Recently, hypoadiponectinemia was found to be associated with coronary artery disease in humans (1). Conversely, hyperadiponetinemia caused by a transgenic overexpression of the adiponectin gene prevented atherosclerosis in the mouse with genetic preponderance to it (2,3). The facts suggest adiponectin has a direct antiatherogenic effect in vivo, as suggested in in vitro studies (4). However, adiponectin is an insulin-sensitizing adipocytokine, and increased insulin resistance (IR) is a well-established atherogenic factor. Therefore, it is possible that the observed correlations (1–3) with adiponectin and atherosclerosis occurred through its insulin-sensitizing effect (3,5). To know if adiponectin possesses a direct antiatherogenic effect beyond its insulin-sensitizing action in an apparently healthy population, we analyzed the relationship among serum adiponectin, heart rate–corrected QT interval (QTc), and the established risk factors of atherosclerosis in Japanese health examinees. Most importantly, measurement of serum-specific immunoreactive insulin (IRI) was included to quantify the degree of IR. QTc was used as a marker of subclinical atherosclerosis because it predicts future cardiac mortality (6) and correlates well with the carotid intima-media thickning (7), both in apparently healthy populations.
The data of 102 consecutive male health examinees (aged 54 ± 11 years) from the Japanese general population were analyzed. Using fasting blood samples, we measured serum adiponectin (8.1 ± 4.4 μg/ml [mean ± SD]), IRI (47.2 ± 27.1 pmol/l), triglycerides (1.62 ± 0.85 mmol/l), total cholesterol (5.38 ± 0.98 mmol/l), HDL cholesterol (1.37 ± 0.31 mmol/l), and plasma glucose (5.7 ± 1.0 mmol/l). Adiponectin was determined by radioimmunoassay using commercially available kits (Linco Research, St. Charles, MO) and IRI by human insulin–specific enzyme immunoassay (Abbott Laboratories, Abbott Park, IL). Anthropometric parameters and blood pressure (125 ± 16/75 ± 10 mmHg) were also obtained and the 12-lead electrocardiogram recorded. QTc (392 ± 17 ms) was determined by computational analysis according to the Bazett’s formulation. Adiposity was measured with impedance method. An index of insulin sensitivity (QUICKI) was 0.36 ± 0.03 (1/[log (insulin in μU/ml) + log (glucose in mg/dl)]).
First, correlation between each clinical variable and QTc was evaluated by Spearman’s rank correlation and linear regression analysis. Adiponectin, percentage adiposity, and age, but none of the other variables, were significantly correlated with QTc. Based on this finding the multiple regression analysis was performed by taking QTc as a dependent variable and adiponectin, percentage adiposity, and age as independent variables. All of the three variables were significantly correlated with QTc, and the correlation was most strong and significant between adiponectin and QTc: adiponectin (β = −0.272, P = 0.0048), percentage adiposity (β = 0.228, P = 0.0330), and age (β = 0.216, P = 0.047). Adiponectin and QUICKI (P = 0.004) were significantly correlated after adjustment for plasma glucose, triglycerides, and BMI. Thus, we confirmed a well-established insulin-sensitizing effect of adiponectin in this population.
Finally, we attempted to establish a relationship between hypoadiponectinemia and abnormal elongation of QTc by multiple logistic regression analysis. To this end, QTc ≥420 ms was adopted as a cutoff for the abnormal QTc (normal QTc<420 ms, n = 95; QTc elongation ≥420 ms, n = 7) because it was associated with a significantly higher cardiovascular mortality in a prospective study of an apparently healthy population (6). After consideration of all variables listed above as possible predictors, low level of adiponectin was the only variable significantly related to the abnormal elongation of QTc (P = 0.047, RR 0.730, 95% CI 0.535–0.995).
We found an unequivocal inverse correlation between adiponectin and QTc, and more importantly, hypoadiponectinemia was the only variable significantly related to abnormal elongation of QTc. In this apparently healthy population, a significant correlation between insulin sensitivity and QTc was absent. Our data strongly suggest that adiponectin possesses a direct antiatherogenic effect in humans during the evolution of atherosclerosis.
