Obesity paradox in elderly patients with cardiovascular diseases

International Journal of Cardiology 155 (2012) 56–65

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International Journal of Cardiology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i j c a r d

Review

Obesity paradox in elderly patients with cardiovascular diseases Thomas E. Dorner ⁎, Anita Rieder Institute of Social Medicine, Center for Public Health, Medical University of Vienna, Vienna, Austria

a r t i c l e

i n f o

Available online 22 February 2011 Keywords: Reverse epidemiology Frailty Geriatrics Malnutrition Heart failure

a b s t r a c t Many elderly people are affected by cardiovascular diseases (CVD) and the majority of CVD patients are elderly people. For both patient populations, studies have shown that a high body mass index (BMI) is associated with lower mortality when compared to normal weight subjects, a fact commonly known as the “obesity paradox”. Whether the correlation between obesity and better survival is based on methodological influences and other non-causal factors alone, or whether there is a causal link between obesity and a better survival in these subjects remains widely unexplored. The interrelation between aging, obesity, CVD, frailty and inflammation is a current issue of intensive research. For the elderly, parameters which include measures of body composition, fat and fat-free mass are of greater importance than BMI. Weight management in elderly people with cardiovascular diseases should aim at improvement and maintenance of physical function and quality of life rather than prevention of medical problems associated with obesity in younger and middle aged patients. Although many studies have shown that weight loss in elderly patients is associated with a poor prognosis, recent data demonstrate that intentional weight reduction in obese elderly people ameliorates the cardiovascular risk profile, reduces chronic inflammation and is correlated with an improved quality of life. An individual approach to weight management that includes the participation of the patient, co-morbidity, functional status, and social support should be aspired. © 2011 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Recent publications have shown that obesity in different populations such as elderly people and patients with cardiovascular diseases (CVD), like heart failure (HF) or coronary artery disease (CAD), is surprisingly not associated with a higher but with a lower mortality risk. This fact has thus been termed “obesity paradox”. A major overlap between those two population groups, in which the obesity paradox is usually observed, should here be taken into account: many elderly people are affected by CVD and the majority of CVD patients are elderly people [1,2]. In the general population overweight and obesity are well-known risk factors for the development of cardiovascular diseases [3,4] like HF [5], ischemic heart diseases [6], abnormal left ventricular geometry, endothelial dysfunction, systolic and diastolic dysfunction and atrial fibrillation [4]. Overweight and obesity increase overall mortality and predict premature death [7–10]. Furthermore obesity is associated with the development of cardiovascular risk factors like increased insulin resistance and type 2 diabetes mellitus, hypertension and dyslipidemia. The majority of studies evaluating

⁎ Corresponding author at: Institute of Social Medicine, Center for Public Health, Medical University of Vienna, Rooseveltplatz 3, 1090 Wien, Austria. Tel.: +43 1 4277 64685; fax: +43 1 4277 9646. E-mail address: [email protected] (T.E. Dorner). 0167-5273/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2011.01.076

obesity-related cardiovascular risk factors have been conducted in middle-aged, not in older adults, however, the prevalences of most of the obesity-related cardiovascular risk factors, such as hypertension and diabetes mellitus increase with age. Prevalence of overweight and obesity are increasing in all age groups, including elderly people [11–13]. On the other hand, until recently, underweight, malnutrition and frailty in elderly people constituted the most important issues. However, the increase in prevalence of overweight and obesity due to an increase in this overall prevalence and due to the ongoing expansion of the elderly proportion in the population in industrial nations has led to a focus of this problem in the elderly, too. Obesity in older subjects is associated with increased morbidity such as infections [14], functional limitations and poor quality of life [15,16], and obese older persons are admitted more frequently to nursing homes compared to those who are not [17]. Additionally, obesity in the elderly is correlated with decreased autonomy and mobility, with increased handicap in activities of daily living (such as personal hygiene, washing and eating) and instrumental activities of daily living (such as climbing stairs and shopping) [18]. A high BMI is associated with a lower quality of life, as a study in 5362 patients with coronary artery diseases one year after their index cardiac catheterization revealed. This is especially marked in subjects with severe obesity [19]. If the role of overweight and obesity in older patients and in patients with heart diseases is controversial, clinical consequences and the role of weight management in elderly patients, in patients

