This study clearly shows that significant improvements in common carotid artery structure occur with an intensive lifestyle intervention in severely obese adults. The physical activity intervention promoted a greater reduction in waist circumference but did not significantly add to the reductions in CIMT or AD, perhaps because of the smaller than desired increase in activity in the Diet+PA arm. The approximately 8% weight loss overall resulted in a mean decrease in common carotid artery AD of 0.07 mm. Though there was not a significant reduction in mean CIMT in the total sample, individuals who achieved at least 5% weight loss experienced a significant reduction in CIMT. Our results demonstrate that an intensive dietary intervention can significantly reverse some of the key adverse cardiometabolic and vascular structural changes brought about by excess weight in severely obese adults. However, the small average increase of 50 minutes in moderate to vigorous activity per week in the Diet+PA arm in this study was insufficient to add significantly to vascular changes over a 6 month time period.Importantly, data from a meta-analysis of 8 large prospective studies suggest that the mean CIMT reduction of 0.02 mm in study subjects who achieved at least 5% weight loss can be expected to reduce incident myocardial infarction and stroke rates by 3% and 4% respectively in the long term. In addition, data from one large prospective study suggest that the overall mean AD reduction of 0.07 mm in this study can be expected to reduce incident coronary heart disease rates by 2% in men and 6% in women over the next 10 years. Thus, the improvements in common carotid artery geometry in this study may wellyieldvery meaningful long-term clinical benefits for these severely obese individuals.
In the severely obese, bariatric surgery generates marked improvements in structural and functional measures of atherosclerosis and arteriosclerosis . This invasive treatment option, however, can have numerous complications and cannot be recommended to all severely obese individuals .This is the first sizable study to report improvements in vascular structure with an intensive lifestyle intervention in severely obese adults, with decreases in carotid diameter being significant in the overall sample and decreases in CIMT being significant in those who achieved at least 5% weight loss. These findings are similar to improvements in vascular structure and function seen with 5-10% weight loss in overweight, class I, and class II obese adults .These improvements are substantially smaller than those seen in a small study (n=14) of severely obese adults who experienced an average of 40% weight lossas a result of a highly intense exercise intervention (mean 3.3 hours of exercise per day) accompanied by moderate caloric restriction over 7 months.However, such an intense exercise intervention would be prohibitively expensive and time consuming to undertake on a large scale. Despite the reality that conventional therapy for severe obesity is often ineffective, intensive but widely manageable lifestyle interventions have been shown to be effective both in the present trial and a recent randomized trial comparing an intensive medical weight loss program in a primary care setting to usual care . The challenging key to the effectiveness of such interventions, however, is consistent and frequent contact with participants .
CIMT has been shown to regress or progress more slowly as cardiovascular risk factors improve with lifestyle modification . In this study, change in CIMT was correlated with changes in leptin, insulin, and several measures of body size. Because CIMT serves as a measure of both early atherosclerosis and vascular adaptation to changes in hemodynamics , increased CIMT could represent not only early atherosclerosis but also an adaptive response to the elevated cardiac output and blood flow that support increased metabolic needs in obese individuals . With the accumulation of excess weight, these hemodynamic alterations, along with concurrent hormonal and neural feedback, can lead to adverse arterial structural changes including increased diameter and intima-media thickening . It is interesting to note that changes in CIMT and AD showed different associations with cardiovascular and metabolic risk factors in this study, a finding that agrees with cross-sectional studies and suggests that distinct adaptive processes are represented by CIMT and AD .
Obese individuals have increased fat mass and fat-free mass, which together promote the aforementioned hemodynamic alterations. Fat-free mass is a strong independent correlate of left ventricular mass, CIMT, and CCA lumen diameter in cross-sectional studies . Excess adipose tissue alters circulating adipocytokine levels, such as leptin, which controls food intake and energy expenditure and increases with increasing body fat. Hyperleptinemia has been associated with greater oxidative stress and insulin resistance, both of whichpromote atherosclerosis. In this study however, the association between change in leptin and change in CIMT was explained by BMI change.
Insulin resistance and compensatory hyperinsulinemia can advance atherosclerosis by promoting interactions between circulating monocytes and the vascular endothelium and by enabling vascular smooth muscle cell migration and proliferation . Similar to this study, a recent study in obese adolescents found that a decrease in homeostatic model assessment of insulin resistance was independently associated with a reduction in CIMT during weight loss. Perhaps in severely obese individuals, the reduction in insulin resistance accompanying weight loss is key to the regression of early atherosclerosis and vascular maladaptation. Interestingly, individuals losing < 5% of their baseline body weight experienced an increase in CIMT. This could have been partly caused by a nonsignificant increase infasting insulin in this subgroup (1.2 μU/mL, SD 1.7), which was significantly different (P=0.0001) from the decrease in insulin (−6.6 μU/mL, SD 1.0) in those achieving at least 5% weight loss. However, as noted, when one influential subject showing a large increase in CIMT was removed from the analysis, the increase in CIMT in those subjects who achieved< 5% weight loss was no longer statistically significant.
Elevated common carotid artery diameter is another structural marker of cardiovascular disease risk that is associated with numerous cardiovascular risk factors and has been shown to predict events .In this study, change in AD was positively correlated with changes in all measures of body size except fat-free mass, and change in abdominal subcutaneous fat was an independent correlate of change in AD. As with CIMT, this reflects the influence of excess body mass on hemodynamic changes leading to vascular adaptation. The distribution of adipose tissue is an important determinant of obesity-associated metabolic and cardiovascular complications. Abdominal visceral fat has been found to be a strong determinant of metabolic dysfunction and of structural and functional vascular alterations in a general population of older adults , class I and II obese adults , and severely obese adults . Although abdominal subcutaneous fat influences insulin resistance , it typically shows weaker associations with metabolic and vascular dysfunction than visceral fat both in the general population and in obese individuals. In severely obese individuals, however, total abdominal fat may be a more important determinant of cardiovascular risk than any abdominal fat compartment . The majority of body fat in obese adults is subcutaneous, thus abdominal subcutaneous fat is a stronger correlate of total abdominal fat and perhaps also of vascular structural alterations in the severely obese.
A major strength of this study was the frequent and structured contact during the intervention, which enabled many participants to achieve meaningful weight loss.One limitation was that only 11% of the participants in this study were men, which restricted our analyses of sex-specific responses. In addition, no participants in this study were diabetic, thus our findings are not generalizable to this large segment of the severely obese population. However, our results indicate the important role of insulin resistance in carotid intima-media thickening even in non-diabetic severely obese individuals. In addition, 40 participants in the parent randomized trial did not have carotid ultrasound scans at both time points, mainly due to scheduling difficulties. We detected no significant baseline differences between individuals with and without complete carotiddata in factors found to influence CIMT or AD changes (results not shown).Moreover, results from sensitivity analyses including individuals with baseline but no follow-up carotid data were very similar to those reported. The small sample size of this study certainly limited our power to detect differences by intervention arm or by subgroups of interest, particularly for the vascular changes, which showed considerable heterogeneity. Finally, no control group was used for the dietary intervention, which prevented us from establishing with certainty the causal effects of the dietaryintervention.
In conclusion, a 6-month intensive dietary intervention either with or without physical activity can result in clinically meaningful improvements in cardiometabolic risk factors and common carotid artery geometry in severely obese adults. Moreover, these data indicate that weight-loss induced reductions in insulin resistance and abdominal fat are particularly associated with improvements in vascular health, benefits that are most evident in the most severely obese.