Dobutamine

Objective: To evaluate left atrial functional reserve in patients with chronic heart failure and nonischemic dilated cardiomyopathy (DCM).

Background: Left ventricular functional status has been investigated using echocardiographic dobutamine.

Methods: In 35 consecutive patients (29 men and 6 women; mean [+ or -] SD age, 42.37 [+ or -] 13.5 years), peak oxygen consumption (V[O.sub.2]max) was measured; the day after, a low-dose dobutamine (5 to 10 [micro]g/kg/min, of 5 min each step) study was performed. Left atrial volumes at mitral valve opening, onset of left atrial systole, and mitral valve closure were measured by using two-dimensional echocardiography. Left atrial active emptying volume (LAEV) [volume at onset of atrial systole - minimal volume] was calculated, as was left atrial active emptying fraction (LAEF): [(volume at onset of atrial systole - minimal volume)/volume at onset of atrial systole] x 100. The changes (values obtained after inotropic stimulation minus those obtained at baseline) of the above-mentioned echocardiographic variables were considered as left atrial functional reserve.

Results: In the entire study group after dobutamine infusion, increases in LAEV (3.34 [+ or -] 7.54 mL, p = 0.01) and LAEF (6 [+ or -] 13.2%, p = 0.01) were observed. The changes in the above-mentioned parameters were correlated with V[O.sub.2]max values (r = 0.73 and r = 0.71, respectively; p < 0.001). After inotropic stimulation, LAEV and LAEF were increased in patients with V[O.sub.2]max values > 14 mL/kg/min (5.62 [+ or -] 7.28 mL and 10.04 [+ or -] 13.13%, respectively) and decreased in patients with V[O.sub.2]max values < 14 mL/kg/min (- 1.08 [+ or -] 6.13 mL and - 1.6 [+ or -] 9.9%, respectively; p = 0.01 for both).

Conclusion: Echocardiographic dobutamine can evaluate left atrial functional reserve in patients with nonischemic DCM.

Key words: dilated cardiomyopathy; echocardiographic dobutamine; heart failure; left atrial functional reserve

Abbreviations: DCM = dilated cardiomyopathy; LAEF = left atrial active emptying fraction; LAEV = left atrial active emptying volume; LAVmax = left atrial maximal volume at the point of mitral valve opening; LAVmin = minimal volume at the point of mitral valve closure; LAVp = left atrial volume at onset of atrial systole; LVEDD = left ventricular end-diastolic diameter; LVEF = left ventricular ejection fraction; LVESD = left ventricular end-systolic diameter; LVFS = left ventricular fractional shortening; NS = not significant; V[O.sub.2]max = peak oxygen consumption

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Although the mechanical characteristics of the left ventricle have been extensively studied, left atrial function is poorly understood despite its key role in optimizing left ventricular function. (1,2) In physiologic investigations, the evaluation of pressure/dimension relationship is the most accurate and representative index of the hemodynamic conditions that exist in cardiac chambers. (3,4) However, these relationships require combined measurement of left atrial chamber pressures and dimensions. Thus, their use has been primarily limited to invasive clinical and experimental studies.

Impaired exercise tolerance is one of the most common clinical manifestations in patients with left ventricular dysfunction. (5) Left atrial fractional shortening at rest reflects left ventricular filling during exercise and therefore predicts cardiac output and stroke volume response to exercise, and exercise capacity. (6) Exercise and left ventricular performance during exercise have been shown to be mainly dependent on left ventricular diastolic filling rather than systolic function. (6) Of note, it has been reported that indexes of left atrial function are related to peak aerobic capacity in patients with congestive heart failure. (7) However, none of the above-mentioned studies have investigated left atrial response during exercise. We have shown that left ventricular changes induced by dobutamine infusion are well correlated with peak oxygen consumption (V[O.sub.2]max) and can be used to evaluate the functional status of heart failure. (8,9) In this respect, we aimed to investigate left atrial functional reserve in patients with chronic heart failure and nonischemic dilated cardiomyopathy (DCM) using echocardiographic dobutamine.

