Normal-Weight Obesity and Subclinical Atherosclerosis Risk
Normal-Weight Obesity and Subclinical Atherosclerosis Risk
In this study, the main findings are as follows: (1) NWO subjects had a higher prevalence of subclinical atherosclerosis. More specifically, NWO subjects were more likely to have soft coronary plaques, independent of other traditional cardiovascular risk factors. (2) NWO subjects had higher risk of having higher PWV value, and also higher risk of the prevalence of having any plaque. (3) The amount of estimated visceral fat itself was an independent risk factor for the above parameters of subclinical atherosclerosis. Altogether, these findings demonstrate that NWO subjects are more prone to carry subclinical atherosclerosis, which may evolve into a significant cardiovascular event in the future.
Several reports have demonstrated that NWO subjects are more likely to have more cardiovascular risk factors than NWL subjects. Although these suggest that these patients are more likely to develop significant future cardiovascular events, there has been a gap of data linking dysregulated cardiometabolic factors and future cardiovascular events. In this aspect, together with a previous study of ours, this study demonstrates that NWO subjects do indeed carry a significant degree of subclinical atherosclerosis. More importantly, we have demonstrated more direct evidence that NWO itself is an independent risk factor for having soft plaques, plaques often referred to as "vulnerable" in the literature. Among various plaques, the soft plaque is a powerful predictor of significant cardiovascular events because of its susceptibility to rupture. The fusion of PET and CCTA have identified increased uptake of FDG in the soft plaque of the coronary artery, suggesting a direct link between the characteristics of the plaque and vascular inflammation. These findings also demonstrate the usefulness of employing various imaging tools for identifying those at highest risk for future cardiovascular events.
Although previous studies on the NWO population have consistently shown that NWO patients are indeed "fat," i.e., they have increased amounts of fat in the body, and that they have elevated systemic inflammatory markers, our study showed no significant association between NWO and PWV, CACS, or coronary stenosis. These findings may imply that the important concept of NWO is in identifying the patients with increased vascular inflammation before the progression of vascular stiffness, calcium deposition, or vascular stenosis. Another explanation would be that NWO subjects may be more prone to develop future acute events, as has been shown in a previous report demonstrating that NWO subjects carry a higher risk for cardiovascular mortality. As already known, even with the same "coronary" event, the pathogenesis of stable angina and acute coronary syndrome is completely different, the former being the chronic stable occlusion of the coronary artery by a slowly progressive "stable" plaque causing coronary obstruction and the latter being the acute thrombotic occlusion by plaque rupture. Therefore, being an NWO subject may be a strong predictor of the latter.
Although we expected an elevation of PWV, CACS, and advanced coronary stenosis in the NWO subjects, we could not find a significant association between these parameters and NWO. PWV is a relatively simple method to detect the progression of atherosclerosis, and the ESH/ESC guidelines have also recommended PWV as a reliable tool to predict cardiovascular mortality. In our study, the elevated OR for the higher tertile of PWV after adjustment for age and sex in NWO subjects was nonsignificant after further adjustment with cardiovascular disease-related risk factors. This may mean that vascular stiffness might be more influenced by age and sex than other fat-related risk factors, at least in normal-weight subjects. On the other hand, this nonsignificant association between PWV and NWO in our study might be because of the different method that we used to measure PWV in our study, ba-PWV and not carotid-femoral PWV, and the different study population.
Coronary calcium scoring is another easy method to detect the progression of coronary atherosclerosis. CACS has been shown to predict outcome and it is recommended by the guidelines also that CACS may be reasonable for cardiovascular risk assessment in patients at intermediate risk. However, although CACS may be useful for mass screening, it tells nothing about the composition of the plaque and the additional value of it over the Framingham risk score – which is basically a calculation of the future cardiovascular risk from traditional risk factors – is marginal at best. In addition, a very low or zero CACS does not guarantee 'zero' future coronary events. The findings of our study demonstrating that NWO subjects have more soft plaques on CCTA are therefore notable and again demonstrates that NWO subjects should be counted as those at a high risk of future cardiovascular events before the initiation of coronary calcium deposition.
Up to now, reports showing that NWO may be associated with future vascular events and cardiovascular mortality have been limited. However, recently, several reports have started to show that BMI might not be a decent predictor of the adverse vascular changes compared to waist circumference or visceral fat. In addition, metabolically abnormal subjects with normal weight seem to exhibit increased subclinical atherosclerosis or vascular inflammation compared to metabolically healthy normal weight or metabolically healthy but obese subjects. In one study, although there was no significant difference in all-cause mortality, cardiovascular mortality was increased in NWO women independent of other cardiovascular disease-related risk factors. In another study, metabolically obese normal-weight subjects — subjects with normal weight but with metabolic dysregulation — also showed higher all-cause and cardiovascular mortality than metabolically healthy normal-weight subjects. The results of those previous papers show that BMI may not be a good predictor of future cardiovascular disease and that a considerable number of normal-weight subjects may be at risk of not being treated properly.
There are some missing links between the metabolically unhealthy normal body weight subjects and future cardiovascular events. Future large-scale, prospective, long-term cohort studies are desperately needed to refute whether these patients are indeed at higher risk for future cardiovascular events. It should also be emphasized that some imaging studies should be complemented as in ours, so as to provide insights into the missing relationship between NWO and cardiovascular events. Furthermore, it will also be important to analyze whether early intervention, either medically or by aggressive lifestyle modification, in NWO subjects would lead to a significant reduction in future events and, if so, who would benefit most by these measures.
