence of asymptomatic amyloid infiltration of the left ventricle suggests that CHF in cardiac amyloidosis is not, as previously believed, primarily a diastolic abnormality, but that longitudinal systolic dysfunction may be a prerequisite.
FIGURE 3. A, Sm at various walls. The values of Sm at basal PW, IVS, Lat, and Inf in the group with CHF were significantly lower than those in the noncardiac amyloid (circles) and/or noCHF (squares) groups. *p <0.05 versus noncardiac amyloid; †p <0.05 versus no-CHF; ‡p <0.01 versus noncardiac amyloid. B, Em at various walls. The values of Em at basal PW, IVS, Lat, and Ant in the no-CHF group were significantly lower than those in the noncardiac amyloid group, and those values at almost all sites in the group with CHF were significantly lower than those in the noncardiac amyloid group. *p <0.05 versus noncardiac amyloid; †p <0.01 versus noncardiac amyloid; ‡p <0.001 versus noncardiac amyloid; §p <0.0001 versus noncardiac amyloid, 㥋p <0.05 versus no-CHF. C, Am at various walls. The values of Am at IVS, and Inf in the CHF group (fractional shortening [FS]>28%, triangles) were significantly lower than those in both the noncardiac amyloid and no-CHF groups. *p <0.05 versus noncardiac amyloid; †p <0.0001 versus noncardiac amyloid; ‡p <0.05 versus no-CHF; §p <0.01 versus no-CHF. Abbreviations as in Figures 1 and 2.
demonstrated among the 3 groups studied. The peak systolic wall motion velocities measured by TDI showed no significant difference between the noncardiac amyloid and no-CHF groups. However, in contrast to preserved fractional shortening, clinical evidence of CHF was associated with reduced values of longitudinal ventricular contraction at all sites measured. These results suggest that cardiac amyloidosis is 1070 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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