Obesity and the Obesity Paradox

Introduction

After smoking, obesity is probably the second leading cause of preventable death in the United States and most of the westernized world. The estimated prevalence of obesity is almost 80 million, with close to 130 million in the United States being overweight, and currently almost 10 million being severely obese. In fact, during the past 50 years, the average life expectancy in the United States has been reduced by a full year due to the impact of obesity, partially offsetting gains made from reduced smoking and improvements in automobile safety ( Fig. 19.1 ). Therefore, attention directed at the prevention and treatment of obesity is especially needed.

Obesity appears to be a risk factor for cardiovascular (CV) disease (CVD) independently of age, lipid levels, blood pressure (BP), glucose levels, and left ventricular hypertrophy. Certainly, obesity places a “heavy” toll on the CV system, negatively affecting many of the established CV and coronary heart disease (CHD) risk factors, including increasing BP and the prevalence of hypertension, worsening plasma lipid levels (in particular increasing triglyceride levels and reducing the cardioprotective high-density lipoprotein cholesterol [HDL-C] levels), increasing glucose levels and the risk of metabolic syndrome and type 2 diabetes mellitus (T2DM), and increasing levels of inflammation. Additionally, obesity has adverse effects on CV structure and function. Combined, these effects increase the risk of CVD, including CHD.

In this chapter, we review the effects of obesity on CHD risk factors and on the prevalence of CHD. We also review the impact of obesity on prognosis in patients with established CHD, including patients following revascularization procedures with percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG). Finally, we will discuss the implications of weight loss in patients with CHD, especially in light of the so-called “obesity paradox.”

Mechanisms Linking Obesity with Increased CHD Risk

The adverse effects of obesity on CHD risk factors and CV structure and function are summarized in Box 19.1 . Excess body weight is one of the most powerful risk factors for increased BP and the development of hypertension, a major CHD risk factor. In a prospective examination of 35- to 75-year-old participants from the Framingham Heart Study, 34% of hypertension cases in men and 62% of hypertension cases in women were attributed to a body mass index (BMI) greater than or equal to 25 kg/m ² based on the estimated population attributable risk. In an analysis of patients with a self-reported BP higher than 140/90 mmHg in the Physicians’ Health Study, which included over 13,500 healthy male physicians, an 8% increase in the risk of incident hypertension was noted for each one-unit increase in BMI during a median 14.5-year follow-up. In this study, although incident hypertension was mostly associated with obesity at baseline, a weight gain of more than 5% in 8 years was also significantly associated with an increased hypertension risk in persons with normal baseline BMI.

Obesity is a leading cause of elevated blood glucose, metabolic syndrome, and T2DM. In an examination of data from the Behavioral Risk Factor Surveillance System from 1990 to 1998, the overall prevalence of T2DM increased by 33%, which was closely related to the increased prevalence of obesity. In fact, a 9% increase in T2DM rate was noted for every 1 kg increase in weight. The association of obesity with insulin resistance and metabolic syndrome appears to significantly increase the risk of T2DM and CVD. Metabolic syndrome, which is defined by abdominal obesity, atherogenic dyslipidemia, hypertension, insulin resistance, and pro-inflammatory and prothrombotic states, is associated with a more than twofold increased risk of CHD, with an attributable risk of 37% in patients older than 50 years. Alexander and colleagues in 2003, in an analysis of the National Health and Nutrition Examination Survey, noted no increase in CHD prevalence in patients who had T2DM but no metabolic syndrome, whereas CHD risk was increased in patients with metabolic syndrome but without T2DM. The highest risk of CHD was noted in those with metabolic syndrome and T2DM. The higher risk is imposed by higher intra-abdominal fat, measured clinically as waist circumference (WC). WC was the strongest predictor of metabolic syndrome, was independently associated with each component of the metabolic syndrome, and was more strongly associated with metabolic syndrome than was BMI.

Atherogenic dyslipidemia and metabolic syndrome in obesity is defined by elevated triglyceride levels, low levels of HDL-C, and increased proportions of small, dense low-density lipoprotein cholesterol (LDL-C), which is more atherogenic than the large, more buoyant LDL-C. Increased circulating fatty acids are taken up by the liver, which results in increased production of triglyceride-rich particles, especially very-low-density lipoproteins. In the setting of high triglycerides, most of the LDL-C is produced in the small, dense form, which is more easily oxidized and more atherogenic.

