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The rising prevalence of obesity is driving an increased focus on its role in promoting cardiovascular disease. Estimates of the age-adjusted prevalence of obesity and severe obesity increased significantly among adults, but not among children and adolescents, in the U.S. between 2001-2004 and 2013-2016.^1,2 During 2013-2016, 38.9% of adults had obesity and 7.6% had severe obesity.² The prevalence estimates for obesity and severe obesity in children and adolescents during that period were 17.8% and 5.8%, respectively.²

The Obesity Medicine Association defines obesity as a chronic, relapsing, multifactorial, neurobehavioral disease wherein an increase in body fat promotes adipose tissue dysfunction and abnormal fat mass physical forces, resulting in adverse metabolic, biomechanical, and psychosocial health consequences.³

Increased Cardiovascular Disease Risk

Obesity has consistently been associated with an increased risk for metabolic diseases and cardiovascular disease. "An increase in body fat can directly contribute to heart disease through atrial enlargement, ventricular enlargement, and atherosclerosis," said Harold Bays, MD, medical director and president of the Louisville Metabolic and Atherosclerosis Research Center in Kentucky. Further, increased body fat indirectly contributes to heart disease, "through promotion of sleep apnea, thromboembolic disease, and onset or worsening of metabolic diseases that are major cardiovascular disease risk factors, including dyslipidemia, type 2 diabetes, high blood pressure, and metabolic syndrome."

In the Cardiovascular Risk in Young Finns Study, repeated measurement of participants' height and weight between 1980 and 2011 showed that trajectories of worsening or persisting obesity were associated with an increased risk of cardiovascular disease in adulthood.⁴ Participants who reduced their elevated childhood body mass index (BMI) to normal levels had a similar risk for dyslipidemia and hypertension compared with those who were never obese or overweight. Another study demonstrated that an increase in BMI between age seven and early adulthood was associated with an increased risk of type 2 diabetes.⁵

A longitudinal cohort study of 67,278 participants, half of whom were obese, found that those with obesity were significantly more likely to have hypertension and diabetes. Over 8 years of follow-up, obesity was strongly associated with a new diagnosis of atrial fibrillation after controlling for age, gender, hypertension, and diabetes.⁶ As of 2015, an elevated BMI accounted for four million deaths globally.⁷ An analysis of data from 3,310 patients in the TOPCAT study found that the risk of all-cause mortality was significantly higher in patients with heart failure with preserved ejection fraction (HFpEF) with abdominal obesity than in those without abdominal obesity.⁸

Pathogenesis of Obesity

The etiology of obesity is multifactorial. Contributors to the pathogenesis include genetic, environmental, sociocultural, physiological, medical, behavioral, and epigenetic factors.

• More than 140 genetic chromosomal regions related to obesity have been identified. Genes related to BMI and general adiposity are highly expressed in the central nervous system⁷
• Obesity genes are thought to act within the hypothalamic homeostatic regulator of energy balance and within neural circuits related to reward-based decision-making, learning and memory, delayed discounting, and spatial orientation⁷
• Epigenetically increased risk for adult obesity can also be transmitted to future generations⁷
• Other factors include disrupted sleep, mental stress, neurologic dysfunction, viral infections, and inflammation³
• Interactions among the causative factors can lead to excessive weight gain and obesity⁷

Gut microbiota also have a role in promoting increased adiposity. Proinflammatory signaling generated in response to bacterial lipopolysaccharide may affect neurobehavioral brain centers and adversely affect adipocyte function, leading to adiposopathy and increased risk for metabolic disease.

Adiposopathy

Adiposopathy refers to the pathogenic enlargement of adipose cells and adipose tissue that results in anatomic and functional abnormalities, leading to metabolic disease and increased cardiovascular disease risk. "Given that adipose tissue has no less potential for disease than any other body organ, the term adiposopathy is intended to identify adipose tissue organ pathology similar with the 'opathies' of other body organs," said Bays. Specifically, adiposopathy is defined as adipocyte and adipose tissue dysfunction caused by positive caloric balance and sedentary lifestyle in genetically and environmentally susceptible individuals.⁹

Anatomic manifestations of adiposopathy include:

• Adipocyte hypertrophy
• Increased visceral, pericardial, perivascular, and other periorgan adiposity
• Growth of adipose tissue beyond its vascular supply with ischemia, cellular death, and inflammation
• Increased adipose tissue immune cells
• Ectopic fat deposits in other organs⁹

