Coronary Artery Disease

Obesity paradox: a myth or reality, time to reveal the fact in a South Asian cohort presenting with STE-ACS undergoing primary percutaneous coronary intervention

Abstract

Objectives Obesity is a globally well-established risk factor for atherosclerotic cardiovascular diseases; however, some studies have witnessed survival benefits among obese patients and this phenomenon is termed ‘the obesity paradox’. Our aim was to evaluate the existence of an obesity paradox in patients with ‘ST-elevation acute coronary syndrome (STE-ACS)’ in our population.

Methods In this observational study, we included patients presenting with STE-ACS undergoing primary percutaneous coronary intervention (PCI). Body mass index (BMI) ‘(weight (kg)/height (m)2) was calculated and patients with BMI ≥30 kg/m2 were categorised as obese. All the patients were observed during their hospital stay for postprocedure in-hospital morbidity (pump failure, contrast-induced nephropathy, major bleeding, cerebrovascular accident/stroke, access site complications or stent thrombosis) and mortality.

Results A total of 1099 patients were included, out of which 78% (857) were men, and mean age was 54.66±10.9 years. The mean BMI was 27.48±4.93 kg/m2 and 23.2% (255) were categorised as obese. The in-hospital morbidity rate was 13.4% (113/844) vs 8.6% (22/255); p=0.042 and in-hospital mortality rate was 1.9% (16/844) vs 4.7% (12/255); p=0.013 for non-obese and obese patients, respectively. On multivariable analysis, obesity showed paradoxical protective effect with adjusted OR of 0.59 (95% CI 0.36 to 0.96, p=0.033) for postprocedure in-hospital morbidity. However, obesity was found to be an independent predictor of in-hospital mortality with an adjusted OR of 3.13 (95% CI 1.37 to 7.15, p=0.007).

Conclusion In conclusion, we have found evidence of the obesity paradox in in-hospital morbidity, but not in mortality, after primary PCI of patients with ST-ACS in our population.

What is already known on this topic

  • Obesity is a well-established modifiable metabolic risk factor for the development and progression of cardiovascular diseases. However, clinical studies have observed a paradoxical protective effect of obesity against mortality and morbidity in patients with cardiovascular diseases, especially after heart failure and acute coronary syndrome.

What this study adds

  • It has been observed that the ‘obesity paradox’ does exit with relatively protective effects against in-hospital morbidity after primary percutaneous coronary intervention (PCI), even after adjustment for the clinically significant factors in multivariable binary logistic regression. However, no such paradoxical association of obesity with in-hospital mortality was observed, in fact, obesity was found to be an independent predictor of in-hospital mortality after primary PCI. The paradoxical protective effect of obesity against morbidity after primary PCI was mainly driven by the significantly lower rate of pump failure among obese patients.

How this study might affect research, practice or policy

  • Contrary to the popular belief, obesity is among the major risk factors of mortality after acute coronary syndrome. Hence, it can be a vital risk stratification marker for clinicians and also it is important to further explore the possible clinical pathway and mechanism behind the paradoxical association of obesity with a lesser rate of poorer outcomes.

Introduction

The modern era brings new health challenges, the booming rate of obesity, especially in moderate-income to high-income countries, is one of the major public health issues of the 21st century.1 It is a multifactorial complex disease defined as a body mass index (BMI) of more than 30 kg/m2 as an indicator of an excessive accumulation of body fat or increased adiposity.2 3 The prevalence of obesity has reached an epidemic proportion in certain population segments and it has been reported to be directly or indirectly associated with an increased risk of premature deaths.4–6

In addition to the metabolic risk, obesity is a well-established risk factor with a direct or indirect role in the progression and development of cardiovascular diseases (CVD).6 The direct mode of action is through function and structural alterations to the heart induced by increased adiposity.6 7 The indirect mode of action is through its strong association with the well-established risk factors for CVD, which included atherosclerosis, diabetes mellitus, metabolic syndrome, hyperlipidaemia, hypertension and obstructive sleep apnoea.6–8 Several pathophysiological mechanisms for obesity-related cardiac structural and functional alterations have been postulated, which included, reduced insulin sensitivity or insulin resistance, hypercoagulability state, cytokine activation, neuro-hormonal changes, lipotoxicity, oxidative stress, and chronic inflammation.5 6 9–11