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with heart disease and in subjects with a combination of both are even more so. Hence, it was the aim of this review to analyze the role of obesity in the elderly in the development of cardiovascular risk factors and CVD. Furthermore, the so called obesity paradox in elderly and in patients with CVD is analyzed and possible explanations discussed. The association of aging, obesity, CVD and mortality and underlying patho-physiological mechanisms are reviewed and the effect of weight loss in elderly subjects and in patients with CVD examined. The recommendations of medical associations in terms of weight management in patients for whom an obesity paradox has been reported are accumulated, and based on the analyzed literature, possible clinical implications are summarized. 2. Definition of obesity Obesity is commonly classified as BMI ≥ 30 kg/m, whereas a BMI b 18.5 is classified as underweight, a BMI of 18.5–24.9 as normal weight and a BMI of 25–29.9 as overweight [20,21]. This classification does not take into account sex or age. In a systematic meta-analysis BMI cut-offs to diagnose obesity showed a pooled sensitivity of only 0.50 (95% CI 0.43–0.57) and a specificity of 0.90 (95% CI 0.86–0.94) [22]. In older persons, age-related changes in body composition like decrease in fat free mass, increase in fat mass and loss of body height due to compression of vertebral bodies and kyphosis alter the relation between BMI and body fat [18,23]. Using body weight and BMI alone could underestimate the degree of adiposity in subjects which have lost large amounts of muscle mass [23]. Especially visceral abdominal fat increases in older men [24] and women [25] despite no significant BMI changes. Furthermore, the amount of fat inside and around muscle tissue increases with age [26]. A definition of obesity proposed by Villareal et al. is “an unhealthy excess of body fat, which increases the risk of medical illness and premature mortality” [18]. For the general population, a study of 360,000 participants in 9 European countries has shown that in addition to BMI, waist circumference and waist to hip ratio are of importance for assessing mortality risk [27]. However, in research and in practice, the most commonly used criteria to measure and classify body weight is BMI and especially studies on the association of obesity and mortality are usually based on BMI-classifications. 3. The obesity paradox An unexpected finding which showed that obese patients with terminal renal insufficiency and hemodialyses seemed to live longer compared to normal weight subjects formed the basis for the “obesity-survival paradox”, first published in 1999 [28]. The fact that obesity and other classical cardiovascular risk factors like hypercholesterolemia and hypertension apparently seemed to decrease and not increase the risk in chronic diseases, like terminal kidney diseases and chronic HF, was acknowledged by introducing the terms “reverse epidemiology”, “risk factor paradox” and accordingly “obesity paradox” [29]. This obesity paradox was later found in other chronic diseases which are associated with a “wasting” component [30] like rheumatoid arthritis [31], patients with severe chronic obstructive pulmonary disease [32], patients with HIV infection under HAART therapy [33,34], patients with metastatic prostate cancer [35] or patients with liver cirrhosis [36,37]. The term “obesity paradox” is also used to describe the fact that the relationship between obesity and mortality is weaker in older than in younger subjects. Studies that found an “obesity paradox” in patients with various diseases that typically affect elderly patients usually did not compare their results with healthy subjects of the same age, so no clear conclusion can be drawn whether or not the obesity paradox reported for a specific disease is not rather an expression of the lower mortality rate in obese healthy subjects. For example, a study group that in earlier studies found an obesity paradox in patients with cardiovascular diseases has

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recently published a lower mortality rate also for overweight and obese people without known coronary heart disease. In a population of 3673 patients (60 SD = 13 years, 36% males) with no history of heart disease and a normal stress SPECT the adjusted hazard rates for all-cause mortality was 0.54 (95% CI 0.43–0.70) for overweight and 0.49 (95% CI 0.38–0.63) for obese subjects [38]. 4. Prevalence of cardiovascular risk factors in the elderly The metabolic syndrome and its components which include excess abdominal fat, insulin-resistance, dyslipidemia, and high blood pressure are highly prevalent in older populations (NCEP, 2002). The prevalence of the metabolic syndrome increases with age and reaches a peak in men aged 50–70 years and women aged 60– 80 years [39]. In the adult population with age fasting plasma glucose and postprandial glucose increase by 1–2 mg/dl and 10–20 mg/dl, respectively, for each decade [40]. As a consequence, the prevalence of type 2 diabetes mellitus, also increases with age and reaches a peak in women aged 85 years and older and in men aged 75–84 years [41]. Also, the prevalence of hypertension has its peak in the elderly population [42,43]. 5. Obesity in the elderly, cardiovascular risk factors and risk of cardiovascular diseases Abdominal obesity is associated with the development of the metabolic syndrome, even in men and women aged 70–79 years [44]. Older adults who are physically active and do not have increased abdominal circumference are much less likely to develop type 2 diabetes mellitus [45]. Obesity and hypertension continue to be correlated, even in old age [46,47]. Dyslipidemia, low HDL-cholesterol and high triglycerides are also associated with abdominal obesity, even in old adults [48–50]. In a cross sectional study of subjects aged 65 years or older enrolled in the Baltimore Longitudinal Study of Aging waist circumference was associated with cardiovascular risk factors like blood pressure, fasting glucose, 2-hour glucose, fasting insulin, homeostasis model assessment insulin resistance, triglyceride, and HDL-cholesterol. In this analysis, there was no significant association of waist circumference with total cholesterol in older men, or with total cholesterol and LDL-cholesterol in older women [51]. BMI and waistto-hip ratio have been shown to be significant predictors of diabetes and hypertension in the Iowa Women's Health Study, a sample of 31,702 women, aged 55–69 years and a mean follow-up of 10 years [52]. In the same study, a high BMI and a high waist to hip ratio were associated positively with mortality from coronary heart disease and other cardiovascular diseases [52]. In the American Cancer Society's Cancer Prevention Study with 62,116 men and 262,019 women, subjects with greater BMI had a greater risk of mortality from cardiovascular disease. This relative risk associated with greater BMI declined with age, but was still significant in men and women aged 65–74 years [53]. In a cohort study of 621 US-American men and 960 women free of coronary heart disease and a mean age of 77 years, a BMI ≥ 27 kg/m² in late middle age increased the risk of coronary heart disease in late life by 70% (95% CI 30–110%). A BMI of 27 or more in old age was, however, not significantly associated with a higher CHD risk, due to weight loss between middle and old age. When those with weight loss of 10% or more were excluded, the risk for CHD in overweight and obese in old age was raised with a relative risk of 1.4 (95% CI 1.0–1.9) [54]. In another cohort study of 1597 70 year old subjects, free from CHD, relative CHD risks for males with the highest waist circumference and BMI quartiles were 1.46 (95% CI 1.00–1.85) and 1.42 (95% CI 1.04–1.92), respectively, after adjusting for cohorts, smoking habits, diabetes, systolic blood pressure, and total cholesterol.

