Volume 1, Issue 2

 

Chronotropic Incompetence and Dobutamine Testing in Overweight and Obese Patients

April 22, 2010

 Abstract

Background

Dobutamine stress testing is a pharmacological alternative to exercise-induced tachycardia and is commonly used as a form of cardiac testing in patients unable to exercise. With adequate heart rate response, the diagnostic accuracy of this mode of testing is comparable to exercise for the detection of coronary artery disease. While the current recommended infusion protocol achieves this target heart rate in the majority of patients, it is uncertain if this is valid across all weight classes. In this study, we evaluate the chronotropic effect of dobutamine on overweight and obese patients.

Methods and Results

285 consecutive patients referred for dobutamine cardiac stress testing were evaluated. Using body mass index (BMI), patients were divided into normal (BMI, 20-24), overweight (BMI, 25-29), obese (BMI, 30-34) and morbidly obese (BMI >35) groups. The ability to reach their age-adjusted target heart rate (THR) with dobutamine alone or with the addition of atropine was evaluated. The percentage of patients achieving THR with dobutamine alone declined with increasing BMI (P<0.0001). In addition, men were less likely than women to reach THR (P<0.0001). This persisted through all BMI groups.

Conclusions

Overweight and obese subjects undergoing dobutamine stress testing were less likely to achieve THR without the addition of atropine after peak infusion. Since dobutamine infusion is weight-adjusted, this difference may reflect a non-linear requirement for dobutamine among patients with increased BMI. Early identification of patients who may need additional chronotropic medication may help facilitate the stress testing study.

Key Words: obesity, tests, pharmacology Cardiac stress testing remains the most common noninvasive procedure to detect coronary heart disease. Its predictive ability is greatest when the patient achieves at least 85% of their maximal predicted heart rate (MPHR) (1). Dobutamine infusion is a popular alternative to cardiac stress testing for patients unable to exercise adequately. While most patients are able to achieve a prespecified target heart rate (THR) based on their age in order to reach optimal statistical accuracy, those who do not require atropine administration after peak dobutamine infusion in order to attain this goal. We sought to determine if the percentage of patients who reach their THR using dobutamine alone is uniform across all body mass index groups.

Methods

Patient Selection

All patients undergoing dobutamine stress testing in our non-invasive cardiac laboratory between January 2003 and February 2005 were included for analysis. These tests were performed as either dobutamine stress echocardiography or dobutamine myocardial perfusion imaging studies. The method of imaging was at the discretion of the ordering physician. The most common reasons for the stress test include chest pain, suspected or known coronary artery disease, shortness of breath, preoperative evaluation, congestive heart failure and syncope. Patients were excluded if they took beta-adrenergic blockers within 24 hours or were unable to discontinue this at least 24 hours prior to the test. Baseline demographics including age, gender, height, weight, medications and medical history were obtained. Body mass index (BMI) is calculated as weight in pounds divided by the square of the height in inches multiplied by 703.

Patients were grouped according to BMI and designated as normal (BMI, 20-24), overweight (BMI, 25-29), obese (BMI, 30-34) and morbidly obese (BMI>35), or groups 1 to 4, respectively.

Dobutamine protocol

The heart rate, blood pressure and 12-lead electrocardiogram were obtained at baseline, at the end of every stage, and every 2 minutes during recovery. The maximal predicted heart rate was based on a standard age-corrected table (2). All patients had continuous heart rate and 3-channel electrocardiographic monitoring throughout the test. They were also evaluated for symptoms of chest pain, dyspnea, fatigue, headache, nausea and dizziness.

Dobutamine was infused using a standard incremental dosing protocol from 5 to 40 μg/kg/min in 3-minute stages. Atropine in divided doses up to 2 mg was given to patients who failed to attain 85% of MPHR, defined as their target heart rate. Test end points include reaching 85% of MPHR, evidence of severe ischemia (severe chest pain, significant ST-segment depression or elevation), hypertension (systolic blood pressure >220 mm Hg or diastolic blood pressure >110 mm Hg), hypotension (>15 mm Hg decrease compared with the baseline measurement), significant arrhythmias, side effects intolerable to the patient or after receiving the maximum dose of atropine.