Pathophysiologic manifestations of adiposopathy include:

• Impaired adipogenesis
• Pathologic adipocyte organelle dysfunction
• Increased circulating free fatty acids
• Pathogenic adipose tissue endocrine and immune responses
• Pathogenic interaction with other organs⁹

These anatomic and pathophysiologic changes result in various clinical manifestations, including high blood glucose, insulin resistance, hypertension, adiposopathic dyslipidemia, metabolic syndrome, atherosclerosis, and a host of other pathologies. In his review of adiposopathic changes that occur with increased body fat, Bays wrote, "A clinical application of Ockham's razor suggests adiposopathy as the primary cause of most cases of metabolic diseases such as high glucose levels, high blood pressure, and dyslipidemia, as well as most cases of cardiovascular disease."⁹

Obesity and Inflammation in Cardiovascular Disease

Obesity promotes systemic inflammation, and inflammation can drive adipogenesis. Chronic systemic inflammation, along with increased accumulation of epicardial adipose tissue has been observed in people with obesity.¹⁰ "Most cardiologists are familiar with the 'inside to in' model of atherosclerosis, wherein atherogenic lipoproteins in the circulation become entrapped in the subendothelium and generate an inflammatory reaction that promotes atheromatous plaque," Bays said. "It is increasingly recognized that the adiposopathic 'sick fat' surrounding the heart can also transmit inflammatory responses that promote heart disease. This is sometimes called the 'outside to in' model of atherosclerosis."

Systemic inflammation promotes the expression of a proinflammatory phenotype in epicardial fat, particularly the adipose tissue surrounding the coronary arteries. Chronic inflammation and accumulation of epicardial fat is strongly associated with the presence, severity, and progression of coronary artery disease, independent of visceral adiposity.¹⁰ Normal epicardial adipocytes are similar, with adipocytes from brown adipose tissue, which burn fatty acids and nourish adjacent tissues. They secrete adiponectin, which minimizes inflammation and fibrosis in the coronary arteries and myocardium.

In contrast, epicardial fat in obese people is more prone to lipolysis, leading to release of fatty acids and reactive inflammation. In obesity, adiponectin secretion from epicardial fat is reduced and proinflammatory adipokines are released, promoting infiltration of macrophages, destruction of microvascular systems, and activation of fibrotic pathways ().¹⁰

The most common myocardial disorder in people with obesity is HFpEF, characterized by ventricular fibrosis and decreased distensibility, along with modestly increased cardiac volume, relatively low natriuretic peptide levels, and impaired renal function. Even modest volume overload leads to cardiac overfilling and disproportionate increase in cardiac filling pressures.¹⁰

Metabolically Healthy Obesity

Metabolically healthy obesity (MHO) refers to obesity without the presence of metabolic syndrome. People with MHO typically have intermediate levels of visceral adiposity and cardiovascular risk between those with normal weight and those with obesity.¹¹ However, studies have found that at least half of participants with MHO at baseline convert to metabolically unhealthy obesity with increased risk of cardiovascular disease.^11,12

"Reports of patients who are metabolically healthy but with obesity are highly dependent upon how healthy is defined," Bays said. "With more strict definitions, it is rare to find such individuals. In these rare cases, the addition of time often transforms the apparently 'healthy' patient with obesity into a patient who ultimately expresses the complications of obesity, and thus becomes unhealthy."

In the Nurses' Health Study, 84% of 3,027 women with MHO at baseline converted to unhealthy phenotypes after 20 years of follow-up.¹² The MESA study reported that 48% of participants with MHO developed metabolic syndrome and an increased risk of cardiovascular disease during a median 12.2 years of follow-up.

"Reports of patients who are metabolically healthy, but with obesity are highly dependent upon how healthy is defined," Bays said. "With more strict definitions, it is rare to find such individuals. In these rare cases, the addition of time often transforms the apparently 'healthy' patient with obesity into a patient who ultimately expresses the complications of obesity, and thus becomes unhealthy. The concept of the obesity paradox is no longer as paradoxical when functionality of adipose tissue is the focus, as opposed to the amount of adipose tissue.

"The degree by which fat is functional or dysfunctional -- from an endocrine and immune standpoint -- is what helps determine the pathogenic potential of increased body fat. This is why the concept of adiposopathy or 'sick fat' is so important."