MATERIALS AND METHODS

Study Patients

Thirty-six consecutive patients with documented DCM were studied. V[O.sub.2]max was calculated the day before the echocardiographic dobutamine study. Thirty-five patients (98%; 26 men and 9 women; mean [+ or -] SD age, 42.37 [+ or -] 13.5 years) with good-quality two-dimensional echocardiography were recruited for analysis. The cause of DCM was idiopathic in all patients assessed by a detailed history and clinical examination, echocardiography, coronary angiography (angiographic lesions < 30% lumen stenosis diameter), and biopsy. All patients were in New York Heart Association functional class III Diagnosis of DCM was based on the echocardiographic findings of a dilated left ventricle (left ventricular end-diastolic diameter [LVEDD] > 60 mm) with severely affected systolic function, left ventricular fractional shortening [LVFS] < 20%. and left ventricular ejection fraction [LVEF] < 35%. In no case was a significant regional wall motion abnormality recorded by two-dimensional echocardiography. All patients were in sinus rhythm and were receiving digoxin. angiotensin-converting enzyme inhibitors, and diuretic drugs in adequate doses. No patients received [beta]-blocker therapy because when our study started this treatment had not yet become an established standard. Patients with rhythm disturbances, ischemic cardiomyopathy, more-than-mild valvular heart disease, or regional wall motion abnormalities were excluded. More specifically, patients with more-than-mild mitral regurgitation were excluded from the study to avoid confounding echocardiographic volumetric measurements.

Transthoracic echocardiography was performed, and the echocardiographic variables were measured at baseline and after dobutamine infusion. In an additional 15 subjects (mean age, 34.7 [+ or -] 6.3 years) with normal left ventricular size and function. and normal left atrial size, an echocardiographic dobutamine study was performed. All patients gave informed consent.

Echocardiography

In all patients, the ultrasound transducer was positioned at the point of maximal cardiac impulse and angled toward the right shoulder until an image was obtained that included all four cardiac chambers and both mitral and tricuspid valves, Thereafter, the transducer was angled to obtained the maximal left atrial and ventricular size while recording portions of both atrioventricular valves. In the apical two-chamber view, the aortic valve and aorta were included when outlining the left atrial cavity. In addition, at least 80% of endocardium had to be seen and the difference in measurements of the left atrial common axis shared by both apical four-chamber and two-chamber views had to be [less than or equal to] 3 mm. Following this, digital tracing (Sonos 1000 or 2500; Hewlett-Packard; Andover, MA) was used and left atrial volumes were measured from apical four-chamber and two-chamber views. The volume determinations were calculated according to method of Dodge et al, (10) using a biplane area-length formula: V = 8A1 x A2/3[pi]L, where A1 and A2 represent the enclosed area of the atrial chamber from two orthogonal views, respectively, and L is the common axis shared and directed from apex to base. The following measurements were made at baseline and after the end of 10 [micro]kg/min of dobutamine infusion: (1) left atrial maximal volume at the point of mitral valve opening (LAVmax), and minimal volume at the point of mitral valve closure (LAVmin). Left atrial volume at onset of atrial systole (LAVp) was considered the volume corresponding to the onset of the P wave in the simultaneous recorded ECG. (2) Left atrial function was evaluated with the left atrial active emptying volume (LAEV) [volume at onset of atrial systole--minimal volume], and with the left atrial active emptying fraction (LAEF): [(volume at onset of atrial systole--minimal volume)/ volume at onset of atrial systole] x 100. Total atrial reservoir function was determined by measuring left atrial maximal volume minus minimal volume. (3) From the parasternal long-axis view and according to American Society of Echocardiography, (11) LVEDD, left ventricular end-systolic diameter (LVESD), and LVFS (LVEDD--LVESD/LVEDD x 100) were calculated. LVEF was measured by using the modified Simpson rule. The changes of the above-mentioned parameters after dobutamine infusion were considered as indexes of left atrial functional reserve. Changes represent values obtained after dobutamine infusion minus those obtained at baseline. All measurements represent the average of the measurements of five consecutive beats. In all eases, echocardiograms were analyzed by two independent expert observers. In eases of discrepancy, the average wits calculated and the mean value was reported.

