SHORT REPORT

Dobutamine Stress Echocardiography:False Positive Scans in ProteinuricPatients with Type 1 Diabetes Mellitusat High Risk of Ischaemic HeartDiseaseM.E. Griffin*1, K. Nikookam1, M.M. Teh1, H. McCann2, N.M. O’Meara1, R.G. Firth1

1Department of Diabetes/Endocrinology, Mater MisericordiaeHospital, Eccles Street, Dublin 7, Ireland2Department of Cardiology, Mater Misericordiae Hospital,Eccles Street, Dublin 7, Ireland

Patients with Type 1 diabetes mellitus have an increased risk of ischaemic heart disease(IHD). When diabetes is complicated by nephropathy this risk is further increased andasymptomatic IHD is common. New techniques for non-invasive cardiac evaluation arenow available and one of these, Dobutamine Stress Echocardiography (DSE), was studiedin subjects with Type 1 DM and nephropathy who had no evidence of IHD. DSE wasperformed on 18 subjects (13 male, 5 female; mean age 37.8 ± 3.4 years), diabetesduration 23.7 ± 1.2 years and nephropathy diagnosed for 10.9 ± 1.3 years. There were 7(38 %) positive scans—suggesting asymptomatic IHD; 16.7 % of subjects studied had asignificant arrhythmia. Coronary angiography was performed in 6 of the 7 subjects withpositive DSEs and was positive in only 2. These results suggest that DSE has a high rateof false positive results in Type 1 DM patients suffering from nephropathy and may limitits usefulness in these subjects. 1998 John Wiley & Sons, Ltd.

Diabet. Med. 15: 427–430 (1998)

KEY WORDS Type 1 diabetes mellitus; nephropathy, ischaemic heart disease; dobutaminestress; echocardiography; false-positive

Received 9 June 1997; revised 13 November 1997; accepted 9 January 1998

Introduction

Patients with Type 1 diabetes mellitus have an increasedrisk of ischaemic heart disease (IHD),1,2 especially whendiabetes is complicated by nephropathy.3–6 AsymptomaticIHD is common in diabetes mellitus and its presence islikely to have prognostic and therapeutic implications.7

Advances in cardiology have introduced new non-invasivecardiac evaluations which can be used in the detectionof asymptomatic IHD. These investigative tools includeExercise Thallium 201 Scintigraphy (ETS), DipyridamoleThallium 201 Scintigraphy (DTS), and more recentlyDobutamine Stress Echocardiography (DSE). The value ofETS and DTS have been discussed elsewhere8–11 but littleinformation is available on the value of DSE in diabeticsubjects. It has been suggested that DSE is superiorto both dipyridamole echocardiography and exerciseelectrocardiography for the diagnosis of coronary arterydisease.12 The sensitivity of DSE in non-diabetic patientswith suspected IHD is 79–97 % with a specificity of 65–

* Correspondence to: Dr. M.E. Griffin, Division of Endocrinology,Department of Internal Medicine, Yale University School of Medicine,333 Cedar Street, New Haven, CT 06520-8020, USA

427CCC 0742–3071/98/050427–04$17.50 1998 John Wiley & Sons, Ltd. DIABETIC MEDICINE, 1998; 15: 427–430

83 %13–15 and it has been shown to be an accurate testwith regard to the exclusion of significant coronary arterydisease in a low risk population.16 In one study of patientswith Type 1 DM and end-stage renal failure (ESRF),DSE was incorporated into pre-transplant assessment andshowed a high prevalence of abnormal tests and determinedthat positive testing was predictive of future cardiacevents.17

The aim of this study was to evaluate the usefulness ofDSE in the detection of asymptomatic IHD in a group ofyoung, high-risk subjects with Type 1 DM and nephropathy,prior to ESRF, in whom there was no overt evidence of IHD.

Subjects and Methods

Inclusion Criteria

Subjects participating in the study were aged , 45 years,with duration of Type 1 DM . 15 years, and fixedproteinuria . 5 years. All subjects were required to haveno clinical, or resting electrocardiographic, evidence ofIHD and no clinical evidence of peripheral vasculardisease. Standard cardiac risk factors were evaluated.Proteinuria was defined as 24 h urinary protein excretion

SHORT REPORTof . 0.3 g. Hypertension was defined as a systolic bloodpressure . 150 mmHg and/or a diastolic blood pressure. 95 mmHg recorded on 3 separate occasions. In anumber of the individuals studied, blood pressure at thetime of the study was controlled on combinationantihypertensive therapy. Retinopathy was defined byophthalmological assessment in the eye departmentwhich all our patients receive on a yearly basis. Thiswas classified by a scoring system from 1 to 12 intonone, background, and proliferative.

