Dobutamine

Study objective: Doppler-derived myocardial performance index (MPI), a measure of combined systolic and diastolic myocardial performance, was assessed at rest and after low-dose dobutamine administration in patients with idiopathic or ischemic dilated cardiomyopathy. MPI also was correlated with other conventional echocardiographic indexes of left ventricular (LV) function, and its ability to assess cardiopulmonary exercise capacity in those patients was investigated.

Settings: A tertiary-care, university heart failure clinic.

Patients: Forty-two consecutive patients (27 men; mean [+ or -] SD] age, 57 [+ or -] 10 years) with heart failure (New York Heart Association [NYHA] class, II to IV) who had received echocardiographic diagnoses of dilated cardiomyopathy. Coronary angiography distinguished the cause of dilated cardiomyopathy.

Interventions: Low-dose IV dobutamine was infused after patients underwent a baseline echocardiographic study. All patients also underwent a cardiopulmonary exercise test using a modified Naughton protocol.

Results: Advanced NYHA class and restrictive LV filling pattern were associated with higher index values. A negative correlation was found between MPI and LV stroke volume, cardiac output, early filling/late filling velocity ratio, and late LV filling velocity, as well as oxygen uptake at peak exercise (r = -0.550; p < 0.001) and at the anaerobic threshold (r = -0.490; p = 0.002). Dobutamine administration produced an improvement in MPI, reducing its value

and decreasing the isovolumic relaxation and contraction times. Stepwise regression analysis revealed that the rest index and the late LV filling velocity were the only independent predictors of cardiopulmonary exercise capacity.

Conclusion: MPI correlates inversely with LV performance, reflects disease severity, and is a useful complimentary variable in the assessment of cardiopulmonary exercise performance in patients with heart failure.

Key words: cardiopulmonary exercise; dobutamine; Doppler index; heart failure

Abbreviations: A = late transmitral filling velocity; E = early transmitral filling velocity; ET = ejection time; ICT = isovolumic contraction time; IRT = isovolumic relaxation time; LV = left ventricle ventricular; MPI = myocardial performance index; NYHA = New York Heart Association; SV = stroke volume; V[O.sub.2] = oxygen uptake; V[O.sub.2]AT = oxygen uptake at anaerobic threshold

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In patients with congestive heart failure, left ventricular (LV) systolic dysfunction is often associated with alterations in diastolic filling, and such abnormalities may play a role in determining the clinical expression of heart failure. (1) The major de terminant of functional status in these patients is the response of cardiac output to exercise, which is dependent on both the contractile and the preload reserve. (2,3)

Studies have shown that not only LV systolic dysfunction but also abnormalities in LV diastolic filling are important independent determinants of reduced exercise capacity, as expressed by cardiopulmonary exercise parameters, in patients with LV systolic dysfunction. (4)

Thus, a measure of combined systolic and diastolic myocardial performance could be a useful predictor of clinical status and a marker of exercise capacity in those patients. In 1999, a noninvasive Doppler-derived interval index that incorporates both systolic and diastolic performance of the LV or right ventricle was reported. (5) This index, which is defined as the sum of isovolumic contraction and relaxation times divided by ejection time (ET) is easily used by any clinician and has shown potential clinical application in various heart disorders. (6,7)

Dobutamine, a predominantly [beta]-adrenergic sympathomimetic agent, is known to increase cardiac performance in patients with heart failure. (8) This increase in performance is achieved mainly by increasing contractility and partly by reducing systemic vascular resistance and increasing heart rate. (9) The changes in echo variables, which express LV systolic function, after dobutamine administration in patients with dilated cardiomyopathy has been found to correlate with cardiopulmonary exercise capacity. (10)

However, there are no studies relating LV myocardial performance index (MPI) to exercise capacity, as expressed by results of a cardiopulmonary exercise test in combination with other noninvasive indexes of LV systolic and diastolic function in patients with ventricular systolic dysfunction. The effect of dobutamine on this index is not known.

In the present study, we assessed the MPI in patients with idiopathic or ischemic dilated cardiomyopathy, analyzed how the MPI correlates with other conventional echocardiographic LV systolic and diastolic indexes, and assessed its incremental prognostic power for cardiopulmonary exercise capacity. We also evaluated the effects of low-dose dobutamine administration on this index and compared those effects to changes in other Doppler echocardiographic variables.

