Electrocardiographic Left Ventricular Hypertrophy in Type ...

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Electrocardiographic Left Ventricular Hypertrophy in Type 1 Diabetes

Prevalence and relation to coronary heart disease and cardiovascular risk factors: the Eurodiab IDDM Complications Study




I n the general population, left ventricular hypertrophy (LVH), either defined by echocardiographic or electrocardiogram (ECG) criteria, is strongly predictive of cardiovascular events, independent of conventional risk factors (1?3).

Normotensive type 1 diabetic patients with nephropathy have an increase in left ventricular mass independent of blood pressure (4) and a decrease in diastolic function (5). In the general population, LVH causes electrical heterogeneity in the heart (6) and is associated with sudden cardiac death secondary to ventricular arrhythmias. Both QT interval duration (QTc) and dispersion (QTd) are affected by electrical heterogeneity and associated with sudden death (7).

The EURODIAB IDDM Complications Study is a cross-sectional clinicbased study of diabetes complications recruiting 3,250 type 1 European diabetic subjects (8) using standardized methods of data collection. We aimed to assess ECG-LVH prevalence and association with coronary heart disease (CHD), microvascular complications, QTc, and QTd in this large cohort.

RESEARCH DESIGN AND METHODS -- Details of the subjects and the procedures of the EURODIAB study have been published elsewhere (8 ? 13). To assess the role of insulin resistance, an estimated glucose disposal rate (GDR) was calculated as previously described (14). Metabolic syndrome was defined according to World Health Organization guidelines (15).

LVH was defined by ECG Cornell voltage-duration product [(RaVL SV3) QRS complex duration] 2,623 mm ms in men and 1,558.7 mm ms in women (16). Compared with echocardiography, these cutoff values give the best sensitivity with a specificity of 95% (16). ECG measurements were made with a ruler on the resting ECG tracings, available for 3,113 of 3,250 (95.8%) patients, and were expressed as the average of three determinations on consecutive QRS complexes. R wave amplitude in aVL and S wave depth in V3 were measured as the distance (in millimeters) from the isoelectric line of their zenith and nadir, respectively. QRS duration was measured from

From the 1Department of Internal Medicine, University of Turin, Turin, Italy; the 2Ospedale Evangelico Valdese, Turin, Italy; the 3Department of Epidemiology and Public Health, University College London, London, U.K.; and the 4International Centre for Circulatory Health and National Heart and Lung Institute, Imperial College, London, U.K.

Address correspondence and reprint requests to Dr. Sara Giunti, Department of Internal Medicine, University of Turin, 14, C.so A.M. Dogliotti, I-10126, Torino, Italy. E-mail: sara_giunti@.

Received for publication 19 May 2005 and accepted in revised form 31 May 2005. Abbreviations: CHD, coronary heart disease; ECG, electrocardiogram; GDR, glucose disposal rate; LVH, left ventricular hypertrophy; sBP, systolic blood pressure; WHR, waist-to-hip ratio. A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion factors for many substances. ? 2005 by the American Diabetes Association.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

the beginning to the end of the QRS complex.

Logistic regression analysis was used to assess variables independently related to LVH. All continuous variables were categorized in quartiles of their distribution apart from age (15?29, 30 ? 44, and 44 years) and albumin excretion rate (20, 20 ?200, and 200 g/min). Since estimated odds ratios (ORs) in the lower quartiles of the waist-to-hip ratio (WHR) were similar, in the final analysis they were aggregated as reference categories and compared with the upper quartile of WHR (0.88 vs. 0.88). All analyses were performed with Stata (Stata Release 7.0; Stata, College Station, TX).

RESULTS -- Age and duration of diabetes were 32.7 10.7 and 14.7 9.3 years (means SD), respectively. ECGLVH prevalence was 3.4% (95% CI 2.8 ? 4.1) higher in women than in men (4.6 vs. 2.3%, OR 2.02 [95% CI 1.34 ?3.02]), even after adjustment for age, duration of diabetes, BMI, systolic blood pressure (sBP) and diastolic blood pressure, and physical activity (2.40 [1.55?3.70]).

Subjects with ECG-LVH compared with those without had significantly higher sBP (129.3 25.9 vs. 121.0 17.4 mmHg, P 0.001) and diastolic blood pressure (78.3 12.8 vs. 75.4 11.3 mmHg, P 0.03), total cholesterol (5.55 1.20 vs. 5.32 1.14 mmol/l, P 0.05), and triglycerides (geometric mean 1.04 vs. 0.93 and interquartile range 0.82?1.62 vs. 0.68 ?1.32, P 0.003). Age and BMI were slightly higher in subjects with ECG-LVH, whereas HbA1c values were similar in the two groups.

