Effect of Inotropic Stimulation on Left Atrial Appendage Function in Atrial Myopathy of Chronic Atrial Fibrillation MASOOR KAMALESH, M.D., T. BURTON COPELAND, M.D., PH.D., and STEPHEN SAWADA, M.D. Veterans Affairs Medical Center, University of Illinois at Urbana-Champaign, Danville, Illinois, and Krannert Cardiology Institute, Indiana University School of Medicine, Indianapolis, Indiana

Atrial fibrillation (AF) leads to remodeling of the left atrium (LA) and left atrial appendage (LAA), resulting in atrial myopathy. Reduced LA and LAA function in chronic AF leads to thrombus formation and spontaneous echo contrast (SEC). The effect of inotropic stimulation on LAA function in patients with chronic AF is unknown. LAA emptying velocity (LAAEV) and maximal LAA area at baseline and after dobutamine were measured by transesophageal echocardiography in 14 subjects in normal sinus rhythm (NSR) and 6 subjects in AF. SEC in the LA was assessed before and after dobutamine. LAAEV increased significantly in both groups. However, the LAAEV at peak dobut- amine in patients with AF remained significantly lower than the baseline LAAEV in patients who were in NSR (P = 0.009). Maximal LAA area decreased significantly with dobutamine in both groups, but LAA area at peak dose of dobutamine inpatients with AF remained greater than baseline area in those in NSR (P = 0.01). Despite the increase in LAAEV, SEC improved i n only two of five patients. We conclude that during AF, the LAA responds to inotropic stimulation with only a modest improvement in function. ( E C H O C A R D I O G W m , Volume 17, May 2000)

atrial appendage, atrial fibrillation, inotropy, thrombosis

Atrial fibrillation (AF) leads to remodeling of the left atrium (LA) and left atrial appendage (LAA), resulting in atrial myopathy.1 Pro- longed tachycardia has been shown to cause a number of electrophysiological changes in the cardiac muscle, including diminished respon- siveness to beta adrenoreceptor stimulation due, among other things, to decreased beta re- ceptor density.2 Reduced LA and LAA function in the setting of Al? or cardiomyopathy leads to thrombus formation3-5 and spontaneous echo- cardiographic contrast (SEC).6

Inotropic therapy can improve contractile function and may decrease SEC in the left ven-

Presented at the American Society of Echocardiography annual meeting, 1999, Washington, D.C.

Address for correspondence and reprint requests: Masoor Kamalesh, M.D., 111, VA Medical Center, 1900 E. Main St., Danville, IL 61832. Fax: 217-477-4820.

tricle,7 but the effect of inotropes on LAA con- tractile function are unknown. There are data that suggest that LA and LAA functions are largely dependent on hemodynamic loading conditions5,s-lO and heart rate.llJ2 Although the LAA is known to possess intrinsic contrac- tile properties?J2 its independent contribution to the LAA ejection fraction in disease and health is not clear. Prior data suggest that LAA emptying is strongly influenced by heart rate in AF but not in sinus rhythrn.l2 We investi- gated the effects of inotropic stimulation on LAA function and addressed two issues. The primary question was whether the myopathic LAA in chronic AF responds to potent inotropic stimulation, and if so, how the response com- pares with that in patients in sinus rhythm. The secondary question was if the LAA does respond to inotropic stimulation, is it clinically signifi- cant; does it lead to an improvement in SEC?

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Methods

Twenty patients were enrolled who under- went transesophageal echocardiography dur- ing dobutamine stress testing for evaluation of known or suspected coronary artery disease. Six patients had chronic AF' (> 2 years), and 14 were in normal sinus rhythm (NSR). Informed consent was obtained from all subjects, and the study was approved by the Institutional Re- view Board of the Veterans Affairs Medical Center, University of Illinois at Urbana-Cham- paign Medical School.

