Our prospective study demonstrates the novel finding that increased baseline obesity is associated with the development of new-onset high-ABI measurements over a mean four-year follow-up, as well as mean ABI increases over time. These associations are independent of cardiovascular risk factors, and are persistent among subjects without diabetes when additionally adjusting for insulin resistance. Trends of baseline characteristics from prior cross-sectional studies are largely consistent with our findings 5, 9, 14
, though one study did not find a significant association between BMI and prevalent high-ABI 3
The precise pathophysiologic mechanisms underlying an elevated ABI are not clearly elucidated, but several mechanisms may be relevant. Calcification of the tunica media in medium-sized muscular arteries due to medial arterial calcification (MAC) is the most commonly invoked process to explain a high-ABI, via its preferential effect on lower extremity artery stiffness 20, 21
. MAC is most commonly associated with diabetes, renal failure and aging, however, and for this reason some have suggested that this may not be the predominant process underlying an elevated-ABI in the general population 14
Through several mechanisms distinct from MAC, insulin resistance may further contribute to a high-ABI. Insulin resistance is thought to blunt the acute insulin-mediated relaxation of arterial muscular tone (within 30-60 minutes), resulting in increased arterial stiffness; the magnitude of this effect correlates with the degree of insulin resistance 12, 22-24
. Insulin resistance is also likely to decrease the less acute (~2 hours) insulin-induced vasodilation of peripheral resistance arteries 11
. Accordingly, when a small sample of type-2 diabetic subjects was started on insulin therapy, which is thought to increase insulin sensitivity, a decrease in a marker for arterial stiffness was observed 25
. Insulin resistance also induces smooth-muscle cell proliferation and the nonenzymatic glycosylation of proteins such as collagen 26, 27
. The aggregate effect of these insulin-related changes may directly increase ABI, particularly if they are shown to preferentially affect lower extremity arteries. An impact on blood pressure pulse-wave reflection 11, 28
, which is altered by changes in arterial compliance and/or caliber, to increase pulse wave velocity in the leg could also elevate the ABI. Thus, mechanisms related to insulin resistance and diabetes may contribute, in part, to the positive association observed between obesity and a high-ABI.
The Strong Heart Study was the first large prospective study to indicate the potential increased all-cause and CVD mortality risk for individuals with an abnormally high-ABI 3
. Its study population of American Indians had a high prevalence of diabetes of over 40%. Some, but not all, studies2
confirming an increased mortality risk associated with a high-ABI were also performed in populations in which MAC would be expected to be common—hemodialysis patients 4
and among the elderly 5
. However, in studies such as our own where the prevalence of diabetes reflects that of the general population (~10%) for both normal and high-ABI groups, and where the prevalence of hypertension is actually lower in the high-ABI versus the normal-ABI group 5, 14
—a finding less consistent with MAC driving an elevated ABI— other etiologies may have greater importance in the development of a high-ABI.
It has been proposed that body composition itself, rather than associated metabolic changes, may underlie a high-ABI measurement. Tabara et al. recently utilized computed tomography to measure trunk and lower extremity composition in relation to a high-ABI 29
. After adjustment for cardiovascular risk factors including insulin resistance, femoral muscle cross-sectional area, but not visceral fat, femoral fat or femoral circumference, was independently associated with a high-ABI. This suggests that increased lower extremity muscle mass, not visceral fat, contributed to a high-ABI in that study population. The authors hypothesize that increased lower extremity muscle mass increases resistance to compression of lower extremity arteries, leading to a higher ABI measurement. Interestingly this study also noted higher daily physical activity in individuals with a high-ABI. Thus, patterns of body composition may significantly influence a high-ABI in certain populations. Accordingly, different anthropometric measures may be expected to vary in their association with high-ABI.
The association we demonstrate of increasing obesity with incident high-ABI likely has a multifactorial etiology. The high-ABI population in our study did have significantly higher HOMA-IR values at baseline, suggesting that insulin-mediated etiologies contribute in part to a high-ABI in our population. The persistence of this positive association among nondiabetic, obese individuals, however, after additionally adjusting for HOMA-IR, suggests that insulin-mediated mechanisms are not the only contributors to a high-ABI. The finding that measures of general obesity were stronger predictors of a high-ABI than were measures of visceral adiposity, while contrary to our hypothesis, may be consistent with the increased lower-extremity muscle mass explanation for increased ABI proposed by Tabara et al. 29
. Though our study lacks the lower extremity CT data to evaluate this further, a higher femoral muscle mass may be indicative of increased generalized muscle mass, which can manifest as greater weight or BMI relative to visceral adiposity measures.
Given the various etiologies that may contribute to increased ABI values, any interpretation of a high-ABI should consider the population in which it was measured. For those in whom MAC or insulin-resistance is thought to be the predominant etiology, the high-ABI population may share increased CVD risk factor profiles with the diabetic population. In other populations, a high-ABI may not be a marker for increased cardiac or vascular risk. In the general population, a high-ABI is most likely measured in a heterogeneous population and would have multifactorial etiologies. This may explain some of the heterogeneity of risk factor associations and mortality findings among studies of high-ABI 1, 3, 5, 7, 14, 30
. Additional studies utilizing data on lower extremity composition by CT or direct measures of arterial stiffness and waveforms may further characterize the predominant contributors to a high-ABI in specific populations.
Strengths of this study include the large sample size, longitudinal data, its geographically and ethnically diverse population, measurement of lower extremity pressures in both legs, allowing for the most inclusive definition of abnormal ABI, and rigorous quality control. Limitations of our study include the possibility that, by excluding participants with clinical cardiovascular disease at baseline, MESA may have differentially excluded individuals at the extremes of both ABI values and obesity. However, participants in all quartiles of anthropometric measures had similar ABI distribution shapes (data not shown), suggesting this bias was not likely. Other potential limitations concern the loss to follow-up, measurement error associated with ABI and anthropometric measures, and lack of visceral adiposity imaging in MESA. In addition, we recognize that inferring relative strengths of association by the comparison of quartiles should be performed cautiously, as these values are population-specific.