Use of metabolic phenotypes concept for cardiovascular risk assessment: literature review

• Anna V. Postoeva
• Dvoryashina Irina V.
• Ekaterina I. Selchenkova

Abstract

Previous studies showed that people with various degrees of obesity and concomitant metabolic disorders had significant differences in cardiovascular risk. One of possible ways for risk assessment in such patients was to divide them into groups of metabolic phenotypes.

Aim of the paper is to discover the role of metabolic phenotype concept in cardiovascular risk prognosis. In literature review we provided historical data concerning metabolic phenotypes. Results of international and Russian trials of cardiovascular and general risk assessment for separate patients’ groups were analyzed. Phenotypes «metabolically healthy obese» and «metabolically unhealthy non-obese» are discussed in a greater extent because previous studies showed controversial results about cardiovascular risk assessment in these groups of patients. Additional subtypes inside classic metabolic phenotypes were also discussed, including patients with overweight among patients without total obesity, with patients with abdominal obesity with different levels of body mass index. Pathogenetic basis for metabolic phenotypes were also provided.

Keywords:metabolic phenotype; obesity; cardiovascular diseases

References

1. Kramer C.K., Zinman B., Retnakaran R. Are metabolically healthy overweight and obesity benign conditions? A systematic review and meta-analysis. Ann Intern Med. 2013; 159 (11): 758–69. DOI: https://doi.org/10.7326/0003-4819-159-11-201312030-00008 PMID: 24297192.

2. van Vliet-Ostaptchouk J.V., Nuotio M.L., Slagter S.N., et al. The prevalence of metabolic syndrome and metabolically healthy obesity in Europe: a collaborative analysis of ten large cohort studies. BMC Endocr Disord. 2014; 14: 9. DOI: https://doi.org/10.1186/1472-6823-14-9 PMID: 24484869; PMCID: PMC 3923238.

3. Pujia R., Tarsitano M.G., Arturi F., et al. Advances in phenotyping obesity and in its dietary and pharmacological treatment: a narrative review. Front Nutr. 2022; 9: 804719. DOI: https://doi.org/10.3389/fnut.2022.804719 PMID: 35242796; PMCID: PMC 8885626.

4. Vague J. The degree of masculine differentiation of obesities: a factor determining predisposition to diabetes, atherosclerosis, gout, and uric calculous disease. Am J Clin Nutr. 1956; 4 (1): 20–34. DOI: https://doi.org/10.1093/ajcn/4.1.20 PMID: 13282851.

5. Ruderman N.B., Schneider S.H., Berchtold P. The «metabolically-obese», normal-weight individual. Am J Clin Nutr. 1981; 34 (8): 1617–21. DOI: https://doi.org/10.1093/ajcn/34.8.1617 PMID: 7270486.

6. Reaven G.M. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988; 37 (12): 1595–607. DOI: https://doi.org/10.2337/diab.37.12.1595 PMID: 3056758.

7. Wilson P.W., D’Agostino R.B., Sullivan L., et al. Overweight and obesity as determinants of cardiovascular risk: the Framingham experience. Arch Intern Med. 2002; 162 (16): 1867–72. DOI: https://doi.org/10.1001/archinte.162.16.1867 PMID: 12196085.

8. Fox C.S., Massaro J.M., Hoffmann U., et al. Abdominal visceral and subcutaneous adipose tissue compartments: association with metabolic risk factors in the Framingham Heart Study. Circulation. 2007; 116 (1): 39–48. DOI: https://doi.org/10.1161/CIRCULATIONAHA.106.675355; PMID: 17576866.

9. Kytikova O.Y., Antonyuk M.V., Kantur T.A., et al. Prevalence and biomarkers in metabolic syndrome. Ozhirenie i metabolism [Obesity and Metabolism]. 2021; 18 (3): 302–12. DOI: https://doi.org/10.14341/omet12704 (in Russian)

10. World Health Organization (WHO) [Electronic resource]. Obesity and Overweight. URL: www.who.int (date of access April 28, 2023).

11. Alberti K.G., Eckel R.H., Grundy S.M., et al.; International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; International Association for the Study of Obesity. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009; 120 (16): 1640–5. DOI: https://doi.org/10.1161/CIRCULATIONAHA.109.192644; PMID: 19805654.