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In females, the adjusted relative risks for the highest waist circumference and BMI quartiles were 1.47 (95% CI 1.06–2.04) and 1.42 (1.04–1.92), respectively [55]. In elderly subjects after hip fracture, overweight and obese patients had no excess risk of cardiac complications. Underweight patients, however, have been found to have a higher risk of developing any adverse cardiac events like myocardial infarction, angina pectoris, congestive HF, or new-onset arrhythmias within 1-year of surgery. The odds ratio, adjusted for age, sex, year of surgery, use of beta-blockers and the Revised Cardiac Risk Index, was 1.56 (95% CI 1.22–1.98) [56]. 6. Obesity and mortality in older people In the general population, all-cause mortality as well as mortality due to cardiovascular diseases depending on the BMI show a J-shaped curve. Both a low and a very high BMI are associated with increased overall as well as cause-specific mortality [3,57,58]. In the general population the nadir of this J-shaped curve was found at a BMI of 23.5 to 24.9 in men and 22.0 to 23.4 in women [57]. For older people, a Uor J-shaped mortality curve depending on the BMI has also been described, with the difference that this curve is shifted to the right. In the elderly population (age 50–80 years), the nadir of the mortality curve was found at a BMI of 28.2 kg/m² for men and 27.1 kg/m² for women [59]. In a systematic review all studies examining the association between BMI and mortality in older people (between 65 and 103 years) which were published between 1966 and 1999 were analyzed. The analysis included 13 studies, the total sizes varied between 1437 and 46,954 subjects. The findings were controlled for age, smoking, and baseline health status. Overweight was not associated with a higher all-cause mortality risk in either of these analyses. A BMI ≥ 32 kg/m², however, increased mortality risk. In all of the included studies obesity was not associated with the same extent of increased mortality as in the general (younger) population. In the systematic review, the nadir in mortality in elderly subjects was found at a BMI of 27–30 kg/m² [60]. In another cohort study with 6193 obese subjects a median follow-up time of 15 years also revealed that with increasing age, the obesity-associated mortality was not that pronounced. The oldest age group analyzed in this cohort was 50– 74 years [61]. In the Longitudinal Study of Aging, a cohort of 7527 subjects aged 70 years and above, a high BMI (top 15%) was associated with a low mortality rate. These findings were robust after adjusting for demographic factors, utilization of health care facilities and functional status (hazard ratio: 0.86, 95% CI 0.77–0.98). A low BMI (lowest 10%), however, was associated with a higher mortality (hazard ratio 1.46, 95% CI 1.30–1.64) [62]. 7. Obesity and mortality in patients with heart failure In a meta-analysis examining the mortality in HF patients by BMI, nine observational studies were analyzed, including a total sample of 28,209 subjects [63]. The mean age in these studies ranged from 51 to 72 years, the proportion of females ranged from 13 to 39%. In all of these studies overweight and obesity were associated with a lower all-cause mortality risk compared to normal weight, although this association was not statistically significant in either of the studies. The pooled odds ratio for overweight was 0.84 (95% CI 0.79–0.90) and for obesity 0.67 (0.62–0.73). Underweight or low-normal body weight, however, was associated with a higher risk for all-cause mortality, pooled OR 1.25 (95% CI 1.19–1.31). In four of those a combined riskadjusted analysis was performed. The pooled results of a Cox proportional hazards regression model, adjusted for age, sex, New York Heart Association class/severity of CHF, race, hypertension, cardiothoracic ratio, bilirubin, anemia, C-reactive protein, brain natriuretic peptide, current angina ejection fraction, diabetes, serum creatinine, etiology of HF, presence of arrhythmia, duration of HF,

