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The Obesity Paradox and Cardiorespiratory Fitness in Men and Women with Known or Suspected Coronary Artery Disease

Alis Bonsignore*, Gabriela LM Ghisi, Paul Oh

Faculty of Kinesiology and Physical Education, University of Toronto, 100 Devonshire Pl, Toronto, ON Canada M5S 2C9

Abstract: It has been suggested that cardiorespiratory fitness may alter the association between obesity and risk of mortality among individuals with coronary artery disease (CAD). A systematic search of the literature was conducted to evaluate the joint association of cardiorespiratory fitness and obesity with mortality in the CAD population. Literature published from database inception was searched using the MEDLINE, CINAHL, EMBASE and EBM databases and incorporated 3 concepts: (1) condition (i.e., coronary disease, myocardial infarction) (2) fitness (i.e., oxygen consumption) and fatness (i.e., body mass index (BMI)) and (3) outcomes (all-cause or cardiovascular mortality). A total of 3 articles were identified including 22,835 (n = 162 female) individuals with known or suspected CAD. Results of these investigations suggest that individuals with low cardiorespiratory fitness had a higher risk of overall-mortality across BMI categories of normal weight, overweight or obese with normal weight-high cardiorespiratory fitness as the reference group. Moreover, individuals who were overweight or obese with high cardiorespiratory fitness had a lower or similar risk of overall-mortality compared to those with low cardiorespiratory fitness across all BMI categories. Higher cardiorespiratory fitness may reduce the risk of mortality to a greater extent when compared to obesity among the CAD population.

Keywords: obesity, coronary artery disease, cardiopulmonary fitness, mortality, body mass index

Citation: Alis Bonsignore, Gabriela LM Ghisi, Paul Oh, The Obesity Paradox and Cardiorespiratory Fitness in Men and Women with Known or Suspected Coronary Artery Disease. Journal of Physical Activity Research, 1 (1). 36-43. January 2016. doi:10.12691/jpar-1-1-8

1. Introduction

Obesity is increasingly recognized as a public health epidemic and appears to increase the risk of cardiovascular disease (CVD) and mortality among the adult population. [1] In 2002 Gruberg and colleagues [2] first described the term the “obesity paradox” in patients with coronary artery disease (CAD) who underwent percutaneous coronary intervention based on their findings that normal weight patients carried an increased risk of in hospital complications and cardiac related death compared to their overweight and obese counterparts. Moreover, recent epidemiological data from the Swedish Coronary Angiography and Angioplasty Registry indicates a U shape association between body mass index (BMI) and mortality with the risk for mortality decreasing with increasing BMI up to ∼35 kg.m² and then increases thereafter among patients with known CAD. [3] However, conflicting evidence from the Aerobics Centre Longitudinal Study (ACLS) suggest that higher levels of adiposity increased the risk of mortality in men, although higher cardiorespiratory fitness (CRF) attenuated this relationship. [4] Accordingly, recent investigations have sought to determine if CRF might mediate the relationship between measures of obesity and mortality in those with known or suspected CAD.

CRF is an important prognostic marker of all-cause mortality among individuals with and without CAD. [5] Indeed, compelling evidence suggest that a 1 metabolic equivalent (MET) increase is CRF is associated with a 13% reduction in mortality in men with and without CAD suggesting it might play an imperial role in modulating relationship between obesity and mortality in the CAD population. [5] In a recent systematic review and meta-analysis of the literature including 10 studies that assessed the joint association between “fatness” and fitness on overall mortality, Barry and Colleagues (2014) [6] found that unfit individuals had twice the risk of mortality regardless of BMI compared to their fit-normal weight counterparts. Moreover, overweight and obese-fit individuals had similar mortality risks as normal weight-fit individuals. Importantly, these authors also concluded that the only significant moderator for obese-fit individuals was chronic disease status demonstrating that individuals with diseases were more likely to die when compared to normal weight-fit individuals. Accordingly, there is strong evidence to suggest that CRF might be a stronger indicator of mortality risk when compared to obesity measures in both healthy individuals and those with chronic diseases.