Transesophageal echocardiography was per- formed with an Acuson 128 W/10 (Mountain View, Calif) machine equipped with a 3.5-,5.0-, and 7.0-MHz omniplane probe. A topical anes- thetic agent was used along with an intrave- nous sedative. Two-dimensional views of the LA and LAA were obtained in multiple planes. The images were stored in a cine-loop format for the subsequent measurement of LA and LAA areas. The maximum and minimum areas of the LAA from the vertical view were mea- sured using planimetry. Pulsed-wave Doppler was used to record LAA emptying velocities in the vertical plane. The pulsed-wave sample volume was placed at the mouth of the LAA, and emptying velocity was measured. Care was taken to minimize the angle of incidence while measuring velocities. LAA emptying velocities were measured over three cardiac cycles, and mean velocity was determined by averaging all forward velocities. The LA SEC was defined as the appearance of swirling smoke-like echoes.12 SEC was classified qualitatively as absent, mild, or severe. Dobutamine infusion was be- gun at 10 pg/kg/min and increased in incre- mental doses of 10 pg/kg/min every 3 minutes to a maximum of 40 pg/kg/min or until 85% of the predicted maximum heart rate (220 - pa- tient's age) was achieved. If the target heart rate was not achieved, intravenous atropine was used in increments of 0.4 mg up to a max- imum of 2.0 mg.

Statistical Analysis

A paired t-test was used for a comparison of measurements obtained at baseline and peak dobutamine dose within each subject popula-

tion. Comparison of measurements between patients with NSR and AF' was performed with an unpaired t-test. A P value of < 0.05 was considered significant.

Results

None of the patients had significant valvular lesions. Peak dobutamine hemodynamics were similar in both groups, with peak pulse being 132 2 18 in the AF group and 136 2 10 in the NSR group (P = NS), whereas peak systolic blood pressure was 171 t 36 in the AF' group and 161 2 25 in the NSR group (P = NS). One patient in each group had significant left ven- tricular systolic dysfunction (ejection frac- tion < 0.40). The peak 2 SD dose of dobut- amine used was 30 2 9 pg/kg/min in patients with NSR and 35 2 8 pg/kg/min in patients in AF' (P = NS). Significant wall motion abnor- mality due to induced ischemia was seen in only one patient in the NSR group (1 of 20). In the remainder of patients, the test was either negative for inducible ischemia (17 of 20) or positive for ischemia in a small area in postero- base in two patients in the AF' group (2 of 20). Baseline LAA emptying velocities were signif- icantly higher in patients with NSR (1.07 2 0.26 v 0.36 2 0.04, P < 0.0001; Fig. 1). LAA emptying velocities increased significantly both in patients in NSR (from 1.07 2 0.26 to 1.23 t 0.22, P = 0.032; Fig. 2, A and B) and in those with chronic AF' (from 0.36 2 0.04 to 0.59 2 0.17, P = 0.0004; Fig. 3, A and B).

-c Sinus Rhythm (N=14)

-Atrial Fibrillalion

1 LNg%nfdence Interval

0 4.. .

Rest Dobutamine

Figure 1. Comparison of peak left atrial append- age velocities (mlsec) between patients with and without atrial fibrillation. All comparisons are highly significant. *P = 0.009 compared with base- line left atrial appendage velocity in normal sinus rhythm. See text for details.

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A

3

Figure 2. A. Baseline left atrial appendage emptying velocity in a subject in normal sinus rhythm. B. Peak dobutamine left atrial appendage emptying velocity in same subject.

However, the LAA velocity at the peak dose of dobutamine in patients with AF' remained sig- nificantly lower than the baseline LAA velocity in patients who had sinus rhythm (0.59 5 0.17 vs 1.07 -+ 0.26 d s e c , P = 0.009).

In the one patient with significant baseline left ventricular dysfunction and inducible isch- emia, LAA velocities at baseline and peak were markedly lower than those in the remainder of the subjects in NSR (0.54 and 0.85 m/sec)

At baseline, the maximal LAA area was sig- nificantly greater in those with AF (389 5 73 vs 246 5 64 mm', P < 0.001). Maximal LAA area with dobutamine decreased in both of the study groups, but LAA area at the peak dose of do- butamine in patients with AF remained greater than the baseline area in those with sinus rhythm (343 2 95 vs 246 ? 64, P = 0.01).

None of the patients in NSR had evidence of

LA SEC. In the AF group, one patient had no SEC, four had mild SEC, and one had severe SEC at baseline. With dobutamine, an im- provement in SEC was seen in only two pa- tients (Table I). In these two patients, peak LAA emptying velocity improved during dobut- amine in one (patient 6) but LAA velocity also improved in two of three patients who had no improvement in SEC.

Discussion

We investigated the effects of pharmacologic inotropic stimulation on LAA size and function in subjects with NSR and those with AF and provide useful mechanistic information and in- sight into LAA physiology in AF and its re- sponse to dobutamine.

