Performances of doppler echocardiography for diagnosis of acute, mild, or moderate cardiac allograft rejection

ELSEVIER

Performances of Doppler Echocardiography for Diagnosis of Acute, Mild, or Moderate Cardiac AIIograft Rejection L. Fauchier, A. Sirinelli, M. Aupart, D. Babuty, M. Marchand, and J.-M. Pottier vm/s

H E R E C O G N I T I O N of acute allograft rejection ( A R ) remains one of the most important problems in the follow-up of patients after cardiac orthotopic transplantation (COT). Cyclosporine (CyA) has improved the survival of patients with COT, but this treatment induces a more insidious development of A R with a possible delayed diagnosis. The gold standard for diagnosis of A R is endomyocardial biopsy (EB), an invasive technique that provides only located information. 1 Doppler echocardiography seems to be one of the more promising techniques for the detection of mild or moderate AR. 2-6 The objective of this study was to evaluate prospectively the value of several echocardiographic and Doppler parameters for the diagnosis of acute allograft rejection.

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MATERIALS AND METHODS Twenty-three patients (21 men, 2 women) aged 26 to 63 (mean 49.2 _*- 10.4) were studied and followed from September 1991 to September 1995. Preoperative diagnoses were idiopathic dilated cardiomyopathy in 12 and ischemic heart disease in 11.

Doppler Echocardiography Studies The Doppler echocardiographic studies were performed using an ATL (Advanced Technology Laboratories) Ultramark 9, by a single investigator to exclude interobserver variability and without knowledge of the endomyocardial biopsy data. The following measures were obtained, according to the American Society of Echocardiography: left ventricular end-diastolic diameter (LVEDD), interventricular septum thickness (S), and LV posterior wall thickness (PW). Left ventricular mass index (LVMI) was calculated using the formula: LVMI = [LVEDD/2 + (S + PW)/2]2- (LVEDD/2) 2 and was indexed on the body surface.: The Doppler analysis was performed after the patient had rested 10 minutes. Using an apical four-chamber view, the sample volume was placed in the left ventricular inflow. The measures included mitral pressure half-time (PHT, ms), maximum early diastolic flow velocity (VE max, m/s), mitral time velocity integral during diastole (MTVI) allowing calculation of VE max/MTVI ratio, and isovolumic relaxation time (IVRT, ms) while the sample volume was located in the medial portion of the left ventricle along the basal segment of the septum (Fig 1).

Endomyocardial Biopsy The EB was performed the same day as the Doppler echocardiographic study. The histologic analysis of EB was done without

Fig 1.

Measure of IVRT and PHT on aortic and mitral Doppler analysis. A = velocity of mitral flow at time of atrial contraction; E = initial peak velocity of mitral flow; IVRT = isovolumetric relaxation time (aortic valve closure to mitral valve opening); PHT = mitral pressure half-time; and T = time.

knowledge of the clinical status and the echocardiographic data. The rejection was classified according to the Billingham's classification: 7"~ the mild rejection includes an interstitial oedema and a perivascular and endocardial infiltrate of lymphocytes without myocyte necrosis; the moderate rejection is characterized by an increased infiltrate with myocyte damage; and the severe rejection is characterized by a myocyte necrosis with focal hemorrhage. When EB showed a fibrosis and could not allow any conclusion, the Doppler and echocardiographic data were not taken into account. During the first 3 months after heart transplantation, each patient had weekly EB and echocardiography. The echographic and Doppler measurements on the third week were the reference examination if the EB did not show a concomitant rejection because of the geometric modifications of L V 9-11 and disturbances of the LV filling parameters ~2'~3soon after COT. In the case of rejection, the reference echocardiographic examination was the first examination after the third week without AR on EB. From the fourth to the

From the Department of Cardiology, Cardiac Surgery and Echocardiography, Trousseau Hospital, Tours, France Address reprint requests to L. Fauchier, MD, Cardiology B., Trousseau Hospital, 37044 Tours, Cedex, France.

