**4. Rationale for the "obesity paradox"**

(2.5% vs. 2.1% vs. 2.8%; *p* = 0.53) between normal weight, overweight, and obese patients,

**Table 1.** Overview of literature addressing the "obesity paradox" in patients suffering from stable coronary artery

**Mortality Myocardial infarction**

Ellis et al. [14] 1996 3571 12 + – – + + Gurm et al. [15] 2002 3634 60 + n.a. n.a. n.a. – Gruberg et al. [11] 2002 9633 12 + – – + – Poston et al. [19] 2004 1631 12 – n.a. – n.a. n.a. Nikolsky et al. [20] 2005 1301 12 – – – n.a. n.a.

Hastie et al. [16] 2010 4880 60 + n.a. n.a. n.a. n.a. Akin et al. [21] 2012 5806 12 – – – – –

**Target vessel revascularization**

45 + n.a. n.a. n.a. n.a.

46 + n.a. n.a. n.a. n.a.

**Renal insufficiency** **Vascular complications**

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 [22]. BMI and mortality rates shared an inverse relationship (9.2% vs. 6.1% vs. 4.7%; *p* < 0.001) irrespective of demographic age and sex distribution. The KAMIR registry yielded similar results in its 3824 ST‐elevation myocardial infarction patient collective [23]. The baseline characteristics defined an older group of normal weight patients, with impairment of left ventricular ejection fraction and having a higher comorbidity index. The study eventually summarized that normal weight patients were associated with higher mortality rates.

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

respectively (**Table 1**).

Oreopoulos et al. [17] 2009 31,

Romero‐Corral et al. [18]

**3. Acute coronary syndrome**

**Author Year** *n* **Follow‐up** 

184 Adiposity - Omics and Molecular Understanding

2006 250, 152

021

disease undergoing coronary angiography and/or revascularization.

**(months)**

the premise of the "obesity paradox" [26] (**Table 2**).

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 [41]. Similarly, the sheath‐to‐artery size ratio varies in different BMI groups, and this could influence the rates of vascular complications [15]. 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 [43]. 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 [50] producing soluble tissue necrosis factor receptor and hence ensues the protective effect [51].

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 [52].

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 [21], 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

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

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

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 [41]. Similarly, the sheath‐to‐artery size ratio varies in different BMI groups, and this could influence the rates of vascular complications [15]. These superficial differences observed in the context of a periprocedural event can reflect on the perceived improved survival noted among

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 [43]. 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 retrospec-

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

at an earlier stage in comparison with lean patients.

186 Adiposity - Omics and Molecular Understanding

overweight patients [11, 42].

tive registry.

late mortality [48, 49].

present a clear challenge to the "obesity parodoxon" phenomenon.

No conflict of interest for all authors.