Despite the known benefits of higher CRF for reducing mortality risk among the CAD population, controversial evidence exists regarding the influence of CRF and the moderation of the obesity paradox in this patient population. [7,8] Given that CRF and obesity both play an important role in the risk of mortality among the CAD population, accurate assessment of the link between CRF and the obesity paradox in the CAD population is needed. Such information is important for clinicians and patients alike in order to direct patient care with focus on improving risk factors that increase the risk of mortality among individuals with known or suspected CAD. Thus, the aim of this investigation was to systematically review the current literature regarding the joint association of CRF and measures of obesity with overall-mortality in men and women with known or suspected CAD.

2. Methods

2.1. Search Methods for Identification of Studies

Literature published from database inception until August 2014 was searched using the MEDLINE, CINAHL, EMBASE and EBM computerized databases, in conjunction with a subject librarian. Search results were downloaded into bibliographic software. The search strategy incorporated 3 concepts: (1) condition, which was divided into heart diseases and rehabilitation aspects (i.e., coronary disease, myocardial infarction, and cardiac rehabilitation); (2) measures of fitness (e.g. oxygen consumption) and fatness (i.e., BMI, waist circumference, percent body fat); and (3) outcomes (all-cause or cardiovascular mortality). Search terms were specific to each database. The search strategy for 2 databases is shown in Table 1. A snowball hand-search was undertaken after the first selection of articles.

Table 1. Search Strategy

2.2. Inclusion and Exclusion Criteria

The criteria for considering studies for this review were:

(1) Design: peer-reviewed studies were considered for inclusion. Primary or secondary studies were included, whether they were observational or interventional in design. Qualitative studies were not included, however served to inform interpretation of quantitative findings. Reviews were identified as a source of additional primary studies.

(2) Participants: cardiac patients with primary diagnosis of CAD, myocardial infarction, or who have undergone coronary artery bypass graft surgery, or percutaneous coronary intervention. These patients are indicated for cardiac rehabilitation (CR) in clinical practice guidelines, therefore participants attending CR were included in the search strategy. [9] For interpretation purposes we sought to determine if CRF modulates the obesity paradox in those with a primary diagnosis of CAD.

(3) Measures: studies had to report and compare both measures: fitness and fatness. Fitness was specific to cardiorespiratory (aerobic) fitness. Fatness was related to body mass index (BMI), waist circumferences, and body composition.

(4) Outcomes: Studies had to report either mortality rates (all-cause or cardiovascular).

(5) Published in the English language.

2.3. Data Collection and Analysis

Two reviewers (GLMG and AB) independently screened the references identified by the search strategy by title and abstract. In order to be selected, abstracts had to clearly identify cardiac participants, fitness or fatness, and mortality as described above. The full-text reports of all remaining citations were obtained and assessed independently for eligibility by these 2 reviewers, based on the defined inclusion criteria. Any disagreements were resolved through discussion between the two investigators and, if needed, consultation with a third author (PO). Data extraction was undertaken by a single reviewer (AB) and checked by a second reviewer (GLMG). Given the nature of the literature, quantitative synthesis of data was not possible.

3. Results

A total of 497 studies were identified through the search strategy and an additional 20 articles were included through screening of review papers and relevant reference lists. Following the initial screening of abstracts, 81 papers were included for the full text review (Figure 1). Overall 3 articles were identified for inclusion including 22,835 men and women (n = 162 women) with known or suspected CAD. Of these investigations, one study including 855 patients was identified retrospectively in a CR setting. [8] The same author conducted the two additional studies, where data was retrospectively assessed from the ACLS and the Veterans Exercise Testing Study (VETS) respectfully (Table 2). [7,10].

