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H

igh Prevalence of Echocardiographic Abnormalities in Diabetic Youths


ZUHDI A. LABABIDI AND DAVID E. GOLDSTEIN

M-mode echocardiography was performed on 107 young insulin-dependent diabetic subjects aged 2 24 yr (x SE: 13.8 0.4 yr) and 636 age-group-matched controls. All patients were normotensive and free of cardiorespiratory symptoms. Diabetic patients showed a high prevalence of echocardiographic abnormalities that increased with age. Mean dimensions of the left atrium, right ventricle, and left ventricle (systolic and diastolic) were increased significantly in diabetic individuals (P < 0.01). Hypertrophy of the interventricular septum was present in some patients older than 12 yr of age. Mean interventricular septum excursion was markedly decreased in diabetic individuals compared with controls (3.9 0.1 mm versus 5.6 0.2 mm, respectively; P < 0.01). Fifteen percent of the diabetic patients but none of the controls had septal excursions less than 3 mm (2 SD below mean). Patients with decreased septal excursions showed a higher prevalence of other echocardiographic abnormalities than patients with normal septal excursions. Echocardiographic abnormalities did not correlate with either duration of diabetes or glucose control as assessed by hemoglobin A lc and plasma glucose concentrations at the time of echocardiographic testing. The results show a high prevalence of echocardiographic abnormalities in young diabetic subjects that may represent preclinical cardiomyopathy. DIABETES CARE
6: 18-22, JANUARY-FEBRUARY 1983.

he high prevalence of coronary artery disease in diabetes mellitus is well established.1"3 Recent studies in both human beings and experimental animals suggest that diabetes may also be associated with a cardiomyopathy.4"16 The purpose of this study was to assess cardiac function in young type I (insulin-dependent) diabetic individuals without clinical evidence of cardiovascular disease using a noninvasive technique, Mmode echocardiography. We present data showing a high prevalence of echocardiographic abnormalities in young diabetic subjects that are consistent with a preclinical cardiomyopathy.
SUBJECTS AND METHODS

The study population consisted of 107 insulin-dependent (type I diabetes) diabetic children, adolescents, and young adults who were age-group-matched with 636 normal controls. All the diabetic patients were part of a longitudinal study of blood glucose regulation and vascular complications. None of the patients had proteinuria, hypertension, or evidence of other systemic disease known to affect cardiac function. None were

studied during episodes of ketoacidosis. The cardiac assessment consisted of physical examination, blood pressure measurement, electrocardiography, and echocardiography. None of the patients had blood pressures greater than 140/90 mm Hg. No patient had a history of chronic alcoholism or heavy smoking. Echocardiography was performed with a simultaneous electrocardiogram (standard lead II) in the supine position using an Electronics for Medicine Echo IV Echocardiography/Simultrace Recorder (Electronics for Medicine, Honeywell, Pleasantville, New York). A 2.25-MHZ transducer was used for studies in young adults and older children; a 3.5-MHZ transducer was used for the younger children. Echocardiographic recordings of the interventricular septum (IVS), left ventricular posterior wall (LVPW), and left atrium (LA) were obtained in all patients. For analysis of interventricular septal motion, left ventricular posterior wall motion, and for left ventricular measurements, the transducer was directed inferiorly and laterally, i.e., away from the mitral valve, thereby aiming at the level of the chordae tendineae. The sensitivity of the echocardiograph was adjusted to display the simultaneous echoes of the interventricular septum,

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DIABETES CARE, VOL. 6 NO. 1, JANUARY-FEBRUARY 1983