Patients were initially retrieved from a database whichlists all subjects attending the clinic and their currentcomplications. This list is updated annually. Followinginitial contact by letter, telephone contact was madeand subjects invited to participate. Initial screeningmedical examination was performed with a subsequentappointment given for the procedure under evaluation.Thirty-six per cent of subjects responded positively tothe request to participate in the study.

Dobutamine Stress EchocardiogramProtocol

Resting echocardiogram and electrocardiogram wererecorded and dobutamine infused intravenously in astepwise fashion. Subjects were started on10 mg kg−1 min−1 for 4 min, then 20mg kg−1 min−1 for 3min and finally 40 mg kg−1 min−1, aiming for a heartrate of 90 % of the predicted, age-adjusted, maximalheart rate. If this was not achieved atropine wasadministered. The positive inotropic action of dobutamineincreases myocardial oxygen demand and areas ofischaemia are detected by witnessing wall motionchanges on echocardiography.18 Twenty-two segmentsof myocardium were identified in accordance withAmerican Society of Echocardiography guidelines andscored as being normal (1), hypokinetic (2), akinetic (3)or dyskinetic (4) with a resultant mean score. A wallmotion abnormality was defined as a segment scoring 2or greater in at least two different views. All DSEs wereread by two blinded observers who were not aware ofthe diagnosis of diabetes mellitus or the aim of the study.Beta-blockers and calcium antagonists were discontinuedfor 48 h prior to the scans.

Subjects with positive DSEs had follow-up coronaryangiography performed, ideally within 3 months of DSE.The study was approved by the local Ethics committeeand subjects gave informed consent.

Results are presented as mean ± standard error forparametric data and as median ± semi-interquartile rangefor nonparametric data. Continuous data was comparedusing the unpaired Student’s t-test for parametric variablesand Mann-Whitney U for non-parametric variables.Discrete variables were compared using chi-squaredanalysis.

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Results

Table 1 details the clinical characteristics of the groupof 18 subjects (13M, 5F) who participated.

Dobutamine Stress Echocardiogram

All patients achieved the desired heart rate at40 mg kg−1 min−1 and no subject required atropine. Therewere 7 positive scans among the 18 performed. Therewere no cases of negative scans associated with positiveelectrocardiographic changes or symptoms of angina.Those subjects with a positive scan were compared tothose with negative scans and as Table 2 demonstratesthat group with a positive scan had a trend towardslonger duration of proteinuria, higher protein excretion,higher cholesterol and triglycerides, all non-significant.

During the infusions there were 3 (16.7 %) cases ofsignificant arrhythmia: 1 case of symptomatic ventriculartachycardia (in a positive scan) and 2 cases of sympto-matic supra-ventricular tachycardia (1 in a positive and1 in a negative scan). The episode of ventriculartachycardia lasted for a salvo of 20 beats and the patientcomplained of retrosternal discomfort and palpitations.Dobutamine was immediately discontinued with promptresolution of symptoms and electrocardiographicchanges.

Coronary Angiography

Six of the patients with positive DSE scans proceeded tocoronary angiogram within 3 months. The 7th developedunrelated neurological symptoms and signs and wasexcluded from further evaluation. Two subjects hadpositive angiograms—one male, one female. Both sub-jects had severe triple vessel disease which was inoper-

Table 1. Clinical characteristics of subjects

Number 18M:F 13:5Age (yr) 37.8 ± 3.4Duration of Type 1 DM (yr) 23.7 ± 1.2Duration of nephropathy (yr) 10.9 ± 1.324 h urinary protein (g 24 h−1) 0.5 ± 0.64Creatinine (mmol l−1, normal 60–130) 142.6 ± 24.6HbA1C (normal , 6.2 %) 8.3 ± 0.3Cholesterol (mmol l−1) 5.7 ± 0.5Triglycerides (mmol l−1) 1.1 ± 0.6Current smokers 5Family Hx atherosclerosis 3Hypertension 13Neuropathy on clinical exam 7Retinopathy

none 5background 10proliferative 3

Data given as means ± standard errors (as median ± semi-interquartilerange for triglycerides and 24 h urinary protein).