Figure 1. Flow Diagram of Study Selection Process

Table 2. Outcomes of Identified Investigations

With a mean follow-up time of 10.27 yrs a total of 3,693 deaths were reported. The mean age of the participants was 55.8 yrs (range 20- 82 yrs of age reported in all studies). Of these participants, 4,641 had a reported previous myocardial infarction or known CAD, 9,580 were hypertensive, 3,984 had hypercholestoremia or treated with a statin and 2,916 were reported to have diabetes where data was available. Two investigations included individuals with known CAD (documented evidence of ST-elevation myocardial infarction, non-ST elevation myocardial infarction, unstable angina, stable angina or previous revascularization surgery) or those with suspected CAD (chest pain and abnormal exercise ECG). [8,10] One study that assessed outcomes from the VETS data including individuals with suspected CAD and reported rates of CAD and hypertension in 33% and 49% of the population respectfully [7].

3.1. Fatness Measures and Mortality Outcomes

Individual assessment of fatness measures and outcomes of mortality were conducted in each study. With respect to outcomes, all studies identified measured BMI as a “fatness” outcome and reported the risk of mortality across BMI categories (underweight, normal weight, overweight, obese or severely obese). Goel and colleagues (2011) [8] reported a 40% reduction in overall mortality among obese subjects when compared to normal-weight subjects after adjustment for cofounding factors (i.e., cardiac risk factors, age, sex, and comorbid conditions) and hip to waist ratio. When additional adjustments for CRF were made, mortality rates were reduced to greater extent in obese subjects. Conversely, a higher hip to waist ratio was associated with an increased risk of mortality suggesting that abdominal obesity may play an important role in risk of mortality among individuals with CAD. This is consistent with data from the VETS where obese and overweight individuals had a lower risk of mortality compared to their normal weight counterparts [7].

McAuley and colleagues (2012) [10] included three measures of obesity including BMI, percent body fat (measured via hydrostatic weighing or the sum of 7 skin-fold measures) and waist circumference and their associations with all cause and CVD related mortality. With respect to BMI outcomes, overweight and obese individuals had lower or similar rates of all cause and CVD related mortality compared to normal-weight individuals, however those who were severely obese had higher rates of both all cause and CVD related mortality after adjusting for cofounding factors. Similar trends were seen when adjusted for CRF; however, risk of overall mortality was no longer significant and both all-cause and CVD related mortality was reduced to a greater extent across all BMI categories. These results contrast those obtained from the VETS data where severely obese subjects did not carry an increased risk of all-cause mortality compared to their leaner counterparts. [7] Assessment of obesity via body fat percent and its association with all-cause mortality demonstrated a U shape relationship with the lowest risk observed in those in the second tertile. CVD mortality rates were similar across all tertiles; however, when adjusted for CRF, those in the upper two tertiles demonstrated a reduced risk of all cause and CVD related-mortality compared to the individuals in the lowest tertile. Lastly, when waist circumference was considered as a measure of obesity and its association with all-cause and CVD-related mortality, similar trends were observed where those in the upper tertiles carried similar or reduced risk, with the exception of subjects in the upper tertile who carried an increased risk of CVD mortality. When adjusted for CRF, the upper two tertiles carried a reduced risk of all cause and CVD-related mortality. [10] Together, these results suggest that an increase in obesity is associated with similar or reduced risks of mortality in those with known or suspected CAD, however those who are severely obese (when assessed as a measure of BMI) may carry an increased risk of CVD related mortality.

3.2. Fitness Measures and Mortality Outcomes

The influence of CRF on overall mortality was assessed individually in each investigation. The measurement of CRF and classification of fitness level was heterogeneous between each investigation. Only one investigation measured CRF via a cardiopulmonary exercise test on treadmill following an accelerated Naughton protocol to determine measured VO2peak with breath-by breath gas analysis and assessment of oxygen consumption with a metabolic cart. [8] To determine levels of fitness, high and low sex-specific values were used for the whole study population (male < 21.5 mL. kg.min⁻¹; female < 16.8 mL. kg.min⁻¹). The same authors also reported total treadmill time and divided patients into two sex specific groups (< 9.0 mins for males; < 7.0 mins for females). Two studies estimated CRF as peak workload and exercise time estimated by metabolic equivalents (METs), which was measured by the standard Bruce protocol and the modified Bulke protocol. [7,10] Only one investigation grouped individuals based on age specific tertiles, [10] while the other investigation grouped patients on predetermined fitness categories (i.e., low: < 5 METs; moderate: 5.0 to 10 METs; high: > 10 METs). [7] Owing to heterogeneity of the measurements of CRF, classification of fitness levels and type of protocols used, quantitative comparison between each investigation is limited.