HIGH PREVALENCE OF ECHOCARDIOGRAPHIC ABNORMALITIES IN DIABETIC YOUTHS/2. A. LABABIDI AND P. E. GOLDSTEIN

the epicardium, and endocardium of the left ventricular posterior wall. These echoes were timed by their location and characteristic motion with reference to the electrocardiogram (EKG). The left ventricular end-diastolic dimension (LVDD) was measured from the endocardial echo of the left ventricular posterior wall to the left side of the interventricular septum at the Q wave of the EKG, and che left ventricular end-systolic dimension (LVSD) was measured at the point of maximal anterior excursion of the left ventricular posterior wall at the end of the T wave. Calibration was performed by recording a grid of dots representing a vertical distance of 1 cm. The interventricular septum excursion was measured as the distance between the most anterior and the most posterior position of the left side of the septum. Septal excursion was measured at the level of the anterior and posterior mitral leaflets. The septum was viewed from the apex to the subaortic area to assure that all measurements were below the "hinge point." The percent shortening of the left ventricular minor axis was derived from LVDD LVSD/LVDD. The cube of the diastolic dimension (LVDD)3 was used as an estimation of the end-diastolic volume (EDV) and the cube of (LVSD)3 as an estimation of end-systolic volume (ESV). The ejection fraction was derived from EDV ESV/ EDV. Echocardiograms were performed and analyzed without knowledge of the patient's diabetic status.
Assessment of blood glucose control. A blood sample was obtained from each patient for measurement of hemoglobin A Ic 17 and plasma glucose. Assessment of diabetic retinal and renal disease. Ophthal-

TABLE 1 Age distribution of study patients Number of subjects Age (yr) Diabetic

Control 415 109 53 59

<8 8-12
13-15 > 15

9 35 22 41

Seven of 107 patients had mild background retinopathy. None had proliferative eye changes. Statistical analyses. Nonparametric tests (Mann-Whitney and Spearman correlation coefficient) were used for analysis of the data.
RESULTS

T
Age (yr)

mologic evaluation, which included stereo color retinal photos and fluorescein angiograms, was performed on patients within 6 mo of the cardiac evaluation. Twenty-four-hour urine samples were obtained from each patient for measurement of urinary protein. No patients showed proteinuria.

he mean age of the diabetic patient population was 13.8 0.4 yr (x SEM), with a range of 2-24 yr. The mean duration of diabetes was 5.9 0.4 yr with a range of 0.1-21 yr and the mean insulin dosage was 0.80 0.02 U/kg/day with a range of 0.25-1.7 U/kg/day. Table 1 shows the age distribution of the 107 diabetic and 636 control study subjects. Table 2 shows echocardiographic data on the diabetic patients and controls separated into four age groups. Mean values for the left ventricular systolic and diastolic dimensions, the right ventricular dimension, and the left atrial dimension were increased significantly in diabetic patients in most age groups. The prevalence of cardiac chamber enlargement increased with age (Table 3). Minor axis shortening (ALVD) was decreased significantly in diabetic patients older than 15 yr of age. The

TABLE 2 Echocardiographic data in diabetic (D) and control (C) subjects separated by age

<: 8

8-12 C 6.1 5.6 20.3 11.0 22.0 31.1 30.2 64.4 260 1.5 1.1 3.7 3.0 4.0 5.2 6.1 10.0 D 35 7.7 1.0 6.7 dt 1.0 t 25.1 d 2.9* t3.0* 14.4 d 29.0 dt 3.0* 40.7 dt4.0* 29.4 3.6 64.8 5.3 C 109
7.5 dt 6.8 dt 23.3 dt 12.8 dt 26.1 dt 37.0 dt 30.4 dt 64.2 dt 1.8 1.3

13-15

> 15 C 53
8.3 dt 9.1 dt 26.5 dt 13.5 dt 29.1 dt 42.1 dt 30.4 dt 65.3 dt 1.8 1.5

ID N IVS
LVPW

D 22
9.2 8.0 27.2 15.9 31.3 43.3 27.7 61.8 1.8 0.9 3.6 2.7 3.4 4.2 3.9 6.1

I 41
4-8 3.3 4-3 5.0 5.8 9.7
9.9 dt 8.3 dt 29.0 dt 17.4 dt 33.6 dt 46.2 dt 25.0 dt 61.1 dt 2.0 1.1