12. Wildman R.P., Muntner P., Reynolds K., et al. The obese without cardiometabolic risk factor clustering and the normal weight with cardiometabolic risk factor clustering: prevalence and correlates of 2 phenotypes among the US population (NHANES 1999-2004). Arch Intern Med. 2008; 168 (15): 1617–24. DOI: https://doi.org/10.1001/archinte.168.15.1617 PMID: 18695075.

13. Doumatey A.P., Bentley A.R., Zhou J., et al. Paradoxical hyperadiponectinemia is associated with the Metabolically Healthy Obese (MHO) phenotype in African Americans. J Endocrinol Metab. 2012; 2: 51–65. DOI: https://doi.org/10.4021/jem95W PMID: 23293696; PMCID: PMC 3534968.

14. Hamer M., Stamatakis E. Metabolically healthy obesity and risk of all-cause and cardiovascular disease mortality. J Clin Endocrinol Metab. 2012; 97: 2482–8. DOI: https://doi.org/10.1210/jc.2011-3475; PMID: 22508708; PMCID: PMC 3387408.

15. Karelis A.D. To be obese – does it matter if you are metabolically healthy? Nat Rev Endocrinol. 2011; 7 (12): 699–700. DOI: https://doi.org/10.1038/nrendo.2011.181 PMID: 22009160.

16. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001; 285: 2486–97. PMID: 11368702.

17. Kramer C.K., Zinman B., Retnakaran R. Metabolically healthy overweight and obesity. Ann Intern Med. 2014; 160 (7): 516. DOI: https://doi.org/10.7326/L14-5007-7 PMID: 24687080; PMCID: PMC 7477664.

18. Roberson L.L., Aneni E.C., Maziak W., et al. Beyond BMI: the «Metabolically healthy obese» phenotype & its association with clinical/subclinical cardiovascular disease and all-cause mortality – a systematic review. BMC Public Health. 2014; 14: 14. DOI: https://doi.org/10.1186/1471-2458-14-14 PMID: 24400816; PMCID: PMC 3890499.

19. Mathew H., Farr O.M., Mantzoros C.S. Metabolic health and weight: understanding metabolically unhealthy normal weight or metabolically healthy obese patients. Metabolism. 2016; 65 (1): 73–80. DOI: https://doi.org/10.1016/j.metabol.2015.10.019; PMID: 26683798; PMCID: PMC 4750380.

20. Agius R., Fava M.C., Pace N.P., et al. Prevalence rates of metabolic health and body size phenotypes by different criteria and association with insulin resistance in a Maltese Caucasian population. BMC Endocr Disord. 2022; 22: 160. DOI: https://doi.org/10.1186/s12902-022-01071-x

21. Choi D., Gujral U., Vankat Narayan K.M., Patel S. Trends in BMI-Metabolic Phenotypes in the United States from 1999–2018 Using Three Definitions for Metabolic Health. DOI: https://doi.org/10.21203/rs.3.rs-2436662/v1 (date of access January 06, 2023).

22. Gao J.V., You S., Liu Z.Y., et al. Different metabolic phenotypes of obesity and risk of coronary artery calcium progression and incident cardiovascular disease events: the CARDIA study. Arterioscler Thromb Vasc Biol. 2022; 42 (5): 677–88. DOI: https://doi.org/10.1161/ATVBAHA.122.317526

23. Rotar O., Boyarinova M., Orlov A., et al. Metabolically healthy obese and metabolically unhealthy non-obese phenotypes in a Russian population. Eur J Epidemiol. 2017; 32 (3): 251–4. DOI: https://doi.org/10.1007/s10654-016-0221-z; PMID: 28039558.

24. Mustafina S.V., Vinter D.A., Shcherbakova L.V., et al. Gender and age-related features of metabolically healthy obesity phenotype prevalence. Byulleten’ sibirskoy meditsiny [Bulletin of Siberian Medicine]. 2020; 19 (1): 76–84. URL: https://cyberleninka.ru/article/n/ (in Russian) (date of access June 22, 2023).

25. Vinter D.A., Mustafina S.V., Rymar O.D., et al. Behavioral and social risk factors for metabolically unhealthy obesity: data form a 12-year prospective study in the Russian population. Rossiyskiy kardiologicheskiy zhurnal [Russian Journal of Cardiology]. 2022; 27 (5). URL: https://cyberleninka.ru/article/n/ (in Russian) (date of access June 22, 2023).

