5,557

Obesity Paradox in Asian Population: the Protective Effects of Excessive Body Mass

Yau-Huei Lai, Jen-Yuan Kuo

Yau-Huei Lai, Division of Cardiology, Department of Internal Medicine, MacKay Memorial Hospital, Hsinchu, Taiwan
Yau-Huei Lai, Jen-Yuan Kuo, Division of Cardiology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei, Taiwan
Yau-Huei Lai, Jen-Yuan Kuo, MacKay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan
Yau-Huei Lai, Jen-Yuan Kuo, Department of Medicine, MacKay Medical College, Taipei, Taiwan

Correspondence to: Jen-Yuan Kuo, Division of Cardiology, Department of Internal Medicine, MacKay Memorial Hospital, No. 92, Sec. 2, Zhongshan N. Road, Taipei, Taiwan.
Email: jykuo5813@gmail.com
Telephone: +886-2-25433535
Received: May 20, 2015
Revised: June 15, 2015
Accepted: June 20, 2015
Published online: August 10, 2015

ABSTRACT

The link between central obesity and cardiovascular diseases has been firmly established in recent years. On the other hand, numerous studies have observed that excessive body mass may be associated with a relatively favorable prognosis in advanced heart diseases. In this review article, we will summarize the findings from recent Asian and worldwide studies. We will also discuss the underlying mechanisms and other contributing factors of the obesity paradox.

Key words: Obesity paradox; Heart failure; Cardiorespiratory fitness; Adiponectin; Metabolic syndrome

© 2015 The Authors. Published by ACT Group Ltd.

Lai YH, Kuo JY. Obesity Paradox in Asian Population: the Protective Effects of Excessive Body Mass. Journal of Cardiology and Therapy 2015; 2(4): 360-364 Available from: URL: http://www.ghrnet.org/index.php/jct/article/view/1315

INTRODUCTION

Obesity has been well-established as an independent factor in the pathogenesis of heart failure (HF) and cardiovascular diseases (CVD). The term “obesity cardiomyopathy” refers to a clinical syndrome characterized by adverse cardiac structural and hemodynamic changes as a direct result of excessive adiposity[1]. On the other hand, numerous observational studies and meta-analyses have demonstrated that an obesity paradox may exist in advanced heart diseases. Namely, patients who are overweight (BMI 25 to 29.9 kg/m2) or obese (Class I: BMI 30 to 34.9 kg/m2, Class II: BMI 35 to 39.9 kg/m2, Class III: BMI≥40 kg/m2) may have more favorable clinical outcome and long-term survival, especially with chronic HF patients.

We reviewed the adverse effects of obesity on cardiac structure and function in a previous article[2]. In brief, excessive adiposity and body weight leads to increased total blood volume and cardiac output. Systemic vascular resistance then decreases to accommodate the increase in cardiac output[3,4]. This results in adverse changes in hemodynamic status including volume and pressure overload, structural alterations such as left ventricular (LV) hypertrophy and dilation accompanied by increased LV wall stress[5,6]. These effects had been widely observed, including a large Taiwanese retrospective study published by our group[7]. Central obesity is also independently associated with LV diastolic dysfunction, which is closely connected to LV hypertrophy[8-10]. As the remodeling progresses, LV hypertrophy fails to compensate for dilation and wall stress, gradually developing a combined state of systolic and diastolic heart failure, which then produces pulmonary venous hypertension and eventually pulmonary arterial hypertension. In severely obese patients, sleep apnea syndrome may also contribute to pulmonary arterial hypertension. Finally, right ventricular dilation and hypertrophy ensues, leading to concurrent right ventricular failure. Other pathways linking obesity with cardiac disorders include systemic inflammation[11-13], and neurohormonal activities such as insulin resistance, leptin resistance, and activation of the renin-angiotensin-aldosterone system (RAAS)[14,15].

