Novel insights into body fat distribution and cardiometabolic risk

For the podcast associated with this article, please visit https://academic. oup.com/eurheartj/pages/Podcasts. The current increase in body weight is a true epidemic of the modern world.1 The unrestricted availability of nutrients and marked reduction in physical activity have led to an unprecedented increase in the number of obese and morbidly obese individuals. As a consequence, the prevalence and incidence of weight-dependent conditions such as high blood pressure, lipid disorders, and diabetes,2,3 as well as cardiovascular disease4 and heart failure5 have markedly increased. However, it is not just body fat, but also its distribution that results in cardiovascular risk. That this is even important in individuals of normal weight is documented in the article entitled ‘Association between regional body fat and cardiovascular disease risk among post-menopausal women with normal body mass index’ by Qibin Qi and colleagues from the Yeshiva University Albert Einstein College of Medicine in Bronx in New York.6 The authors investigated in 2683 post-menopausal women of the Women’s Health Initiative with a body mass index (BMI) of 18.5–25 kg/m2 free of cardiovascular disease whether regional body fat deposits in the trunk or legs as measured by dual-energy X-ray absorptiometry are associated with cardiovascular disease risk. After adjustment for cardiovascular risk factors, neither whole-body fat mass nor fat percentage was associated with cardiovascular disease risk. However, trunk fat provided an increased risk, with a hazard ratio of 1.91, while leg fat was associated with decreased cardiovascular risk, with a hazard ratio of 0.62 (Figure 1). High trunk and low leg fat was associated with particularly high cardiovascular risk, with a hazard ratio of 3.33. Thus, among post-menopausal women with normal BMI, both elevated trunk fat and reduced leg fat are associated with increased risk of cardiovascular disease. The clinical implications of these novel findings are discussed in an Editorial by Matthias Blüher from the University of Leipzig in Germany.7 Joint association of trunk and leg fat percentages with risk of cardiovascular disease. Results were adjusted for covariates listed for Model 2 in Table 1. There was no significant interaction between trunk and leg fat percentages on cardiovascular disease risk (P-interaction = 0.57). CI, confidence interval; HR, hazard ratio (from Chen G-C, Arthur R, Iyengar NM, Kamensky V, Xue X, Wassertheil-Smoller S, Allison MA, Shadyab AH, Wild RA, Sun Y, Banack HR, Chai JC, Wactawski-Wende J, Manson JE, Stefanick ML, Dannenberg AJ, Rohan TE, Qi Q. Association between regional body fat and cardiovascular disease risk among postmenopausal women with normal body mass index. See pages 2849–2855). Joint association of trunk and leg fat percentages with risk of cardiovascular disease. Results were adjusted for covariates listed for Model 2 in Table 1. There was no significant interaction between trunk and leg fat percentages on cardiovascular disease risk (P-interaction = 0.57). CI, confidence interval; HR, hazard ratio (from Chen G-C, Arthur R, Iyengar NM, Kamensky V, Xue X, Wassertheil-Smoller S, Allison MA, Shadyab AH, Wild RA, Sun Y, Banack HR, Chai JC, Wactawski-Wende J, Manson JE, Stefanick ML, Dannenberg AJ, Rohan TE, Qi Q. Association between regional body fat and cardiovascular disease risk among postmenopausal women with normal body mass index. See pages 2849–2855). Although obesity has been associated with risk of atrial fibrillation,8 the associations of long-term obesity, recent obesity, and weight change with atrial fibrillation are uncertain. Tingting Feng et al. from the Norges Teknisk-Naturvitenskapelige University in Trondheim, Norway address this in their article ‘Weight and weight change and risk of atrial fibrillation: the HUNT study’.9 Of the 15 214 individuals studied, 1149 developed atrial fibrillation. The multivariable-adjusted hazard ratios were 1.2 for a baseline BMI of 25.0–29.9 kg/m2 and 1.6 for a BMI of ≥30 kg/m2 compared with normal weight. Compared with stable BMI over time, both loss and gain in BMI were associated with increased atrial fibrillation risk. Thus—in contrast to some previous studies10—long-term obesity and BMI change are associated with an increased risk of atrial fibrillation, with obesity earlier in life and weight gain being particularly important. These intriguing results are put into context with other findings in an Editorial by Prashanthan Sanders from the University of Adelaide and Royal Adelaide Hospital in Australia.11 Many diets have been recommended to decrease cardiovascular risk, among them those with less, or recently more, fat,12 less meat,13 and less carbohydrates or even functional food.14 However, little is known about the link between recently popular low-carbohydrate diets and mortality. In their article ‘Lower carbohydrate diets and all-cause and cause-specific mortality: a population-based cohort study and pooling of prospective studies’, Maciej Banach and colleagues from the Medical University of Lodz in Poland evaluated this in 24 825 participants of the NHANES study with follow-up of 6.4 years.15 After adjustment, those with the lowest carbohydrate intake in the top quartile had the highest risk of overall (32%), cardiovascular (50%), cerebrovascular (51%), and cancer (36%) mortality. The association of low-carbohydrate diets and mortality was stronger in non-obese than in obese participants. Pooled data of nine cohorts with 462 934 participants supported an overall risk of low-carbohydrate diets of 1.22, of 1.13 for cardiovascular disease, and of 1.08 for cancer mortality (Figure 2). Thus, a potentially unfavourable association of low-carbohydrate diets with overall and cause-specific mortality is seen, both based on analyses of a new cohort and by pooling previous cohort studies. Further studies are needed to ratify these important findings, which, if confirmed, would suggest that low-carbohydrate