0041-1345/97/$17.00 PII S0041-1345(97)00442-9

© 1997 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010

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Transplantation Proceedings, 29, 2442-2445 (1997)

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CARDIAC ALLOGRAFT REJECTION

Table I. Clinical Characteristics and Mean Results of Doppler Echocardiography in Absence or in Presence of Acute Rejection for Each Patient Age

Sex

Exam. (n)

Follow-up (too)

EB + n (%)

LVMI -

LVMI +

PHT -

PHT +

IVRT

Patient

IVRT +

E/MTVI -

E/MTVI +

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

56 50 45 31 55 58 49 53 60 26 43 38 57 43 63 45 32 54 51 64 56 59 44

M M M M M M M M M F M M M M M M M M M M M M F

15 28 36 32 16 30 22 3 7 30 3 32 35 9 21 9 28 4 31 10 24 37 6

7 23 33 44 7 30 20 1 2 21 1 36 24 3 12 3 20 1 31 3 30 39 35

2 (13.3) 2 (8.6) 14 (42.4) 6 (13.6) 1 (14.3) 5 (16.7) 2 (9) 2 (66.7) 4 (57.1) 13 (43.3) 1 (33.3) 4 (12.5) 13 (37.1) 2 (22.2) 0 (0) 4 (44.4) 4 (! 4.3) 0 (0) 10 (32.3) 0 (0) 8 (33.3) 8 (21.6) 1 (16.7)

295 327 383 414 293 289 266 286 316 350 374 313 360 402 295 348 325 247 290 304 297 338 353

338 329 384 410 248 280 280 283 346 350 317 329 376 445 -340 324 m 276 -277 330 345

47.1 57.4 59.3 61.2 54.8 54.9 54.9 48 45 60.9 57.5 61,6 63.5 63.8 46.3 65.8 59 50 56.6 47.6 62.8 65.3 56.9

44 62.5 52.5 53.7 60 57.8 67.5 51 39 58 54 , 61.2 62.8 55.5 -58.5 57.7 -60.6 -54.6 67.6 63

114 118 108 97 101 108 117 105 110 98.1 90 93.5 106 130 93.6 145 109 81.3 99.3 98.5 92 116 123

118 125 111 99.2 110 104 137 80 106 99.6 95 99.5 99.8 143 -141 115 ~ 90.3 -101 114 125

6.85 5.2 5.26 5.26 5.08 6.21 5.58 5.4 5.3 5.62 5.35 6.33 5.28 4.64 7,37 4,76 5.96 6,28 6.31 5.6 5.75 4.85 4.76

6.15 5.3 5.51 5.33 3.5 6.1 4.8 6.05 6.85 6 6 5.62 5.44 5.45 -5.45 5.98 ~-6.74 -5.64 4.63 5.4

EB, endomyocardial biopsy; IVRT, mean of isovolumetric relaxation time (ms); LVMI, mean of left ventricular mass index (mm2/m2); PHT, mean of mitral pressure half-time (ms); VEmax/MTVI, mean of VEmax/M'FVI; - , no acute allograft rejection on endomyocardial biopsy; +, acute allograft rejection on endomyocardial biopsy.

sixth month of follow-up, the patients had examinations at 2-week intervals, and then a monthly examination. In the case of rejection, the patients were seen 1 week later.

Immunosuppres sive Therapy

The immunosuppressive therapy consisted of CyA adjusted to blood levels near 300 ng/mL-l, prednisone (0.15 mg/kg i body weight) and azathioprine (1 mg/kg 1 body weight adjusted to the hematologic tolerance). Azathioprine was given to only 20 patients (86%) because of neutropenia and/or thrombopenia for the 3 others.

