In this study we have found that among elderly cognitively normal patients with type 2 diabetes, that longitudinal measurements of adiposity are associated with indices of carotid stiffness and atherosclerotic plaque volume. Adjustment of the models for several relevant cardiovascular and sociodemographic variables did not attenuate these associations.
This study provides new evidence in several levels. The study focuses on an elderly diabetic population on which there is scarce evidence on relationships of obesity with measures of carotid stiffness and atherosclerotic plaque volume, despite the biological plausibility of this association. Using a broad battery, we have found that adiposity is associated differentially with carotid indices, suggesting that adiposity affects some carotid features more than others. Finally, we have used long-term data of BMI that span approximately 26 years and presented both as mean of all measurements and trajectories of BMI.
Our data provide additional support to the growing evidence on the association of obesity with impaired vascular health. Impaired vascular health in the carotid artery wall was observed as early as in hypertensive children18, healthy pre- and early pubescent children19, adolescents9,20, and physically inactive adults office workers6. In a case control study among adults, obesity was associated with cIMT (but not distensibility)7,21. Increased cIMT and decreased distensibility were observed among adult men22 and women23,24. BMI trajectories were identified from childhood to adulthood in the Cardiovascular Risk in Young Finns Study, providing evidence that increase in childhood BMI resulted in increased cIMT compared with maintenance of normal BMI over time25. Yet in other studies, no association was found between BMI and carotid atherosclerosis in non-diabetic 26 as well as diabetic patients 5,27. We are not aware of any published evidence on the association of carotid elastography and BMI.
Several underlying biological mechanisms may link BMI with impaired vascular health. In our study obese patients were younger, yet had higher triglycerides and blood pressure, and lower HDL cholesterol, all independent risk factors for atherosclerosis in general and carotid artery atherosclerosis in particular28. However, adjusting for these risk factors did not attenuate the BMI-carotid associations suggesting involvement of other mechanisms. Second, adipocytokines, i.e. fat-related inflammatory markers such as IL-6 and leptin, play an important role in atherosclerosis including initial activation of endothelial cells, through atherosclerotic progression and, ultimately, its final complication, thrombosis29. Third, visceral abdominal fat has a direct circulatory connection to the liver. Excessive release of free fatty acids from visceral adipose tissue directly in the portal circulation might lead to insulin resistance and hyperlipidemia, both established risk factors for CVD30.
In this study we have found that BMI is associated with carotid artery stiffening as indicated by carotid distensibility and elastography, in addition to the association with carotid atherosclerosis parameters as indicated by cIMT and carotid plaque volume. Arteries are known to stiffen in healthy aging and with atherosclerosis, diabetes, hypertension and obesity31. Stiffening of the carotid arteries is associated with higher risk for stroke32 and is predictive of white matter hyperintensity volume and total brain volume33. It has been suggested that stiffening of the carotid artery increases the mechanical force on existing plaque and as a result increases the risk for rupture of existing plaques34.
Our study has several limitations. The study is conducted on elderly non-demented type 2 diabetes patients which may reflect a population of “survivors”, so subjects who were eligible for this study were those who were not demented after 2 IDCD follow up visits over approximately four years. The IDCD study focuses on older adults with type 2 diabetes and thus conclusions from this study cannot be extrapolated to non-diabetic populations. We have only cross-sectional carotid artery data so reverse causality cannot be ruled out. However, the BMI trajectories spanned 26 years suggesting that long-term obesity may be a predictor of carotid disease. An additional limitation is that our measure of adiposity was BMI, so we could not directly address aspects of body composition such as visceral fat or fat distribution35,36,37. Strengths of our study include its relatively large-scale, the in depth carotid assessments including novel indices of impaired vascular health, a directly measured (rather than self-reported) diabetes diagnosis, and an exquisite characterization of long-term covariates and of BMI trajectories derived from the Maccabi Diabetes Registry data.