medications, previous hospitalization for HF, medications, previous myocardial infarction, heart rate, blood pressure, clinical signs/ symptoms of HF, and study treatment revealed an adjusted hazard ratio for all-cause mortality for overweight of 0.93 (95% CI 0.89–0.97), for obesity of 0.88 (95% CI 0.83–0.93), and for underweight/low normal weight of 1.11 (95% CI 1.01–1.23) [63]. A recent study, in 1236 HF patients with preserved systolic function (ejection fraction ≥ 50%) with a mean age of 71 years (SD = 12) also found that one-year all-cause mortality decreased with increasing BMI, except at BMI N 45 kg/m². Hazard ratios adjusted for age, history, medications, laboratory and echocardiographic parameters relative to BMI 26–30 kg/m² were 1.68 (95% CI 1.04–2.69) for BMI b 20 kg/m², 1.25 (95% CI 0.92–1.68) for BMI 20–25 kg/m², 0.99 (95% CI 0.71–1.36) for BMI 31–35 kg/m², 0.58 (95% CI 0.35–0.97) for BMI 36–40 kg/m², 0.79 (95% CI 0.44–1.40) for BMI 41–45 kg/m², and 1.38 (95% CI 0.74–2.60) for BMI N 45 kg/m² [64]. In a cohort of 1160 subjects with HF obesity showed to be associated with a higher survival rate compared to normal weight after a mean follow-up of 30.7 years, irrespective of HF etiology. However, overweight subjects with ischemic HF had a similar survival rate compared to those with normal weight, while overweight subjects with nonischemic HF had a similar survival rate to obese subjects [65]. In a retrospective study of 8088 elderly patients (N70 years) with chronic HF (ejection fraction ≤50%) abnormal left ventricular geometry, left ventricular index, and lower BMI were independent predictors of mortality. Although abnormal left ventricular geometry and left ventricular hypertrophy progressively increased with obesity, total mortality was strongly and inversely associated with BMI [66]. This obesity paradox was also confirmed in 7767 stable outpatients with HF [67]. An obesity paradox was also found in 3722 subjects with acute HF. In this sample, obese subjects experienced a lower in-hospital (4.3 vs. 7.2%) and 30-day (7.3 vs. 14.5%) death rate compared to subjects with normal weight. Obese patients in this study were, however, significantly younger compared to normal weight subjects. Underweight patients had the highest in-hospital and 30-day mortality (10.2% and 19.9%) [68]. For patients with acute decompensated HF an analysis of 108,927 hospitalizations of 263 different US-American hospitals was performed. Among those subjects, the in-hospital mortality rate decreased in a nearlinear pattern with higher BMI quartiles. Odds ratio of in-hospital mortality, adjusted for age, sex, blood urea nitrogen, blood pressure, creatinine, sodium, heart rate, and dyspnoea at rest decreased by 10% (95% CI 0.88–0.93) for every 5-U increase in BMI [69]. Although many studies might show a higher survival in obese HF patients, quality of life may be altered through obesity. In a study of 358 patients with HF, although obese patients were significantly younger, obesity showed a significant correlation with altered health related quality of life and with a higher depression score [70]. In contrast to the studies that conclude a lower mortality in obese patients with HF, in a recent German cohort study of 1790 patients the subjects were matched in three BMI groups according to NTproBNP, age, sex, and NYHA class triplets. As has been described in other studies, BMI group was a significant prognostic indicator in the prematched cohort in this study. However, there was no significant association found between BMI and 1-year mortality and 3-year mortality in the matched group, when controlled for the covariates. NTproBNP was the only remaining significant predictor for mortality, independent of obesity. The authors concluded that the obesity paradox in stable chronic heart failure does not persist after matching for disease severity and confounders [71]. 8. Obesity and mortality in patients with ischemic heart disease In a meta-analysis, including 22 cohort studies with a total sample size of 196,084 subjects after coronary revascularization the mortality was analyzed by BMI categories [72]. Out of these there were ten studies on mortality post-percutaneous coronary intervention (PCI).

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The subjects had a mean age between 60 and 67 years and the proportion of females was between 18 and 33%. In the meta-analysis, in the subgroup of post-PCI subjects the odds ratios for 30-day inhospital mortality for overweight and obesity compared to normal weight were 0.71 and 0.63 (95% CI 0.62–0.81 and 0.54–0.73), respectively. Odds ratios for long-term mortality rates (1–5 years) in this group were 0.66 and 0.65 (95% CI 0.55–0.79 and 0.51–0.83) for overweight and obesity, respectively. Overweight and obese subjects in the sub group of post-CABG patients had a lower 30-day in-hospital mortality compared to normal weight, too, with odds ratios of 0.70 and 0.63 (95% CI 0.63–0.77 and 0.56–0.71). There was, however, no significant difference in mortality in overweight and obese subjects post-CABG compared to normal weight subjects, with odds rations of 0.78 and 0.88 (95% CI 0.60–1.00 and 0.60–1.29) [72]. In a systematic review of 250,152 patients with coronary artery disease, in 40 cohort studies followed up for 3.8 years the lowest all-cause and cardiovascular mortality rates were found in overweight subjects with relative risks of 0.87 (95% CI 0.81–0.94) and 0.88 (95% CI 0.75– 1.02) respectively, compared to subjects with normal weight. Obesity was not associated with higher all-cause or cardiovascular mortality rates with relative risks of 0.93 (95% CI 0.85–1.03) and 0.97 (95% CI 0.82–0.94). A lower weight (BMI b20 kg/m²) was associated with significant higher mortality rates with relative risks of 1.37 (95% CI 1.32–1.43) and 1.45 (95% CI 1.16–1.81) for all-cause and cardiovascular mortality, respectively. In this analysis severe obesity (BMI ≥ 35 kg/m²) was associated with a higher risk for cardiovascular mortality with a relative risk of 1.88 (95% CI 1.05–3.34), but not with all-cause mortality with a relative risk of 1.10 (95% CI 0.87–1.41) [73]. In the cohort of 22,576 hypertensive patients with coronary artery disease of the INVEST study (verapamil-SR vs. atenolol) mortality rates were examined by BMI category. In this study, the mean age was 66 (SD = 9.8) years. Compared to patients with a BMI between 20 and 24.9 kg/m², mortality hazard rates for subjects with overweight, class I obesity and class II to III obesity were 0.66, 0.52 and 0.57 respectively (95% CI 0.59–0.74, 0.45–0.59 and 0.49–0.68). In this study, again, a BMI b 20 kg/m² was associated with a higher mortality risk with a hazard rate of 1.56 (95% CI 1.12–2.19) [74]. Another study of 894 patients b80 years of age after myocardial infarction showed a lower 6-month mortality in subjects with overweight or obesity compared to subjects with a BMI b 25 kg/m². Hazard ratios, adjusted for age, cardiovascular risk factors, a history of cardiac diseases and cardiaceffective medication was 0.47 (95% CI 0.26–0.86) for subjects with a BMI of 25 kg/m² and above compared to those with a BMI b 25 kg/m². Among subjects who had already survived 6 months after acute myocardial infarction (AMI), there was no significant difference in the long-term mortality in the different BMI groups with an adjusted hazard ratio of 0.88 (95% CI 0.62–1.24). Overweight and obese subjects had a significant risk of recurrent AMI compared to subjects with a BMI b 25 kg/m² with an adjusted hazard rate of 2.30 (95% CI 1.19–4.46) [75]. In a Scottish cohort of 4880 patients after first-time elective percutaneous coronary intervention (PCI) those with a BMI between 27.5 and 30 kg/m² were found to be at reduced risk of dying when compared to normal weight subjects. Hazard rate, adjusted for age, hypertension, diabetes mellitus, and left ventricular function was 0.59 (95% CI 0.39–0.90). Median age in the different BMI strata varied between 60 and 66 years [76]. Some studies suggest that there are differences in obese and normal weight subjects with CHD in terms of risk profile, severity of the disease, and treatment. Those differences could contribute to the explanation of an obesity paradox in patients with CHD. As an example, in a study of 80,845 patients with non-ST-segment elevation acute coronary syndrome revealed that patients who were overweight or obese were younger and more likely to suffer from comorbidities like diabetes mellitus, hypertension, and hyperlipidemia. In these patients, medications given in the first 24 h and invasive cardiac procedures