C 9.0 8.6 25.7 14.1 29.2 41.3 29.8 63.4 59 2.3 1.6 4.4 3.8 4.8 5.7 6.6 10.8

? t 5.7 d 0.7 5.1 dt 0.5 21.0 dt 1.7 t 10.9 d 4 . 0 23.8 it 1.6 34.2 dt i.r 30.3 dt 3.4 65.7 dt 5.3

LAD RVD
LVSD LVDD ALVD

EF

4.2 3.7 4.1 5.2 7.2 10.1

3.7* 3.7* 3.9* 4.4' 5.1* 6.6

*At least P < 0.05. Values are means SD. Measurements are in mm, except for EF and ALVD, which are in percent. N = number of subjects. IVS = interventricular septum width; LVPW = left ventricular posterior wall width; LAD = left atrial dimension; RVD = right ventricular end-diastolic dimension; LVDD = left ventricular end-diastolic dimension; LVSD = left ventricular end-systolic dimension; ALVD = change in left ventricular dimension (percent shortening); and EF= ejection fraction.

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HIGH PREVALENCE OF ECHOCARDIOGRAPHIC ABNORMALITIES IN DIABETIC YOUTHS/Z. A. LABABIDI AND D. E. GOLDSTEIN

TABLE 3 Prevalence of cardiac chamber enlargement by age in diabetic youths Age (yr)

<8 RVD LAD LVDD LVSD 29 0 0 0

8-12 20' 26' 29' 40'

13-15 36* 18 23 36'

> 15 49* 39* 68* 56'

showed a much higher prevalence of cardiac chamber enlargement than patients with septal excursions greater than 3 mm (x = 4-2 mm) and showed an increased prevalence of other echo abnormalities, including decreased ejection fraction (mean SD = 56.8 4-3% versus 64.0 10.0% in age group 15 yr; P < 0.05) and interventricular septum hypertrophy.
DISCUSSION

"The mean chamber dimension is significantly greater than in the agematched control group (P < 0.05). Values are percent of patients with cardiac chamber dimension greater than 1 SD above the mean for age-matched controls. RVD = right ventricular end-diastolic dimension; LAD = left atrial dimension; LVDD = left ventricular end-diastolic dimension; LVSD = left ventricular end-systolic dimension.

or many years cardiac disease in patients with diabetes mellitus was attributed to coronary atherosclerosis. '"3 Recent investigations in both human beings and experimental animals have shown that diabetes is also associated with abnormalities in cardiac performance in the absence of demonstrable coronary atherosclerosis, socalled "diabetic cardiomyopathy. ')4~16 Cardiac muscle from rats with streptozotocin-induced diabetes shows both delayed relaxation and depressed velocity of shortening.' H In human beings several studies have documented diabemean ejection fraction was not decreased significantly in any of the age groups. In contrast to the high prevalence of cardiac chamber enlargement, cardiac muscle hypertrophy was not present except for increased width of the interven^ tricular septum in some diabetic patients older than 12 yr of age. The most consistent echocardiographic abnormality in the diabetic subjects was a marked decrease in the interventricular septum excursions. During the normal cardiac cycle, the interventricular septum moves toward the left ventricular posterior wall in systole and returns toward the right ventricular anterior wall during diastole. The mean septal excursion was decreased significantly in diabetic compared with control subjects (3.9 0 . 1 mm versus 5.6 0.2 mm, respectively; P < 0.001). Figure 1 shows typical echocardiograms from a diabetic patient and a control subject. Septal excursions were decreased in the diabetic patients in all age groups but less so in the younger diabetic subjects; in control but not diabetic subjects, septal excursions increased slightly with age (Figure 2). Figure 3 compares the frequency distribution of septal excursions in diabetic and control subjects; there was a marked "leftward shift" for the diabetic patients. The interventricular septal excursion correlated significantly with the ejection fraction in patients older than 12 yr (r = 0.40, P < 0.001). In contrast to the altered interventricular septum excursions, movement of the left ventricular posterior wall appeared normal in all patients, although the excursions were not quantified as were the septal excursions. Figure 1 illustrates the striking difference between motion of the septum and the posterior wall in an affected diabetic individual. Table 4 compares various characteristics of diabetic patients with septal excursions less than or greater than 3 mm (x 2 SD). Sixteen of 107 diabetic subjects, but none of 53 age-group-matched controls, had septal excursions less FIG. 1. Echocardiograms from a normal subject (upper panel) and a than 3 mm. Septal excursion was not correlated significantly diabetic patient (lower panel) to demonstrate differences in interventri' with age, duration of diabetes, blood pressure (systolic or cular septum excursion. RV = right ventricle; IVS = interventricular diastolic), plasma glucose, or hemoglobin AJc. Diabetic pa- septum; MV = mitral valve; and D/PW = left ventricular posterior tients with septal excursions less than 3 mm (x = 1.7 mm) wall.

