Association between plasma insulin and angiographically documented significant coronary artery disease

characteristics and feasibility of prehospital initiation of thrombolytic therapy. J Am Cd Cardiol 1990; 15:925-93 1. 4. Weaver WD, Cerqueira M, Hallstrom AP, Litwin PE, Martin JS, Kudenchuk PJ, Eisenberg M, for the Myocardial Infarction Triage and Intervention Project Group. Prehospital-initiated vs. hospital-initiated thrombolytic therapy: The Myocardial Infarction Triage and Intervention trial. JAMA 1993:270:1211-1216. 5. Wagner GS, Freye CJ, Palmeri ST, Roark SF, Stack NC, Ideker RE, Hare11 FE, Selvester RH. Evaluation of a QRS scoring system for estimating myocardial in-

fact Gze. I. Specificity and observer agreement. Circularion 1982;65:342-347. 6. Clemmensen P, Ohman EM, Sevilla IX, Peck S, Wagner NB, Quigley PS, Lee KL, Wagner GS. Changes in standard electrocardiographic ST-segment elevation predictive of successful repafusion in evolving acute myocardial infarction. Am ./ Cardiol 1990:66:1407-1411. 7. Hackett D, Davies G, Chierchia S, Masai A. Intermittent coronary occlusion in acute myocardial infarction: value of combined thrombolytic and vasodilator therspy. N Enfil J Med 1987;317:1055-1059.

Association Between Plasma Insulin and Angiographically Documented Significant Coronary Artery Disease Paolo Spallarossa, MD, Renzo Cordera, MD, Gabriella Andraghetti, BSc, Giovanni Bertero, MD, Claudio’Brunelli, MD, and Salvatore Caponnetto, MD ew data are available on the relation between plasma insulin and angiographic evidence of coronary athF erosclerosis.1,2If hyperinsulinemia is associatedwith the clinical end points of coronary atherosclerosis-myocardial infarction or cardiac deathS5--then a similar association should also be found between hyperinsulinemia and angiographic evidence of coronary artery disease (CAD). The present study in nondiabetic men examines whether plasma insulin levels, both fasting and after an oral glucose load, are correlated with angiographically documented significant CAD. One hundred thirty-six consecutive men undergoing elective coronary angiography formed the study population. Eligible patients met the following criteria: (1) no history of diabetes; (2) normalfasting blood glucose; (3) no treatment with lipid-lowering drugs; and (4) no antecedent history of myocardial infarction, coronary artery bypass, or angioplasty. The study was approved by the local ethics committee and each patient gave informed consent. Cardiovascular medications including B blockers, calcium antagonists, nitrates, aspirin, angiotensin-converting enzyme inhibitors, and diuretics were not discontinued before the study.Both current and former smokers were included. Selective coronary angiography was performed by standard techniques with multiple injections of 4 to 8 ml of iohexol(647 mglml) in the anteroposterior, right, and left oblique views with various cranial and caudal angulations. Angiograms were examined by 3 observers unaware of the results of plasma insulin, glucose, and lipoprotein determinations. The luminal percent diameter narrowings were estimated by a consensusof the observers or by the mean of different measurements.Diameter stenoses250% were considered significant, and thesepatients were assigned to the CAD+ group. Overall severity of CAD was assessedaccording to the 15segmentcoding systemof the American Heart Association6 Each segment was given a numerical value corresponding to the percent diameter reduction, from 0 From the Departments of Internal Medicine, and Endocrinology and Metabolism, University of Genoa, Viale Bendetto XV, 6, 16124 Genoa, Italy. This work was supported in part by the Association for the Progress of Cardiology, Genoa, and by P. F. Ingegneria Genetica-CNR, Rome. Manuscript received August 19, 1993; revised manuscript received and accepted December 20, 1993.

in the case of a normal segmentto 100 in the case of a total occlusion. Segmentswith <2.5% stenosiswere considered normal. The total CAD score was obtained by summation of each segmentvalue. A standard oral glucose tolerance test wasperformed within 3 days of coronary angiogruphy. After 12-hour fasting, venous blood was drawn for measurementsof glucose, insulin, triglycerides, and lipoproteins. A 75 g glucose load was subsequently administered and blood specimensfor insulin and glucose determinations were collected after 1 and 2 hours. Normal glucose tolerance, impaired glucose tolerance, and non-insulin-dependent diabetes mellitus were diagnosed according to World Health Organization criteria.7 Results are expressed as mean f. SEM. Betweengroup comparisons of mean values were per$ormed using the unpaired 2-tailed Student’s t test. Differences among >2 groups were assessedby analysis of variance; multiple comparisons were then made with Duncan’s method.Differencesbetweenproportions were compared by chi-square test. Univariate correlations betweenvariables were analyzed using the Spearmancorrelation co-

TABLE I Characteristics of Study Population by Coronary Angiography Significant Coronary Artery Disease Absent Number of subjects Age (years) Body mass index (kg/m*) Total cholesterol (mmol/L) LDL cholesterol (mmol/L) HDL cholesterol (mmol/L) Triglycerides (mmol/L) Number of smokers Number of hypertensives Treatment 8 blockers Calcium antagonists Nitrates Aspirin Angiotensin-converting enzyme inhibitors Diuretics