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recommended in several guidelines were used more commonly. In this sample, again, mortality risk, adjusted for covariates, was lower in overweight and obese subjects, but higher in underweight and extremely obese patients [77]. In a sample of 15,550 patients who were candidates for coronary artery bypass graft, overweight and obesity was found to be associated with a higher prevalence of hypertension, diabetes mellitus, and dyslipidemia, but with a lower prevalence of left main disease according to preoperative angiography. The authors concluded that obese patients are more likely to be referred for coronary artery bypass graft in earlier stages of coronary involvement [78]. An analysis of 140,139 hospitalizations for coronary artery disease from 409 United States hospitals revealed that increasing BMI was associated with better use of guidelinerecommended medical treatment like aspirin, beta blockers, ACE inhibitors, and lipid-lowering therapy. Overweight and obese patients were more likely to undergo invasive procedures, and they had significant lower mortality [79]. These facts show that some of the obesity paradox might be related to more aggressive management. However, in a sample of 2024 patients (66.8 SD = 10.1 years; 31.7% women) hypertensive patients with chronic heart disease risk factor control rates worsened with increasing BMI category, i.e. overweight and obese subjects had a lower control of blood pressure, low-density lipoprotein cholesterol level and diabetes [80]. A study of 89 patients (mean age 62 SD = 11 years) showed that obesity was surprisingly associated with a smaller infarction size compared to subjects with normal weight [81]. Another study of 164 patients who underwent successful primary PCI found, however, no association between BMI and infarction size. Furthermore, in this study no significant difference was found in 30-day mortality in different BMI strata [82]. 9. Possible explanations for the obesity paradox The so called obesity paradox in elderly subjects and in patients with cardiovascular diseases has been critically analyzed by a number of review articles [83–86]. The studies that show a significant statistic association between a high BMI and reduced overall mortality are all observational studies and not randomized clinical trials. Based on this design, no clear conclusions can be drawn with regards to causality. A number of potential methodological influences and other plausible, non-causal explanations have been discussed in reviews and by the authors of the studies themselves to be responsible for the observed association. They are summarized in Table 1. On the other side, also potential biological reasons and causal links to a better survival in obese subjects with various clinical conditions have been presented. Those are summarized in Table 2. 10. Association between aging, obesity, cardiovascular diseases and mortality and possible involved patho-physiological mechanisms The association between aging, obesity, cardiovascular diseases and mortality and the role of frailty and inflammation in this cascade are depicted in Fig. 1. In this figure also potential explanations which are discussed to be involved in the obesity paradox are outlined. Aging is not only an independent risk factor for cardiovascular diseases and mortality, aging is also associated with fat redistribution. With age, body composition changes with an increase in fat mass and a decrease in muscle mass. The amount of fat increases with age even without changes in body weight and BMI [23]. Therefore, physiological changes caused by aging and life style factors are involved. Dietary calorie intake does not increase with age, it rather declines [99,100]. However, decreases in resting metabolic rate and the thermic effect of food reduce basal energy needs ever further. Additionally, physical activity and energy expenditures decrease with age. Both factors result in a positive energy balance and contribute to the accumulation of body fat mass with age. The consequences of these lifestyle factors are facilitated through hormonal changes, including a reduced production of growth

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Table 1 Possible methodological and other plausible, non-causal explanations for a lower mortality in elderly obese subjects or obese patients with cardiovascular diseases compared to normal weight subjects. Publication bias