Age- and sex-adjusted risks of LVH were higher in subjects with CHD (OR 2.85 [95% CI 1.75? 4.64]), hypertension (1.69 [1.10 ?2.61]), macroalbuminuria (2.21 [1.25?3.93]), and prolonged QTc (3.24 [2.13? 4.94]). No increased ORs were observed in subjects with retinopathy, neuropathy, and microalbuminuria.



Electrocardiogram left ventricular hypertrophy

Table 1--Results of unconditional regression analysis of variables independently associated with ECG-LVH in the EURODIAB cohort*

Model 1

Model 2

Model 3

Sex Women Men

CHD Absent Present

sBP (mmHg) 109 109?118 119?129 129

QTc (s) 0.44 0.44

Albumin excretion rate (g/min)

20 20?200 200 Triglycerides (mmol/l) 0.67 0.67?0.85 0.86?1.16 1.16 WHR 0.88 0.88

1.00 1.92 (1.21?3.04)

1.00 2.48 (1.46?4.23)

1.00 1.46 (0.72?2.97) 2.15 (1.09?4.20) 1.61 (0.79?3.29)

1.00 2.90 (1.84?4.58)

1.00 1.02 (0.59?1.77) 2.66 (1.39?5.10)

1.00 2.22 (1.22?4.04)

1.00 2.56 (1.29?5.07)

1.00 1.52 (0.65?3.56) 2.52 (1.12?5.66) 1.13 (0.45?2.82)

1.00 2.30 (1.27?4.17)

1.00 0.90 (0.45?1.79) 0.87 (0.28?2.70)

1.00 1.03 (0.32?3.26) 3.47 (1.37?8.82) 2.42 (0.93?6.29)

1.00 2.86 (1.57?5.22)

1.00 2.58 (1.35?4.83)

1.00 1.41 (0.64?3.10) 2.13 (1.00?4.55) 1.09 (0.48?2.48)

1.00 2.45 (1.41?4.24)

1.00 1.02 (0.32?3.24) 3.86 (1.54?9.67) 2.47 (0.97?6.23)

1.00 2.20 (1.22?3.98)

Data are OR (95% CI). *Variables were adjusted for age, sex, diabetes duration, and all other variables in the model.

This is consistent with previous studies suggesting the association between insulin resistance and LVH in both hypertensive subjects (18) and type 1 diabetic patients with nephropathy (4,5) and extends previous observations to normoalbuminuric subjects. Higher risk in macroalbuminuric patients was mainly explained by triglycerides, suggesting insulin resistance as the factor underlying LVH and overt diabetic nephropathy. We found decreasing age- and sex-adjusted ORs of ECG-LVH across quartiles of GDR; however, this finding was not confirmed in multivariate analysis, probably due to misclassification bias of this estimate, which determines a bias toward the null value of significance test. This study provides the first evidence of an independent association between ECG-LVH and CHD in type 1 diabetic patients and extends to them findings obtained in the general population by the Framingham Study (2). ECG-LVH prevalence was independently associated with QTc, consistent with the results from the Insulin Resistance Atherosclerosis Study (19). In addition, this result, together with previous reports showing that QTc is associated with both blood pressure (12,19) and sudden death (7), supports the hypothesis that LVH is the factor linking blood pressure to QTc prolongation and increased cardiovascular mortality (19).

A tendency toward decreasing risk of LVH with increasing estimated GDR values was evident (OR 0.61 [95% CI 0.34 ? 1.08] in the upper versus lower quartiles). Frequencies of subjects with ECG-LVH were similar in subjects with and without metabolic syndrome (4.0 vs. 3.3%, P 0.43; age- and sex-adjusted OR 1.24 [0.75?2.04]).

In multivariate logistic regression analysis (Table 1), variables independently related to ECG-LVH after adjustment for age, sex, and diabetes duration were CHD, QTc, macroalbuminuria, and sBP. When quartiles of triglycerides were included in this model, the association between ECG-LVH and macroalbuminuria was reduced from 2.66 to 0.87, whereas ORs for triglycerides were 3.47 and 2.42 in the upper quartiles. WHR contributed to the final model with OR 2.20 in subjects with WHR 0.88. The contribution of estimated GDR to models was not significant, even after removal of

variables associated with insulin resistance syndrome (sBP, WHR, and triglycerides). Results were similar even when restricting analyses to either subjects without CHD or with normoalbuminuria.

CONCLUSIONS -- T h i s s t u d y shows a twofold-higher risk of ECG-LVH in women than in men and the association of ECG-LVH with triglycerides, WHR and sBP, QTc, and CHD.

Overall prevalence of ECG-LVH was 3.4%, three times greater than that reported in the general population of similar age using ECG criteria (3) and twofold-higher in women than in men, independent of known risk factors (sBP, BMI, and physical activity). Similarly, we recently observed a threefold-higher ECG-LVH risk in type 2 diabetic women from the Casale Monferrato Study (17).

Risk of ECG-LVH was strongly and independently associated with higher triglyceride levels and with WHR 0.88.

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