- Email: [email protected]
Obesity paradox in peripheral vascular disease
Atherosclerosis 229 (2013) 509e510
Contents lists available at SciVerse ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Invited commentary
Obesity paradox in peripheral vascular disease Johji Kato* Frontier Science Research Center, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan
a r t i c l e i n f o Article history: Received 1 May 2013 Accepted 1 May 2013 Available online 15 May 2013 Keywords: Peripheral vascular disease Underweight Obesity Mortality
To prevent cardiovascular diseases, it is essential to control risk factors, among which obesity is a world-wide issue that we are currently facing [1]. Obesity was found to be an independent cardiovascular risk factor by the Framingham Heart study, in which the participants were followed up over 26 years; a higher risk was observed in both men and women whose body weights increased after the young adult years [2]. It has been shown that obesity, particularly visceral obesity, is closely related not only to classical cardiovascular risk factors such as dyslipidemia, diabetes, and hypertension, but also to insulin resistance, abnormal blood coagulation, chronic kidney disease, sleep apnea syndrome, and so on [1,3,4]. Endothelial dysfunction, a phenomenon recognized as an early stage of atherosclerosis, was also shown to be associated with obesity [5]. The mechanisms by which obesity has detrimental effects on the development or progression of atherosclerosis, have recently been studied vigorously. In obese patients, enlarged adipocytes were shown to secrete a wide range of bioactive substances called adipokines, such as interleukin-6, tumor necrosis factor-a (TNF-a) and angiotensinogen, which act as pro-atherogenic factors [6]. Indeed, these adipokines levels in the adipose tissue and blood are reduced following reduction of body weight in obese patients [7]. Meanwhile, in a large-scale prospective cohort study, “J”- or “U”-shaped curves were observed in the relationship between mortality and body mass index (BMI): not only higher but also lower BMIs were associated with higher mortality from cardiovascular diseases, cancer, or other causes of death [8]. Comparable
DOI of original article: http://dx.doi.org/10.1016/j.atherosclerosis.2013.04.030. * Tel./fax: þ81 985 85 9718. E-mail address: [email protected]. 0021-9150/$ e see front matter Ó 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.atherosclerosis.2013.05.004
with the higher mortality at lower BMI, there have been a number of studies in which overweight or obese patients with various chronic diseases, such as heart failure, coronary artery disease, stroke and end-stage renal disease, showed better prognoses than those with lower BMIs or underweight [9e12]. We can call these phenomena the “obesity paradox”. The hypothesis of the obesity paradox was examined in patients with peripheral vascular disease (PVD) in a paper published by Golledge et al. in this issue of Atherosclerosis [13]. In the present study, 1472 PVD patients with varying BMI were followed up for a certain period of time with an inter-quartile range of 0.3e3.5 years. The authors found that underweight patients with BMI <18.5 showed the lowest survival rate and there was an inverse correlation between BMI and mortality, confirming the close correlations between BMI and abdominal subcutaneous or intra-abdominal fat volume determined by CT scan. The result of this study appears to be a typical example of the obesity paradox seen in patients with PVD. When we discuss the results of clinical studies investigating the relationship between obesity and the development or progression of cardiovascular diseases, it is essential to realize whether these studies are observational or interventional. For example, it was reported by an observational study that hypertensive overweight patients had a better prognosis than lean patients; but of course, we do not recommend that hypertensive patients to become overweight or obese [14,15]. This study by Golledge et al. is an observational, prospective cohort study; however, the findings presented in their paper clearly demonstrated an important issue for which we currently have no clear answers in patients with PVD, as discussed below [13]. There are two simple, but important questions in treating patients with PVD: 1) whether overweight or obese patients should
510
J. Kato / Atherosclerosis 229 (2013) 509e510