Studies which present unexpected, paradox results are more likely to be published in journals with a high impact factor and can bias metaanalyses [86]. Selection bias Young and middle-aged overweight and obese subjects have a higher risk to develop a disease in younger ages. In most studies overweight and obese subjects with heart diseases are younger compared to normal or underweight patients. Younger patients often receive a more aggressive therapy and this therapy can lead to an apparently higher life expectancy [63,85,86]. Higher levels of medication Obese patients may tolerate and be treated with higher levels of cardioprotective medications, be treated more often according to guidelines or with a more aggressive therapy [63,77–79]. NTproBNP Overweight and obese HF patients, additionally have lower levels of circulating B-type natriuretic peptide (NTproBNP). Reduced levels of BNP may lead to increased volume and symptoms of dyspnea and therefore obese patients with heart failure present earlier with less severe disease, are managed more effectively and enjoy better prognosis [85,87,88]. Survival bias Middle-aged adults whose health is sensitive to obesity are less likely to survive into old age. Especially, heart failure is a common final pathway of a number of cardiovascular diseases, all of which are associated with higher mortality. The patients who reach this end stage of the disease, the survivors, are possibly different to those who die earlier and not so much vulnerable to cardiovascular risk factors [30]. Lead time bias Overweight and obese subjects represent a population with a conspicuous phenotype which is associated with a high cardiovascular risk. It is possible that in this population cardiovascular diseases are discovered earlier compared to normal weight subjects which results in a longer time between diagnosis and death, which is, however, not a consequence of a better prognosis [30,74]. Confounder Known confounders, such as smoking, which is associated with a lower BMI and a higher mortality could be responsible for the observed association between BMI and mortality in patients with heart diseases. In some studies for known confounders an adjustment has been made. There could, however, also be unknown confounders like systemic diseases, which could be responsible for unintentional weight loss and cause higher mortality and thus could lead to the paradox results [86]. Reverse causation It could be that not BMI is the cause of a better outcome in wasting diseases like heart diseases, but the disease itself is the cause of a low BMI and the associated worse prognosis. Normal weight subjects included in studies might be former overweight and obese subjects, which have been exposed to the higher cardiovascular risk through a high BMI, but have lost weight unintentionally due to the severity of their disease. In this case, normal weight and the associated higher mortality risk would be the expression of a higher severity of the disease and not of lower cardiovascular risk [30,83] Time discrepancy of competitive A high BMI is a known risk factor that leads to a higher mortality after years and decades (“long-term killer”). Since most obesity-related risk factors sequelae take years to develop, those who become obese in old age may die of non-obesity-related diseases before the adverse effects of obesity become apparent. Populations with adverse long-term prognosis have a high risk to experience the adverse effects of weight loss and undernutrition (“short-term killer”) on mortality which are known risk factors in patients with heart diseases [30,63,75,89]. Classification of BMI Classification of obesity by using BMI does neither differentiate between fat and fat free mass, nor between the distribution of body fat, e.g. abdominal vs. gluteal fat distribution. Other parameters like waist circumference, waist to hip ratio, direct measurement of visceral body fat, or classifications which incorporate parameters of body composition, the relation between fat and fat free mass and the concept of sarcopenic obesity have been proposed to be more valid parameters for mortality risk assessment in the elderly and for patients with cardiovascular diseases [86]. Reliability of diagnoses In most of the studies on mortality in heart failure only clinical criteria for the diagnosis of heart failure like dyspnoea, edema and pulmonary rhonchus have been used. These symptoms are, however, also common in obese patients without heart failure. A wrong classification, based on clinical criteria only, could contribute to the explanation of a lower mortality rate in obese subject [83]. No control to healthy subjects of the Studies suggest an obesity paradox in the elderly population. A great number of them are affected by cardiovascular diseases or other same age wasting diseases. On the other hand, an obesity paradox has been reported in patients with cardiovascular diseases, which are predominantly elderly patients. Since none of the studies have compared their findings with healthy people of the same age no conclusions can be drawn about the relationship of obesity, age, cardiovascular diseases and mortality.

hormone and testosterone and a decreased responsiveness to the effects of thyroid hormone and leptine [18]. The changes in body composition where fat increases without changes of BMI led to the concept of sarcopenic obesity [101,102]. A BMI in the obese range in the elderly increases the risk of frailty by 3.5 [103] and 96% of community-dwelling subjects aged 65–80 are classified as frail [104]. Not only increased BMI, especially sarcopenia and sarcopenic obesity are associated with frailty [105,106]. Frailty in elderly subjects is associated with increased mortality [107]. On the other hand, not only obesity, but also underweight, the other extreme on the BM scale [107,108] can be responsible for the development of frailty. This fact seems paradoxical, however, the way underweight and obesity lead to frailty follow different pathophysiological paths with only the same outcome, frailty. A good nutritional status can contribute to the prevention of frailty through the prevention of underweight and adiposity. Obesity is also associated with chronic inflammation [109]. Adipose tissue produces pro-inflammatory cytokines and inflammatory mediators such as interleukin 6 (IL-6) and C-reactive protein (CRP) [110]. Chronic inflammation increases the risk of mortality. Biomarkers of inflammation and of malnutrition like CRP, like transthyretin and 1-acid glycoprotein predict early mortality in elderly subjects [111]. Chronic inflammation is also part of the frailty syndrome in the elderly [106,112–114]. Adipose tissue [115] is discussed to be involved in the development of inflammation in frail elderly subjects. There is also a link between frailty and inflammation with cardiovascular diseases. Frail elderly people are through the definition

of frailty “in a state of increased vulnerability to stressors” [116], which include also a higher risk of cardiovascular diseases [117,118]. Authors indicate that frailty is a clinical manifestation of cardiovascular disease, especially of HF. The association of frailty with chronic inflammation and the understanding of these markers as risk factors for coronary heart disease link HF and frailty together [119]. Chronic inflammation and elevated inflammation markers like CRP are involved in the development of cardiovascular events [109]. TNF-α is also involved in the development of HF and is associated with a worse prognosis in these patients [91]. However, as mentioned above, the soluble TNF-α receptor is also produced by adipose tissue and can neutralize the adverse effects of TNF-α [90]. This mechanism has been discussed to contribute to the explanation of lower mortality in obese elderly people and patients with cardiovascular diseases. 11. Effects of weight loss in the elderly There are several observational studies in which the effect of weight loss on mortality in older age groups has been evaluated. Most studies show that recent weight loss is associated with increased mortality [120–122]. In a review of 17 studies of weight loss and allcause mortality the conclusion was that those who remained weightstable had the lowest mortality rate [123]. In a prospective study of 5722 Swedish overweight and obese, but otherwise healthy men who lost weight were found to have a higher non cancer-related mortality compared to weight-stable men in the same weight range [124].