MATERIALS AND METHODS

Patients

The study population consisted of 42 consecutive patients enrolled from the heart failure clinic of our hospital, who had received an echocardiographic diagnosis of dilated cardiomyopathy, which was defined as LV fractional shortening of < 25% on M-mode echocardiography, LV end-diastolic dimensions of > 60 mm, and an increased E-point septal separation of > 5 mm.

There were 27 men and 15 women in the study, with a mean ([+ or -] SD) age of 57 [+ or -] 10 years. Inclusion criteria were as follows: symptomatic heart failure (New York Heart Association [NYHA] functional class, II to IV); LV ejection fraction of < 40%, as determined by radionuclide angiography; and preserved sinus rhythm. Patients with valvular stenosis, chronic lung disease, chronic renal failure, cancer, or other noncardiac conditions that might limit exercise capacity were excluded from the study. Patients with severe mitral valve regurgitation or atrioventricular contraction disorders were also excluded.

Patients were allowed to continue therapy with medications such as digitalis, diuretics, and angiotensin-converter enzyme inhibitors. Each patient gave informed consent to the investigative nature of the study, which was approved by the ethics committee of our institution.

Echocardiographic Examination

M-mode, two-dimensional, and Doppler echocardiography were performed in all patients using a device (Sonos 2500; Hewlett-Packard; Palo Alto, CA) with a 2.5 or 3.5 MHz, wide-angle, phased-array transducer. All examinations were recorded on videotape, and calculations were made offline using the internal analysis software of the echocardiographic device. M-mode recordings were obtained from the parasternal window, and all measurements were made according to the recommendations of the American Society of Echocardiography. (11) LV volumes were measured from the apical view of the two-dimensional echocardiogram using a modified Simpson's rule algorithm. (12)

Spectral Doppler echocardiography recordings of the mitral inflow were obtained from the apical four-chamber view in order to assess LV filling dynamics. The pulsed-wave Doppler echocardiography sample volume was positioned between the tips of the mitral leaflets in order to derive the following variables: peak early transmitral filling velocity (E) and late transmitral filling velocity (A), their ratio (E/A), the time velocity integral of the E and A velocity, their ratio, the atrial filling fraction (calculated by dividing the component time-velocity integral by the total time-velocity integral), and the deceleration time of E and A (from the peak E or A to the baseline).

Patients were divided into restrictive and nonrestrictive Doppler echocardiography categories on the basis of the E/A ratio and E deceleration time criteria. The restrictive filling pattern was defined as an E/A ratio [greater than or equal to] 2 or the combination of an E/A ratio between 1 and 2 and an E deceleration time of [less than or equal to] 140 ms. The nonrestrictive pattern was defined as an E/A ratio of [less than or equal to] 1 or an E/A ratio between 1 and 2 with an E deceleration time of > 140 ms.

The presence and magnitude of mitral regurgitation were assessed by color Doppler echocardiography, and the mitral regurgitant jet area/left atrium area method was used to determine a grade of mild (ie, < 20%), moderate (ie, 20 to 40%), or severe (ie, > 40%). (13)

The LV outflow velocity pattern was recorded from the apical long-axis view with the pulsed-wave Doppler echocardiography sample volume positioned just below the aortic valve. Stroke volume (SV) was calculated by the formula, SV = ([pi]/4 x [[aortic diameter].sup.2] x [aortic velocity-time integral]), in which aortic diameter was measured in a two-dimensional, parasternal, long-axis view just below the aortic orifice from inner to inner echo, since this is thought to remain constant during exercise. (14) Cardiac output was calculated as the product of SV and heart rate. For each variable, five successive measurements were averaged.

LV MPI

The Doppler MPI ([a - b]/b) was measured from five consecutive beats and was averaged from mitral inflow and LV outflow velocity time intervals as follows (Fig 1).

[FIGURE 1 OMITTED]

The interval a from the cessation to the onset of mitral inflow is equal to the sum of LV isovolumic contraction time (ICT), ET, and LV isovolumic relaxation time (IRT). LV ET, b, was measured from the duration of the LV outflow velocity curve. The sum of ICT and IRT was obtained by subtracting b from a. The index of combined LV systolic and diastolic function (ie, the sum of ICT and IRT divided by ET) was calculated as (a - b)/b. In addition, IRT was measured by subtracting the interval between the ECG R wave and the cessation of LV outflow from the interval between the R wave and the onset of mitral inflow. ICT was calculated by subtracting the IRT from the interval of a - b. Two independent observers made all measurements. In the event of a disagreement, the average measurement was calculated.