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HIGH PREVALENCE OF ECHOCARDIOGRAPH1C ABNORMALITIES IN DIABETIC YOUTHS/Z. A. LABAB1DI AND D. E. GOLDSTEIN

DIABETIC

CONTROL

6 -

5 -

4 -

0-1

1-2

2-3

3-4

4-5

5-6

6-7

7-8

8-9

2 SEPTAL EXCURSION (mm)

FIG. 3. Frequency distribution of interventricular septum excursion in 107 diabetic youths and 53 age-matched controls.

M-mode echocardiography is a very sensitive and reliable noninvasive tool that can measure chamber dimensions, myAGE (YEARS) ocardial wall thickness, motion, and function. In the present FIG. 2. Interventricular septum excursion by age in diabetic and controlstudy we used this technique to assess cardiac function in a large group of diabetic youths. Results indicated a high prevsubjects. Vertical bars and lines represent means SEM of values in alence of echocardiographic abnormalities. Prominent find107 diabetic and 53 control subjects. ings included increased dimensions of the left and right ventricles and of the left atrium, and decreased excursions of the tes-associated abnormalities of cardiac performance in pa- interventricular septum while movement of the left ventrictients without evidence of coronary artery disease.4'6"9'11 Ahmed ular posterior wall appeared normal. Cardiac muscle hyperet al. ,4 using a noninvasive technique to assess left ventricular trophy was limited to thickening of the septum, which was function, measured systolic time intervals in 25 diabetic patients without systemic hypertension or clinically apparent microvascular disease. Diabetic subjects showed shorter left TABLE 4 Comparison of diabetic patients with or without decreased septal excursions ventricular ejection time, longer pre-ejection period, higher ratio of pre-ejection period/left ventricular ejection time, and Septal excursions (mm) prolonged isovolumic time compared with controls. Rubier <3 > 3 et al.16 showed similar findings in regard to isovolumic times and also altered cardiac responses to alcohol in diabetic com16 N 91 pared with control subjects. Septal excursions 1.7 0.2 4.2 0.1 78 Shapiro et al. ' performed systolic time interval and ech(0.6-2.9) (3.0-6.9) ocardiographic studies on 212 diabetic patients, most of whom Duration of diabetes 4.6 0.7 5.9 0.3 showed evidence of microvascular disease. Results were sim(0.1-21.0) (0.1-19.0) ilar to those reported by Ahmed et al.4 but in addition, beat- Age (yr) 13.8 1.3 13.8 0.4 (4.0-24.0) (1.1-21.0) to-beat variation was decreased, and interval from minimal 9.3 0.4 9.3 0.2 dimension to mitral valve opening was increased compared Hemoglobin Alc (%) (7.1-12.7) (5.6-16.3) with controls. Ventricular hypertrophy (posterior wall or sepInsulin dose (U/kg/day) 0.78 0.04 0.81 0.02 tum) was found only in patients with systemic hypertension. (0.25-1.40) (0.25 1.70) Left ventricular dimensions were normal in all subjects without clinical evidence of heart failure. The presence of cardiac Septal excursion in 53 age-matched control subjects was 5.59 2.8 (x functional abnormalities was related closely to severity of 2 SD) mm with a range of 3.3-9.0 mm. diabetic microvascular complications. N = number of subjects.
< 8 8-12 13-15 > 15