26. Liu J., Zhang Y., Lavie C.J., Moran A.E. Trends in metabolic phenotypes according to body Mass Index Among US adults, 1999–2018. Mayo Clin Proc. 2022; 97 (9): 1664–79. DOI: https://doi.org/10.1016/j.mayocp.2022.02.013; PMID: 35691704.

27. Wang J.S., Xia P.F., Ma M.N., et al. Trends in the prevalence of metabolically healthy obesity among US adults, 1999–2018. JAMA Netw Open. 2023; 6 (3): e232145. DOI: https://doi.org/10.1001/jamanetworkopen.2023.2145 PMID: 36892842; PMCID: PMC 9999245.

28. Blüher M. Metabolically healthy obesity. Endocr Rev. 2020; 41 (3): bnaa004. DOI: https://doi.org/10.1210/endrev/bnaa004 PMID: 32128581; PMCID: PMC 7098708.

29. Smith G.I., Mittendorfer B., Klein S. Metabolically healthy obesity: facts and fantasies. J Clin Invest. 2019; 129 (10): 3978–89. DOI: https://doi.org/10.1172/JCI129186 PMID: 31524630; PMCID: PMC 6763224.

30. Tsatsoulis A., Paschou S.A. Metabolically healthy obesity: criteria, epidemiology, controversies, and consequences. Curr Obes Rep. 2020; 9 (2): 109–20. DOI: https://doi.org/10.1007/s13679-020-00375-0 PMID: 32301039.

31. Mongraw-Chaffin M., Foster M.C., Anderson C.A.M., et al. Metabolically healthy obesity, transition to metabolic syndrome, and cardiovascular risk. J Am Coll Cardiol. 2018; 71 (17): 1857–65. DOI: https://doi.org/10.1016/j.jacc.2018.02.055 PMID: 29699611; PMCID: PMC 6002856.

32. Eckel N., Li Y., Kuxhaus O., et al. Transition from metabolic healthy to unhealthy phenotypes and association with cardiovascular disease risk across BMI categories in 90 257 women (the Nurses’ Health Study): 30-year follow-up from a prospective cohort study. Lancet Diabetes Endocrinol. 2018; 6 (9): 714–24. DOI: https://doi.org/10.1016/S2213-8587(18)30137-2; PMID: 29859908.

33. Morkedal B., Vatten L.J., Romundstad P.R., et al. Risk of myocardial infarction and heart failure among metabolically healthy but obese individuals: HUNT (Nord-Trondelag Health Study), Norway. J Am Coll Cardiol. 2014; 63 (11): 1071–8. DOI: https://doi.org/10.1016/j.jacc.2013.11.035; PMID: 24345592.

34. Caleyachetty R.M.B.B., Thomas G.N., Toulis K.A., et al. Metabolically healthy obese and incident cardiovascular disease events among 3,5 million men and women. J Am Coll Cardiol. 2017; 70 (12): 1429–37. DOI: https://doi.org/10.1016/j.jacc.2017.07.763

35. Iacobellis G., Sharma A.M. Obesity and the heart: redefinition of the relationship. Obes Rev. 2007; 8 (1): 35–9. DOI: https://doi.org/10.1111/j.1467-789X.2006.00257.x PMID: 17212794.

36. Iacobellis G. Epicardial adipose tissue in contemporary cardiology. Nat Rev Cardiol. 2022; 19: 593–606. DOI: https://doi.org/10.1038/s41569-022-00679-9

37. Romero-Corral A., Montori V.M., Somers V.K., 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 (9536): 666–78. DOI: https://doi.org/10.1016/S0140-6736(06)69251-9 PMID: 16920472.

38. Khadir A., Kavalakatt S., Madhu D., et al. Spexin as an indicator of beneficial effects of exercise in human obesity and diabetes. Sci Rep. 2020; 10 (1): 10635. DOI: https://doi.org/10.1038/s41598-020-67624-z PMID: 32606431; PMCID: PMC 7327065.

39. Corres P., Fryer S.M., Aguirre-Betolaza A.M., et al. A metabolically healthy profile is a transient stage when exercise and diet are not supervised: long-term effects in the EXERDIET-HTA study. Int J Environ Res Public Health. 2020; 17 (8): 2830. DOI: https://doi.org/10.3390/ijerph17082830 PMID: 32326133; PMCID: PMC 7216152.