be advised to reduce their body weight; 2) whether underweight patients should be advised to increase their body weight. If an obese PVD patient has multiple risk factors, such as dyslipidemia and diabetes associated with high levels of plasma insulin and insulin resistance, many medical practitioners or those specialized in cardiovascular medicine would say “Yes” to the former question. As mentioned above, reduction of body weight by obese patients should not only alleviate dyslipidemia and diabetes, but also lower plasma levels of pro-atherogenic adipokines [6,7]. Meanwhile, the present study by Golledge et al. raised the possibility that the answer is not always “Yes”, although the specific group of patients to whom we should say “No” remained to be elucidated in this study [13]. On the other hand, we may take an approach to underweight patients with PVD, which is essentially different from that to those overweight or obese. Clearly, if a PVD patient is underweight or malnourished, we should specify the cause of being underweight before or while carrying out interventional management of PVD. A wide range of causes needs to be considered, including malnutrition secondary to stenosis of the mesenteric artery, as pointed out by the present report. It remains to be clarified whether any specific nutritional support can improve the prognosis of underweight PVD patients, while such an approach may be necessary for some cases in clinical practice. As discussed by the authors, there are significant limitations that we need to take into account in interpreting the present findings [13]. The sample size of the underweight group was quite small compared with the other groups and, indeed, myocardial infarction and stroke were more frequent in the underweight group, but the difference was insignificant (Table 2). The main focus of this study was the relationship between BMI and mortality, while causes of death were not specified. It therefore remains to be clarified whether PVD patients who are overweight or obese have lower cardiovascular morbidity or mortality. Certainly, a large-scale observational or secondary prevention study is essential to answer to the important questions mentioned above. Until we have clear evidence, we need to treat PVD patients who are underweight or obese on a case-by-case basis, probably depending on their cardiovascular risk factors or complications, or on the degree of underweight or obesity.
Conflict of interest The author declares that there is no conflict of interest regarding this commentary.
References [1] World Health Organization. Obesity. Preventing and managing the global epidemic. Geneva: WHO; 2000. [2] Hubert HB, Feinleib M, McNamara PM, Castelli WP. Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham Heart Study. Circulation 1983;67:968e77. [3] Matsuzawa Y, Nakamura T, Shimomura I, Kotani K. Visceral fat accumulation and cardiovascular disease. Obes Res 1995;3(Suppl. 5):645Se7S. [4] Nomura I, Kato J, Kitamura K. Association between body mass index and chronic kidney disease: a population-based, cross-sectional study of a Japanese community. Vasc Health Risk Manag 2009;5:315e20. [5] Sciacqua A, Candigliota M, Ceravolo R, et al. Weight loss in combination with physical activity improves endothelial dysfunction in human obesity. Diabetes Care 2003;26:1673e8. [6] Fasshauer M, Paschke R. Regulation of adipocytokines and insulin resistance. Diabetologia 2003;46:1594e603. [7] Moschen AR, Molnar C, Geiger S, et al. Anti-inflammatory effects of excessive weight loss: potent suppression of adipose interleukin 6 and tumour necrosis factor a expression. Gut 2010;59:1259e64. [8] Calle EE, Thun MJ, Petrelli JM, Rodriguez C, Heath Jr CW. Body-mass index and mortality in a prospective cohort of U.S. adults. N Engl J Med 1999;341: 1097e105. [9] Oreopoulos A, Padwal R, Kalantar-Zadeh K, Fonarow GC, Norris CM, McAlister FA. Body mass index and mortality in heart failure: a meta-analysis. Am Heart J 2008;156:13e22. [10] Romero-Corral A, Montori VM, Somers VK, et al. Association of bodyweight with total mortality and with cardiovascular events in coronary artery disease: a systematic review of cohort studies. Lancet 2006;368:666e78. [11] Ovbiagele B, Bath PM, Cotton D, Vinisko R, Diener HC. Obesity and recurrent vascular risk after a recent ischemic stroke. Stroke 2011;42:3397e402. [12] Jialin W, Yi Z, Weijie Y. Relationship between body mass index and mortality in hemodialysis patients: a meta-analysis. Nephron Clin Pract 2012;121: c102e111. [13] Golledge J, Cronin O, Iyer V, Bradshaw B, Moxon JV, Cunningham M. Body mass index is inversely associated with mortality in patients with peripheral vascular disease. Atherosclerosis 2013;229(2):549e55. [14] Menotti A, Giampaoli S, Pasquali M, Seccareccia F, Stuart K. Prognosis of lean and fat hypertensives. Cardiology 1988;75:448e57. [15] Stamler R, Ford CE, Stamler J. Why do lean hypertensives have higher mortality rates than other hypertensives? findings of the hypertension detection and follow-up program. Hypertension 1991;17:553e64.