SHORT REPORTTable 2. Comparison of patients with positive DSE to those with negative DSEs

DSE +ve DSE −ve p valuen = 7 n = 11

M:F 6:1 7:4 0.596Smoking 3 (43 %) 2 (18 %) 0.326

R-R = 2.36 (0.52–10.75)Hypertension 3 (43 %) 10 (91 %) 0.093

R-R = 0.47 (0.2–1.13)Fam Hx 0 3 (27 %) 0.245Daily insulin dose (u kg−1) 0.54 ± 0.04 0.48 ± 0.4 0.607Duration of proteinuria (yr) 11.3 ± 2.4 9.3 ± 1.4 0.254Creatinine (mmol l−1) 171.5 ± 64.0 125.3 ± 12.8 0.382(60–130)24 h urinary proteina 0.23 ± 0.68 0.5 ± 2.13 0.421(g 24h−1)Total cholesterol (mmol l−1) 6.4 ± 0.7 5.3 ± 0.3 0.051Triglycerides (mmol l−1)a 1.6 ± 0.9 1.0 ± 0.44 0.071HbA1C (%) , 6.2 % 8.6 ± 0.4 8.2 ± 0.2 0.460

aCompared using Mann-Whitney U, remainder compared using unpaired t-test.

able in the male subject while the female subject waslisted for coronary artery bypass surgery.

Discussion

This is the first reported study documenting the incidenceof positive DSE in a population of diabetic subjects atrisk of IHD who were entirely asymptomatic. A surpris-ingly high prevalence of positive scans was found in thisyoung population. The 38 % positive scan rate in thisstudy is identical to that reported previously in subjectswith Type 1 DM and ESRF on a pre-transplant assessmentprogramme.17 We studied patients with no overt evidenceof IHD, while 38 % of subjects in the previous studyhad an abnormal 12 lead ECG. That study detected only1 false positive scan in the 18 subjects studied with bothangiography and DSE while 4 of 6 in this study showedfalse positive scanning suggesting a positive predictivevalue for DSE in this cohort of 33 % (CI 4 %– 78 %).

The high prevalence of false positive DSE may beexplained in a number of ways. Firstly these subjectswith a long duration of DM and microvascular diseasemay be at risk of diabetic cardiomyopathy. This entityhas been described previously19 and could explain wallmotion abnormality in the absence of coronary arterydisease. Alternatively the presence of microvasculardisease20 may, theoretically, yield a positive DSE withangiography showing normal coronary circulation. Cer-tainly the accuracy of exercise thallium 201 scintigraphyin the diabetic population has been questioned for thisreason.9 Finally these studies may represent true inducibleischaemia in subjects with intermediate grade coronarystenosis. Certainly DSE has been shown to prognosticatefor the occurrence of cardiac events both in Type 1DM17 and in non-diabetic subjects.15,21 These data arenot yet available to us in this cohort but will be ofinterest in the future.

There were no significant differences between the two

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1998 John Wiley & Sons, Ltd. Diabet. Med. 15: 427–430 (1998)

groups for standard cardiac risk factors though a trendwas seen towards a longer duration of nephropathy, ahigher 24 h protein excretion, and a higher level ofcholesterol and triglycerides.

This study recorded a higher rate of occurrence ofsignificant arrhythmias in a diabetic cohort than issuggested by the current literature which is derived frominvestigations performed on non-diabetic subjects.15,22

Interestingly, the only reported case of non-ischaemicsustained ventricular tachycardia during DSE, that isventricular tachycardia occurring in a patient with normalcoronary arteries on angiography, was in a subject whohad a history of Type 2 DM.23 Autonomic denervationmay render the diabetic patient more sensitive tocirculating cathecholamines though this is only speculat-ive as autonomic function tests were not available onthe cohort studied here.

In conclusion, we found the value of DobutamineStress Echocardiography to be limited in this group ofsubjects with Type 1 DM and nephropathy due to ahigh incidence of false positive scans.

Acknowledgements

M.E. Griffin was supported by a grant from BayerDiagnostics, Newbury, Berkshire, UK.

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