Discussion
In this study, the main findings are as follows: (1) NWO subjects had a higher prevalence of subclinical atherosclerosis. More specifically, NWO subjects were more likely to have soft coronary plaques, independent of other traditional cardiovascular risk factors. (2) NWO subjects had higher risk of having higher PWV value, and also higher risk of the prevalence of having any plaque. (3) The amount of estimated visceral fat itself was an independent risk factor for the above parameters of subclinical atherosclerosis. Altogether, these findings demonstrate that NWO subjects are more prone to carry subclinical atherosclerosis, which may evolve into a significant cardiovascular event in the future.
Increased Prevalence of Soft Plaque in NWO
Several reports have demonstrated that NWO subjects are more likely to have more cardiovascular risk factors than NWL subjects. Although these suggest that these patients are more likely to develop significant future cardiovascular events, there has been a gap of data linking dysregulated cardiometabolic factors and future cardiovascular events. In this aspect, together with a previous study of ours, this study demonstrates that NWO subjects do indeed carry a significant degree of subclinical atherosclerosis. More importantly, we have demonstrated more direct evidence that NWO itself is an independent risk factor for having soft plaques, plaques often referred to as "vulnerable" in the literature. Among various plaques, the soft plaque is a powerful predictor of significant cardiovascular events because of its susceptibility to rupture. The fusion of PET and CCTA have identified increased uptake of FDG in the soft plaque of the coronary artery, suggesting a direct link between the characteristics of the plaque and vascular inflammation. These findings also demonstrate the usefulness of employing various imaging tools for identifying those at highest risk for future cardiovascular events.
Although previous studies on the NWO population have consistently shown that NWO patients are indeed "fat," i.e., they have increased amounts of fat in the body, and that they have elevated systemic inflammatory markers, our study showed no significant association between NWO and PWV, CACS, or coronary stenosis. These findings may imply that the important concept of NWO is in identifying the patients with increased vascular inflammation before the progression of vascular stiffness, calcium deposition, or vascular stenosis. Another explanation would be that NWO subjects may be more prone to develop future acute events, as has been shown in a previous report demonstrating that NWO subjects carry a higher risk for cardiovascular mortality. As already known, even with the same "coronary" event, the pathogenesis of stable angina and acute coronary syndrome is completely different, the former being the chronic stable occlusion of the coronary artery by a slowly progressive "stable" plaque causing coronary obstruction and the latter being the acute thrombotic occlusion by plaque rupture. Therefore, being an NWO subject may be a strong predictor of the latter.
No Significant Association of PWV, CACS, and Advanced Coronary Stenosis in NWO
Although we expected an elevation of PWV, CACS, and advanced coronary stenosis in the NWO subjects, we could not find a significant association between these parameters and NWO. PWV is a relatively simple method to detect the progression of atherosclerosis, and the ESH/ESC guidelines have also recommended PWV as a reliable tool to predict cardiovascular mortality. In our study, the elevated OR for the higher tertile of PWV after adjustment for age and sex in NWO subjects was nonsignificant after further adjustment with cardiovascular disease-related risk factors. This may mean that vascular stiffness might be more influenced by age and sex than other fat-related risk factors, at least in normal-weight subjects. On the other hand, this nonsignificant association between PWV and NWO in our study might be because of the different method that we used to measure PWV in our study, ba-PWV and not carotid-femoral PWV, and the different study population.
Coronary calcium scoring is another easy method to detect the progression of coronary atherosclerosis. CACS has been shown to predict outcome and it is recommended by the guidelines also that CACS may be reasonable for cardiovascular risk assessment in patients at intermediate risk. However, although CACS may be useful for mass screening, it tells nothing about the composition of the plaque and the additional value of it over the Framingham risk score – which is basically a calculation of the future cardiovascular risk from traditional risk factors – is marginal at best. In addition, a very low or zero CACS does not guarantee 'zero' future coronary events. The findings of our study demonstrating that NWO subjects have more soft plaques on CCTA are therefore notable and again demonstrates that NWO subjects should be counted as those at a high risk of future cardiovascular events before the initiation of coronary calcium deposition.
Stronger Association of NWO Itself With Cardiovascular Disease Than BMI
Up to now, reports showing that NWO may be associated with future vascular events and cardiovascular mortality have been limited. However, recently, several reports have started to show that BMI might not be a decent predictor of the adverse vascular changes compared to waist circumference or visceral fat. In addition, metabolically abnormal subjects with normal weight seem to exhibit increased subclinical atherosclerosis or vascular inflammation compared to metabolically healthy normal weight or metabolically healthy but obese subjects. In one study, although there was no significant difference in all-cause mortality, cardiovascular mortality was increased in NWO women independent of other cardiovascular disease-related risk factors. In another study, metabolically obese normal-weight subjects — subjects with normal weight but with metabolic dysregulation — also showed higher all-cause and cardiovascular mortality than metabolically healthy normal-weight subjects. The results of those previous papers show that BMI may not be a good predictor of future cardiovascular disease and that a considerable number of normal-weight subjects may be at risk of not being treated properly.
There are some missing links between the metabolically unhealthy normal body weight subjects and future cardiovascular events. Future large-scale, prospective, long-term cohort studies are desperately needed to refute whether these patients are indeed at higher risk for future cardiovascular events. It should also be emphasized that some imaging studies should be complemented as in ours, so as to provide insights into the missing relationship between NWO and cardiovascular events. Furthermore, it will also be important to analyze whether early intervention, either medically or by aggressive lifestyle modification, in NWO subjects would lead to a significant reduction in future events and, if so, who would benefit most by these measures.
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