Present

29 (21%) 53.6 f 1.8 25.0 + 0.6 4.62 k 0.03 3.13*0.12 0.97 f 0.06 1.10~0.12 22 (75%) 17 (59%) 7 IO 13 15 8

(24%) (34%) (45%) (52%) (29%)

3 (10%)

107 (79%) 59.7 f 0.9* 26.3 I? 0.3 4.82 f 0.09 3.33 f 0.10 0.93 f 0.04 1.32 f 0.07 74 (69%) 50 (47%) 40 63 67 83 34

(37%) (59%)t (63%) (78%)t (32%)

15 (14%)

‘p <0.001; tp co.05. Data are expressed as mean f SEM.

BRIEF REPORTS 177

eficients. Stepwise discriminant analysis and multivariate linear regression were pe$ormed to evaluate the independence of risk factor eflects on presence (CAD+ vs CAD-) and severity of CAD (total score). The influence of /3 blockers, diuretics, and angiotensin-converting enzyme inhibitors was assessed by including these parameters in the analyses. In all statistical analyses, triglyceride and insulin concentrations were log transformed. A p value co.05 was considered signtficant. Signijicant coronary narrowings were present in 107 patients (CAD+ group) and were absent in 29 patients (CAD- group). Patients with sign@cant CAD were older (Table I). More patients in the CAD+ group received aspirin and calcium antagonists. Plasma insulin levels were significantly higher in CAD+ subjects, whereas blood glucose levels were the same (Figure 1) in both groups. Fasting (r = 0.197) and 2-hour (r = 0.203) plasma insulin levels were significantly associated with the total CAD score (p ~0.05). The study population was divided into quartiles of insulin concentrations (Figure 2) and total CAD score increased with increasing insulin concentrations. Fasting plasma insulin levels also signtficantly correlated with triglycerides (r = 0.264; p
500

21%), and a greater proportion of them (p ~0.05) were receiving treatment with aspirin. Interestingly, mean fasting (54.4 f 4 vs 36.6 f 3; p
This study demonstrates the existence of relationships between plasma insulin levels and coronary angiographic findings in terms of the presenceof CAD and overall coronary artery lesion severity in nondiabetic men. Plasma insulin concentrations were higher in patients with significant coronary diseasethan in patients with ~50% diameter stenoses,and also correlated significantly with coronary artery lesion severity. Fasting and 2-hour plasma insulin concentrations were independent predictors of severity and presence of CAD. Zamboni et al’ observed in a small number of nondiabetic patients that plasma insulin levels correlated with the severity of coronary artery narrowings, but were not different between patients with CAD and patients with normal angiograms.Tzagournis et al2 found higher concentrations of plasma insulin in patients with myocardial

T

450 .. 400 .‘ii 2

350 -.

g 300 -z

250 -.

+

200 --

g

150 -. 100 .50 -.

FASTING FAST

1 HOUR

Ill

II

I

01

IV

INSULIN

2 HOURS

I I 350

300

/

-7

/_1111.___; 0 ’ FAST

1 HOUR

2 HOURS

FIGURE 1. Insulin (upper paaal) and gkcose (lower pane/) concentrations during the oral glucose tolerance test in patients with (CAD+) and without (CAD-) coronary artery disease; *p ~0.05. FAST q fasting.

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THE AMERICANJOURNALOF CARDIOLOGY@’VOLUME74

I

I

Ill

II 2 HOUR

IV

INSULIN

FIGURE 2. Mean total coronary artery .~ disease score in patients grouped according to qualtiles of fasting (up per panel) and 2410~ insulin (lower paaal). Differeaces (analysis of variance) were sigaifkant (p eO.05) for fasting insulin, and borderline (p q 0.05) for P-hour insulin.

JULY 15, 1994

infarction or angina pectoris than in control subjects; however, only a few patients underwent coronary angiography. These results are consistent with previous studies in patients with cerebrovascul& and peripheral vascular disease.9 The positive association we found between plasma insulin levels and angiographically documented significant CAD strengthens the epidemiologic view that hyperinsulinemia may be associated with an increased risk for CAD mortality and nonfatal myocardial infarction. 1. Zambani M, Armellini F, Sheiban 1, De Marchi M, Todesco T, Bergamo-Andreis IA, Cominacini L, Bosello 0. Relation of body fat distribution in men and degree of coronary namxvings in coronary artery disease. Am J Cardiol 199270: 1135-l 138. 2. Tzagoumis M, Chiles R, Ryan JM, Skillman TG. Interrelationships of hyperinsulinism and hypatriglyceridemia in young patients with coronary heart disease.

