Dobutamine Stress Echocardiography and Troponin T as a Marker of Myocardial Injury

INTRODUCTION AND OBJECTIVES

In recent years dobutamine stress echocardiography (EDOB) has become one of the combination of tests that are used routinely in the diagnosis and prognosis of patients who consult for chest pain or known coronary artery disease.¹ The response of the myocardium to dobutamine infusion is useful not only in the diagnosis of coronary artery disease (CAD), but also in evaluating its severity. The ischemia threshold determined by the ischemia-free time and the dilation of the left ventricle with peak stress have been correlated with its severity.² We must be aware, nonetheless, of some of the limitations of the technique. In the first place, the sensitivity of EDOB is moderate and approximately 20% of patients with CAD have a negative EDOB;³ in second place, there is no truly quantitative approach to the analysis of results. Finally, it would be interesting to find more precise signs to establish the severity of CAD, which would help in decisions regarding invasive evaluations in high-risk patients.

Recently it has been demonstrated that troponin T (TnT) is a very trustworthy marker of myocardial damage.^4-8 However, there is hardly any information available about its behavior after EDOB.^9-12 Our hypothesis is that measurement of TnT after the infusion of dobutamine could increase the diagnostic power of EDOB and increase the capacity of the test to identify patients with severe CAD. We report the results obtained in a cohort of 63 patients in whom EDOB was performed and TnT was measured in blood at baseline and in the 24 h after the stress test.

METHODS

Serial TnT measurements were made in 63 patients who underwent EDOB for a clinical indication (mean age 69±9 years, 38 men). Of the 63 patients, 31 had known CAD and 32 had suspected CAD; 19 had a history of previous myocardial infarction. As far as coronary risk factors were concerned, 40 were hypertensive, 31 dyslipidemic, 18 diabetic, and 19 smokers. Coronary angiography was performed in 36 patients. The decision to carry out angiography was taken by the referring cardiologist, who had the results of EDOB.

Echocardiography with dobutamine

Monitoring with bidimensional echocardiography was carried out during the infusion of dobutamine and up to 10 min after it finalized. In the first 40 patients, dobutamine was administered with a continuous infusion pump, beginning with 10 g/kg/min and increasing by 10 g/kg/min every 3 min until reaching a maximum dose of 40 g/kg/min, which was maintained for 6 min. In the last 23 patients a short protocol was used.¹³ The short protocol consisted of two stages lasting 3 min each, at a rhythm of perfusion of 20 g/kg/min for the first stage and 40 g/kg/min for the second stage; therefore, the maximum dose was the same. If the patient had not reached 85% of maximum heart rate or any criterion for discontinuing the test when finishing the dobutamine infusion, 1 mg of atropine was administered. A 12-lead electrocardiogram was recorded and blood pressure was taken in baseline conditions and every 3 min up to 10 min after either concluding the infusion or obtaining negative test results, if it had been positive. The criteria for discontinuation were routine: reaching maximum theoretical heart rate, intense angina, appearance of ventricular arrhythmia complexes, systolic blood pressure over 220 mm Hg or diastolic blood pressure over 130 mm Hg, and Mobitz II second-degree or third-degree atrioventricular block.

The division of the segments is that proposed by the American Society of Echocardiography,¹⁴ which includes 16 segments. These segments were studied on the parasternal long axis and short axis using the apical four-chamber, three-chamber, and two-chamber planes. Each segment was scored from 1 to 4 according to its mobility: 4, dyskinesia or akinesia; 3, severe hypokinesia; 2, mild hypokinesia, and 1, normal or hyperkinesia. The sum of the segmental scores was divided by the number of segments visualized to calculate the ventricular mobility score index. This is a semiquantitative indicator of left ventricular systolic function. The test was considered positive when the contractility of any of the segments worsened with respect to baseline contractility. Image acquisition was synchronized with the electrocardiographic signal. Images were digitized for analysis. The studies were also recorded by conventional video.

Measurement of cardiac troponin T

TnT determinations in serum were made using the Elecsys 1010 system of Boehringer Mannheim. The technique uses Troponin T STAT Elecsys reagents and third-generation calipers. The limit of detection for the technique is 0.01 ng/ml. The upper limit of the reference interval in healthy individuals (99%) is 0.01 ng/ml, according to information facilitated by the manufacturer. Samples were extracted by peripheral venous puncture and left at room temperature until the clot formed, then frozen at 20^oC. They were analyzed in series corresponding to each patient after thawing. We considered, in accordance with the standards of the National Academy of Clinical Biochemistry,⁴ that the elevation of TnT was significant if baseline TnT was less than 0.01 and in later determinations it was higher than 0.01, or if baseline TnT is above 0.01 and in later determinations the value is 20% higher than baseline value.

Coronary angiography

Coronary angiography was performed according to the Judkins technique. We defined severe CAD as the presence of stenosis of more than 50% measured by quantitative angiography. The quantitative analysis of lesions was made with the Coronary Measurement System (CMS) of Medis, which is a digitized system for automatic measurement of edges.