Obesity paradox in cardiovascular disease

The paradoxical protective effect of obesity has been widely explored in current literature for more than a decade[16-18], and this observation is not solely limited to severe HF. For example, one prospective study on diabetic patients from Taiwan showed lower noncancer mortality in obese people[19]. The first large-scale meta-analysis performed a database search of more than 28000 HF patients with an average span of 2.7 years[20]. After adjusting for baseline variables, both overweight [adjusted hazard ratio (HR) 0.93, confidence interval (CI) 0.89-0.97] and obesity (adjusted HR 0.88, CI 0.83-0.93) remained protective against mortality. No significant change in these results was observed after excluding underweight individuals. In other words, overweight and obesity patients still had survival advantage even when compared with normal-BMI people. A recent meta-analysis on more than 21000 patients with history of acute coronary syndrome and 5 years of follow-up also showed that overweight (RR 0.70, CI 0.64-0.76), obese (RR 0.60, CI 0.53-0.68) and severely obese (RR 0.70, CI 0.58-0.86) patients had lower mortality compared with normal BMI group[21].

The U- or J-shaped association between weight status and mortality has been well-documented[22], with highest mortality appearing in the lowest and highest BMI groups. Most recently, a systematic review on 97 prospective studies representing more than 2.88 million individuals in the general population showed that overweight was associated with decreased all-cause mortality, whereas increased mortality was present in Class II and III obesity[23]. In a Taiwanese study on coronary artery disease (CAD) patients with 10-year follow-up[24], the obesity paradox was more pronounced in underweight subjects during the first 5 years. The aforementioned J-curve developed after the 5-year mark (Figure 1). Further meta-analysis confirmed that a J-shaped relationship exists between BMI and total mortality beyond 5-year follow-up[25].

Role of body fat composition

Although BMI is a very simplistic and cost-effective method, it has often been criticized for not reflecting real adipose tissue burden, and could be confounded by several clinical variables. Furthermore, it provides no information on fat distribution at specific sites, hence failing to describe the anatomy of visceral adipose depots[26]. As a result, there had been investigations on whether fat mass or lean mass plays a stronger role in the obesity paradox[27,28. So far, more evidence has been in favor of the combined effects of body fat percentage coupled with BMI. In other words, patients with simultaneously low body fat and BMI seem to have particularly high long-term mortality. In a three-year observational study by Lavie et al[27], combination of low body fat and low BMI translated to a 4.24-fold increase in mortality rate (CI 1.76-10.23, p=0.001).

Role of cardiorespiratory fitness

There had also been discussions on whether exercise function should be factored into the prognosis of heart failure patients. It stands to reason that people with higher fat mass also has more sufficient muscle strength and higher cardiac reserve. Several recent studies have demonstrated an inverse relationship between BMI and plasma B-type natriuretic peptide (BNP) concentration in subjects with[29] and without[30] heart failure. There is evidence that lower BNP level was associated with increased muscle mass[31]. It is believed that the obesity paradox is actually limited to only people with low exercise function in terms of cardiorespiratory fitness[32-34]. For example, a study by McAuley et al[33] showed no difference in cumulative survival across any anthropometric parameter (including BMI and body fat) in people with normal or high fitness (Figure 2). Lavie et al[34] also demonstrated that the obesity paradox was masked by the presence of higher aerobic capacity in terms of peak VO2 (oxygen uptake). In another large study with 11-year follow-up, men who lost fitness had higher all-cause and CVD mortality risks regardless of BMI change after multivariate analysis. Every 1-MET improvement was associated with 15% and 19% decreases in all-cause and CVD mortality, respectively[35]. These findings implied that cardiorespiratory fitness, especially when assessed by aerobic exercise performance, may have a larger impact than obesity on the prognosis of chronic heart failure patients.