T.E. Dorner, A. Rieder / International Journal of Cardiology 155 (2012) 56–65 Table 2 Possible causal explanation for a lower mortality in elderly obese subjects or obese patients with cardiovascular diseases compared to normal weight subjects. Soluble TNF-α receptor Chronic inflammation and a high level tumor necrosis factor-α (TNF-α) in elderly patients and in patients with cardiovascular disease are correlated with a bad prognosis. In adipose tissue the soluble TNF-α receptor is produced and that could play a protective role in obese patients with diseases in which chronic inflammation is involved through neutralization of the adverse effects of TNF-α on mortality [90,91]. Lipopolysaccharides In obese subjects higher circulating lipoproteins may bind and neutralize lipopolysaccharides that play a role in stimulating the release of inflammatory cytokines, which may contribute to the protective effect of obesity in these patients [30,63,92]. Antioxadative effect of Since weight loss is often associated with muscle loss, muscle tissue especially in the elderly, the oxidative metabolism of skeletal muscles and the oxidative capacity can be affected, which leads to an increased oxidative stress, chronic inflammation and a worse outcome [63,93]. Neutralization of toxic In patients in a catabolic metabolism toxic metabolites can metabolites emerge which can be neutralized in adipose tissue in obese patients [30,94]. Metabolic reserve Heart failure is a catabolic state and obese and overweight patients with HF have more metabolic reserve [29,84,85,95]. Endocrinologic Overweight and obese patients with HF could have an reasons attenuated sympathetic nervous system and responses in the renin–angiotensin system. A high activity of the sympathetic and the rennin–angiotensin system are linked to a bad prognosis in heart failure [63,96]. Morphologic reasons Obese patients might present with smaller infarction size [81], have low-risk coronary anatomy [97] or less coronary calcification [98].

However, in most of the studies BMI is based on self-reported data on weight change, which does not distinguish between weight loss in obese and lean subjects. Furthermore, studies in the elderly population do not distinguish between intentional weight loss and unintentional weight loss. Unintentional weight loss, however, is a common complication of many serious diseases, including heart diseases, which could confound the interpretation of weight loss effects on mortality [18]. In middle aged subjects (aged 40–65 years) several studies of intentional weight loss found a reduced mortality,

Fig. 1. Association of aging and mortality via obesity, cardiovascular diseases (CVD), frailty, and mortality (bold lines) and discussed antagonizing mechanisms of the obesity paradox (thin lines).

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especially for those with additional cardiovascular risk factors [125– 127], whereas others found no effect of intentional weight loss on mortality [128–130]. Studies examining the effect of intentional weight loss in elderly subjects on mortality are scarce. A prospective study of 4869 men aged 56 to 75 years showed that unintentional but not intentional weight loss was associated with increase in all-cause mortality compared with men without weight change, after adjustment for lifestyle parameters and pre-existing disease. The adjusted relative risk was 1.71 (95% CI 1.33–2.19) for those with unintentional and 1.00 (95% CI 0.91–1.10) for those with intentional weight loss. Those who lost weight intentionally as a result of personal choice showed a reduced all-cause mortality and especially cardiovascular mortality with relative risks of 0.59 (95% CI 0.34–1.00) and 0.36 (95% CI 0.15–0.87) [131]. In the Arthritis, Diet and Activity Promotion Trial a total of 318 subjects with a mean age of 69 (SD = 6) years and a mean BMI of 34 (SD = 5) kg/m² were randomly assigned in a weight loss group. Weight loss was achieved through dietary and exercise changes. Weight loss after 18 months in this group was −4.8 kg. The group with intentional weight loss had a lower mortality rate compared to the control group with a hazard ratio of 0.5 (95% CI 0.3–1.0). Adjustment for age, gender, baseline weight status, or magnitude of weight loss had little influence on those results [132]. Intentional weight loss in the elderly has been shown to be of benefit for other diseases, especially in controlling cardiovascular risk factors. A systematic review of 16 articles on weight loss interventions in overweight or obese subjects aged 60 years or older showed significant benefits for those with osteoarthritis, coronary heart disease, and type 2 diabetes mellitus. There was a slightly negative effect on bone mineral density and lean body mass [133]. In four studies, an improvement in metabolic control with better glucose tolerance and increased insulin sensitivity associated with intentional weight loss in elderly people have been shown [134–137]. In another study, weight loss in older people (aged 60 to 79 years) was associated with an improvement of blood pressure and a reduction in antihypertensive drugs [138]. Additionally, intentional weight loss was shown to reduce the production of pro-inflammatory cytokines in adipose tissue and increased the expression of anti-inflammatory cytokines like IL-10 [139]. In a randomized controlled trial with 316 community-dwelling overweight or obese men and women aged 60 years or older the effect of intentional weight loss on inflammatory markers were observed. In this study the diet-induced weight loss intervention resulted in reductions in concentrations of CRP, IL-6 and soluble TNF-α receptor. Changes in soluble TNF-α receptor 1 but not in CRP or IL-6 correlated with changes in body weight [140]. The decrease of CRP in this study was 0.13–0.18 mg/l, while some researchers regard a drop in CRP of 1 mg/l to be clinically important [141]. In one study the effect of intentional weight loss on mortality among overweight and obese coronary patients was examined. In this retrospective study of 529 subjects, intentional weight loss in the frame of a cardiac rehabilitation and exercise training program, overweight and obese subjects with greater weight loss significantly reduced their BMI and body fat, improved peak oxygen consumption, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, CRP and fasting glucose. Additionally, they could improve their quality of life. In this sample 3-year mortality was significantly lower in subjects who were initially overweight or obese compared to those with normal weight, however, there was only a small, non-significant decrease in mortality in those with intentional weight loss. The authors concluded that these results support the safety and potential long-term benefits of intentional weight loss in overweight and obese subjects with coronary heart disease [142]. The effect of weight loss and fat loss was analyzed in two cohort studies: the Tecumseh Community Health Study with 1890 subjects with a mean age of 40.3 (SD = 14.1) years and the Framingham heart Study with 2731 subjects with a mean age of 50.0 (SD = 7.9) years. The