Dobutamine Infusion

Dobutamine was infused IV in two steps after establishment of a stable hemodynamic state for each step (heart rate, BP). The duration of each step was 5 min, and the maximal end-dose of dobutamine infused was 10 [micro]g/kg/min. (12) At each step, dobutamine infusion was increased by 5 [micro]g/kg/min, reaching 10 [micro]kg/min at the second step Every minute during the protocol, systolic, diastolic, and hence mean arterial BP (Sirecust 888; Siemens; Erlangen, Germany), heart rate and a 12-lead ECG were recorded.

Cardiopulmonary Exercise Testing

Exercise testing with respiratory gas exchange measurements was performed while patients exercised on a treadmill according to the Dargie protocol. (13) Oxygen consumption, carbon dioxide production, and respiratory exchange ratio were measured continuously during exercise using an automated gas exchange measuring system (CPX/MAX; Medgraphics; Minneapolis, MN). BP was measured with a mercury sphygmomanometer, and the ECG was monitored continuously with a computer-assisted system (Marquette Electronics; Milwaukee, WI). V[O.sub.2]max at peak exercise was calculated as the mean of values during the last minute of exercise.

Statistical Analysis

All values are expressed as mean [+ or -] SD. A paired t test was applied to compare variables between groups before and after dobutamine infusion. An unpaired t test was applied to compare variables between different groups. Correlation analysis (linear regression analysis) was used in order to evaluate the relations between V[O.sub.2]max values and the echocardiographic parameters. Reproducibility (interobserver and intraobserver variability) of our laboratory have been reported previously. (8,9) A p value < 0.05 was considered statistically significant.

RESULTS

No major side effects were reported during dobutamine infusion. The V[O.sub.2]max measured in all patients ranged from 10 to 21.8 mL/kg/min (mean, 15 [+ or -] 2.9 mL/kg/min).

Echocardiographic Measurements

The echocardiographic measurements of the normal group and the heart failure group at baseline and after dobutamine infusion and their changes are shown in Table 1. Systolic BP was unchanged after low-dose dobutamine infusion (from 112.1 [+ or -] 10.9 to 113.1 [+ or -] 8.7 mm Hg), whereas R-R interval was significantly decreased (from 759.4 [+ or -] 50.6 to 732.3 [+ or -] 57 ms, p = 0.01). After dobutamine infusion, statistically significant decreases in LAVp and in LAVmin (both p < 0.001) were recorded, while LAEV and LAEF were significantly increased (both p < 0.01). LVEDD was unchanged after dobutamine infusion, whereas LVESD was significantly decreased (-4.4 [+ or -] 4.7 mm, p = 0.0001) after inotropic stimulation. LVFS and LVEF were significantly increased: 6.7 [+ or -] 7.3% (p = 0.0002) and 5.8 [+ or -] 3.6% (p = 0.0001), respectively. The changes in LAEV (r = 0.73, p = 0.001), LAEF (r = 0.71, p = 0.001), LAVmin (r = - 0.66, p = 0.001) and LVESD (r = 0.79, p = 0.001) were highly correlated with V[O.sub.2]max values (Fig 1).