Role of cytokines

The adipose tissue secretes various cytokines that regulate energy balance in the human body. One of them is adiponectin, which can protect healthy individuals from developing CVD[36,37], due to its anti-inflammatory and anti-atherogenic properties[38]. Although adiponectin is secreted only from fat tissue, plasma adiponectin level is paradoxically decreased in obese subjects[39]. However, in patients with HF, higher adiponectin level was instead associated with increased mortality independent of other clinical variables[40]. This phenomenon also exists in patients with history of acute coronary syndrome (ACS)[41]. In a two-year follow-up of post-ACS patients in the PROVE IT-TIMI 22 trial[41], adiponectin was inversely related to BMI but was independently associated with an increased risk of death or myocardial infarction (HR 1.58, CI 1.10-2.28) and heart failure (HR 2.17, CI 1.21-3.89). Therefore, adiponectin has been suggested as a possible mediator of the obesity paradox. One possible explanation is the increased energy expenditure and muscle wasting process, which may be detrimental to heart failure.

In a recent Taiwanese study on the prognosis of patients who underwent coronary artery bypass grafting (CABG)[42], higher BMI was associated with less cardiovascular mortality even after multivariate adjustment (HR 0.912 per 1kg/m2 BMI increase, CI 0.833-0.998). However, additional adjustment for preoperative adiponectin, hs-CRP or NT-proBNP levels attenuated this inverse relationship, suggesting that these cytokines might play a stronger role in the obesity paradox. Further supporting this notion was that all three cytokines predicted mortality in patients with normal weight, rather than in overweight or obese patients. This finding was in concordance with international large studies such as the AtheroGene Study[43], in which increased adiponectin levels were predictive of adverse cardiovascular outcome in patients with documented CAD (either chronic stable angina or ACS).

Role of metabolic status

Recent interest has focused on the term “metabolically healthy overweight/obese” (MHO), namely individuals with isolated high BMI yet relatively normal metabolic status that doesn’t fit the metabolic syndrome criteria. In contrast, people with metabolic syndrome but normal BMI are termed “metabolically obese normal weight” (MONW). There are distinctive characteristics between these two phenotypes. Generally, MHO subjects tend to be younger and have a shorter duration of obesity and healthier lifestyle. MONW mostly develops at an older age and has a more malicious presentation with unintentional weight loss and cachexia. It remains controversial how much advantage the former group really has in terms of cardiovascular morbidity and mortality[44,45].

In a meta-analysis that included eight studies and more than 61000 patients, MONW patients (RR 3.14, CI 2.36-3.93) had the highest risk for all-cause mortality and cardiovascular events compared to overweight (RR 2.70, CI 2.08-3.30) and obese patients with metabolic syndrome (RR 2.65, CI 2.18-3.12). This is partially compatible with the obesity paradox. However, when compared with metabolically healthy normal-weight people, MHO still had increased risk for adverse events after more than 10 years of follow-up (RR 1.24, CI 1.02-1.55)[46]. This implies that obesity cannot be regarded as a purely benign condition even in the absence of metabolic derangements. Furthermore, the weight of metabolic status seems to overwhelm any protective effect that obesity may have in the diseased population.

Conclusion

In conclusion, overwhelming evidence supports the importance of obesity in the pathogenesis of cardiovascular disease. Excessive weight is associated with the development of subclinical metabolic and vascular dysfunction that ultimately leads to increased incidence of adverse cardiovascular events and long-term mortality. On the other hand, the obesity paradox does exist in certain populations, most notably in heart failure. Possible mechanisms include preservation of energy and muscle strength, protective cytokines. The interaction between other factors such as body fat composition, distribution, cardiorespiratory fitness and metabolic status should also be considered.

CONFLICT OF INTERESTS

There are no conflicts of interest with regard to the present study.

REFERENCES

1 Alpert MA. Obesity cardiomyopathy; pathophysiology and evolution of the clinical syndrome. Am J Med Sci 2001;321:225–36.

2 Lai YH, Sung KT, Hung CL, Kuo JY. Effects of obesity and adiposity on cardiac mechanical properties. Journal of Cardiol Ther 2014;1:176-180.