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Tecumseh Community cohort was followed for 16 years and the Framingham community for 8 years. In both studies weight loss was associated with increased and fat loss with decreased mortality. In the Tecumseh Community Health Study each standard deviation of weight loss (4.6 kg) increased the hazard rate by 29% (95 CI 14–47%) and each standard deviation of fat loss (10.0 mm in skin folds) decreased mortality by 15% (95% CI 4–25%). In the Framingham Heart Study a weight loss of 6.7 kg increased the hazard rate by 39% (95 CI 25–54%) and fat loss of 4.8 mm decreased hazard mortality rate by 17% (95% CI 8– 25%) [143]. 12. Recommendation for weight loss in the elderly with CVD The American Heart Association recommends weight reduction in patients with HF and with a BMI of N40 kg/m². Weight loss should not be encouraged in patients with HF if the BMI is b30 kg/m2, but patients should rather be encouraged to monitor for loss of appetite, unexpected weight loss, and muscle wasting [144]. There is no specific recommendation for elderly people with HF, but in the recommendation it is stated that the vast majority of persons with HF seen in clinics and hospitals are older adults. The European Society of Cardiology, however, recommends weight reduction in obese (BMI ≥ 30 kg/m²) patients with HF in order to prevent the progression of HF, decrease symptoms, and improve well-being (Task force, 2008). For patients with coronary heart disease, the European Society of Cardiology recommends weight reduction when the BMI is ≥ 30 kg/m² and when waist circumference is N102 cm in men or N88 cm in women [145]. The American Society for Nutrition, the North American Association for the Study of Obesity and the Obesity Society make the following recommendations for weight management in the elderly population: Weight loss therapy is recommended for older persons who are obese and who have functional impairments or metabolic complications that can benefit from weight loss. Weight loss should minimize muscle and bone losses. The aim of weight management in the elderly is to improve and maintain physical function and quality of life and prevent dependence and institutionalization rather than prevention of medical problems associated with obesity. Weight loss should be reached through a modest reduction in energy intake (500–750 kcal/day) and the diet should contain sufficient amounts of high-quality protein, vitamins and minerals, especially vitamin D and calcium should be supplemented, if necessary. Regular physical activity is of particular importance in obese older persons to improve physical function and help preserve muscle and bone mass. Exercise should start at a low-tomoderate intensity, duration, and frequency and gradually progress over several weeks or months. Exercise should include the sports motor components flexibility, endurance, and strength. Even very old or frail persons can participate in physical activity [18]. Weight management in the elderly should be based on an individual approach. Conditions such as sarcopenia and sarcopenic obesity and the related muscle protein loss should be taken as much into account as other individual characteristics such as co-morbid conditions, functional status, and social and financial issues [146]. 13. Conclusion The clinical implications of the observed interrelation between a high BMI and a lower mortality in the elderly and in patients with cardiovascular diseases remain inconclusive. Since there is a big overlap between elderly patients and patients with CVD, it remains unclear which medical condition causes the so called obesity paradox. Intentional weight reduction as a result of personal choice even in elderly patients with obesity, especially with severe obesity, seems to be beneficial with regard to the cardiovascular risk profile, chronic inflammation, and quality of life. On the other hand, signs of unintentional weight loss, loss of appetite, and muscle and bone

Table 3 Recommendations for weight management in elderly people. • Intentional weight reduction as result of personal choice even in elderly patients with obesity seems to be beneficial in regard of cardiovascular risk profile, chronic inflammation and quality of life. • In elderly patients with or without cardiovascular diseases for signs of unintentional weight loss should be searched. Unintentional weight loss in the elderly is always hazardous and demands careful clinical evaluation for the underlying cause. • In weight assessment and weight management in the elderly central fat or parameters of body composition which distinguish between fat and fat-free mass are probably more important than BMI. • The identification of elderly subjects with sarcopenic obesity is of clinical and prognostic relevance. • The aim of weight management in the elderly is to improve and maintain physical function and quality of life and prevent dependence and institutionalization rather than prevention of medical problems associated with obesity. • Weight management in the elderly should be based on an individual approach. Individual characteristics like co-morbidity, sarcopenia, functional status, social support, and particularly the attitude and willingness of the patients self. • Weight loss should minimize muscle and bone losses • Weight loss should be reached through a modest reduction in energy intake and the diet should contain sufficient amounts of high-quality protein, vitamins and minerals, especially vitamin D and calcium should be supplemented, if necessary. • Regular physical activity is of particular importance in obese older persons to improve physical function and help preserve muscle and bone mass. Balance, strength, flexibility and endurance training should be incorporated in a training plan. Even very old or frail persons can participate in physical activity.

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