[FIGURE 1 OMITTED]

At baseline, left ventricular inflow pattern presented an E-wave velocity of 62.3 [+ or -] 9.3 cm/s and an A-wave velocity of 42.1 [+ or -] 13.9 cm/s. The ratio between the early peak transmitral flow velocity and the late peak velocity (1.6 [+ or -] 0.7) was correlated with V[O.sub.2]max (r = -0.56, p < 0.001) and with the dobutamine-induced changes in LAEV (r = - 0.50, p < 0.001) and in LAEF (r = - 0.54, p < 0.001). Pulmonary artery systolic pressure measured at baseline (40.2 [+ or -] 4.6 mm Hg) was not significantly correlated with exercise capacity and with left atrial functional reserve. Pulmonary artery systolic pressure was calculated by using the following formula: 4 x tricuspid regurgitation peak velocity (2) + 10 mm Hg.

Atrial response to dobutamine in patients with high vs low V[O.sub.2]max. The heart failure group was further divided in two groups: group 1 (n = 23) comprised patients with V[O.sub.2]max values > 14 mL/kg/min (mean, 16.6 [+ or -] 2.1 mL/kg/min); and group 2 patients (n = 12) had V[O.sub.2]max values < 14 mL/kg/min (mean, 12 [+ or -] 1.2 mL/kg/min).

The values of the echocardiographic variables of each group both before and after inotropic stimulation as well as their changes are shown in Table 2. Systolic BP was similarly increased in both groups (1 [+ or -] 8.3 mm Hg for group 1 and 0.8 [+ or -] 7.6 mm Hg for group 2). R-R interval was similarly decreased in both groups (-23.4 [+ or -] 53.4 ms for group 1 and -34.2 [+ or -] 59.4 ms for group 2).

Dobutamine-induced changes in LAVp were similar between groups. In contrast, LAVmin, although similar at baseline, was decreased more in group 1 (-7.5 [+ or -] 7.7 mL) than in group 2 (-2.6 [+ or -] 5 mL) [p = 0.02]. However, LAEV and LAEF, although similar at baseline, after dobutamine infusion were increased in group 1 (5.6 [+ or -] 7.3 mL and 10 [+ or -] 13.1%, respectively) and decreased in group 2 (-1.1 [+ or -] 6.1 mL and -1.6 [+ or -] 9.9%, respectively) [p = 0.01 for both]. The changes in LVEDD were similar before and after dobutamine infusion, while LVESD was decreased in group 1 (-7.1 [+ or -] 2.7 mm) and increased in group 2 (0.7 [+ or -] 3.5 mm) [p = 0.0001]. LVFS and LVEF were increased more in group 1 (9.9 [+ or -] 5.5% and 7.1 [+ or -] 2.6%, respectively; p = 0.001 for both) than in group 2 (0.4 [+ or -] 6.1% and 3.4 [+ or -] 4.2%, respectively).

Of note, plotting the variables V[O.sub.2]max vs the changes in LAEV and LAEF (Fig 2), we can make the following observations. Firstly, the trend line of the above-mentioned variables cuts the x-axis near the value 13 mL/kg/min for V[O.sub.2]max, indicating that we may expect an improvement in atrial contractile reserve even for values of V[O.sub.2]max < 14 mL/kg/min. Secondly, dobutamine-induced changes in the above-mentioned variables that correspond to the range of 10 to 14 mL/kg/min of V[O.sub.2]max fall very near to the zero line, and some of them are even positive or negative, expressing an improvement in atrial contractile reserve.

[FIGURE 2 OMITTED]

At baseline, mitral E-wave velocity and pulmonary systolic pressure were similar between groups (62.4 [+ or -] 9.3 cm/s and 40.1 [+ or -] 5.1 mm Hg for group 1 and 62.1 [+ or -] 9.9 cm/s and 40.4 [+ or -] 4 mm Hg for group 2, respectively; p = not significant [NS]). However, mitral A wave was higher in group 1 (46.5 [+ or -] 14.1 cm/s) than in group 2 (33.7 [+ or -] 9.3 cm/s), p < 0.01. The ratio between the early peak transmitral flow velocity and the late peak systolic velocity was of borderline significance (p = 0.07), higher in group 2 (1.9 [+ or -] 0.6) than in group 1 (1.5 [+ or -] 0.6).