3 Alexander JK, Alpert MA. Hemodynamic alterations with obesity in man. In: Alpert MA, Alexander JK, editors. The Heart and Lung in Obesity. Armonk, NY: Futura Publishing Company, 1998:45-56.

4 Messerli FH, Sundgaard-Riise K, Reisin E, Dreslinski G, Dunn FG, Frohlich E. Disparate cardiovascular effects of obesity and arterial hypertension. Am J Med. 1983;74:808-12.

5 Alpert MA, Terry BE, Mulekar M, et al. Cardiac morphology and left ventricular function in morbidly obese patients with and without congestive heart failure and effect of weight loss. Am J Cardiol 1997;80:736–40.

6 Alpert MA, Lambert CR, Panayiotou H, et al. Relation of duration of morbid obesity to left ventricular mass, systolic function and diastolic filling, and effect of weight loss. Am J Cardiol 1995;76:1194–7.

7 Lai YH, Liu CC, Kuo JY, Hung TC, Wu YJ, Yeh HI, Bulwer BE, Hung CL. Independent effects of body fat and inflammatory markers on ventricular geometry, midwall function, and atrial remodeling. Clin Cardiol. 2014;37:172-177.

8 Ammar KA, Redfield MM, Mahoney DW, Johnson M, Jacobsen SJ, Rodeheffer RJ. Central obesity: association with left ventricular dysfunction and mortality in the community. Am Heart J 2008;156:975–981

9 Russo C, Jin Z, Homma S, Rundek T, Elkind MS, Sacco RL, Di Tullio MR. Effect of obesity and overweight on left ventricular diastolic function: a community-based study in an elderly cohort. J Am Coll Cardiol 2011;57:1368–1374

10 Canepa M, Strait JB, Abramov D, Milaneschi Y, AlGhatrif M, Moni M, Ramachandran R, Najjar SS, Brunelli C, Abraham TP, Lakatta EG, Ferrucci L. Contribution of central adiposity to left ventricular diastolic function (from the Baltimore Longitudinal Study of Aging). Am J Cardiol. 2012;109:1171-1178.

11 Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AWJ. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112:1796 –1808.

12 Lumeng CN, DeYoung SM, Bodzin JL, Saltiel AR. Increased inflammatory properties of adipose tissue macrophages recruited during dietinduced obesity. Diabetes. 2007;56:16 –23.

13 Huo Y, Guo X, Li H, Wang H, Zhang W, Wang Y, Zhou H, Gao Z, Telang S, Chesney J, Chen YE, Ye J, Chapkin RS, Wu C. Disruption of inducible 6-phosphofructo-2-kinase ameliorates diet-induced adiposity but exacerbates systemic insulin resistance and adipose tissue inflammatory response. J Biol Chem. 2010;285:3713–3721.

14 Odegaard JI, Ricardo-Gonzalez RR, Red Eagle A, Vats D, Morel CR, Goforth MH, Subramanian V, Mukundan L, Ferrante AW, Chawla A. Alternative M2 activation of Kupffer cells by PPARδ ameliorates obesity-induced insulin resistance. Cell Metab. 2008;7:496–507.

15 Langenberg C, Bergstrom J, Scheidt-Nave C, Pfeilschifter J, Barrett-Connor E. Cardiovascular death and the metabolic syndrome: role of adiposity-signaling hormones and inflammatory markers. Diabetes Care 2006;29:1363-1369.

16 Horwich TB, Fonarow GC, Hamilton MA, et al. The relationship between obesity and mortality in patients with heart failure. J Am Coll Cardiol 2001;38:789–95.

17 Lavie CJ, Osman AF, Milani RV, Mehra MR. Body composition and prognosis in chronic systolic heart failure: the obesity paradox. Am J Cardiol 2003;91:891–4.