Outcomes of these investigations are constant with the current literature demonstrating that improved CRF is associated with a reduced risk of mortality among the CAD population. [5] Goel and colleagues (2011) [8] reported that 1 mL. kg.min⁻¹ increase CRF was associated with a 9% improvement in overall survival, while those in the lowest fitness category experience a 3-fold increase risk of death. This is constant with findings from the VETS outcome data which proposed that when compared to the high-fitness group, those with moderate to low fitness experienced a 2 to 3-fold increase in mortality when outcomes where adjusted for BMI status. [7] Lastly, data presented from the ACLS demonstrated that men in the middle and upper age-specific tertiles for CRF had a 28% and 35% reduced risk of overall-mortality compared to those in the lowest tertile after adjustment for cofounding factors (age, baseline examination year, and CVD risk factors). [10] Collectively, these investigations demonstrate imperial evidence regarding the importance of CRF for reducing the risk of mortality among the CAD population.

3.3. Joint Association of Fitness and Fatness Measures and Mortality Outcomes

The joint association of CRF and obesity on mortality outcomes in individuals with known or suspected CAD was determined in each investigation with conflicting results. Two investigations from the same author demonstrated that fit individuals who were overweight and obese had improved (in one investigation) or similar (in the other investigation) outcomes of survival compared to their normal-weight and high fitness counterparts. [7,10] Moreover, one investigation demonstrated similar mortality outcomes among the fit-overweight or fit-obese subjects compared to fit-normal weight individuals although there was a non-significant trend towards an increase risk of all cause mortality in those who were overweight and obese among the fit individuals. [8] Lastly, one investigation included a severely obese-fit group and demonstrated no increased risk of overall mortality compared to the normal weight-fit individuals [10].

All three of these investigations demonstrate evidence of the obesity paradox among unfit individuals. Individuals who were normal weight-low fitness carried a higher risk of all-cause mortality, while this risk was reduced in the low fit-overweight and low fit-obese individuals but still remained higher compared to normal weight- fit individuals when obesity was determined by BMI. [7,8,10] One study included a severely obese-unfit group who carried an increased risk of all-cause mortality compared to the unfit-normal weight group. Similar trends were observed for all-cause mortality when waist circumference and body fat percent were used as a measure of obesity. [10] However, significantly increased risk of mortality was noted in both centrally obese-low fitness and centrally obese-high fitness groups when obesity was measured by hip to waist ratio. [8] The joint relationship between obesity and CRF and the mediating role on all-cause mortality is presented in Figure 2. For consistency purposes, only BMI categories reported in each study are presented.

Figure 2. Risk of Death Across Body Mass Index and Fitness Categories

CVD related mortality was also reported accounting for 4% of the deaths in one investigation. [10] Among the high-fitness groups, CVD related mortality did not differ across all BMI categories from normal weight individuals with a trend toward reduced risk in the overweight and obese individuals. Individuals with low fitness, had an increased risk of CVD related mortality compared to the high-fitness and normal weight individuals across all BMI categories. A U shape relationship was also apparent among the low-fitness group with the normal weight and obese individuals carrying the largest risk of CVD related mortality.

4. Discussion

There are significant key messages that are highlighted in this review. Collectivity, these investigations indicate that CRF is an important mediator in the risk of mortality associated with an increase in obesity whereby those who are overweight or obese with high fitness carry similar or reduced risk of mortality compared to their leaner-fit counterparts. Two of the studies demonstrated that those with high fitness who were overweight or obese carry a similar risk of mortality compared to their fit -leaner counterparts [8,10]; whereas one study demonstrated that those with high fitness who were overweight or obese carry a reduced risk of mortality compared to their fit -leaner counterparts. [7] Moreover, it appears that the obesity paradox persists among unfit individuals with known or suspected CAD with a reduced risk of mortality observed with an increase in BMI. However, those with low-fitness across all BMI categories do not attain similar mortality benefits compared to their fit counterparts. Moreover, this evidence also suggests that overweight or obese individuals carry a reduced or similar risk of all-cause mortality compared to normal weight individuals in those with known or suspected CAD. Further, convincing evidence highlights that CRF is an important indicator of longevity in those with known or suspected CAD and those with higher CRF are at a reduced risk of mortality.