Atrial Response to Dobutamine in Patients With V[O.sub.2]max Values > 14 mL/kg/min

Since in the above-mentioned groups there was a statistically significant change both in left ventricular and left atrium functional reserve, to further investigate the role of left atrial functional status we divided group 1 in two subgroups according to median value of V[O.sub.2]max (15.8 mL/kg/min). Group 1a represents patients (n = 12) with V[O.sub.2]max values above (18.2 [+ or -] 1.7 mL/kg/min) the V[O.sub.2]max median value, and group 1b represents patients (n = 11) with V[O.sub.2]max values below (14.9 [+ or -] 0.2 mL/kg/min) the V[O.sub.2]max median value.

Interestingly, the dobutamine induced changes in LVEDD (0.2 [+ or -] 3.1 mm for subgroup 1a and -0.4 [+ or -] 3.2 mm for subgroup 1b, p = NS), LVESD (-7.9 [+ or -] 3 mm for subgroup 1a and -6.2 [+ or -] 2 mm for subgroup 1b, p = NS), in LVFS (12 [+ or -] 6.4% for subgroup 1a and 7.2 [+ or -] 3.5% for subgroup 1b, p = NS), and LVEF (6.1 [+ or -] 3.3% for subgroup 1a and 6.8 [+ or -] 2.5% for subgroup 1b, p = NS) were similar between subgroups. Moreover, the dobutamine-induced changes in LAVmax and LAVp were similar between subgroups. However, LAEV and LAEF were increased more in subgroup 1a (10.7 [+ or -] 5.7 mL and 19 [+ or -] 9.5%, respectively; p = 0.0001 for both) than in subgroup 1b (0.09 [+ or -] 3.9 mL and 0.2 [+ or -] 8.7%, respectively) [Table 3, Fig 3].

[FIGURE 3 OMITTED]

Twelve-Month Follow-up

During the 12-month follow-up period, two patients from group 2 died and two patients underwent heart transplantation. From group 1 (more specifically, subgroup 1b), one patient died during the follow-up period.

DISCUSSION

The results of this study suggest that after inotropic stimulation in patients with chronic heart failure and nonischemic DCM, there is an improvement of left atrial volumetric indexes. Importantly, this study indicates that left atrial functional reserve, detected by echocardiographic dobutamine, might differentiate patients with V[O.sub.2]max values > 14 mL/kg/min higher or < 14 mL/kg/min. Interestingly, these findings also suggest that in the evolution of heart failure in this group of patients, left atrial might precede left ventricular contractile reserve impairment.

Left Atrial Function After Dobutamine Infusion

The hemodynamic effects of [beta]-adrenergic stimulation with IV dobutamine have been extensively studied in animals (14) and in human beings. (15,16) Left atrial function includes three phases: reservoir, conduit, and contraction. Left atrial reservoir function is influenced by left atrial relaxation (17) and stiffness, (18) left ventricular contraction, (19) and pulmonary circulation. (20)

In this study, although LAVmax was similar both before and after dobutamine infusion, total atrial reservoir function was increased probably as a result of the improvement of left atrial and ventricular contraction and left atrium stiffness. (21) Contrasting effects of dobutamine on pulmonary circulation have been reported with some studies showing a decrease, (22) no changes, (23) or even an increase (24) in pulmonary artery pressure, suggesting a different response to dobutamine on left atrial reservoir phase.

