lipoproteins in young survivors of myocardial infarction. Circulation 1986;73:1097–1110.10. Gensini GG. Coronary arteriography. In: Braunwald E, ed. Heart Disease.Philadelphia, Pennsylvania: WB Saunders, 1980:352–353.11. Festa A, d’Agostino R, Howard G, Mykkanen L, Tracy RP, Haffner SM.Inflammation and microalbuminuria in nondiabetic and type 2 diabetic subjects:the Insulin Resistance Study. Kidney Int 2000;58:1703–1710.12. Jensen JS, Myrup B, Borch-Jonsen K, Jensen G, Jensen T, Feldt-Rasmussen

B. Aspects of haemostatic function in healthy subjects with microalbuminuria: apotential atherosclerotic risk factor. Thromb Res 1995;77:423–430.13. Gruden G, Cavallo-Perin P, Bazzan M, Stella S, Vuolo A, Pagano G. PAI-1and factor VIII activity are higher in IDDM patients with microalbuminuria.Diabetes 1994;43:426–429.14. Winocour PH, Harland JOE, Millar JP, Laker MF, Alberti KG. Microalbu-minuria and associated cardiovascular risk factors in the community. Atheroscle-rosis 1992;93:71–81.

Clinically Unrecognized Q-Wave Myocardial Infarctionin Patients With Diabetes Mellitus, Systemic

Hypertension, and Nephropathy

David Aguilar, MD, Samuel Z. Goldhaber, MD, Daniel J. Gans, MS,Andrew S. Levey, MD, Jerome G. Porush, MD, Julia B. Lewis, MD,Jean-Lucien Rouleau, MD, Tomas Berl, MD, Edmund J. Lewis, MD,Marc A. Pfeffer, MD, PhD, and the Collaborative Study Group

During the Irbesartan Diabetic Nephropathy Trial,1,387 participants with type 2 diabetes mellitus, hy-pertension, and nephropathy underwent serial elec-trocardiograms for the identification of Q-wave myo-cardial infarction (MI). During a mean follow-up of2.5 years, 14 of 99 first nonfatal MIs in this groupwere clinically unrecognized, accounting for 14% ofall first nonfatal MIs. �2004 by Excerpta Medica,Inc.

(Am J Cardiol 2004;94:337–339)

Patients with diabetes mellitus are considered par-ticularly susceptible to the development of clini-

cally unrecognized myocardial infarction (MI). TheIrbesartan Diabetic Nephropathy Trial (IDNT) pro-vided an opportunity to evaluate the incidence ofclinically unrecognized Q-wave MI in a large cohortof type 2 diabetic patients with hypertension andnephropathy.

• • •The IDNT was a prospective, randomized trial of

1,715 hypertensive patients with nephropathy andtype 2 diabetes mellitus designed to test the effects ofirbesartan or amlodipine on the progression of ne-

phropathy compared with placebo in the presence ofother background antihypertensive therapy.1 The cri-teria for eligibility included age 30 to 70 years, doc-umented type 2 diabetes mellitus, hypertension (base-line seated blood pressure �135/85 mm Hg ortreatment with antihypertensive medication), and pro-teinuria with a urinary protein excretion of �900mg/24 hours. The serum creatinine had to range from1.0 to 3.0 mg/dl in women and from 1.2 to 3.0 mg/dlin men. In the absence of insulin therapy, type 2diabetes mellitus was defined as a history of fastingplasma glucose �140 mg/dl on 2 occasions, therapywith an oral hypoglycemic agent, or fasting C-peptidelevel greater than or equal to the normal of the locallaboratory. For patients receiving insulin therapy, thetime from the diagnosis of type 2 diabetes mellitus toinsulin use was required to be �1 year.

Investigators at each center reported potential car-diovascular events, including cardiovascular deathand nonfatal MI, and these events were reviewed andadjudicated by a clinical end point committee blindedto therapy assignment. The definitions for the patientcardiovascular outcomes have been previously de-scribed.2 In an effort to detect clinically unrecognizedMI, electrocardiograms were performed at baselineand were submitted to the core laboratory at theBrigham and Women’s Hospital for interpretation by2 independent reviewers without knowledge of treat-ment assignment or the clinical status of the partici-pants. At baseline, the core laboratory evaluated elec-trocardiograms for abnormalities, such as left bundlebranch block, paced rhythms, left ventricular hyper-trophy with poor R-wave progression, and Wolf-Par-kinson-White syndrome or preexisting pathologic Qwaves that would obscure the electrocardiographicdiagnosis of a new Q-wave MI. Patients with thesebaseline abnormalities were excluded from follow-upevaluation by the core laboratory. The remaining1,387 patients were scheduled for follow-up electro-cardiograms at 6, 12, 24, 36, and 48 months.