Contents lists available at SciVerse ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Invited commentary
Obesity paradox in peripheral vascular disease Johji Kato* Frontier Science Research Center, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan
a r t i c l e i n f o Article history: Received 1 May 2013 Accepted 1 May 2013 Available online 15 May 2013 Keywords: Peripheral vascular disease Underweight Obesity Mortality
To prevent cardiovascular diseases, it is essential to control risk factors, among which obesity is a world-wide issue that we are currently facing [1]. Obesity was found to be an independent cardiovascular risk factor by the Framingham Heart study, in which the participants were followed up over 26 years; a higher risk was observed in both men and women whose body weights increased after the young adult years [2]. It has been shown that obesity, particularly visceral obesity, is closely related not only to classical cardiovascular risk factors such as dyslipidemia, diabetes, and hypertension, but also to insulin resistance, abnormal blood coagulation, chronic kidney disease, sleep apnea syndrome, and so on [1,3,4]. Endothelial dysfunction, a phenomenon recognized as an early stage of atherosclerosis, was also shown to be associated with obesity [5]. The mechanisms by which obesity has detrimental effects on the development or progression of atherosclerosis, have recently been studied vigorously. In obese patients, enlarged adipocytes were shown to secrete a wide range of bioactive substances called adipokines, such as interleukin-6, tumor necrosis factor-a (TNF-a) and angiotensinogen, which act as pro-atherogenic factors [6]. Indeed, these adipokines levels in the adipose tissue and blood are reduced following reduction of body weight in obese patients [7]. Meanwhile, in a large-scale prospective cohort study, “J”- or “U”-shaped curves were observed in the relationship between mortality and body mass index (BMI): not only higher but also lower BMIs were associated with higher mortality from cardiovascular diseases, cancer, or other causes of death [8]. Comparable
DOI of original article: http://dx.doi.org/10.1016/j.atherosclerosis.2013.04.030. * Tel./fax: þ81 985 85 9718. E-mail address: [email protected]. 0021-9150/$ e see front matter Ó 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.atherosclerosis.2013.05.004
with the higher mortality at lower BMI, there have been a number of studies in which overweight or obese patients with various chronic diseases, such as heart failure, coronary artery disease, stroke and end-stage renal disease, showed better prognoses than those with lower BMIs or underweight [9e12]. We can call these phenomena the “obesity paradox”. The hypothesis of the obesity paradox was examined in patients with peripheral vascular disease (PVD) in a paper published by Golledge et al. in this issue of Atherosclerosis [13]. In the present study, 1472 PVD patients with varying BMI were followed up for a certain period of time with an inter-quartile range of 0.3e3.5 years. The authors found that underweight patients with BMI <18.5 showed the lowest survival rate and there was an inverse correlation between BMI and mortality, confirming the close correlations between BMI and abdominal subcutaneous or intra-abdominal fat volume determined by CT scan. The result of this study appears to be a typical example of the obesity paradox seen in patients with PVD. When we discuss the results of clinical studies investigating the relationship between obesity and the development or progression of cardiovascular diseases, it is essential to realize whether these studies are observational or interventional. For example, it was reported by an observational study that hypertensive overweight patients had a better prognosis than lean patients; but of course, we do not recommend that hypertensive patients to become overweight or obese [14,15]. This study by Golledge et al. is an observational, prospective cohort study; however, the findings presented in their paper clearly demonstrated an important issue for which we currently have no clear answers in patients with PVD, as discussed below [13]. There are two simple, but important questions in treating patients with PVD: 1) whether overweight or obese patients should
510
J. Kato / Atherosclerosis 229 (2013) 509e510