A widely acceptable aetiological explanation of obesity is the ‘chronic positive energy balance’, which means lesser expenditure and higher energy intake.10 Emerging patterns of multiple dietary and lifestyle factors can be attributed to the increasing burden of obesity in our societies. These factors mainly include ‘poor dietary choices’ characterised by excessive calorie intake and ‘sedentary lifestyle’ characterised by massive declines in physical activity (occupational/non-occupational).8 10 12

On one hand, obesity is reported to be associated with an increased risk of development and progression of CVD, and on the other hand, in several studies, it has been observed to play a paradoxical role characterised by favourable immediate-term, short-term and long-term outcomes in obese CVD patients as compared with their non-obese counterparts, commonly known as the ‘obesity paradox’.3 11 13–15 On the other hand, various studies have also negated the existence of the ‘obesity paradox’ at all or its existence is limited to particular subgroups, such as the elderly age group, female patients or patients with intact regenerative capacity.3 13 16–18 Hence, considering the geographical variations in the epidemiology of obesity,19 it is important to understand this phenomenon in a geographical context. Therefore, in this study, our aim was to evaluate the existence of an ‘obesity paradox’ in a South Asian cohort of patients with ‘ST-segment elevation acute coronary syndrome (STE-ACS)’ presented to a tertiary cardiac care hospital in Pakistan.

Materials and methods

This single-centre observational study was conducted at a tertiary care cardiac hospital in Pakistan, namely the ‘National Institute of Cardiovascular Diseases, Karachi, Pakistan’. In accordance with the Declaration of Helsinki verbal consent was obtained from all the patients or attendants and study proposal was approved by the ethical review board of the hospital (ERC-01/2022). Study was conducted between January 2022 and June 2022. We analysed prospectively collected data from the cohort of patients diagnosed with ‘STE-ACS’ undergoing primary percutaneous coronary intervention (PCI). The inclusion criteria for the study were patients diagnosed with STE-ACS, adult patients (≥18 years) of either gender shifted to the cardiac catheterisation laboratory for primary PCI as per the hospital protocol. Patients who refused to participate in the study were excluded.

STEMI was diagnosed based on history and a 12-lead ECG. Patients with a history of ‘typical chest pain for at least 20 min’ and 12-lead ECG finding of ‘ST elevation in at least two contiguous leads >2 mm in men or >1 mm in women in leads V2 to V3 and/or >1 mm in other contiguous chest leads or limb leads’. BMI ‘(weight (kg)/height (m)2)’ was calculated and patients with a BMI of ≥30 kg/m2 were categorised as obese. The obesity was further categorised into three groups; class I obesity (BMI from 30 kg/m2 to 34.9 kg/m2), class II obesity (BMI from 35 kg/m2 to 39.9 kg/m2) and class III obesity (BMI ≥40 kg/m2).

As per the hospital policy, all the primary PCI procedures were performed free of cost in accordance with standard clinical practice guidelines. All the patients received dual antiplatelet therapy, which included aspirin and clopidogrel, unfractionated heparin, along with the infusion of glycoprotein inhibitors (IIb/IIIa). The demographic, clinical and angiographic characteristics were obtained using a predefined proforma. All the patients were observed during their hospital course, and postprocedure complications and outcomes, including mortality, were observed. The postprocedure in-hospital morbidity was defined as either pump failure (symptoms and/or signs suggestive of structural and/or functional cardiac abnormality accompanied by evidence of pulmonary or systemic congestion), contrast-induced nephropathy (either relative increase of 25% or absolute increase of 0.5 mg/dL in postprocedure serum creatinine), major bleeding (required blood transfusion), cerebrovascular accident (CVA)/stroke, access site complications or stent thrombosis (acute/subacute).

Patients were stratified into two groups, obese and non-obese, as defined above. Two study groups were compared in terms of the distribution of demographic, clinical and angiographic characteristics and postprocedure complications and outcomes. Summary statistics are mean±SD/median (IQR) or frequency (%), appropriately. Appropriate statistical tests such as independent sample t-test (for normally distributed variables)/Mann-Whitney U test (for non-normal variables) or χ2 test/Fisher’s exact test were used for the comparison. The univariate binary logistic regression analysis was performed for in-hospital mortality for all clinically significant potential predictors of mortality including female gender, age (years), total ischaemic time (hours), random blood glucose level, Killip class III/IV at presentation, hypertension, diabetes, smoking, obesity (BMI ≥30 kg/m2), preprocedure left ventricular end-diastolic pressure (mm Hg), preprocedure ejection fraction (%) and multivessel disease. Variables with a p value of <0.20 in the univariate analysis were taken to the multivariable logistic regression analysis for in-hospital mortality. The OR (95% CI) was reported for both univariate and multivariable binary logistic regression analyses. All the statistical analyses were performed using IBM SPSS V.21 and a p value <0.05 was considered statistically significant.