18 Bechlioulis A, Vakalis K, Naka KK, Bourantas CV, Papamichael ND, Kotsia A, Tzimas T, Pappas K, Katsouras CS, Michalis LK. Paradoxical protective effect of central obesity in patients with suspected stable coronary artery disease. Obesity (Silver Spring). 2013;21:E314-321.

19 Tseng CH. Obesity paradox: differential effects on cancer and noncancer mortality in patients with type 2 diabetes mellitus. Atherosclerosis. 2013;226:186-92.

20 Oreopoulos A, Padwal R, Kalantar-Zadeh K, et al. Body mass index and mortality in heart failure: a meta-analysis. Am Heart J 2008;156:13–22.

21 Niedziela J1, Hudzik B, Niedziela N, Gąsior M, Gierlotka M, Wasilewski J, Myrda K, Lekston A, Poloński L, Rozentryt P. The obesity paradox in acute coronary syndrome: a meta-analysis. Eur J Epidemiol. 2014;29:801-12

22 Allison DB, Faith MS, Heo M, Kotler DP. Hypothesis concerning the U-shaped relation between body mass index and mortality. Am J Epidemiol. 1997;146:339-49.

23 Flegal KM, Kit BK, Orpana H, Graubard BI. Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-analysis. JAMA. 2013;309:71-82.

24 Lin GM, Li YH, Lin CL, Wang JH, Han CL. Relation of body mass index to mortality among Asian patients with obstructive coronary artery disease during a 10-year follow-up: a report from the ET-CHD registry. Int J Cardiol. 2013;168:616-20.

25 Li YH, Lin GM, Lin CL, Wang JH, Han CL. Relation of body mass index to mortality among patients with percutaneous coronary intervention longer than 5 years follow-up: a meta-analysis. Int J Cardiol. 2013;168:4315-8.

26 Cornier MA, Després JP, Davis N, Grossniklaus DA, Klein S, Lamarche B, Lopez-Jimenez F, Rao G, St-Onge MP, Towfighi A, Poirier P. Assessing adiposity: a scientific statement from the American Heart Association. Circulation. 2011;124:1996-2019.

27 Lavie CJ, De Schutter A, Patel D, Artham SM, Milani RV. Body composition and coronary heart disease mortality--an obesity or a lean paradox? Mayo Clin Proc. 2011;86:857-64.

28 Lavie CJ, De Schutter A, Patel DA, Romero-Corral A, Artham SM, Milani RV. Body composition and survival in stable coronary heart disease: impact of lean mass index and body fat in the "obesity paradox". J Am Coll Cardiol. 2012;60:1374-80.

29 Mehra MR, Uber PA, Park MH, Scott RL, Ventura HO, Harris BC, Frohlich ED. Obesity and suppressed B-type natriuretic peptide levels in heart failure. J Am Coll Cardiol. 2004;43:1590-5.

30 Wang TJ, Larson MG, Levy D, Benjamin EJ, Leip EP, Wilson PW, Vasan RS. Impact of obesity on plasma natriuretic peptide levels. Circulation. 2004;109:594-600.

31 Das SR, Drazner MH, Dries DL, Vega GL, Stanek HG, Abdullah SM, Canham RM, Chung AK, Leonard D, Wians FH Jr, de Lemos JA. Impact of body mass and body composition on circulating levels of natriuretic peptides: results from the Dallas Heart Study. Circulation. 2005;112:2163-8.

32 Goel K, Thomas RJ, Squires RW, et al. Combined effect of cardiorespiratory fitness and adiposity on mortality in patients with coronary artery disease. Am Heart J 2011;161:590–7.

33 McAuley PA, Artero EG, Sui X, et al. The obesity paradox, cardiorespiratory fitness, and coronary heart disease. Mayo Clin Proc 2012;87:443–51.

34 Lavie CJ, Cahalin LP, Chase P, Myers J, Bensimhon D, Peberdy MA, Ashley E, West E, Forman DE, Guazzi M, Arena R. Impact of cardiorespiratory fitness on the obesity paradox in patients with heart failure. Mayo Clin Proc. 2013;88:251-8.