Dobutamine (Stress Echocardiography) Administration

IV dobutamine was infused beginning at 2.5 [micro]g/kg/min and increasing to 5, 7.5, and 10 [micro]g/kg/min at 3-min intervals in all patients after the baseline echocardiographic study. A continuous 12-lead ECG recording was performed throughout the test, and BP was measured every 3 min.

All the previously mentioned echocardiographic parameters were obtained and measured at peak dobutamine infusion, as were the peak heart rate and peak systolic BP.

Exercise Testing Protocol and Gas Exchange Analysis

All patients underwent an exercise test using a treadmill device (MAX 1; GE Medical Systems; Milwaukee, WI) after at least 3 h without ingesting food or coffee, or smoking cigarettes. A graded, symptom-limited test was performed using a modified Naughton protocol. A 12-lead ECG was monitored continuously, with recordings made every 2 min at the end of each stage. BP was measured with a sphygmomanometer during the final 30 s of each work stage.

Gas exchange data were collected continuously with an automated breath-by-breath system (Oxycon A, version 3.1; Jaeger; Hoechburg, Germany). These instruments were calibrated before every test using standard gases.

The exercise duration was defined as the time from the start of exercise until its cessation because of dyspnea or fatigue. Oxygen uptake (V[O.sub.2]) at peak exercise was calculated as the average V[O.sub.2] value over the final 30 s of exercise. V[O.sub.2] at the anaerobic threshold (V[O.sub.2]AT) was defined as the level at which an increase in the ventilatory equivalent of oxygen without a simultaneous increase in the ventilatory equivalent of carbon dioxide was observed. The test was performed within a mean of 6 [+ or -] 5 days before or after the rest-stress echocardiographic study was performed.

Coronary Angiography

All patients who participated in the study underwent cardiac catheterization and coronary angiography, which was used as the "gold standard" for distinguishing between ischemic and nonischemic cardiomyopathy according to the presence of significant coronary artery stenosis. Significant coronary artery stenosis was defined as the presence of > 70% luminal diameter stenosis in any of the three major epicardial coronary vessels or > 50% luminal diameter stenosis of the main left artery, as assessed visually by two independent observers. Cardiomyopathy was considered nonischemic only if the coronary arteries were normal.

Statistical Analysis

Descriptive statistics of continuous variables are given as mean [+ or -] SD. Comparisons between the restrictive and nonrestrictive groups were made using Student t test for independent samples. Rest-to-stress changes were evaluated with the paired-samples t test. The associations among peak V[O.sub.2], V[O.sub.2]AT, and various echo-derived variables were assessed with the Pearson correlation coefficient. Variables that were significantly correlated with V[O.sub.2] and V[O.sub.2]AT were entered in a stepwise linear regression model to determine which ones could be used as independent predictors. The criteria for entry into and removal from the stepwise model were 5% and 10%, respectively. All other tests were performed at the 5% level of significance.

RESULTS

Table 1 shows the clinical profile and the echocardiographic findings in the patients with heart failure who participated in the study. The mean resting value of the MPI tended to be higher in patients categorized as being in advanced NYHA functional classes (Fig 2) and in patients with restrictive, as opposed to nonrestrictive, LV filling patterns (1.18 [+ or -] 0.25 vs 0.75 [+ or -] 0.15, respectively; p < 0.001).

[FIGURE 2 OMITTED]

Simple linear regression analysis revealed that MPI correlated with the ratio of early to late LV filling velocity and correlated negatively with resting cardiac output, SV, and LV late filling velocity. There was also a marginal negative correlation with the LV ejection fraction but not with the left atrial or LV dimensions, or end-systolic and end-diastolic volumes (Table 2).

No correlation was found between the MPI and the resting heart rate (r = 0.120; p = 0.213) or the systolic BP (r = 0.110; p = 0.303). There was also a strong negative correlation between MPI and peak V[O.sub.2] (r = -0.550; p < 0.001) and V[O.sub.2]AT (r = -0.490; p = 0.002) [Fig 3], but there was no correlation with the maximum exercise duration, the minute ventilation/V[O.sub.2] ratio, or the minute ventilation/carbon dioxide output ratio.