Results

A total of 1099 patients were included in this study, out of which 78% (857) were men and mean age was 54.66±10.9 years. The mean BMI was 27.48±4.93 kg/m2 and 23.2% (255) were categorised as obese, out of which 74.6% (190/255) were categorised as class I, 17.6% (45/255) as class II and remaining 7.8% (20/255) was class III obesity.

Patients in Killip class III/IV at presentation (2.4% vs 1.5%) were relatively higher among obese patients. Gender (male: 75.3% vs 78.8%; p=0.238) and age (54.58±10.97 vs 54.68±10.88 years; p=0.902) distribution and prevalence of hypertension (56.5% vs 51.9%; p=0.200) and diabetes (36.1% vs 34.6%; p=0.664) were equally in both obese and non-obese patients, respectively. However, prevalence of smoking (18.8% vs 25.1%; p=0.038) was lower and history of ischaemic heart diseases (8.2% vs 4.5%; p=0.020) was higher for obese and non-obese patients, respectively (table 1).

Table 1
|
Comparison of demographic and clinical characteristics between diabetic and non-diabetic patients

Similarly, angiographic findings, such as number of involved vessels (p=0.725), culprit segment (p=0.533) and preprocedure thrombolysis in myocardial infarction flow (p=0.272) had not association with obesity status (table 2).

Table 2
|
Comparison of angiographic characteristics between diabetic and non-diabetic patients

The incidence rate of in-hospital morbidity was observed to be 12.3% (135), it was observed to be significantly higher among non-obese patients with the incidence rate of 13.4% (113/844) vs 8.6% (22/255); p=0.042 for non-obese and obese patients, respectively. The incidence of various complications was not statistically significant between the obese and non-obese patients with incidence rate of 2% vs 3%; p=0.390 for contrast-induced nephropathy (CIN), 11.4% vs 12.6%; p=0.613 for slow-flow/no-reflow, 0.4% vs 0.7%; p=0.575 for access site complication, 0.4% vs 0.4%; p=0.932 for CVA/stroke. However, rate of heart failure (3.1% vs 7.5%; p=0.014) was significantly lower and in-hospital all-cause mortality (4.7% (12/255) vs 1.9% (16/844); p=0.013) and cardiovascular mortality (3.9% (10/255) vs 1.3% (11/844); p=0.015) were significantly higher among obese and non-obese patients (figure 1).

Figure 1
Figure 1

Comparison of rate post-procedure complications and outcome between obese and non-obese patients.

On multivariable analysis, obesity showed paradoxical protective effect with adjusted OR of 0.59 (95% CI 0.36 to 0.96, p=0.033) for postprocedure in-hospital morbidity. While, Killip class III/IV, hypertension and diabetes were round to be significant predictors of postprocedure in-hospital morbidity with adjusted OR of 2.48 (95% CI 1.13 to 5.47, p=0.024), 2.10 (95% CI 1.38 to 3.19, p<0.001) and 1.61 (95% CI 1.08 to 2.41, p=0.020), respectively (table 3). However, obesity was found to be an independent predictor of in-hospital mortality with an adjusted OR of 3.13 (95% CI 1.37 to 7.15, p=0.007) along with Killip class III/IV (12.97 (95% CI 4.82 to 34.94, p<0.001)) and multivessel diseases (3.4 (95% CI 1.11 to 10.45, p=0.033)), as reported in table 3.