Baseline LAA function was markedly re-

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B Figure 3. A. Baseline lef% atrial appendage emptying velocity in a subject in atrial fibrillation. B. Peak dobutamine left atrial appendage emptying velocity in same subject.

duced in patients with AF, which is consistent with prior studies.3-5 With high-dose dobut- amine stimulation, there was a significant im-

TABLE I

Change in SEC with Dobutamine

Patient Baseline SEC

1 None (0.35) 2 Mild (0.31) 3 Mild (0.33) 4 Mild (0.44) 5 Mild (0.38) 6 Severe (0.40)

Postdobutamine SEC

None (0.58) Mild (0.30) None (0.30) Mild (0.45) Mild (0.68) Mild (0.54)

SEC = spontaneous echocardiographic contrast. Peak LAA velocity ( d s e c ) is given in parentheses.

provement in peak LAA emptying velocity. De- spite this significant improvement, the LAA emptying velocities in patients with AF re- mained lower than the baseline LAA emptying velocities in patients with sinus rhythm. This suggests that although the fibrillating LAA re- sponds to pharmacologic stimulation, the de- gree of improvement achieved is modest. Fur- thermore, dobutamine stimulation did not uni- formly resolve SEC in patients with AF. SEC is frequently seen in patients with AF and is in- dependently associated with strokes. Antico- agulation therapy is ineffective in resolving SEC.6 Although a prior study using a canine model with acute myocardial infarction by Mike11 et al.7 has shown the disappearance of acutely induced ventricular SEC with dopa-

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mine infusion (the rhythm was sinus), only two of five patients in our study had an improve- ment in SEC with dobutamine. The lack of resolution of SEC in three of five patients in our study suggests that mechanical dysfunc- tion may not be the only determinant of SEC in chronic AF. A number of hematologic abnor- malities have been described in patients with A F 7 that could play a major role in formation of SEC.

Prior studies have stressed the importance of heart rate, hemodynamics, and altered loading conditions in determining the LA and LAA emptying velocities.5,8-12 Akosah et a1.12 hy- pothesized that LAA emptying is due to extrin- sic compression by the adjacent ventricle filling in diastole and concluded that in AF, LAA emp- tying velocity is inversely related to heart rate. In contrast, increasing the heart rate with do- butamine in patients with AF in the present study increased the LAA emptying velocity, suggesting that despite the chronotropic effect that would have reduced the LAA emptying velocity, the potent inotropic effect of dobut- amine actually increased the LAA emptying velocity. An important point to be noted here is that our patients with AF were more homoge- neous in that they all had chronic AF for > 2 years, thus possibly having a greater degree of LAA myopathy and its attendant cellular and beta receptor derangements2 The lack of im- provement in LAA emptying velocity in the one patient in NSR who had significant inducible ischemia at peak stress is consistent with prior observations that left ventricular function and loading condition modulate LA and LAA emp- tying.8-10

The effect of dobutamine stimulation on LAA maximal area was less impressive than that seen on LAA emptying velocity. Although there was some decrease in the mean maximal LAA size in patients with AF, it was not statistically significant.

Study Limitations

Because our study included only patients with chronic AF, these results may not apply to patients with recent-onset AF. We considered only the acute effects of inotropic stimulation

on LAA function. This does not rule out any benefit that may be achieved with the long- term administration of inotropic stimulation. Despite a relatively small number of patients studied, the changes were sufficiently substan- tial to be highly significant. As mentioned, LA function is modulated by changes in left ven- tricular filling parameters.10 These were not measured in our study and could possibly affect LAA function. The inotropic agent used in our study was a beta agonist. The use of an ino- trope with a different mechanism of action, such as amrinone, may have a different effect on LAA emptying because it does not use beta receptors for its action.

Conclusions and Clinical Implications

The results of the present study provide in- sights into the acute effects of high-dose dobut- amine on atrial and appendicular function in health and disease. Our data suggest that im- provement in LAA appendage function with dobutamine is due to an increase in the intrin- sic contractile function of the appendage. Dur- ing chronic AF, the myopathic LAA responds to inotropic stimulation with dobutamine, but only a modest improvement in function can be achieved compared with the response seen in sinus rhythm. The clinical significance of this response remains to be determined.

Acknowledgments: The authors wish to acknowledge Wil- , liam Colwell for his help in preparing the tables.

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