Overview of literature addressing the “obesity paradox” in patients suffering from stable coronary artery disease undergoing coronary angiography and/or revascularization.
The impact of obesity can be better understood by studying the growing medical and socioeconomic burden of this often neglected public health epidemic. Traditionally associated with cardiovascular risk factors like hypertension, hyperlipidemia, and diabetes mellitus, morbid obesity has increasingly contributed to mortality among Western as well as Third World populations. Contemporary evidence has also consistently linked this patient cohort with a greater risk to develop coronary artery disease. Recent population‐based registries indicate that 43 and 24% of all cases of coronary revascularization were performed in overweight and obese patients, respectively. In this context, although popular thought has reaffirmed the positive correlation between obesity and increased cardiovascular morbidity, some authors have opined a better clinical outcome in overweight and obese patients, a phenomenon they termed “obesity paradoxon.” Conflicting data and the possibility of confounding bias have festered an ongoing debate challenging this “obesity paradox.” In this review article, we present updated evidence and discuss the validity of the “obesity paradoxon” in a variety of clinical settings.
- coronary stent
- obesity paradox
Obesity has traditionally been defined as a body mass index (BMI) value >30 kg/m2, and its prevalence in the Western world, according to recent epidemiological data, could be as high as 36.5% . Evidence of the growing prevalence of obesity can be inferred from the USA, where almost 70% of the population has been classified as obese; a significant increase from the 25% reported forty years ago . The clinical relevance of obesity and its cluster of associated disorders, like arterial hypertension, dyslipidemia, diabetes mellitus, and sleep apnea syndrome, are demonstrated by its persistent link to an increased morbidity as well as mortality [3, 4]. It is for this reason that initiatives detailing the primary and secondary prevention of cardiovascular disease in overweight and obese patients have laid specific emphasis on the significance of weight loss so as to modify cardiovascular risk [5–7]. Obese patients have an increased preponderance to develop atherosclerotic disease, especially coronary artery disease, which is characterized by a reduced sensitivity to insulin, enhanced free fatty acid turnover, increased basal sympathetic tone, a hyper‐coagulable state, and finally with promotion of systemic inflammation [8, 9]. Population‐based data suggest that 43 and 24% of all coronary revascularization in recent years were carried out in overweight and obese patients, respectively . It has been speculated that the obese patient cohort is somehow associated with a clinical outcome far worse than that of a normal weight patient, and this theory is further substantiated by the existence of evidence describing the causative association of morbid obesity in cardiovascular disease. Interestingly, contemporary studies have recently elucidated the role of an “obesity paradoxon,” describing the protective effect of obesity (when considering postoperative morbidity and mortality) in patients receiving either surgical or minimally invasive coronary revascularization . This observation suggesting a better clinical outcome for obese patients is not only restricted to the clinical setting of coronary revascularization, as similar data have also been reported in cases of an acute myocardial infarction and heart failure [12, 13].
In this review article, we attempt to present an overview and summarize the evidence documented on “obesity paradoxon” in coronary artery disease.