Table 3
|
Univariate and multivariable binary logistic regression analysis for post-procedure in-hospital morbidity and mortality

Discussion

Obesity is a well-established modifiable metabolic risk factor for the development and progression of CVDs. However, clinical studies have observed a paradoxical protective effect of obesity against mortality and morbidity in patients with CVDs, especially after heart failure and acute coronary syndrome.3 11 13–15 In this study, our aim was to evaluate this paradoxical clinical scenario in our population. It has been observed that the ‘obesity paradox’ does exit with relatively protective effects against in-hospital morbidity after primary PCI, even after adjustment for the clinically significant factors in multivariable binary logistic regression with adjusted OR of 0.59 (95% CI 0.36 to 0.96, p=0.033). However, no such paradoxical association of obesity with in-hospital mortality was observed, in fact, obesity was found to be an independent predictor of in-hospital mortality after primary PCI with an adjusted OR of 3.13 (95% CI 1.37 to 7.15, p=0.007). The paradoxical protective effect of obesity against morbidity after primary PCI was mainly driven by the significantly lower rate of pump failure among obese patients (3.1% vs 7.5%; p=0.014). It has been reported in the literature that the diagnosis of congestive heart failure is relatively difficult among obese patients due to masking of peripheral oedema and pathologically pre-existence of symptoms such as shortness of breath and fatigue making it harder to differentiate and leading to underestimation of the event.20

In the literature, the obesity paradox has been evaluated by multiple studies in varying multiple clinical scenarios and it has been validated in various subpopulations. For example, Fukuoka et al13 conducted a study with a sample of 1634 patients undergoing primary PCI, the obesity paradox was observed in elderly patients with a higher risk of all-cause mortality among non-obese patients during a follow-up period of 620 (344 to 730) days with a HR of 1.69 (95% CI 1.12 to 2.55, p=0.012). However, there was no evidence of an obesity paradox for young patients, and on the contrary, obesity was observed to be an independent predictor of all-cause mortality among young patients with a HR of 2.77 (95% CI 1.19 to 6.45, p=0.018).13 In continuation of these findings, Keller et al16 reported a lower incidence of in-hospital mortality among obese patients with a 0.54-fold risk for death during in-hospital in a study of a nationwide database of 122 607 acute myocardial infarction patients of more than 70 years of age in the German population.16 The obesity paradox was also observed in long-term follow-up, a study single-centre retrospective study of 6496 by Kanic V et al11 reported an obesity paradox in all-cause mortality rate during a median follow-up of 6 years after PCI. This study further reported an inverse J-shaped relationship between all-cause mortality rate and BMI with both higher and lower BMI associated with adverse outcomes. In a study of a population-based sample of prevalent CVD cases by Chang et al14 reported obesity paradox with 18% to 36% lower hazard of death for class I obese patients in comparison of the normal weight patients. In another study of 19 499 ST-ACS patients above 64 years, a U-shaped association between mortality within 3 years after discharge and BMI categories was observed and mild obesity was found to be associated with a lower risk of long-term death.5

Although, a concise mechanism behind this paradoxical effect is not established. However, multiple studies have narrowed down to subgroups with paradoxical phenomena. For example, Mehta et al3 in their study reported an obesity paradox in coronary artery disease patients with intact regenerative capacity reflected by higher circulating progenitor cell counts.3 In a study conducted by Won KB et al15 the greater benefits of statin therapy were observed in obese patients after acute myocardial infarction and it has been associated with the phenomenon of obesity paradox.15 Other possible physiological pathways behind the obesity paradox included higher catabolic reserve in obese patients to cater to catabolic stress in acute states such as acute myocardial infarction and heart failure.21 22 Additionally obesity-related inflammatory and neuro-hormonal processes such as interleukin-10, renin-angiotensin responses, tumour necrosis factor, the detoxification of lipopolysaccharides, sympathetic nervous system responses, circulating atrial natriuretic peptides, and leptin are the few possible pathways behind the paradoxical phenomenon of the lesser rate of adverse events in obese patients.21–23

Limitations

Even though, possibly this is the first and largest study on the obesity paradox in STE-ACS patients in our population. Certain limitations need to be recognised, first and foremost it was a single-centre experience, second, the criteria of BMI value ≥30 kg/m2 for obesity can be an overestimation, considering the anthropological and structural differences of our population compared with the western population, and finally, lack of follow-up. Hence, further studies are needed to ascertain the existence or non-existence of the obesity paradox in our population.

Conclusion

In conclusion, we have found evidence of the obesity paradox in in-hospital morbidity, but not in mortality, after primary PCI of patients with STE-ACS in our population. It is important to further explore the possible clinical pathway and mechanism behind the paradoxical association of obesity with a lesser rate of poorer outcomes.