Imaging procedure

Patients undergoing dobutamine stress echocardiography had baseline echocardiograms using standard two-dimensional views. Subsequent echocardiograms were acquired at the end of every dobutamine stage and at peak stress. Images were digitalized online in a cineloop fashion and displayed in a quad format.

Patients who had myocardial perfusion imaging were studied using a same-day rest-stress ECG-gated imaging approach with either Tc-99m labeled sestamibi or tetrofosmin. The isotope was injected during peak heart rate. Tomographic imaging was performed at rest followed by stress images taken 30-60 minutes after dobutamine infusion. Data were acquired using a gamma camera with an 180˚ semicircular orbit and a 64 X 64 matrix in a step-and-shoot format.

Statistical analysis

Continuous variables are presented as mean + SD. Statistical analysis for the groups was performed using two-way analysis of variance (ANOVA). Comparisons between the groups were made by Student t test or chi-square test. P<0.05 was considered significant.

Results

Patient characteristics

Table 1 summarizes their clinical characteristics. 285 patients were included in the study. Two times as many women as men were referred for this type of study. Most patients were either overweight or obese. The largest group of patients was in the morbidly obese category, accounting for 42 percent of the total. The majority of patients were hypertensive. After excluding the use of beta-adrenergic blocking agents, the most common medical regimen include angiotensin converting enzyme inhibitors, statins and diuretics. Other significant comorbidities were diabetes mellitus and hypercholesterolemia.

Overall heart rate response to dobutamine

At peak dobutamine infusion, there is an inverse trend in the ability to achieve 85 percent or greater of MPHR with increasing BMI. As shown in Figure 1, a higher mean % MPHR is achieved overall as the BMI approaches normal. Group 1 reached 86.6 + 12.3%; group 2, 79.6 + 15.3%; group 3, 77.2 + 14.5%; and group 4, 70.4 + 13.6% of MPHR respectively. The difference between these groups is significant (p<0.0001). The ability of atropine to increase the heart rate sufficiently to reach THR is also impaired with increasing BMI (Figure 2). 75% of patients in group 1 achieved target heart rate, compared to 51% in group 2, 42% in group 3 and 19% in group 4, respectively (P<0.0001). As a result, the likelihood of receiving supplemental atropine after peak dobutamine infusion rises with increasing BMI. In spite of receiving atropine, most patients did not reach 85% of MPHR.

Subgroup analysis

There were 95 men and 190 women in the study. 26% of men versus 41% of women achieved THR using dobutamine alone (P<0.0001). When only obese men (n=54) and obese women (n=138) were studied, a similar difference was found (9% of men versus 28% of women) for those achieving THR with dobutamine alone (P<0.0001).

While this trend appears in all age groups, it did not achieve statistical significance when grouped into decades of life (P=0.84, Figure 3).

Overweight and obese men and women were more likely to receive atropine than their normal-weight counterparts. Additionally, subjects younger than 50 years of age were more likely to receive atropine, the majority being overweight or obese (Table 2). All of these differences achieved statistical significance (P<0.0001).

Discussion

Dobutamine stress testing is commonly used for patients unable or unwilling to perform exercise testing. It is safe and has excellent sensitivity and specificity in the diagnosis of coronary artery disease (3-7). Its accuracy is dependent upon the patient’s ability to reach THR, however (8).

Currently, the method dobutamine stress testing remains the same regardless of the patient’s BMI. This includes both the infusion protocol and use of atropine as well as THR determination. While dobutamine stress testing has been reported to be as safe in obese patients as their normal-weight counterparts, we are unaware of studies evaluating the chronotropic effects of dobutamine with respect to BMI (9). This is the first study looking at heart rate response to dobutamine stress testing as a function of BMI.

The clinical significance of heart rate response in this setting is uncertain. It has recently been shown that inability to achieve 85% of MPHR using dobutamine stress testing was associated with worse outcomes and an independent predictor of events including cardiac death and non-fatal myocardial infarction (10). The continued use of beta-blockers in 26% to 34% of study subjects represents a confounding variable in this study, however. Whether this negative prognostic marker applies to overweight and obese patients remains to be determined.