Although the association of obesity with increased CVD has been established independently and in association with such major risk factors as hypertension, metabolic syndrome/T2DM, and atherogenic dyslipidemia, the exact mechanisms linking obesity, especially abdominal obesity, with insulin resistance and other factors influencing the risk of CVD have not been fully elucidated. Fat-related hormones and cytokines, termed adipokines , are secreted by the adipocytes and macrophages in adipose tissue. Several clotting factors, including fibrinogen, von Willebrand factor, and factor VII and VIII, are increased in obesity and insulin resistance. Plasminogen activator inhibitor type-I levels increase with BMI and WC, which may inhibit endogenous fibrinolysis. Mechanisms involved with increasing BP include insulin-mediated vasoconstriction, increased insulin-mediated renal sodium reabsorption, insulin-related stimulation of the sympathetic nervous system, increased vasoconstriction related to elevated free fatty acids, and production of components of the renin-angiotensin-aldosterone system by adipose tissue.

Leptin levels also increase in obesity, and chronically elevated leptin levels have been related to increased atherosclerosis, in-stent restenosis, and inflammation. Interleukin-6, tumor necrosis factor, adiponectin, and C-reactive protein (CRP) may also be elevated and be involved in atherosclerosis and CHD events.

Association of Obesity with CVD Events

Considering the multiple pathogenic mechanisms associated with obesity described above, there is no surprise that obesity is related to increased risk of most CVD, including hypertension, heart failure (HF), atrial fibrillation (AF), as well as CHD and CHD events. Many of these factors are associated with inflammation, prothrombotic states, and increased risk of atherosclerosis. Many large prospective studies, including the Framingham Heart Study, the Nurses Health Study, and the Manitoba Study, have documented obesity as an independent predictor of CVD. The potential relationship between BMI categories and incidence of non-ST-segment elevation myocardial infarction (NSTEMI) were assessed retrospectively in a cohort of over 110,000 patients with unstable angina and NSTEMI in which obesity was the strongest risk factor was associated with NSTEMI at younger age, ahead of tobacco abuse. In fact, compared with normal-weight individuals, the mean age incidence of NSTEMI was 3.5, 6.8, 9.4, and 12.0 years earlier in overweight (BMI 25–29.9 kg/m ² ), Class I obesity (BMI 30–34.9 kg/m ² ), Class II obesity (BMI 35–39.9 kg/m ² ), and Class III obesity (BMI ≥ 40 kg/m ² ), respectively. Considering the increased prevalence of obesity and more severe obesity, there is concern for marked increases in the occurrence of acute CVD events in younger individuals in upcoming decades.

Several recent reports have also demonstrated that severe Class III obesity is a significant predictor of premature myocardial infarction (MI) at very young ages. However, obesity, especially when only mild to moderate in severity, may have a different impact regarding infarct size and severity of coronary artery disease (CAD). In fact, recent data demonstrated that obese patients with MI had less severe CAD than thinner patients with MI. Also, the size of MI in NSTEMI was different to that in ST-segment elevation MI (STEMI), with obese patients having greater infarct size in NSTEMI, but smaller infarct size in STEMI.

Impact of Obesity on Prognosis in CHD: The Obesity Paradox

Given the well-known adverse effects of overweight and obesity on major CVD risk factors discussed above, not surprisingly almost all CVD, including CHD, is increased in the setting of higher weight. However, many studies of patients with established CVD, including hypertension, HF, AF, as well as CHD, have demonstrated surprisingly good prognosis in overweight and obese patients, which has been termed the obesity paradox . In fact, despite challenges at the time of CV revascularization in obese patients, these patients have tended to have a better overall prognosis following revascularization with PCI and CABG, and following MI, compared with leaner patients, with similar findings seen in patients with stable CHD.

Following Revascularization with PCI

Because of the higher prevalence of CAD, overweight and obese patients will frequently undergo coronary revascularization. In fact, population-based registries and databases have reported the prevalence of overweight and obesity to be as high as 70% among patients undergoing PCI or CABG. Various risk stratification systems have described obesity as a risk factor for worse clinical outcomes after coronary revascularization due to increased wound infections, longer hospital stay, and higher postprocedure mortality among more obese patients, although this may apply more to CABG than to PCI, as CABG may be postponed or declined due to obesity. However, there have been contradictory results in various studies describing the association between BMI and subsequent MI and CVD mortality, as well as other morbidity.