40. Laforest S., Michaud A., Paris G., et al. Comparative analysis of three human adipocyte size measurement methods and their relevance for cardiometabolic risk. Obesity (Silver Spring). 2017; 25 (1): 122–31. DOI: https://doi.org/10.1002/oby.21697

41. Ler P., Li X., Hassing L.B., et al. Independent and joint effects of body mass index and metabolic health in mid- and late-life on all-cause mortality: a cohort study from the Swedish Twin Registry with a mean follow-up of 13 years. BMC Public Health. 2022; 22: 718. DOI: https://doi.org/10.1186/s12889-022-13082-3

42. Putra I.C.S., Kamarullah W., Prameswari H.S., et al. Metabolically unhealthy phenotype in normal weight population and risk of mortality and major adverse cardiac events: a meta-analysis of 41 prospective cohort studies. Diabetes Metab Syndr. 2022; 16 (10): 102635. DOI: https://doi.org/10.1016/j.dsx.2022.102635; PMID: 36240685.

43. Nolan C.J., Ruderman N.B., Kahn S.E., et al. Insulin resistance as a physiological defense against metabolic stress: implications for the management of subsets of type 2 diabetes. Diabetes. 2015; 64 (3): 673–86. DOI: https://doi.org/10.2337/db14-0694 PMID: 25713189; PMCID: PMC 4338588.

44. De Lorenzo A., Soldati L., Sarlo F., et al. New obesity classification criteria as a tool for bariatric surgery indication. World J Gastroenterol. 2016; 22 (2): 681–703. DOI: https://doi.org/10.3748/wjg.v22.i2.681 PMID: 26811617; PMCID: PMC 4716069.

45. Hashemipour S., Esmailzadehha N., Hamid H., et al. Association of metabolic syndrome components with insulin resistance in normal weight population: the Qazvin Metabolic Diseases study. J Endocrinol Invest. 2015; 38 (10): 1111–5. DOI: https://doi.org/10.1007/s40618-015-0302-y; PMID: 25952300.

46. Xu X., Bhagavathula A.S., Zhang Y., et al. Sex differences in the TyG index and cardiovascular risk factors in metabolically obese normal weight phenotype. Int J Endocrinol. 2022; 2022: 1139045. DOI: https://doi.org/10.1155/2022/1139045 PMID: 35371258; PMCID: PMC 8970881.

47. De Lorenzo A., Martinoli R., Vaia F., Di Renzo L. Normal weight obese (NWO) women: an evaluation of a candidate new syndrome. Nutr Metab Cardiovasc Dis. 2006; 16 (8): 513–23. DOI: https://doi.org/10.1016/j.numecd.2005.10.010; PMID: 17126766.

48. Cruz-Jentoft A.J., Bahat G., Bauer J., et al.; Writing Group for the European Working Group on Sarcopenia in Older People 2 (EWGSOP2), and the Extended Group for EWGSOP2. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing. 2019; 48 (1): 16–31. DOI: https://doi.org/10.1093/ageing/afy169 PMID: 30312372; PMCID: PMC 6322506.

49. Liu C., Cheng K.Y., Tong X., et al. The role of obesity in sarcopenia and the optimal body composition to prevent against sarcopenia and obesity. Front Endocrinol (Lausanne). 2023; 14: 1077255. DOI: https://doi.org/10.3389/fendo.2023.1077255 PMID: 36936175; PMCID: PMC 10016224.

50. Batsis J.A., Villareal D.T. Sarcopenic obesity in older adults: aetiology, epidemiology and treatment strategies. Nat Rev Endocrinol. 2018; 14 (9): 513–37. DOI: https://doi.org/10.1038/s41574-018-0062-9 PMID: 30065268; PMCID: PMC 6241236.

51. Brown R.J., Araujo-Vilar D., Cheung P.T., et al. The diagnosis and management of lipodystrophy syndromes: a multi-society practice guideline. J Clin Endocrinol Metab. 2016; 101 (12): 4500–11. DOI: https://doi.org/10.1210/jc.2016-2466; PMID: 27710244; PMCID: PMC 5155679.

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