Circularion 1968;38: 1156-l 163. 3. Welbom TA, Weame K. Coronary heart disease incidence and cardiovascular mortality in Busselton with reference to glucose and insulin concentrations. Diabetes Care 1979;2:154-160. 4. Pyiir?il% K, Savolainen E, Kaukola S, Haapakoski J. Plasma insulin as coronary heart disease risk factor: relationship to other risk factors and predictive value during 9X year follow up of the Helsinki Policemen Study population. Acta Med Stand 1985:7Ol(suppl):38-52. 5. Fontbame A, Charles MA, Thibult N, Richard IL, Claude JR, Warnet JM, Ross&n GE, Eschwege JE. Hypwinsulinaemia as a predictor of coronary heat disease mortality in a healthy population: the Paris Prospective Study, 15.year followup. Diabetolo@a 1991;34:35&361. 5. Austen WC, Edwards JE, Frye RL, Gemini GG, Gott VL, Griffith LSC, McGoon DC, Murphy MC. Roe BB. A reporting system on patients evaluated for corenay artery disease. Report of the ad hoc committee for grading of coronary artery disease, Council on Cardiovascular Surgery, American Heart Association. Circularion 1975;5O(suppl V):V-7-v-40. 7. WHO Expert Committee on Diabetes Mellitus. Second Report. WHO Technical Report Series No. 646: 1980. 8. Gertler MM, Leetma HE, Koutrouby RJ, Johnson ED. The assessment of lipids, glucose and insulin in ischemic thrombotic cerebrovascular disease. Sh.oke 1975;6: 77-84. 9. Sloan JM, Mackay IS, Sheridan B. Glucose tolerance and insulin response in atherosclerosis. Br Med J 1970;4:586-588.

Safety of Thrombolytic Therapy in Normally Menstruating with Acute Myocardial Infarction

Women

Patricia L. Lanter, MD, C. Foster Jennings, MD, Charlotte S. Roberts, RN, and Robert L. Jesse, MD, PhD arly initiation of thrombolytic therapy can signifiE cantly decreaseboth mortality and morbidity in the setting of acute myocardial infarction.’ The finding of acute myocardial infarction in women should mandate the sameaggressivetreatment strategiesas those applied to men. The indications and contraindications for the use of these agents are no different in the female versus the male population. However, the presenceof active bleeding is currently considered an absolute contraindication to the use of thrombolytic therapy, which raises the issue of whether normal menstruation should then be considered a contraindication to the use of thrombolytic therapy in acute myocardial infarction. The aggregate data regarding the use of thrombolytic agents in this situation is quite limited. 24 We report herein data from 6 women who were actively menstruating when they were treated with thrombolytic therapy for acute myocardial infarction. From January 1991 through December 1992, 3 women who were actively menstruating at the time they presentedto our emergencydepartmentswere diagnosed as having acute myocardial infarction. The decision was made to treat all 3 aggressively, including aspirin, heparin, and thrombolytic drugs. They were advised of the risks and benej?tsof this treatment. Two of the patients received recombinant tissue-typeplasminogen activator (Genentech, Inc., South San Francisco, California) in the standard 3-hour regimen (10 mg bolus, 50 mg over the$rst hour, 20 mglhour over the next 2 hours) and I From the Division of Cardiology, Department of Medicine, Box 105 MCV Station, Medical College of Virginia/Virginia Commonwealth University, Richmond, Virginia 23298.0105. This research was sup ported in part by a Grant-in-Aid from the American Heart Association, Virginia Affiliate and a training grant from the National Institutes of Health, Bethesda, Maryland. Manuscript received August 23, 1993; revised manuscript received December 15, 1993, and accepted December 16.

in an accelerated dosing regimen (15 mg bolus, 50 mg over thefirst 30 minutes, and 35 mg over the subsequent hour). One patient received streptokinase in the standard dosing regimen of 1.5 million U over 1 hour. All 3 received aspirin at the time of presentation and early intravenous heparin given as a 5,000 U bolus followed by 1,000 Ulhour, with subsequent infusion rates based on maintaining the activated partial thromboplastin time at 2.5 to 3.0 times control. Hemoglobin on admission and the hemoglobin at nadir on day 3 (chosen to avoid confounding changes in hemoglobin due to thrombolytic therapy, per se, with those resulting from other etiologies such as invasive procedures) were recorded. A retrospective control population was composedof all female patients aged ~60 years who received thrombolytic therapyfor acute myocardial infarction at the Medical College of Virginia Hospitals (n = 10) during the reported period. All nadir hemoglobin values reported for both patients and controls were obtained before any invasive procedures were performed. GenentechInc., the manufacturer of tissue-typeplasminogen activator, and Astra Inc. (Westborough,Massachusetts), the distributor of streptokinase, were contacted to obtain accessto information that either might have concerning the use of thrombolytic therapy in menstruating women. Astra was unable to provide us with any information. Genentech had compiled brief case summaries of 14 women who had been treated with tissue-type plasminogen activator while menstruating (data on$le, Genentech,Inc.), among which 3 had data for both admission and nadir hemoglobins, but none noting the timing of the nadir relative to invasive procedures. For the other 11 women, there was, at the minimum, some comment regarding menstrual flow rates, and in a few cases, comments regarding other clinical events,or the absence thereof Demographic data were BRIEFREPORTS

179