From the Division of Cardiology, University of Texas Health ScienceCenter, Houston, Texas; Brigham and Women’s Hospital, HarvardMedical School, Boston, Massachusetts; Bristol-Myers Squibb Pharma-ceutical Research Institute, Pennington, New Jersey; Tufts-New En-gland Medical Center, Boston, Massachusetts; Brookdale UniversityHospital and Medical Center, Brooklyn, New York; Vanderbilt Uni-versity College of Medicine, Nashville, Tennessee; the University ofMontreal, Montreal, Quebec, Canada; the University of ColoradoMedical School, Denver, Colorado; and Rush-Presbyterian-St. Luke’sMedical Center, Chicago, Illinois. The Irbesartan Diabetic Nephrop-athy Trial was sponsored with grant support by Bristol-Myers SquibbPharmaceutical Research Institute, Pennington, New Jersey, andSanofi-Synthelabo, Inc., New York, New York. Dr. Aguilar’s addressis: University of Texas Health Science Center, Department of Cardiol-ogy, 6431 Fannin, MSB 1.246, Houston, Texas 77030. E-mail:david.aguilar@uth.tmc.edu. Manuscript received February 29, 2004;revised manuscript received and accepted April 15, 2004.

337©2004 by Excerpta Medica, Inc. All rights reserved. 0002-9149/04/$–see front matterThe American Journal of Cardiology Vol. 94 August 1, 2004 doi:10.1016/j.amjcard.2004.04.028

A MI was designated by the core laboratory whennew pathologic (�30 ms) Q waves were visuallydetected in �2 contiguous leads. The electrocardio-graphic core laboratory transmitted the determinationof a new Q-wave MI to the data-coordinating centerfor integration with existing clinical information. Aclinically unrecognized MI was defined as a core

laboratory–determined MI in the ab-sence of a reported clinical eventfrom the clinical center.

For recognized and unrecognizednonfatal MI, participants in the studywere followed to the development ofend-stage renal disease (the initiationof dialysis, renal transplantation, orserum creatinine �6.0 mg/dl), death,or study completion in December2000. Only the first occurrences ofnonfatal MI were analyzed. Differ-ences in baseline characteristics andoutcomes after randomization werecompared between patients with clin-ically unrecognized MI and thosewith clinically recognized MI usingStudent’s t tests for continuous vari-ables and Fisher’s exact tests for di-chotomous variables.

Of the 1,715 participants in theIDNT, 1,689 (98%) had baselineelectrocardiograms performed. Threehundred two participants (18%) hadabnormalities that obscured the elec-trocardiographic identification of aclinically unrecognized Q-wave MIand were thus excluded. Therefore,our analysis used the 1,387 partici-pants who were eligible for the elec-trocardiographic core laboratory de-termination of a subsequent Q-waveMI (Figure 1). We reviewed 5,527electrocardiograms, with a mean pa-tient follow-up of 2.5 years. Themean number of electrocardiogramsperformed per patient was 4.

During the follow-up period, a to-tal of 108 first MI events occurred.Of these, 9 were fatal and 99 werenonfatal. The diagnosis of clinicallyunrecognized MI was confirmed in 14of these cases, representing 14.1%(95% confidence interval 8.2% to22.9%) of all first nonfatal MIs in thisclinical trial. The incidence of clini-cally unrecognized MI was 4/1,000patient-years. The baseline charac-teristics of those with clinically rec-ognized and unrecognized MI arelisted in Table 1. No statistical dif-ference was noted between those pa-tients with clinically recognized andunrecognized MI.

During the follow-up period, 2 ofthe participants with clinically unrecognized MI died,and 21 of the participants with clinically recognizedMI died. Although the relatively small number ofevents limits the ability to identify differences in out-comes between those with clinically recognized andunrecognized MI, no significant differences werenoted in the outcomes of heart failure, cardiovascular

FIGURE 1. Study design. ECG � electrocardiogram; LBBB � left bundle branch block;LVH � left ventricular hypertrophy; Paced � paced rhythm; WPW � Wolfe-Parkin-son-White syndrome.