35 Lee DC, Sui X, Artero EG, Lee IM, Church TS, McAuley PA, Stanford FC, Kohl HW 3rd, Blair SN. Long-term effects of changes in cardiorespiratory fitness and body mass index on all-cause and cardiovascular disease mortality in men: the Aerobics Center Longitudinal Study. Circulation. 2011;124:2483-2490

36 Pischon T, Girman CJ, Hotamisligil GS, Rifai N, Hu FB, Rimm EB. Plasma adiponectin levels and risk of myocardial infarction in men. JAMA. 2004; 291:1730–1737.

37 Otsuka F, Sugiyama S, Kojima S, Maruyoshi H, Funahashi T, Matsui K, Sakamoto T, Yoshimura M, Kimura K, Umemura S, Ogawa H. Plasma adiponectin levels are associated with coronary lesion complexity in men with coronary artery disease. J Am Coll Cardiol. 2006;48:1155-62.

38 Okamoto Y, Kihara S, Ouchi N, Nishida M, Arita Y, Kumada M, Ohashi K, Sakai N, Shimomura I, Kobayashi H, Terasaka N, Inaba T, Funahashi T, Matsuzawa Y. Adiponectin reduces atherosclerosis in apolipoprotein E-deficient mice. Circulation.2002; 106: 2767–2770.

39 Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K, Kuriyama H, Nishida M, Yamashita S, Okubo K, Matsubara K, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun. 1999; 257: 79–83.

40 Kistorp C, Faber J, Galatius S, Gustafsson F, Frystyk J, Flyvbjerg A, Hildebrandt P. Plasma adiponectin, body mass index, and mortality in patients with chronic heart failure. Circulation. 2005;112:1756-62.

41 Wilson SR, Sabatine MS, Wiviott SD, Ray KK, De Lemos JA, Zhou S, Rifai N, Cannon CP, Morrow DA; TIMI Study Group. Assessment of adiponectin and the risk of recurrent cardiovascular events in patients presenting with an acute coronary syndrome: observations from the Pravastatin Or atorVastatin Evaluation and Infection Trial-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22). Am Heart J. 2011;161:1147-55.

42 Sung SH, Wu TC, Huang CH, Lin SJ, Chen JW. Prognostic impact of body mass index in patients undergoing coronary artery bypass surgery. Heart 2011;97:648-54.

43 Schnabel R, Messow CM, Lubos E, Espinola-Klein C, Rupprecht HJ, Bickel C, Sinning C, Tzikas S, Keller T, Genth-Zotz S, Lackner KJ, Münzel TF, Blankenberg S. Association of adiponectin with adverse outcome in coronary artery disease patients: results from the AtheroGene study. Eur Heart J. 2008;29:649-57.

44 Arnlöv J, Ingelsson E, Sundström J, Lind L. Impact of body mass index and the metabolic syndrome on the risk of cardiovascular disease and death in middle-aged men. Circulation. 2010;121:230-6.

45 Voulgari C, Tentolouris N, Dilaveris P, Tousoulis D, Katsilambros N, Stefanadis C. Increased heart failure risk in normal-weight people with metabolic syndrome compared with metabolically healthy obese individuals. J Am Coll Cardiol. 2011;58:1343-50.

46 Kramer CK, Zinman B, Retnakaran R. Are metabolically healthy overweight and obesity benign conditions?: A systematic review and meta-analysis. Ann Intern Med. 2013;159:758-69.

Peer reviewer: Luca Gondoni, UO RRF ad Indirizzo Cardiologico, IRCCS – Ospedale San Giuseppe, Via Cadorna, 90, 28824 Piancavallo di Oggebbio (VB), Italy.

Refbacks

  • There are currently no refbacks.


Creative Commons License
This work is licensed under a Creative Commons Attribution 3.0 License.