[FIGURE 3 OMITTED]

Table 3 shows the changes in echocardiographic variables after dobutamine infusion. At the peak of dobutamine infusion, the heart rate and systolic BP increased slightly, but not significantly, whereas the cardiac SV and the cardiac output increased significantly. There was an improvement in MPI (before infusion, 0.91 [+ or -] 0.25; after infusion, 0.72 [+ or -] 0.26; p < 0.001) and a shortening of the IRT (before infusion, 118 [+ or -] 26 ms; after infusion, 98 [+ or -] 27 ms; p < 0.001) and the ICT (before infusion, 98 [+ or -] 24 ms; after infusion, 81 [+ or -] 28 ms; p < 0.001).

Simple regression analysis revealed a negative correlation between MPI changes and LV late diastolic filling velocity changes after dobutamine infusion (r = -0.499; p < 0,001), indicating the significant effect of preload reserve (ie, the augmentation in A velocity) on LV performance. There was also a significant negative correlation between the changes in MPI after dobutamine infusion and the changes in cardiac output and SV (Table 4).

When we divided the patients into restrictive and nonrestrictive groups, we found that MPI changes were negatively correlated with A-wave changes in the restrictive group (r = -0.70; p = 0.005) but not in the nonrestrictive group. Although there was a weak negative correlation between MPI changes after dobutamine infusion and the peak V[O.sub.2] (r = -0.324; p = 0.050), but not at the anaerobic threshold, both correlations were significant in patients with restrictive patterns (MPI changes: r= -0.57; p = 0.013; peak V[O.sub.2]: r = -057: p = 0.035), whereas both were nonsignificant in the nonrestrictive group.

When all these variables, measured with the patient resting and after dobutamine infusion, were entered into a stepwise linear regression analysis, the resting A-wave velocity and the resting MPI were independent prognostic factors at peak V[O.sub.2] (resting A-wave velocity: [R.sup.2] = 0.403; p < 0.001; resting MPI: [R.sup.2] = 0.291; p = 0.005) and at V[O.sub.2]AT (resting A-wave velocity: [R.sup.2] = 0.216; p = 0.004; and resting MPI: [R.sup.2] = 0.220; p = 0.005).

DISCUSSION

Two-dimensional and Doppler echocardiography facilitate the evaluation of different periods of the cardiac cycle, allowing the acquisition of a combined systolic and diastolic index of LV performance in a simple, reproducible, and reliable manner. (6,15,16) This index, which is independent of heart rate and BP, according to our data and those of others, has been found to correlate well with invasive measures of LV systolic and diastolic function such as changes in the maximum rate of rise of LV pressure (peak plus first derivative of pressure) and [tau] value. (17)

In this study, we found that the LV MPI showed a negative correlation with the functional status of the patients (as expressed by NYHA functional class), with the systolic LV indexes SV and cardiac output, and with diastolic indexes such as LV filling pattern and A-wave velocity. Because myocardial contractility and relaxation are energy-dependent, (18,19) myocardial dysfunction results in the prolongation of the isovolumic intervals. When the LV dysfunction is more severe, the ejection period shortens. Thus, the result of the formula (a - b)/b tends to increase, and the MPI increases accordingly.

Patients with advanced NYHA classifications or patients with the restrictive LV filling pattern, which reflects higher pulmonary wedge pressure, advanced congestive heart failure, (20) and shortened IRT, (21) also exhibited increased MPI values.

There was a negative correlation between MPI and the peak V[O.sub.2] and V[O.sub.2]AT in our patients. In patients with systolic dysfunction, exercise capacity is better correlated with diastolic filling rather than with systolic LV function. (22,23) Thus, an index combining both systolic and diastolic performance that is well-correlated with diastolic as well as systolic LV function could be a good marker of cardiopulmonary exercise performance.