Statistical Analysis The measurements were expressed in absolute value (LVMI, PHT, IVRT, and VE mardM~I~¢I), in percentage of variation of the reference examination (% ref LVMI, % ref PHT, % ref IVRT, and % ref VE max/MTVI) a~ld in percentage of variation of the last examination with concon~Litantnegative EB (% last LVMI, % last PHT, % last IVRT, % last VE max/MTVl). The data were expressed as mean values +_ standard deviation. The differences between data were assessed using Student's t test or Wilcoxon test for paired data, as appropriate. For the parameters with significantdifferences in the presence of AR, we calculated the sensitivity and the specificityfor the diagnosis of AR with different dichotomy levels and we computed receiver operator characteristics (ROC) curves.

RESULTS

A total of 466 Doppler echocardiographic examinations were performed and compared with EB. Each patient had 20.2 _+ 11.9 examinations (range 3 to 37) with a mean follow-up of 18.5 -+ 10.4 months. The echocardiographic and Doppler measures were available in 99.1% of the cases for LVMI, 98.1% for PHT, 97.4% for IVRT, and 96.6% for VE max/MTVI. One hundred and six EB (22.7%) showed a mild or moderate AR and were considered positive, whereas 360 (77.3%) were considered negative. There was no EB with a severe AR. We did not distinguish the two subgroups of mild and moderate AR because the mild rejection episodes can progress to a severe allograft dysfunction and need early treatment as well as a moderate AR. 14 Twenty patients (86%) had at least one episode of AR. The clinical characteristics and the Doppler echocardiographic data during the presence or absence of AR for each patient are shown in Table 1. The comparisons of the Doppler echocardiographic measures according to the presence of AR are displayed in Table 2 and show that the only parameter with a significant difference during AR is the percentage of variation of PHT compared to the last examination with negative EB, significantly decreased during AR. However, when considering the sensitivities and specificities for the diagnosis of AR, the performances of this index remain Jnsutficient, with a sensitivity of 36% and

FAUCHIER, SIRINELLI, AUPART E-I-AL

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Table 2. Mean -+ Standard Deviation of Doppler Echocardiography Parameters in Absence or in Presence of Acute Rejection for All Patients EB LVMI PHT IVRT VE Max/MTVl % ref LVMI % ref PHT % ref IVRT % ref VE Max/MTVI % last LVMI % last PHT % last IVRT % last VE Max/MTVI

(mm2/m 2) (ms) (ms)

326.2 57.9 103.1 5.71 --4.43 +9.5 +19.6 +3.9 +0.1 +2.32 +2.11 +1.71

(%) (%) (%) (%) (%) (%) (%) (%)

_+ 50.6 _+ 10.6 _+ 17.6 _+ 1.03 _+ 13.4 - 26.8 _+ 28.7 ___19.2 + 11.6 + 22 + 16.9 _+ 18.7

EB + 338.7 57.76 106.1 5.68 -1.96 +9.64 +20.79 +3.39 -0.32 -2.76 +3.99 +4.11

_+ 55 _+ 10.76 ___17.6 _+ 1.08 __ 12.2 _+ 26.2 _+ 25.3 _+ 19.8 _+ 11.5 _+ 21.5 _+ 14.8 _+ 20.6

P NS NS NS NS NS NS NS NS NS 0.04 NS NS

% last = percentage of variation of the parameter compared to the last examination with negative EB; % ref = percentage of variation of the parameter compared to the reference examination; other abbreviations as in Table 1.

a specificity of 72% for a level of variation of 10%, and a sensitivity of 23% and a specificity of 86% for a level of variation of 20% (Fig 2). DISCUSSION

This prospective and continuous study about the usefulness of serial Doppler echocardiography for the diagnosis of cardiac allograft A R seems to show little value of the several parameters that were studied. Only percentage of variation of PHT compared to the last examination was significantly decreased in the presence of AR, but this parameter had a poor diagnosis performance and was not reliable alone for the diagnosis of mild or moderate AR. The first echographic index used for the detection of mild or moderate A R in patients with a normal LV systolic Decrease in PHT Sensibility Specificity Positive PV Negative PV 5% 10% 15% 20%