be advised to reduce their body weight; 2) whether underweight patients should be advised to increase their body weight. If an obese PVD patient has multiple risk factors, such as dyslipidemia and diabetes associated with high levels of plasma insulin and insulin resistance, many medical practitioners or those specialized in cardiovascular medicine would say “Yes” to the former question. As mentioned above, reduction of body weight by obese patients should not only alleviate dyslipidemia and diabetes, but also lower plasma levels of pro-atherogenic adipokines [6,7]. Meanwhile, the present study by Golledge et al. raised the possibility that the answer is not always “Yes”, although the specific group of patients to whom we should say “No” remained to be elucidated in this study [13]. On the other hand, we may take an approach to underweight patients with PVD, which is essentially different from that to those overweight or obese. Clearly, if a PVD patient is underweight or malnourished, we should specify the cause of being underweight before or while carrying out interventional management of PVD. A wide range of causes needs to be considered, including malnutrition secondary to stenosis of the mesenteric artery, as pointed out by the present report. It remains to be clarified whether any specific nutritional support can improve the prognosis of underweight PVD patients, while such an approach may be necessary for some cases in clinical practice. As discussed by the authors, there are significant limitations that we need to take into account in interpreting the present findings [13]. The sample size of the underweight group was quite small compared with the other groups and, indeed, myocardial infarction and stroke were more frequent in the underweight group, but the difference was insignificant (Table 2). The main focus of this study was the relationship between BMI and mortality, while causes of death were not specified. It therefore remains to be clarified whether PVD patients who are overweight or obese have lower cardiovascular morbidity or mortality. Certainly, a large-scale observational or secondary prevention study is essential to answer to the important questions mentioned above. Until we have clear evidence, we need to treat PVD patients who are underweight or obese on a case-by-case basis, probably depending on their cardiovascular risk factors or complications, or on the degree of underweight or obesity.
Conflict of interest The author declares that there is no conflict of interest regarding this commentary.
References [1] World Health Organization. Obesity. Preventing and managing the global epidemic. Geneva: WHO; 2000. [2] Hubert HB, Feinleib M, McNamara PM, Castelli WP. Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham Heart Study. Circulation 1983;67:968e77. [3] Matsuzawa Y, Nakamura T, Shimomura I, Kotani K. Visceral fat accumulation and cardiovascular disease. Obes Res 1995;3(Suppl. 5):645Se7S. [4] Nomura I, Kato J, Kitamura K. Association between body mass index and chronic kidney disease: a population-based, cross-sectional study of a Japanese community. Vasc Health Risk Manag 2009;5:315e20. [5] Sciacqua A, Candigliota M, Ceravolo R, et al. Weight loss in combination with physical activity improves endothelial dysfunction in human obesity. Diabetes Care 2003;26:1673e8. [6] Fasshauer M, Paschke R. Regulation of adipocytokines and insulin resistance. Diabetologia 2003;46:1594e603. [7] Moschen AR, Molnar C, Geiger S, et al. Anti-inflammatory effects of excessive weight loss: potent suppression of adipose interleukin 6 and tumour necrosis factor a expression. Gut 2010;59:1259e64. [8] Calle EE, Thun MJ, Petrelli JM, Rodriguez C, Heath Jr CW. Body-mass index and mortality in a prospective cohort of U.S. adults. N Engl J Med 1999;341: 1097e105. [9] Oreopoulos A, Padwal R, Kalantar-Zadeh K, Fonarow GC, Norris CM, McAlister FA. Body mass index and mortality in heart failure: a meta-analysis. Am Heart J 2008;156:13e22. [10] Romero-Corral A, Montori VM, Somers VK, et al. Association of bodyweight with total mortality and with cardiovascular events in coronary artery disease: a systematic review of cohort studies. Lancet 2006;368:666e78. [11] Ovbiagele B, Bath PM, Cotton D, Vinisko R, Diener HC. Obesity and recurrent vascular risk after a recent ischemic stroke. Stroke 2011;42:3397e402. [12] Jialin W, Yi Z, Weijie Y. Relationship between body mass index and mortality in hemodialysis patients: a meta-analysis. Nephron Clin Pract 2012;121: c102e111. [13] Golledge J, Cronin O, Iyer V, Bradshaw B, Moxon JV, Cunningham M. Body mass index is inversely associated with mortality in patients with peripheral vascular disease. Atherosclerosis 2013;229(2):549e55. [14] Menotti A, Giampaoli S, Pasquali M, Seccareccia F, Stuart K. Prognosis of lean and fat hypertensives. Cardiology 1988;75:448e57. [15] Stamler R, Ford CE, Stamler J. Why do lean hypertensives have higher mortality rates than other hypertensives? findings of the hypertension detection and follow-up program. Hypertension 1991;17:553e64.