The results of this study also showed that after dobutamine infusion there is an improvement of left atrial emptying, during ventricular relaxation and diastole (left atrium conduit phase). This is in keeping with previous reports suggesting that dobutamine infusion decreases left ventricular end-diastolic pressure in patients with normal left ventricular function, (16) and increases early filling velocity (15) in patients with systolic heart failure, leading to an increase in left atrial conduit volume. (25)

Dobutamine, by its well-known inotropic stimulation, acts through [[beta].sub.1] and [[beta].sub.2] receptors and increases the contractility of both left atrium and left ventricle. (26) In this respect, as observed in this study following dobutamine infusion, there is an improvement in LAEV and LAEF. Additionally, and in keeping with previous reports, LVESD, LVFS, and LVEF are also improved. Interestingly, the results of this study suggest that both left atrial and ventricular contractile reserve (8) can distinguish patients with different exercise capacity (V[O.sub.2]max values > 14 mL/kg/min or < 14 mL/kg/min). Of note, it has been reported that exercise and left ventricular performance during exercise are mainly dependent on left ventricular diastolic filling, which to some extent is dependent on left atrial systolic function. (6) Indeed, the results of this study suggest that there is a different response of atrial functional reserve to inotropic stimulation, presumably because of information transferred from a diseased ventricle to the corresponding atrium. (27) The different atrial response to dobutamine is in accordance with previous reports showing the reduced and different contractile response of severely failing human hearts to [beta]-adrenergic stimulation. (28) Moreover, it has been suggested that the same indexes of left atrial function reported in this study are related to peak aerobic capacity in patients with heart failure. (7)

Reflux of left atrial blood into the pulmonary veins during atrial contraction has not been considered in this study. In this respect, left atrial ejection fraction might not be quite analogous to LVEF. However, left atrial functional reserve, as assessed by echocardiographic dobutamine-induced changes, can be estimated regardless of the amount of blood ejected into the pulmonary veins during atrial contraction.

The results of this study confirm the findings of previous studies by showing that there is a correlation between V[O.sub.2]max and baseline left ventricular diastolic filling pattern, (29) and extend this knowledge by demonstrating a correlation between baseline left ventricular diastolic filling pattern and left atrial functional reserve.

Left atrial function has received considerably less attention than has left ventricular function even though evidence suggests that left atrial myopathy and failure may exist as an isolated entity, precede left ventricular myopathy, or coexist with left ventricular myopathy and failure. (30) In this study, we observed that in patients with V[O.sub.2]max > 14 mL/kg/min, although left ventricular contractile reserve is similar between subgroups differentiated by the median value of V[O.sub.2]max, left atrial functional reserve is different, suggesting that left atrial might precede left ventricular contractile reserve impairment.

Limitations

Various factors such as beam-angulation chamber foreshortening and improper endocardial definition may account for two-dimensional echocardiographic volumetric discrepancy. However, the purpose of this study was not to determine the precise left atrial volume measurements but to measure the changes induced by dobutamine infusion. The heterogeneous contractile responses to dobutamine observed in this study among patients with chronic heart failure have been reported previously, (31) and may reflect differences in [beta]-adrenoreceptor density, which was not investigated in this study. However, it has been suggested that the magnitude of the effects of the drug appears to decline as heart function deteriorates accompanied by a reduction in [beta]-adrenoreceptor density. (32)

CONCLUSION

Echocardiographic dobutamine can evaluate left atrial functional reserve in patients with chronic heart failure and nonischemic DCM. Furthermore, left atrial functional reserve detected by echocardiographic dobutamine may differentiate patients with V[O.sub.2]max values > 14 mL/kg/min or < 14 mL/kg/min. Interestingly, in this group of patients, left atrial contractile reserve impairment might be an earlier finding in the process of heart failure.

ACKNOWLEDGMENT: The authors thank Mrs. Polymnia Anthopoulou for nursing assistance and Miss Eleni Binou for secretarial assistance.

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* From the Second Department of Cardiology, Onassis Cardiac Surgery Center, Athens, Greece.

Manuscript received November 12, 2001; revision accepted April 16, 2002.

Correspondence to: Ioannis A. Paraskevaidis, MD, Onassis Cardiac Surgery Center, Second Department of Cardiology, 356 Syngrou Ave, 176 74 Athens, Greece; e-mail: elbee@ath. forthnet.gr

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