Management

Weight loss is recommended for all overweight or obese patients with comorbid conditions such as prediabetes, diabetes, hypertension, and dyslipidemia.⁶ "Recognizing the pathogenic potential of adipose tissue may afford a clearer rationale toward recommending weight reduction to overweight patients. In other words, discussing how fat weight gain causes fat to become 'sick' and how losing body weight causes fat to become more 'healthy' might prove to be more productive than discussing the individual diagnostic components defining the metabolic syndrome," Bays said.

The goals for management of adults with overweight or obesity are to improve health, quality of life, and body weight and composition.³ Because of the heterogeneity of obesity etiology and pathophysiology, response to treatment varies among patients. The rate of initial weight loss is the most consistent factor that predicts long-term weight loss success.⁷ An initial weight goal of 5-10% over 6 months is recommended, with an emphasis on dietary changes, increased physical activity, and behavior modification delivered by a multidisciplinary team. Additional interventions include weight loss medications, medical devices, and bariatric surgery.⁷

Evidence suggests that added sugar and certain saturated fat-containing foods increase the risk for cardiometabolic disease by metabolic mechanisms that are not mediated solely by positive energy balance and fat gain. Certain dietary patterns or components appear to increase "energy in" or "energy storage as fat" through mechanisms not explained solely by their specific caloric contribution to the "energy in" side of energy balance.¹³

Sufficient polyunsaturated fat in the diet, with corresponding decrease in saturated fat, results in major blood lipid reduction. Replacement of saturated fatty acids with n-6 fatty acids is associated with lower cardiovascular disease risk; replacement with refined carbohydrates has a neutral or adverse effect.¹³ Consumption of fructose, high-fructose corn syrup, or sucrose leads to greater increases in risk factors for cardiometabolic disease than isocaloric amounts of starch.¹³

Bariatric surgery reduces body fat, including epicardial fat, decreases inflammation, and improves adipocyte and adipose tissue function, leading to reduced lipid levels and improvements in metabolic diseases.¹⁰ Cardiovascular disease risk factors are improved, including glucose metabolism, blood pressure, factors related to thrombosis, kidney function, adipocyte and adipose tissue function, inflammatory markers, and vascular markers.

"Some bariatric surgeries not only substantially improve cardiovascular disease risk factors but also reduce overall cardiovascular disease mortality," Bays noted. Candidates for bariatric surgery include patients with a BMI ≥35 with one or more adverse health consequences and those with a BMI ≥40 with or without adverse health consequences.³

The Obesity Algorithm

The Obesity Algorithm³ developed by the Obesity Medicine Society is a good place to start in developing management strategies for patients with overweight or obesity. It is a free education and patient management resource formatted in over 300 downloadable PowerPoint slides. "The Obesity Algorithm is a simplified, yet comprehensive discussion of obesity management, which can help clinicians develop strategies for treatment of patients with obesity," Bays said.

Diets for Weight Loss

Several diets, as shown , have the potential to promote weight loss and lower cardiovascular disease risk, but they must be calorie-restricted to be effective.³

References

1. Hales CM, et al. JAMA 2018;319:2419-2429.

2. Ogden CL, et al. JAMA 2018;319:2410-2418.

3. Bays HE, et al. Obesity Algorithm, presented by the Obesity Medicine Association, available at: obesityalgorithm.org.

4. Buscot MJ, et al. Eur Heart J 2018;Apr 4:[Epub ahead of print].

5. Bjerregaard LG, et al. New Engl J Med 2018;378:1302-1312.

6. Foy AJ, et al. Am J Cardiol 2018;121:1072-1075.

7. Gadde KM, et al. J Am Coll Cardiol 2018;69-84.

8. Tsujimoto T, Kajio H. J Am Coll Cardiol 2017;70:2739-2749.

9. Bays H. Curr Atheroscler Rep 2014;16:409.

10. Packer M. J Am Coll Cardiol 2018;71:2360-2372.

11. Mongraw-Chaffin M, et al. J Am Coll Cardiol 2018;71:1857-1865.

12. Eckel N, et al. Lancet Diabetes Endocrinol 2018;May 28:[Epub ahead of print].

13. Stanhope KL, et al. Obes Rev 2018;May 14:[Epub ahead of print].

14. Bays HE, et al. J Clin Lipidol 2016;10:33-57.

15. Bays H, et al. Surg Obes Relat Dis 2016;12:468-495.

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