The key finding in this study is that baseline cardiovascular autonomic neuropathy (measured by E/I ratio) strongly correlates with both arterial stiffness (measured by both augmentation index and augmentation pressure) and reduced estimated myocardial perfusion (measured by SEVR) in childhood-onset type 1 diabetes some 18 years later. Along with cardiovascular autonomic neuropathy, known cardiovascular risk factors such as reduced HDL cholesterol and cigarette smoking were also predictive of the increased stiffness indexes AIx and AP. Poorer glycemic control (higher baseline HbA1) in this population was also associated with higher AP and with lower SEVR. However, because we did not have PWA measures at baseline and cannot be certain that these factors are true predictors of incidence, it seems likely that cardiovascular autonomic neuropathy may exert a major pathophysiological role in the development of arterial stiffening.
E/I ratio was predictive, multivariately, of both AIx and Ln(AP). This finding is consistent with the finding by Ahlgren et al. (14
) of a significant correlation between E/I ratio and aortic stiffness (measured as aortic distensibility using ultrasonography) in females, but not in males, with type 1 diabetes. However, because of limited sample size in our study, sex-stratified analyses are not conclusive. In our type 1 diabetes population, diabetic autonomic neuropathy has been associated with increased all-cause mortality, and specifically cardiovascular mortality, as well as nonfatal cardiovascular events (7
). Cardiovascular autonomic neuropathy has also been shown to be associated with left ventricular hypertrophy and diastolic dysfunction in type 1 diabetes (15
). As arterial stiffness indexes are shown to contribute to left ventricular diastolic dysfunction (16
), arterial stiffness may be a critical link between AN and cardiovascular disease. Type 1 diabetic patients without neuropathy, nephropathy, or retinopathy have been observed to have preserved vascular function (17
), which suggests an intimate relationship between vascular dysfunction and these complications.
Lower HDL cholesterol, a traditional cardiovascular risk factor but not higher non-HDL cholesterol, was independently predictive of AIx and Ln(AP). In a study of healthy subjects, Duprez et al. (18
) showed that low HDL cholesterol was significantly correlated to AP and AIx in women but not in men. However, the study examined only univariate correlations. The results of the present study are generally consistent with baseline HDL cholesterol being associated with both AIx and Ln(AP) in partial correlations and in multivariate sex-adjusted models; in sex-stratified analyses, lower HDL cholesterol remained significantly associated with higher AIx and higher AP in women and with higher AP in men.
A history of smoking was significantly associated with all three outcomes. This finding is not surprising, since cigarette smoking is known to be associated with arterial stiffness indexes, particularly in individuals with hypertension (19
). A higher baseline HbA1
was also associated with increased AP and decreased SEVR in the present study. This is consistent with the notion that the formation of advanced glycation end products (AGEs) is one of the primary mechanisms involved in arterial stiffening, especially in individuals with diabetes. Arterial wall exposure to AGEs can cause cross-linking of collagen molecules, which in turn reduces arterial elasticity (20
). AGEs are shown to be associated with increased arterial AIx in individuals with hypertension (21
). Schram et al. (22
) showed that AGEs, specifically, pentosidine, Nepsilon-(carboxymethyl)lysine, and Nepsilon-(carboxyethyl)lysine, were all significantly associated with increased pulse pressure in individuals with type 1 diabetes cross-sectionally, whereas A1C was not. However, Gordin et al. (23
) did find a concurrent association between A1C and AIx in a small study of 22 healthy males with type 1 diabetes. In our study, concurrent A1C also was not significantly associated with PWA measures (data not shown). Baseline HbA1
level may better represent the historic exposure to hyperglycemia that leads to AGE exposure than concurrent A1C.
Many of the factors associated with AIx were also associated with AP in this study. This is not surprising, since AIx is merely AP/PP × 100. AP is the measure of contribution that the wave reflection makes to the systolic arterial pressure, and it is obtained by measuring the reflected wave coming from the periphery to the center. As the reflected wave returns earlier in the cardiac cycle, there is a disproportionate rise in systolic blood pressure and therefore an increase in PP. It has been shown that AIx increases with age in the healthy population until ~55 years of age, when diastolic blood pressure may plateau or fall, contributing to higher PP. AP, however, steadily increases with age without reaching a plateau (24
); thus, AP may be a better representation of vascular aging when PP rises, since this will result in lower AIx. This may be true in individuals with type 1 diabetes at a younger age, since type 1 diabetes is associated with accelerated vascular aging (25
). Because poorer glycemic control is also associated with increased PP (22
), this may explain why baseline HbA1
was associated multivariately with AP, but not with AIx.
While nearly half (48.6%) of our study population showed evidence of cardiovascular autonomic neuropathy (E/I ratio <1.1) on exam at baseline, a much smaller proportion of the population (14.5%) was experiencing symptomatic autonomic neuropathy at baseline. Also, at baseline, no objective measures of autonomic neuropathy in other end-organs were obtained (e.g., gastroparesis, impaired bladder function, impotence, etc.). Because we did not see any difference in univariate analyses when individuals with symptomatic autonomic neuropathy were excluded, we hypothesize that individuals with autonomic neuropathy are more likely to have increased arterial stiffness irrespective of concomitant symptoms.
This study has significant limitations. For one, the sample size was relatively limited, and, as such, P values <0.10 have been reported. However, this study is the largest to date to assess PWA measures (AIx, AP, and SEVR) in type 1 diabetes. Also, this study lacks PWA measurements at baseline. Thus, significant factors in this study can only be considered potential predictors of the arterial stiffness indexes measured and need to be confirmed prospectively in a type 1 diabetes population, before designation as true predictors. Another limitation is that this population is essentially a survivor population in that those who were either deceased or unable to attend at the 18-year follow-up examination because of poor health may represent individuals with greater risk for complications and/or those most affected by increased arterial stiffness. Also, compared with individuals at the 18-year follow-up but without PWA measures, the PWA study group had significantly lower follow-up AER measures and waist-to-hip ratio and therefore may represent a healthier segment of our type 1 diabetes population (data not shown). However, these limitations are more likely to hinder finding significant relationships between baseline factors and follow-up PWA measures than demonstrate false relationships.
Furthermore, this is the first study to examine multiple potential risk factors for arterial stiffness in a type 1 diabetes population. The findings of this study have clinical significance, since we show potentially modifiable risk factor states (notably cardiovascular autonomic neuropathy, cigarette smoking, poor glycemic control, and low HDL cholesterol levels) are associated with increased arterial stiffness and lower estimated myocardial perfusion later in life in type 1 diabetes. The results of this study also confirm that the use of antihypertensive medications, specifically ACE inhibitors/ARBs, is associated with lower arterial stiffness indexes but does not necessarily improve coronary artery perfusion. Thus, early testing and treatment for autonomic neuropathy may be effective in reducing arterial stiffness and, in turn, cardiovascular morbidity and mortality in individuals with type 1 diabetes.