Guest Editorial: Inflammation in Obesity and Cardiovascular Disease

Introduction                            

Obesity is a chronic, relapsing, heterogenous disease characterized by impaired energy regulation and inflammation that leads to cardiometabolic, biomechanical, and psychosocial health consequences.^1-3 The prevalence of obesity has reached epidemic proportions, contributing to increased morbidity, mortality, and healthcare costs.⁴ Obesity is a major risk factor for the development of cardiometabolic diseases including atherosclerosis, hypertension, coronary artery disease, heart failure, type 2 diabetes, obstructive sleep apnea, and non-alcoholic fatty liver disease. The pathophysiology of obesity includes proinflammatory and thrombogenic mechanisms that have significant implications for the development and progression of atherosclerosis and cardiovascular disease. Treatment of obesity with lifestyle changes, medications, and/or metabolic surgery with the goal of weight loss is an intervention with pleiotropic benefits.

Pathophysiology

Peripheral Inflammation: Adipose Tissue

Adipose tissue is more than a storage depot of excess calories; it is an active endocrine and paracrine organ that becomes remodeled in the progression of obesity. Adipose tissue consists of many different cell types including adipocytes, immune cells, and endothelial cells. Adipocytes respond to excess energy (e.g., overfeeding) via hyperplasia or hypertrophy. Histological observations of visceral adipose tissue have characterized it with hypertrophy, localized hypoxia, and increased fatty acid flux that trigger an inflammatory cascade.^2,5 This response includes the recruitment of inflammatory cells including M1 macrophages, neutrophils, and lymphocytes, which release proinflammatory cytokines such has tumor necrosis factor-α (TNFα), interleukin-1β (IL-1β), and interleukin-6 (IL-6), with downstream effects on insulin intracellular signaling leading to progressive insulin resistance.⁵ TNFα, IL-1, and IL-6 stimulate the production of C-reactive protein (CRP), a serum marker of inflammation.⁶ In this proinflammatory polarization, adipocytes release adipokines such as leptin and resistin with a commensurate reduction of anti-inflammatory adipokines such adiponectin.^1,7 Leptin is proportional to the degree of adiposity and it induces expression of proinflammatory cytokines in macrophages and T-cells.⁶ Resistin affects hepatic cholesterol storage and locally increases proinflammatory cytokines within the adipocyte.⁶ Adiponectin has anti-inflammatory properties, and it modulates lipoprotein metabolism, thus improving insulin sensitivity.⁶ This shift to a proinflammatory state causes both local and systemic insulin resistance within visceral adipose tissue, liver, skeletal muscle which contributes toward glucose and fatty acid dysregulation.⁸

Central Inflammation: Hypothalamus

The inflammatory effect of obesity is not limited to the periphery but also seen centrally within the arcuate nucleus of the hypothalamus, which is the center of weight regulation and energy homeostasis within the brain. Rodents showed increased levels of proinflammatory cytokines in the hypothalamus within 48 hours of exposure to a high-fat diet, and after a week, they showed reactive gliosis in the arcuate nucleus, which is a response to neuronal injury.⁹ After 8 months on a high-fat diet, this reactive gliosis was associated with a 25% reduction in the number of pro-opiomelanocortin (POMC) neurons, which are responsible for suppressing appetite.⁹ The gliosis within POMC neurons is reversible with return to a chow diet.¹⁰ Since evidence of neuronal damage occurs as early as 48 hours, prior to significant weight gain, scientists hypothesize that a high-fat or hypercaloric diet induces neuronal inflammation and damage within the region of the brain that mediates energy homeostasis, thereby limiting the capacity of those neurons to respond to humoral or neuronal input pertinent to weight control and thus causing obesity.²