diets should not be routinely recommended in practice. The manuscript is accompanied by an Editorial by Sonia S. Anand from the McMaster University in Hamilton, Canada.16 Probability of all-cause death by carbohydrate and protein intake (from Mazidi M, Katsiki N, Mikhailidis DP, Sattar N, Banach M, on behalf of the International Lipid Expert Panel (ILEP) and the Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group. Lower carbohydrate diets and all-cause and cause-specific mortality: a population-based cohort study and pooling of prospective studies. See pages 2870–2879). Probability of all-cause death by carbohydrate and protein intake (from Mazidi M, Katsiki N, Mikhailidis DP, Sattar N, Banach M, on behalf of the International Lipid Expert Panel (ILEP) and the Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group. Lower carbohydrate diets and all-cause and cause-specific mortality: a population-based cohort study and pooling of prospective studies. See pages 2870–2879). Carotid stiffness17 and atherosclerosis18,19 are strongly associated with cardiovascular disease.20 In their article entitled ‘Serum metabolic signatures of coronary and carotid atherosclerosis and subsequent cardiovascular disease’, Ioanna Tzoulaki and colleagues from the Imperial College London in the UK characterized serum metabolic signatures associated with atherosclerosis in the coronary or carotid arteries and their association with incident cardiovascular disease in 3867 participants from the MESA study, with replication in the Rotterdam and LOLIPOP studies,21 using untargeted one-dimensional serum metabolic profiling by proton nuclear magnetic resonance (NMR) spectroscopy. Atherosclerosis was assessed by coronary artery calcium and carotid intima-media thickness. Overall, 30 metabolites measured by NMR were associated with coronary calcium and/or intima-media thickness which were attenuated after adjustment for cardiovascular risk factors. Metabolites associated with atherosclerosis were involved in lipid and carbohydrate metabolism, branched-chain and aromatic amino acid metabolism, as well as oxidative stress and inflammatory pathways. Cardiovascular events were inversely related to creatine, creatinine, and phenylalanine, and directly to mannose, acetaminophen glucuronide, lactate, and apolipoprotein B. Thus, metabolites associated with atherosclerosis predominantly tag pathways that overlap with the cardiovascular risk factors. These novel findings are put into context in an Editorial by Taavi Tillmann from the University College London in the UK.22 Although group-level effectiveness of lipid, blood pressure, glucose, and aspirin treatment for prevention of cardiovascular disease is well established23–25 and part of the most recent guidelines,26–28 important differences in absolute effectiveness exist between individuals. In their article ‘Prediction of individual life-years gained without cardiovascular events from lipid, blood pressure, glucose, and aspirin treatment based on data of more than 500 000 patients with type 2 diabetes mellitus’, Frank L.J. Visseren and colleagues from the University Medical Center Utrecht in The Netherlands developed and validated the Diabetes Lifetime-Perspective Prediction-Model in 389 366 diabetics of the Swedish National Diabetes Registry.29 C-statistics for prediction of cardiovascular disease were 0.83 and 0.64–0.65 for internal and external validation, respectively. Thus, this study provides an interactive calculator at www.U-Prevent.com that combines model predictions with relative treatment effects from trials to predict individual benefit from preventive treatment. As a complementary Current Opinion to the most recent ESC Diabetes Guidelines, Francesco Cosentino from the University Hospital Solna in Stockholm, Sweden presents on behalf of the ESC Cardiovascular Round Table their article entitled ‘Addressing cardiovascular risk in type 2 diabetes mellitus: a report from the European Society of Cardiology Cardiovascular Roundtable’.30 They remind us that two sodium–glucose co-transporter-2 inhibitors (i.e. empagliflozin and canagliflozin) and two glucagon-like peptide-1 receptor agonists (i.e. liraglutide and semaglutide) improved cardiovascular outcomes in Type 2 diabetics. Despite the rigorous outcome data, the implementation of these findings in diabetes care has been suboptimal. Indeed, all Type 2 diabetics with cardiovascular disease or at high risk should be treated with glucose-lowering drugs that have proven effects on outcomes. To accomplish this, an interdisciplinary approach between cardiologists, diabetologists, and primary care practitioners is urgently needed, and health insurances should reimburse the costs of such drugs. The issue is further complemented by four Discussion Forum contributions. In the first entitled ‘Lifecourse trajectories of body mass index and adult cardiometabolic risk: is early life a sensitive period?’, Laura N. Anderson and colleagues from McMaster University in Hamilton, ON (Canada) comment on the article ‘Distinct child-to-adult body mass index trajectories are associated with different levels of adult cardiometabolic risk’, while Marie-Jeanne Buscot and colleagues from the University of Tasmania Menzies Institute for Medical Research in Australia respond to their comments.31,32 In another Discussion Forum entitled ‘Aspirin for primary cardiovascular prevention: is there a need for risk stratification?’ Raffaele De Caterina and colleagues from Chieti, Italy comment on the article ‘Efficacy and safety of aspirin for primary prevention of cardiovascular events: a meta-analysis and trial sequential analysis of randomized controlled trials’.33,34 Anthony A. Bavry and colleagues from the University of Florida in Gainesville, USA, who authored the article in question, respond to the article in their own contribution.35 The editors hope that readers of this issue of the European Heart Journal will find it of interest. With thanks to Amelia Meier-Batschelet for help with compilation of this article.