TABLE 1 Baseline Characteristics and Outcomes of Participants

Variable

NonfatalUnrecognized MI

(n � 14)

NonfatalRecognized MI

(n � 85) p Value*No MI

(n � 1279)

Age (yrs) (mean � SD) 59 � 12 60 � 8 0.7 58 � 8Men 12 (86%) 63 (74%) 0.5 820 (64%)Body mass index (kg/m2) 29 � 7 32 � 5 0.1 31 � 6Blood pressure (mm Hg)

Systolic 156 � 27 162 � 20 0.3 159 � 19Diastolic 88 � 15 85 � 10 0.5 87 � 11

Insulin use at entry 8 (57%) 60 (71%) 0.4 695 (54%)Duration of diabetes (yrs) 16 � 7 15 � 8 0.8 15 � 8Retinopathy 7 (58%) 59 (72%) 0.3 853 (70%)Serum creatinine (mg/dl) 1.5 � 0.4 1.7 � 0.5 0.2 1.7 � 0.6Protein excretion rate (mg/d)† 2,685 � 2,146 3,846 � 2,970 0.1 2,962 � 2,348Glycosylated hemoglobin

(HbA1C) (%)8.3 � 1.7 8.3 � 1.8 1.0 8.1 � 1.7

Neuropathy 6 (43%) 40 (50%) 0.8 605 (50%)Cardiovascular disease 7 (50%) 53 (62%) 0.4 517 (40%)Angina pectoris 3 (21%) 15 (18%) 0.7 162 (13%)Heart failure 2 (14%) 7 (8%) 0.6 78 (6%)Outcomes

Death 2 (14%) 21 (25%) 0.5 157 (12%)End-stage renal disease 2 (14%) 13 (15%) 1.0 224 (18%)Cardiovascular death 1 (7%) 16 (19%) 0.5 67 (5%)Heart failure 7 (50%) 29 (34%) 0.4 127 (10%)Cardiovascular death or

heart failure7 (50%) 37 (44%) 0.8 176 (14%)

Means, SD, and percentages reflect patients with nonmissing data.*Clinically unrecognized MI versus clinically recognized nonfatal MI.†Geometric mean.

338 THE AMERICAN JOURNAL OF CARDIOLOGY� VOL. 94 AUGUST 1, 2004

death, or the development of end-stage renal disease(Table 1).

• • •In our study of patients with type 2 diabetes, hyper-

tension, and nephropathy, we found that 14% of firstnonfatal MIs were clinically unrecognized. This finding,in a group demonstrated to be at high risk for cardiovas-cular complications,3 is less than the estimates of 20% to40% established in observational studies of patients withand without diabetes in the general population.4–14

Differences in the study design of the IDNT andpopulation-based studies may explain the smaller pro-portion of unrecognized MI. By participating in arandomized, controlled clinical trial, subjects mayhave received more counseling and additional surveil-lance, thus leading to the increased clinical recogni-tion of MI. Participants may have had greater aware-ness of the manifestations of coronary heart diseaseand may have been more likely to seek medical atten-tion for atypical symptoms than those in the generalpopulation. In the Heart and Estrogen/Progestin Re-placement Study, a randomized, controlled trial ofhormone replacement therapy in women with knowncoronary heart disease, only 4.3% of MIs went unrec-ognized.15 Of note, none of the clinically unrecog-nized MIs in the Heart and Estrogen/Progestin Re-placement Study occurred in women with diabetes.

Although the proportion of MIs that was clinicallyunrecognized is less than that previously described inpopulation-based studies, approximately 1 of every 7nonfatal MIs was nonetheless clinically unrecognizedin the participants of the IDNT. Given the probableincreased counseling and surveillance of a clinicaltrial, the proportion of unrecognized MI is substantial.Additionally, the total number of unrecognized MIsmay have been underestimated, because we did notstudy non–Q-wave MIs that escaped clinical recogni-tion. Previous studies have shown that 11% to 37% ofasymptomatic diabetic patients referred for nuclearperfusion imaging have perfusion abnormalities con-sistent with a previously unrecognized MI.16,17

In summary, our study suggests that clinically un-recognized Q-wave MI remains a significant clinicaloccurrence despite the link between diabetes, hyper-tension, nephropathy, and coronary events.

1. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E,Atkins RC, Rohde R, Raz I. Renoprotective effect of the angiotensin-receptorantagonist irbesartan in patients with nephropathy due to type 2 diabetes. N EnglJ Med 2001;345:851–860.2. Berl T, Hunsicker LG, Lewis JB, Pfeffer MA, Porush JG, Rouleau JL, DruryPL, Esmatjes E, Hricik D, Parikh CR, et al. Cardiovascular outcomes in theIrbesartan Diabetic Nephropathy Trial of patients with type 2 diabetes and overtnephropathy. Ann Intern Med 2003;138:542–549.3. Gerstein HC, Mann JF, Yi Q, Zinman B, Dinneen SF, Hoogwerf B, Halle JP,Young J, Rashkow A, Joyce C, et al. Albuminuria and risk of cardiovascularevents, death, and heart failure in diabetic and nondiabetic individuals. JAMA2001;286:421–426.4. Rosenman RH, Friedman M, Straus R, Jenkins CD, Zyzanski SJ, Wurm M.Coronary heart disease in the Western Collaborative Group Study. A follow-upexperience of 4 and one-half years. J Chronic Dis 1970;23:173–190.5. Boland LL, Folsom AR, Sorlie PD, Taylor HA, Rosamond WD, ChamblessLE, Cooper LS. Occurrence of unrecognized myocardial infarction in subjectsaged 45 to 65 years (the ARIC study). Am J Cardiol 2002;90:927–931.6. Medalie JH, Goldbourt U. Unrecognized myocardial infarction: five-yearincidence, mortality, and risk factors. Ann Intern Med 1976;84:526–531.7. Kannel WB, Abbott RD. Incidence and prognosis of unrecognized myocardialinfarction. An update on the Framingham study. N Engl J Med 1984;311:1144–1147.8. Grimm RH Jr, Tillinghast S, Daniels K, Neaton JD, Mascioli S, Crow R,Pritzker M, Prineas RJ. Unrecognized myocardial infarction: experience inthe Multiple Risk Factor Intervention Trial (MRFIT). Circulation 1987;75:II6 –II8.9. Yano K, MacLean CJ. The incidence and prognosis of unrecognized myocar-dial infarction in the Honolulu, Hawaii, Heart Program. Arch Intern Med 1989;149:1528–1532.10. Nadelmann J, Frishman WH, Ooi WL, Tepper D, Greenberg S, Guzik H,Lazar EJ, Heiman M, Aronson M. Prevalence, incidence and prognosis ofrecognized and unrecognized myocardial infarction in persons aged 75 years orolder: the Bronx Aging Study. Am J Cardiol 1990;66:533–537.11. Sigurdsson E, Thorgeirsson G, Sigvaldason H, Sigfusson N. Unrecognizedmyocardial infarction: epidemiology, clinical characteristics, and the prog-nostic role of angina pectoris. The Reykjavik Study. Ann Intern Med 1995;122:96 –102.12. de Bruyne MC, Mosterd A, Hoes AW, Kors JA, Kruijssen DA, van BemmelJH, Hofman A, Grobbee DE. Prevalence, determinants, and misclassification ofmyocardial infarction in the elderly. Epidemiology 1997;8:495–500.13. Jonsdottir LS, Sigfusson N, Sigvaldason H, Thorgeirsson G. Incidence andprevalence of recognised and unrecognised myocardial infarction in women. TheReykjavik Study. Eur Heart J 1998;19:1011–1018.14. Sheifer SE, Gersh BJ, Yanez ND III, Ades PA, Burke GL, Manolio TA.Prevalence, predisposing factors, and prognosis of clinically unrecognized myo-cardial infarction in the elderly. J Am Coll Cardiol 2000;35:119–126.15. Shlipak MG, Elmouchi DA, Herrington DM, Lin F, Grady D, Hlatky MA.The incidence of unrecognized myocardial infarction in women with coronaryheart disease. Ann Intern Med 2001;134:1043–1047.16. Nesto RW, Watson FS, Kowalchuk GJ, Zarich SW, Hill T, Lewis SM, LaneSE. Silent myocardial ischemia and infarction in diabetics with peripheral vas-cular disease: assessment by dipyridamole thallium-201 scintigraphy. Am Heart J1990;120:1073–1077.17. De Lorenzo A, Lima RS, Siqueira-Filho AG, Pantoja MR. Prevalence andprognostic value of perfusion defects detected by stress technetium-99m sesta-mibi myocardial perfusion single-photon emission computed tomography inasymptomatic patients with diabetes mellitus and no known coronary arterydisease. Am J Cardiol 2002;90:827–832.

BRIEF REPORTS 339