44% 36% 29% 23%

61% 72% 81% 86%

27 % 28% 32% 34%

78 % 78% 78% 78%

PV=wedictivevalue

Sensibility (%) t00

90

.J

80

70 60

J

5O ,0

20 10 0

20

40

60

80

100

100- Specificity (%)

Diagnostic performance of percentage of variation of PHT for diagnosis of mild or moderate AR (ROC curve). Fig 2.

function was the increase of LVMI. This parameter had a good sensitivity for the patients treated by corticosteroid and azathioprine, alone. However, for the patients treated with CyA, it is probably less effective, 15 as shown by our study. The changes of left ventricular filling, assessed by Doppler echocardiography during AR, were described by Desruennes et al and Valantine et al. 3-5 They observed a restrictive pattern of left ventricular filling during mild or moderate AR, maybe due to a cellular infiltration of myocardium. 16 Desruennes et al found a sensitivity of 88% and a specificity of 87% for the diagnosis of mild or moderate A R when PHT was decreased by 20%. IVRT had a lower sensitivity (60%) and a similar specificity with the same decrease of 20%. Valantine et al observed similar abnormalities of PHT and IVRT, and found in addition that VE max was increased during AR. Nevertheless, Desruennes et al did not find such modifications. The restrictive pattern of LV filling disappeared in most patients after A R recovery. 4'17 However, these parameters have shown limited reliability for the diagnosis of A R in two prospective studies. Holzmann et a118 in a series of 8 pediatric cardiac transplant recipients, and Spes et a119 in a study of 31 adult heart transplant recipients, found that PHT and VE max had a poor performance for diagnosis of A R with many misclassifications. Several factors may explain these difficulties for the diagnosis of AR. Loading conditions, heart rate, medical treatment with diuretics, vasodilatators, and prednisone (provoking volume retention) are known to influence the left ventricular filling.2°-2z Another factor is that atria of both donor and recipient have different rates. According to the timing of the contraction of the recipient atrium, the left ventricular filling parameters can be modified by 15%. 23,24 In this study, we tried to exclude the beats with systolic recipient atrial contractions for the analysis and to analyze at least five beats. However, the P wave is not easy to see on simultaneous ECG recording, and this may explain that we obtained measures in more than 95% of the cases, whereas in some other studies they were possible in only 70% of the

CARDIAC ALLOGRAFT REJECTION

cases. 3'4 As in other studies, it seems that the left ventricular filling parameters have an important interpatient but also intrapatient variability.18"19 Even when establishing a normal pattern of the LV filling in the absence of A R and making intrapatient comparisons, the diagnosis performances remain low. Spes et al also found that all left and right ventricular filling parameters varied considerably between consecutive rejection-free examinations, and that these parameters rarely exceeded the calculated 95% confidence limits during mild AR. To our knowledge, this is the first study about Doppler left ventricular filling parameters for diagnosis of A R including the measure of VE mardMTVI. It has been suggested that the nonnormalized peak early flow velocity does not directly reflect the relations with left ventricular pressures. Miki et al, in 15 patients with coronary artery disease, found that the normalized peak early flow velocity had the best correlations with the left ventricular enddiastolic and mitral valve opening pressures. 25 However, we did not find in our study that this parameter improves the performances of Doppler echocardiography for the diagnosis of AR. CONCLUSION

This prospective study about echocardiographic and Doppler parameters on the follow-up of heart transplant recipients showed a limited value of LVMI and of the LV filling parameters for the diagnosis of mild or moderate AR, even for the normalized peak early flow velocity. This may be explained by the several hemodynamic factors, all which being interrelated, influencing the left ventricular filling, and by a marked intrapatient variability of these parameters with the need to obtain several normal posttransplant values for each patient, whereas most rejection episodes occur in the early months of follow-up of patients after COT. 26 After one year of follow-up, hemodynamic status is more stable and episodes of A R become more rare. The instability of the echocardiographic and Doppler measures could then be of better interest for diagnosis of AR. REFERENCES

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