RESULTS

Behavior of cardiac troponin T

Baseline TnT values were unappreciable in 26 patients; in the other 37, mean baseline TnT was 0.017±0.024. After EDOB, the following TnT levels were obtained: 0.034±0.023 at 3 h; 0.034±0.019 at 6 h; 0.024±0.028 at 12 h, and 0.018±0.022 at 24 h. In Figure 1 is shown the behavior in time of the serum TnT levels. There were no differences in the behavior of TnT in the patients in which the usual protocol for dobutamine infusion was used and in those in which the short protocol was used. The TnT values in the first 40 patients were: baseline, 0.01±0.017; 3 h, 0.029±0.019; 6 h, 0.031±0.013; 12 h, 0.017±0.020, and 24 h, 0.012±0.018. For the last 23 patients, we obtained mean values of: baseline, 0.029±0.03; 3 h, 0.048±0.05; 6 h, 0.046±0.03; 12 h, 0.039±0.04, and 24 h, 0.032±0.02.

Fig. 1. The behavior of troponin T (TnT) levels in time; it is evident that there is an increment in TnT values with respect to baseline value and that a peak value is reached between 3 h and 6 h after performing dobutamine stress echocardiography (EDOB).

Relation between dobutamine stress echocardiography and cardiac troponin T levels (Table 3)

Of the 29 patients with positive EDOB, 15 showed TnT elevation in relation to the baseline values (51%). The EDOB was negative in the other 34 patients and TnT increased in only 7 of them (20%; P<.01) (Table 1). The increment in TnT values (difference between peak TnT - baseline TnT) was greater in patients with a positive response to EDOB (0.033±0.02 versus 0.0263+0.01; P<.01). A greater index of ischemia was observed in patients with a positive EDOB and significant increment in TnT levels (0.41±0.31 versus 0.38±0,20; P=.01). The correlation was 0.44 (P<.05). The patients who presented an elevation in TnT showed ECG changes more frequently (92% versus 34% ; P<.01) and angina (42% versus 9%; P<.01) during EDOB.

Coronary angiography

Coronary angiography was performed in 36 patients, of whom 29 had CAD. The EDOB was positive in 24 patients (22 with coronary artery disease) and TnT rose in 15 patients (14 with CAD). Therefore, 76% of the patients with CAD had positive EDOB versus 48% in which TnT rose (P<.01). Of the 29 patients with CAD, 25 (86%) had positive EDOB and/or elevation of TnT (Table 2).

DISCUSSION

The most important finding of this study is that dobutamine infusion at the doses used in stress echocardiography can induce myocardial damage, as demonstrated by an increase in serum levels of TnT with respect to baseline values. The increase in TnT levels was mild, so the damage to the myocardium can be considered minimal. Another interesting aspect of the study is that TnT did not increase after 24 h of dobutamine infusion. The increasing-decreasing TnT curve, with a peak located 3h to 12 h after dobutamine infusion, is a sure marker of myocardial damage.^15,16 The behavior in time of TnT levels observed coincided with other studies,^17,18 in which a peak TnT was obtained around 10 h after the onset of ischemia, and normal values 20 h after the ischemic episode.

Theoretically, TnT could identify a group of patients with more severe CAD in which a more interventionist attitude should be adopted, including a possible revascularization procedure. This aspect has not been assessed in the literature.

A special group was made up of patients with negative EDOB but with an increment in TnT. No definitive inferences can be drawn from a group of 7 patients, but all the patients pertaining to this group who had a coronary angiography study (n=3) had significant CAD. These patients could have had CAD that was not detected by EDOB. Conceptually, subendocardial ischemia may not induce asynergy, although TnT could increase. On the other hand, localized ischemia may not be visible during echocardiographic analysis in patients with a deficient acoustic window.

Troponin has been determined after EDOB in two studies. Meluzin et al⁹ did not find any increment in TnT in 27 patients with CAD, but they used a qualitative test to determine TnT and made only one venous sample 20 h after dobutamine was given. As we have seen in our results, TnT can return to normal values by this time. Beckmann et al¹¹ observed that troponin I did not increase over the range of reference (0.60 ng/mL) in 20 patients with CAD and regional contractility disturbances. The samples were made within 7 h of EDOB. We found that elevation took place in almost all of them between 3 and 12 h. Taking 5 blood samples for TnT measurements is not feasible in outpatients. According to our results, 14% of the patients in whom TnT rose had normal values at 3h and 23% at 6 h. Studies should be made to determine if there is an time interval between 3 h and 6 h in which most of the patients are detected.

If we follow the new definition of infarction recommended by the European Society of Cardiology and the American College of Cardiology,¹⁹ 6 patients had a myocardial infarction after EDOB was performed. This definition is being questioned in broad sectors of the scientific community.^20,21 In order to be accepted definitively, would it be necessary to stop performing stress tests for the diagnosis of CAD? This engrossing question is far from being answered.

We recognize that no definitive conclusions can be established about the usefulness of assessing TnT levels after EDOB, but our work opens a new area of investigation in the exciting field of the noninvasive diagnosis of coronary artery disease. From a practical vantagepoint, the combination of EDOB and the TnT determination could help us to ascertain if a patient has coronary artery disease. In addition, TnT values could provide a better prognostic profile of these patients. Increased TnT levels could be used to support the decision to perform coronary angiography, since they suggested more severe CAD.

CONCLUSION

After the infusion of dobutamine in the doses administered in EDOB, mild myocardial damage takes place, as demonstrated by TnT elevation. The combination of the results of EDOB and TnT could improve the diagnostic performance of isolated EDOB.

See editorial

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Correspondence: Dr. J.A. San Román.
Instituto de Ciencias del Corazón (ICICOR). Hospital Universitario.
Ramón y Cajal, 3. 47011 Valladolid. España
E-mail: [e-mail]