Previous investigations including patients with or without CAD have demonstrated that individuals with higher BMI are at a reduced risk of all-cause mortality compared to their leaner counterparts. [2,11,12] This is consistent with results observed in these investigations whereby those with a higher BMI had similar or reduced risk of all-cause mortality compared to those with a lower BMI. Only one investigation demonstrated evidence of the obesity paradox, with a decrease in risk of death with an increase in BMI. [7] The other two investigations suggested that the risk of death was reduced [10] or similar [8] in overweight individuals and similar in obese individuals. [8,10] One investigation including retrospective data from the ACLS indicated that those who were severely obese had an increased risk of all cause and CVD related mortality compared to their leaner counterparts; however when corrected for fitness levels only an elevated risk of CVD related mortality persisted. [10] These results are similar to those of a recent systematic review and meta-analysis including 250,00 patients with CAD suggesting that those who are overweight and obese had better outcomes for CVD and total mortality, however CVD related mortality but not all cause mortality was elevated in the severely obese groups. [13] These results suggest that the an increase in BMI is associated with similar or reduced risk of all-cause mortality in those with known or suspected CAD, although caution is warrant regarding CAD related mortality among severely obese individuals when interpreting these results.

Collectively, very few studies regarding the obesity paradox in men and women have addressed measures of obesity using outcomes other than BMI or body weight. Indeed, of the studies conducted in patients with known or suspected CAD, measures of waist circumference, body percent fat and waist to hip ratio were also considered yielding conflicting results. Outcomes of one investigation highlighted in this review demonstrates that when the waist to hip ratio is considered as a measure of obesity the risk of death increased with an increase in central obesity in patients with CAD attending cardiac rehabilitation. [8] Conversely, the same findings were not supported when measures of waist circumference or percent body fat were considered. [10] Outcomes of the later are consistent with a recent investigation by Lavie and colleagues (2011) who demonstrated that combined low body fat percent and low BMI was a strong predictor of mortality in 581 patients with CVD with only a 3 year follow up. [14] However, it was unexpected that a higher waist circumference was associated with reduced risk of mortality among individuals with known or suspected CAD given that an increase central obesity as a measure of the waist to hip ratio or waist circumference are related to an increase in overall and CAD related mortality in individuals without CVD. [15] Potential reasons to explain discrepancies in these results might be due to differences in the populations including individuals with known CAD verses those with suspected CAD. Moreover, the individuals included in the investigation where higher central obesity was associated with an increase in mortality risk were substantially older and may to some extent explain the confounding results.

Several studies have attempted to explain conflicting evidence surrounding obesity and the risk of all cause and CVD related mortality in healthy and CVD populations. For example, data from the ACLS including 2,603 older adults (> 60 yrs of age) found that an increase in BMI, waist circumference and body fat percent was associated with an increase in CVD and all-cause mortality, however correction for fitness depreciated these results. [16] These results are similar to those obtained in other investigations including healthy and men with hypertension [4,17] suggesting that fitness modifies the relationship between obesity and CVD and overall mortality risk. These results are similar to those obtained in the investigations highlighted here demonstrating that the obesity paradox exists among unfit individuals, whereby an increase in BMI significantly reduces their risk of mortality. However, they do not obtain similar benefits for reduced risk of all-cause mortality compared to their lean, overweight or obese high fitness counterparts. Interestingly, among those who are fit, only one investigation including data from the VETS investigation demonstrated that an increase in BMI was associated with a lower risk of all-cause mortality [7], while the other two investigations concluded that the risk was similar in overweight and obese individuals compared to the leaner groups. [8,10] This is consistent with results of a recent meta-analysis that suggest that the obesity paradox does not exist in fit individuals, although individuals with low CRF carry a 2-fold increase in mortality risk. [6] Accordingly, it appears that CRF is a powerful modifier of the risk of mortality in overweight and obese individuals with known or suspected CAD. An increase in fitness may negate the increased risk of mortality associated with obesity, although further research is needed to determine what factors mediate the relationship between obesity and mortality in unfit individuals with known or suspected CAD.