2. Stable coronary artery disease
The correlation of BMI with clinical endpoints in the setting of interventional coronary revascularization from a single‐center experience in patients (
The Scottish Coronary Revascularization Register offers another perspective to this debate. In contrast to previous all‐comers trials, this study included only those patients (
In the TAXUS trials, of the 1307 patients stratified according to BMI and type of stent used (BMS versus DES) , higher rates of BMS in‐stent restenoses were observed in obese and overweight patients than in normal‐weight patients (29.2% vs. 30.5% vs. 9.3%;
|Author||Year||Follow‐up (months)||Mortality||Myocardial infarction||Target vessel revascularization||Renal insufficiency||Vascular complications|
|Ellis et al. ||1996||3571||12||+||–||–||+||+|
|Gurm et al. ||2002||3634||60||+||n.a.||n.a.||n.a.||–|
|Gruberg et al. ||2002||9633||12||+||–||–||+||–|
|Poston et al. ||2004||1631||12||–||n.a.||–||n.a.||n.a.|
|Nikolsky et al. ||2005||1301||12||–||–||–||n.a.||n.a.|
|Romero‐Corral et al. ||2006||250,152||45||+||n.a.||n.a.||n.a.||n.a.|
|Oreopoulos et al. ||2009||31,021||46||+||n.a.||n.a.||n.a.||n.a.|
|Hastie et al. ||2010||4880||60||+||n.a.||n.a.||n.a.||n.a.|
|Akin et al. ||2012||5806||12||–||–||–||–||–|
3. Acute coronary syndrome
The essential difference between stable coronary artery disease and an acute myocardial infarction is the existence of a pro‐inflammatory state with different forms of hemodynamic, rhythmogenic, and hemostatic disturbance in the latter. Although the “obesity paradoxon” phenomenon has been evaluated in the patient population, there is lack of homogenous data establishing a potential link between BMI and clinical events in patients with acute myocardial infarction. Data analyses of the 6359 acute coronary syndrome (ACS) patients included in the PREMIER and TRIUMPH registries drawn to establish a relationship between BMI and survival rate yielded novel results . BMI and mortality rates shared an inverse relationship (9.2% vs. 6.1% vs. 4.7%;
An attempt to reaffirm this inverse relationship between BMI and clinical outcome in this scenario, however, was not possible in many other similarly conducted trials [24, 25]. Our research working group analyzed data from 890 patients diagnosed with ST‐elevated myocardial infarction and followed them up for a duration of 12 months. This group also constituted patients diagnosed with cardiogenic shock. Interestingly, results indicated that clinical events did not vary significantly between all three weight groups, thus challenging the premise of the “obesity paradox”  (Table 2).
|Author||Year||N||Follow‐up (months)||Mortality||Myocardial infarction||Target vessel revascularization||Renal insufficiency||Vascular complications|
|Kosuge et al. ||2008||3076||hospital||–||n.a.||n.a.||n.a.||n.a.|
|Kang et al. ||2010||3824||12||+||–||–||n.a.||n.a.|
|Camprubi et al. ||2012||824||hospital||–||n.a.||n.a.||n.a.||n.a.|
|Bucholz et al. ||2012||6359||12||+||n.a.||n.a.||n.a.||n.a.|
|Li et al. ||2013||1429||12||–||–||–||n.a.||n.a.|
|Shehab et al. ||2014||4379||1||–||–||–||n.a.||n.a.|
|Akin et al. ||2015||890||12||–||–||–||–||–|
4. Rationale for the “obesity paradox”
The growing incidence of obesity can be construed from data suggesting an increase of 37% from 13.6 to 18.6%, in the cases of self‐reported obesity, among men aged 35–49 since 1970. Epidemiological factors attributed to the development of obesity and cardiovascular disease like arterial hypertension and diabetes mellitus are also on the rise [29, 30]. Recent efforts directed to reducing cholesterol levels and prevention of damaging smoking habits have helped sustain a decline in mortality from an acute coronary event. Frequent vessel revascularization has also possibly played a role in this positive development [31–33]. This, however, does not discount the influence of the metabolic syndrome and its link to various cardiovascular risk factors. Overweight and obese patients are derivatives of this syndrome, and the continual process of endothelial dysfunction and inflammation is often associated with the risk of developing atherosclerosis.
Evidence of this correlation constitutes an interesting paradox where better survival rates in an acute coronary event are real despite an increased incidence of obesity. This pertinent question has festered an ongoing debate as to the existence of the “obesity paradoxon” phenomenon in the spectrum of coronary artery disease [10–26].
An examination of current literature indicates that certain published data, essentially that comprising retrospective information, have claimed a U‐shaped nonsignificant trend to suggest lower survival among underweight patients as compared to normal or mildly overweight patients. This, however, could be the result of a technical bias, which unfortunately cannot be fully corrected by statistical means.
A detailed analysis of these patient groups has suggested that up to 2% of patients who are underweight are likely to suffer from comorbid conditions, including malignancies, heart failure, malnutrition, and multi‐organ dysfunction (MODS). This patient group also happens to constitute a significantly older age group demographic as compared to normal and obese patients [10, 11, 15], and clear evidence has linked elderly and frail patients to significantly poorer clinical outcomes regardless of management or reperfusion strategy [34, 35]. An interesting highlight in this respect is the influence of increasing age with its concomitant comorbidities on weight change [36–38]. The possibility of chronic disease leading to gradual weight loss had not been factored into presented trials. Another important confounding observation was the increased tendency of obese patients receiving diagnosis and treatment at an earlier stage in comparison with lean patients.