In PCI, establishing femoral access can be more difficult in obese patients, as is accomplishing hemostasis afterward; this may be less of an issue with more recent use of radial artery approach. Thigh and pelvic hematoma recognition may be delayed, as are the other physical examination findings associated with acute blood loss in patients with obesity. Nevertheless, despite the potential for access complications in obese patients, several studies have suggested a protective effect associated with obesity with regards to bleeding and vascular complications of PCI, similar to the paradox observed with other outcomes. Several studies have suggested that underweight and normal-BMI patients have higher bleeding complications than obese patients. Although the highest risk of bleeding occurred in patients with the lowest BMIs, a bimodal relationship was observed with also a high complication rate in those with the highest BMIs ( Fig. 19.2 ). Patients were more likely to undergo radial artery access as BMI increased, and both obese and nonobese patients have less vascular complications with this approach. Nonradial access was the strongest independent predictor of vascular complications in obese patients with PCI. Potentially lower bleeding in obese patients could have been related to younger age, better renal function, and lower relative doses of antithrombotic agents that are not dosed according to body weight.

We recently examined 26 studies of patients undergoing PCI, with data on age ( Table 19.1 ) and major events (total mortality, CVD mortality, and MI; Table 19.2 ). After a mean follow-up of approximately 1.7 years, compared with normal BMI subjects, the highest rate of mortality, CVD mortality, and MI occurred in underweight patients following PCI, being increased by 2.7-, 2.8-, and 1.9-fold, respectively. The overweight patients (BMI 25–29.9 kg/m ² ) had the lowest risk, with significant reductions in total mortality and CVD mortality of 32% and 22%, respectively, with a trend for 6% lower risk of MI. The mildly obese had a significant 36% reduction in mortality and a trend for 6% lower CVD mortality, whereas those with BMI of 35 kg/m ² or above had a trend for 19% lower mortality that was not statistically significant.

TABLE 19.1

Mean Age of Patients Undergoing PCI and CABG in Various BMI Categories

Reproduced with permission from Sharma A, Vallakati A, Einstein AJ, et al. Relationship of body mass index with total mortality, cardiovascular mortality, and myocardial infarction after coronary revascularization: evidence from a meta-analysis. Mayo Clin Proc . 2014;89:1080-1100.

	Mean Age (y)
BMI (kg/m 2 )	PCI	CABG
<20	69.3	67.9
20–24.9	65.0	64.6
25–29.9	62.3	64.0
30–34.9	60.1	61.9
≥35	58.3	60.5

BMI, Body mass index; CABG, coronary artery bypass graft; PCI, percutaneous coronary intervention.

TABLE 19.2

Results Summary: Outcomes after Coronary Revascularization Procedures as per BMI

Reproduced with permission from Sharma A, Vallakati A, Einstein AJ, et al. Relationship of body mass index with total mortality, cardiovascular mortality, and myocardial infarction after coronary revascularization: evidence from a meta-analysis. Mayo Clin Proc 2014;89:1080-1100.

	LOW BMI	Normal BMI	Overweight	Obese	Severely Obese
Total mortality	2.59 (2.09–3.21)	1	0.72 (0.66–0.78)	0.73 (0.61–0.87)	0.78 (0.64–0.96)
PCI	2.65 (2.19–3.20)	1	0.68 (0.62–0.74)	0.64 (0.56–0.73)	0.81 (0.61–1.07)
CABG	2.66 (1.51–4.66)	1	0.83 (0.67–1.02)	0.92 (0.64–1.34)	0.76 (0.55–1.04)
Cardiac mortality	2.67 (1.63–4.39)	1	0.81 (0.68–0.95)	1.03 (0.69–1.55)	1.47 (0.74–2.89)
PCI	2.76 (1.67–4.56)	1	0.78 (0.66–0.93)	0.94 (0.62–1.44)	1.16 (0.66–2.03)
CABG	0.98 (0.06–16.97)	1	1.06 (0.52–2.13)	1.57 (0.49–5.1)	4.07 (1.4–11.85)
Myocardial infarction	1.79 (1.28–2.50)	1	0.92 (0.84–1.01)	0.99 (0.85–1.15)	0.93 (0.78–1.11)
PCI	1.85 (1.28–2.67)	1	0.94 (0.86–1.03)	1.04 (0.87–1.25)	0.96 (0.77–1.19)
CABG	1.47 (0.64–3.4)	1	0.85 (0.64–1.14)	0.84 (0.67–1.05)	0.89 (0.66–1.20)

BMI, Body mass index; CABG, coronary artery bypass graft; PCI, percutaneous coronary intervention.