Several notions have been put forth to explain the obesity paradox including that obese individuals are younger [18], receive optimal medical treatment [19], or have improved body composition including an increase in muscle mass. [20] However, due to the retrospective design of the investigations included in this review it is difficult to determine if medical treatment status or body composition can explain the obesity paradox observed in unfit individuals. Moreover, one study demonstrated that an increase in obesity was associated with an increase in physical inactivity, lower peak METs, and a decrease in age supporting the notion that obese subjects might be younger compared to their leaner counterparts and thus may survive longer. [10] Results from Goel and colleagues (2011) [8] support this hypothesis as individuals who were fit or obese also tended to be younger compared to individuals who were leaner or unfit. Importantly, the number of individuals in these investigations who were fit-obese was scarce and was reported to represent only 3% of the entire cohort in one investigation. [7] Accordingly, it is possible that obese subjects might be more likely to be unfit and thus predisposing individuals to increased risk of mortality. However, if individuals are able to improve fitness through structured exercise program or cardiac rehabilitation despite being overweight or obese, these individuals might increase their likelihood of survival.

Caution is warranted when interpreting these results. There were limited studies identified through the review process, although the studies collectively included over 20,000 participants. However, majority of these participants were men, and make it difficult to draw conclusions regarding women. Heterogeneity of assessments used to measure obesity and fitness also restricted our ability to quantitatively assess the data. Moreover, the retrospective data obtained in these investigations limits conclusions that can be made regarding factors that mediate the risk of mortality associated with obesity status in individuals with known or suspected CAD. Further research would benefit from assessing factors responsible for the obesity paradox in the unfit cohort including the influence of age and medical treatment status. Lastly, the use of more sophisticated measures to assess obesity that quantify lean versus fat mass would also improve our understanding of the role of the “obesity paradox” in those with CAD.

In conclusion, these findings provide evidence that CRF rather than BMI is a better predictor of mortality in individuals with known or suspected CAD. Moreover, it appears that the obesity paradox might exist among individuals who are unfit with known or suspected CAD, however among fit individuals the risk of all-cause mortality is similar or reduced across BMI categories. These findings also suggest that CVD related mortality might be increased among severely obese individuals; however data on the role of CRF in mediating this risk is limited. Interventions should focus on increasing CRF, rather than reducing obesity to improve mortality outcomes among individuals with known or suspected CAD.

Acknowledgements

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Gabriela Lima de Melo Ghisi was supported by the Heart & Stroke/Richard Lewar Centre of Excellence Fellowship Award. Alis Bonsignore was supported by the Canadian Institute of Health Research Frederick Banting and Charles Best Canada Graduate Scholarships Doctoral Award.

Thank you to Dr. Scott Thomas, University of Toronto for providing support for editing and manuscript design.

Statement of Competing Interest

This work has been accepted (in part) for a poster presentation at the Canadian Cardiovascular Prevention and Rehabilitation Symposium (October 2015), Toronto Canada.

Dr. Paul Oh provides an advisory role for the following for-profit health care companies: Amgen Canada, Inc; Merck & Co., Inc; Pfizer, Inc and AstraZeneca Canada.

Abbreviations

Coronary artery disease (CAD)

Body mass index (BMI)

Cardiovascular disease (CVD)

Aerobics center longitudinal study (ACLS)

Cardiorespiratory fitness (CRF)

Metabolic equivalent (MET)

Cardiac rehabilitation (CR)

Veterans exercise testing study (VETS).

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