A recent survey of >130,000 patients suggested that patients with higher BMI adhere more sincerely to guidelines with regard to the use of standard drugs such as aspirin, beta‐blockers, acetylcholinesterase inhibitors, angiotensin II receptor blockers, as well as lipid‐lowering drugs and are increasingly likely to undergo invasive diagnostic and therapeutic interventions [15, 18, 21]. Additionally, overweight and obese subjects tended to be more stable at presentation, with the general constellation describing a patient lacking hemodynamic compromise, having a lower Killip class and also a preserved or less impaired ventricular function, which in turn proffers a better prognosis to the existing clinical scenario. These preliminary results present a clear challenge to the “obesity parodoxon” phenomenon.
Novel theories explaining the post‐PCI “obesity paradoxon” hypothesize that obese patients have “larger vessels” somehow instituting a beneficial effect. A further consolidation of this hypothesis naturally suggests that post‐PCI outcome is significantly worse in patients with smaller vessels [39, 40]. The pharmacology of antithrombotic drugs is another interesting topic of discussion in this regard. The use of a standard dose rather than weight‐adjusted dosages precludes accurate measurement of the pharmacokinetic and pharmacodynamic effects of these medications in each patient. For example, the standard dose could very well be too high for an underweight patient (as calculated by BMI) resulting in significant bleeding events and is associated with a higher mortality rate . Similarly, the sheath‐to‐artery size ratio varies in different BMI groups, and this could influence the rates of vascular complications . These superficial differences observed in the context of a periprocedural event can reflect on the perceived improved survival noted among overweight patients [11, 42].
An absolute limiting factor in most studies centers around the use of BMI as a measure of obesity. The inadequate documentation of obesity distribution questions the plausibility of several results as this vital information has a significant impact in the clinical scenario. For example, central obesity has been associated with a poorer clinical outcome . Other parameters such as waist circumference, waist‐to‐hip ratio, and weight change have not found mention in several of these trials [44–47]. Additionally, the inherent limitation of all these trials hypothesizing the “obesity paradoxon” is that they are an observational retrospective registry.
The failure to analyze potentially confounding variables such as physical inactivity, unintended weight loss, the influence of socioeconomic factors, as well as the short follow‐up of these registries may have contributed to additional bias. Any existing relationship between obesity and in‐hospital and short‐term survival may have been lost, and the longer patients were followed. The possible buildup of the detrimental effects of obesity overtime could also have been studied in an extended follow‐up period, perhaps establishing a link to increased late mortality [48, 49].
The “obesity paradoxon” hypothesis hinges on certain questionable data. The proponents of this theory claim that replete adipose tissue plays the role of an endocrine organ  producing soluble tissue necrosis factor receptor and hence ensues the protective effect .
Conversely, higher levels of thrombotic factors as well as elevated plasminogen activator inhibitor‐I in patients who are morbidly obese (BMI > 40 Kg/m2) probably contribute to the higher adjusted rates of post‐PCI mortality seen in this patient group .
The suggestion, in early studies, that there exists an inverse relationship between underweight patients and outcomes in heart failure is what heralded the concept of “obesity paradoxon.” However, an in‐depth analysis of recently published data questions any such claim in the setting of coronary artery disease and modern coronary intervention. In fact, there is insufficient evidence or even proof of concept to veer away from the classic relationship between risk factors, confounding variables and prognostic outcomes. These association studies are limited not only by the lack of pathophysiological underpinnings, but also hindered by the use of descriptive notions and confounding variables with unknown impact to substantiate their results. While analyzing the neutralizing results of the German DES.DE Registry , the perception of obesity demonstrating a protective effect on outcomes post‐PCI is seriously held in doubt and the provocative construct of an “obesity paradoxon” debased, as this hypothesis was never really substantiated in the clinical setting of coronary artery disease and PCI.
Finally, the support expressed by associative studies (in light of little or no statistical and biological evidence) leading to the hypothesis of an “obesity paradox” has been effectively debunked by the interpretation of recent clinical data. A contrarian concept would only hold traction if supported by plausible pathophysiology. In the context of coronary artery disease and PCI, there are hardly any convincing explanation and certainly no clinical data to justify an “obesity paradoxon.”
Conflict of interest
No conflict of interest for all authors.
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