Our present study shows that the percentage of patients achieving THR during dobutamine stress testing with or without atropine declines as the BMI increases. Several possible reasons may explain this finding. The pharmacokinetics and actions of dobutamine should be considered. Obese individuals have expanded intravascular volume (11, 12). A possible “dilutional” effect, with less drug per unit volume of blood may be a cause of lowered heart rate response.

Elevated body mass has direct and indirect effects on heart size. Prior observations have reported an association with obesity and increased left ventricular mass although recent reports have not consistently demonstrated this (13-17). While obesity itself may stimulate cellular hypertrophy, secondary causes may be contributory. One of the most profound cardiovascular effects of obesity is systemic hypertension which in turn may lead to increases in cardiac mass (15, 18). Analagous to the dilutional effect stated above, less exposure to circulating dobutamine per gram of cardiac tissue should be considered.

The majority of obese humans have high circulating concentrations of leptin (19). This 167 amino acid peptide hormone has numerous actions that influence autonomic, cardiovascular and endocrine function (20, 21). While leptins have been shown to activate sympathetic nerve traffic, they do not increase heart rate when infused into obese rats (22). Whether this is due to increased norepinephrine turnover as seen in experimental rat models is unclear (23). How this interaction potentially interferes with intravenous dobutamine remains to be seen.

Conclusions

This is the first study evaluating heart rate response to dobutamine infusion as a function of body mass index. There is an inverse relationship with the patient’s ability to achieve target heart rate and their BMI. Although dobutamine infusion is weight-adjusted, this effect may reflect a non-linear chronotropic effect of dobutamine with increasing BMI. The mechanism of this impaired response, as well as the prognostic implications, remains to be determined.

 

References

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 Table 1. Baseline Clinical Characteristics of All Patients

Clinical feature

 

Age, y

61 + 13

Male gender, %

95 (33.3)

Body mass index, kg/m2

34.2 + 8.6

            BMI <25

28 (9.8)

            BMI 25-29

65 (22.8)

            BMI 30-34

73 (25.6)

            BMI >35

119 (41.8)

Hypercholesterolemia

87 (30.5)

Diabetes mellitus

94 (33.0)

Hypertension

212 (74.4)

Medications

 

            Angiotensin converting enzyme inhibitors

92 (32.3)

            Angiotensin receptor blockers

36 (12.6)

            Calcium channel blockers

59 (20.7)

            Statins

87 (30.5)

            Oral hypoglycemic agents

48 (16.8)

            Insulin

26 (9.1)

            Aspirin

91 (31.9)

            Nitrate preparations

50 (17.5)

            Diuretics

86 (30.2)

Heart rate, bpm

72 + 13

Systolic blood pressure,  mmHg

141 + 25

Diastolic blood pressure, mmHg

79 + 13

Values are reported as n (%) unless otherwise specified.

Table 2. Patients Within Subgroups Requiring Atropine

Group

N (%)

Age<50 overall

47 (89)*

            Group 1

0

            Groups 2-4

46 (92)†

Age>50 overall

135 (58)

            Group 1

3 (11)

            Groups 2-4

130 (63)

Gender

 

            Women overall

112 (59)‡

            Men overall

70 (74)

            Group 1 women

0

            Group 1 men

3 (25)§

            Groups 2-4 women

117 (65)

            Groups 2-4 men

70 (82)

 

* P<0.0001 compared to age >50 overall.

† P<0.0001 compared to age >50 groups 2-4.

‡ P<0.0001 compared to men overall.

§ P<0.0001 compared to groups 2-4 men. Figure 1. Mean % MPHR Achieved In Each BMI Subgroup with Dobutamine Infusion Alone

Figure 2. Percent of Patients Who Reached THR With and Without Atropine and Percent of Patients Requiring Atropine Supplementation

P < 0.0001

 

Figure 3. Percent Reaching THR as a Function of Age and Gender