DIABETES CARE, VOL. 6 NO. 1, JANUARY-FEBRUARY 1983

HIGH PREVALENCE OF ECHOCARDIOGRAPHIC ABNORMALITIES IN DIABETIC YOUTHS/Z. A. LABABIDI AND D. E. GOLDSTEIN

present only in older (>12 yr of age) patients who demon- coronary arteries in juvenile diabetes mellitus. Am. J. Med. 1978; strated concomitant cardiac chamber enlargement and de- 64:211-30. 4 Ahmed, S. S., Jaferi, G. A., Narang, R. M., and Regan, T. creased excursions of the septum. The presence of the echJ.: Preclinical abnormality of the left ventricular function in diabetes ocardiographic abnormalities was related to age but not to mellitus. Am. Heart J. 1975; 89:153-58. duration or control of diabetes. 5 Regan, T. J., Ettinger, P. O., Khan, M. I., Jesrani, M. U., Few other studies of cardiac function in diabetic youths Lyons, M. M., Oldewurtel, H. A., and Weber, M.: Altered myu have been reported. Friedman et al. performed echocar- ocardial function and metabolism in chronic diabetes mellitus withdiograms on 25 diabetic children and adolescents. Mean ejec- out ischemia in dogs. Circ. Res. 1974; 47:222-37. 6 tion fraction and minor axis shortening were significantly Rynkiewicz, A., Semetkowska-Jurkiewicz, E., and Wyrzkowski, decreased in their patients, but interventricular septum ex- B.: Systolic and diastolic time intervals in young diabetics. Br. Heart J. 1981; 44:280-84. cursion data were not presented. 7 Shapiro, L. M., Howat, A. P., and Calter, M. M.: Left venAlthough the etiology of the present findings is unknown, there was no evidence for coronary artery disease. Also, few tricular function in diabetes mellitus. Br. Heart J. 1981; 45:122patients with cardiac abnormalities showed any evidence of 28. 8 Shapiro, L. M., Leaderdale, B. A., Mackinon, J., and Fletcher, diabetic microvascular diseases. The findings could reflect a R.: Left ventricular function in diabetes mellitus. Br. Heart J. 1981; cardiomyopathic process since the cardiac chamber and in- 45:129-32. terventricular septum abnormalities are similar to those de9 Sanderson, J. E., Brown, D. J., Rivellese, A., and Kohner, E.: scribed in known cardiomyopathies such as with certain drugs Diabetic cardiomyopathy? An echocardiographic study of young 18 20 (e.g., alcohol, adriamycin) and viral infections. " diabetics. Br. Med. J. 1978; 1:404-407. 10 Similar findings\have also been described with large leftFein, F., Kornstein, L., Strobeck, J., Compasso, J., and Son21 to-right shunts and volume overload, but we have no evi- nenblick, E.: Altered myocardial mechanics in diabetic rats. Circ. dence of these abnormalities in our patients. The mechanism Res. 1980; 47:922-33. 11 Friedman, N. E., Levitsky, L. L , Edidin, D. V., Vitullo, D. of the isolated hypertrophy of the interventricular septum is A., Lacina, S. J., and Chiemmongkoltip, P.: Impaired myocardial also unknown. However, the association between decreased septal motion and septal hypertrophy has been described in performance in children with type I (insulin-dependent) diabetes mellitus. Diabetes 1980; 29 (Suppl.):22. patients with idiopathic hypertropic cardiomyopathy.22 It is 12 Ladet, T : Diabetic cardiomyopathy. Acta Pathol. Microbiol. of particular interest that transient hypertrophy of the in- Scand. [A] 1976; 84:421-28. 13 terventricular septum has been described in newborn infants Factor, S. M., Okum, E. M., and Minase, T.: Capillary miof diabetic mothers.23 croaneurysms in the human diabetic heart. N. Engl. J. Med. 1980; The significance of the present findings is unknown. Ech- 302:384-88. 14 Fein, F. S., Strobach, J. E., Malhetra, A., Scheues, J., and ocardiography is a very sensitive technique and none of our Sonnenblick, E. H.: Reversibility of diabetic cardiomyopathy with patients with abnormal echoes showed any clinical evidence of cardiac disease. Longitudinal studies will be necessary to insulin in rats. Circ. Res. 1981; 49:1251-62. 15 Dillmann, W. H.: Diabetes mellitus induces changes in cardiac determine if our findings represent an early preclinical phase myosin of the rat. Diabetes 1980; 29:579-82. of serious cardiovascular abnormalities that are so common 16 Rubier, S., Sajadi, R. M., Araoye, M. A., and Holford, F. in diabetic individuals. D.: Non-invasive estimation of myocardial performance in patients
ACKNOWLEDGMENTS:

The authors thank Jack E. England for his assistance with data analysis, Daniel P. Mayfield for his efforts in producing the echocardiograms, and Melissa B. Robnett and Cheryl L. Schwartze for their assistance in the preparation of this manuscript. The study was supported in part by USPHS Research Grant HL-13632. From the Department of Child Health, University of MissouriColumbia, School of Medicine, Columbia, Missouri. Address reprint requests to Zuhdi A. Lababidi, M.D., Professor of Pediatrics, Pediatric Cardiology, University of Missouri, Hospital and Clinics, Columbia, Missouri 65212.
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1 Kannel, W. B., andMcGee, D. L : Diabetes and cardiovascular risk factors; the Framingham study. Circulation 1979; 59:8-13. 2 Blumenthal, H. T., Moris, A., and Goldenberg, S.: A study of lesions of the intramural coronary artery branches in diabetes mellitus. Arch. Pathol. 1960; 70:13-28. 1 Crall, F. V., and Roberts, W. C.: The extramural and intramural

with diabetes. Effect of alcohol administration. Diabetes 1978; 27:12734. 17 Goldstein, D. E., Peth, S. B., England, J. D., Hess, R. L , and DaCosta, J.: Effects of acute changes in blood glucose on HbA,c. Diabetes 1980; 29:623-29. 18 Wherat, A. F, and Perloff, J. K.: Ethyl alcohol and myocardial metabolism. Circulation 1973; 47:915-17. 19 Ulems, H. S.: Assessment of cardiotoxicity to adriamycin. J. Pediatr. 1977; 90:851. 20 Ayuthya, P. S. N., Jayavasu, J., and Pongpanich, B.: Coxsackie group B virus and primary myocardial disease in infants and children. Am. Heart J. 1974; 88:311-14. 21 Kerber, R. E., Dippel, W. P., and Abbound, F. M.: Abnormal motion of the interventricular septum in right ventricular volume overload. Experimental and clinical echocardiographic studies. Circulation 1973; 48:86-96. 22 Sawaya, J., Longo, M. R., and Schlant, R. C : Echocardiographic interventricular septal wall motion and thickness: a study in health and disease. Am. Heart J. 1974; 87:64-88. 23 Mace, S., Hirshfield, S. S., Riggrit, C , Fanaroff, A. A., and Merkatz, I. R.: Echocardiographic abnormalities in infants of diabetic mothers. J. Pediatr. 1979; 95:1013-19.

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