Dobutamine infusion produced an improvement in the MPI, reducing its value and the isovolumic contraction and relaxation times, which indicate an acceleration in LV relaxation and contraction rates. Dobutamine stimulates [beta]-adrenergic receptors, producing a positive inotropic response via the action of cyclic adenosine 3',5'-monophosphate, which increases inward the conductance of calcium via L-type calcium channels, therefore presenting more free calcium to the contractile apparatus. (24) Also, [beta]-adrenergic receptor stimulation accelerates relaxation through the action of cyclic adenosine 3',5'-monophosphate to accelerate the reuptake of calcium by the sarcoplasmic reticulum, to reduce the calcium sensitivity of the contractile apparatus, and to accelerate the rate of myofilament cross-bridge detachment. (25,26) Thus, dobutamine reduces the LV isovolumic relaxation and contraction times, and increases LV ET, causing a reduction in the MPI.

The LV MPI changes after dobutamine infusion showed a negative correlation with the augmentation in late LV filling velocity and with cardiopulmonary exercise capacity in patients with restrictive filling patterns, indicating that in those patients the capacity of the LV to increase late diastolic filling is a major determinant of the SV response and, consequently, of exercise performance. These data are in agreement with those of a previous study by Dahan et al, (27) who reported that the SV response to exercise correlated significantly with the peak late mitral velocity during exercise in patients with LV systolic dysfunction.

The MPI and the late LV filling velocity were independent predictors of peak V[O.sub.2] and V[O.sub.2]AT. Thus, we are in agreement with the results of a previous study (4) showing that peak A velocity is an independent predictor of cardiopulmonary exercise capacity in patients with dilated cardiomyopathy. However, in patients with a nonrestrictive filling pattern, the augmentation in SV seems to result mainly from an increase in LV contractility, rather than from an increase in LV filling.

Neither the MPI nor other Doppler echocardiography variables were correlated with maximum exercise duration. This may be explained by the fact that, in patients with systolic dysfunction, additional compensatory peripheral or noncardiac factors contribute to maximum exercise duration. (28)

The value of the MPI has been demonstrated in many pathologic situations. Tei et al (6) reported a negative correlation between the MPI and clinical outcome in healthy patients, patients with intermediate level of disease, and pretransplant patients with dilated cardiomyopathy, while Dujardin et al (29) also found it to be a significant prognostic index in a similar patient population. Our findings agree with those of the latter study regarding the correlation between the MPI and other echocardiographic parameters of systolic and diastolic LV function. In cardiac amyloidosis, (30) an index value of > 0.77 identified patients with high NYHA functional class, a lower ejection fraction value, a higher degree of diastolic dysfunction, and a higher mortality rate. In patients with primary hypertension, (7) it has been reported that the index correlates well with severity of disease and the clinical outcome.

Limitations

A universally accepted method that completely reflects the systolic and diastolic LV performance does not exist. All parameters that are in use have their limitations. As with other methods, the MPI may be affected to some degree by loading conditions. (31)

Our patients were all receiving diuretic medication. On the other hand, we excluded patients with severe mitral valve regurgitation, so we believe that there was not a significant alteration in preload in our patients. We also excluded patients with severe mitral valve regurgitation in order to avoid the influence of the filling pattern that is due to increased E velocity, which results in an elevated E/A ratio, as well as patients with atrial fibrillation or atrioventricular conduction defects, because of the difficulty of obtaining MPI values in patients with these abnormalities. The effects of loading conditions and arrhythmias on this index remain to be elucidated.

We neither related the index changes after dobutamine infusion to alteration in LV wall motion nor analyzed the influence of age or gender on this index. Further studies will be necessary to determine whether such a relationship exists.

Clinical Implications and Conclusions

The MPI, combining systolic and diastolic time intervals as an expression of global myocardial performance, correlates with overall cardiac function and seems to be a useful, complimentary marker in assessing cardiopulmonary exercise capacity in patients with primary LV systolic dysfunction. It is a simple, reproducible measure, and its changes after the patient has received dobutamine may give us accurate information regarding the quantitative assessment of global cardiac function. This index might be useful in the planning of pharmacologic management, or in decisions regarding possible heart transplantation, in patients with congestive heart failure.

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* From the Cardiology Department, Heraklion University Hospital, Crete, Greece.

Manuscript received March 13, 2001; revision accepted November 12, 2001.

Correspondence to: Panos E. Vardas, MD, PhD, Cardiology Department, Heraklion University Hospital, PO Box 1352, Stavrakia, Heraklion, Crete, Greece; e-mail: cardio@med.uoc.gr

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