Inflammation, Obesity and Atherosclerosis

Atherosclerosis and the formation of the atheroma is mediated by inflammation. The normal artery is comprised of 3 layers: the tunica intima, media, and adventitia. Endothelial dysfunction and vessel wall damage shifts the homeostasis toward plaque formation by increasing expression of vascular adhesion molecules and chemoattractant proteins which recruit inflammatory cells to the tunica intima.¹¹ These inflammatory cells further propagate inflammation by secreting proinflammatory cytokines that promote vascular smooth muscle proliferation leading to an expanded intima.¹¹ Eventually apoptosis and failed clearance by phagocytes promotes the development of a necrotic, lipid laden core with a fibrous cap covering the atheroma.¹¹ The expanded intima causes gradual stenosis of the vessel and plaque rupture releases the prothrombotic lipid core into the vessel lumen leading to acute thrombosis with ischemia and infarction.

Inflammation, observed in obesity, contributes mechanistically to atheroma formation. The initiation of atheroma formation with endothelial dysfunction is enhanced by conditions that promote systemic inflammation like obesity.8 The fatty acid flux and increased triglyceride rich lipoproteins seen in obesity and insulin resistance promote increased cholesterol delivery for formation of foam cells and are involved with increased recruitment of inflammatory cells, upregulation of adhesion molecules and promotion of smooth muscle cell proliferation.⁸ Visceral, and pertinently, epicardial adipose tissue consisting of hypertrophied adipocytes is characterized by an ischemic, proinflammatory, and thrombogenic microenvironment that can contribute to plaque formation in coronary arteries.¹

Management

Treatment of obesity with the goal of achieving clinically significant weight loss reduces inflammation and the risk of cardiometabolic diseases. Clinically significant weight loss, defined as ≥ 5%, is associated with benefits in several obesity-related comorbidities such as hypertension, prediabetes/type 2 diabetes, and hyperlipidemia (Table 1).^12,13 Weight loss can be achieved through lifestyle modification, anti-obesity medications and/or metabolic surgery.

Table 1. Metabolic Benefits of Weight Loss

Metabolic benefits with degree of weight loss. SBP (systolic blood pressure), DBP (diastolic blood pressure), HbA1c (hemoglobin A1c).

Lifestyle Modification:

Lifestyle changes encompass nutrition, physical activity, and behavior modification. The Obesity Society, American Heart Association, and American College of Cardiology recommend adopting a sustainable, hypocaloric nutrition plan for significant weight reduction with multiple consultation sessions from lifestyle interventionalists such as registered dietitians.¹² Physical activity should include at least 150 minutes per week of moderate-intensity activity and ideally, two days per week of strength training.¹⁴ Behavior modification entails strategies such as food logging, activity tracking, and stimulus management.

Lifestyle modification has been shown to reduce leptin levels precipitously with caloric restriction, with levels eventually correlating with degree of weight loss.^15,16 Similarly, hypocaloric diets show a reduction in circulating TNF alpha and CRP levels.⁶ The Look AHEAD trial which randomized adults with type 2 diabetes (T2D) to intensive behavioral therapy or standard diabetes education showed improved cardiometabolic markers with regards to lipids and blood pressure.¹⁷ Average weight loss of 6.0% over 13.5 years did not result in a significant reduction in cardiovascular events, but a post-hoc analysis revealed that there was a reduction in cardiovascular events in those who had achieved at least 10% weight loss.^17,18

Pharmacotherapy:

Medical management of obesity is recommended for individuals with a body mass index (BMI) of ≥ 30 kg/m² or ≥ 27 kg/m² with comorbidities. Five anti-obesity medications (AOMs) are FDA-approved for long-term use: orlistat (Xenical/Alli), naltrexone/bupropion (Contrave), phentermine/topiramate (Qsymia), liraglutide 3.0 mg (Saxenda), and semaglutide 2.4 mg (Wegovy). Average placebo-subtracted weight loss ranges from about 3% to 12% with these AOMs.^38,39 The newest agent expected to be approved for obesity is tirzepatide, a dual agonist at the glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors. Tirzepatide is currently approved for type 2 diabetes but has demonstrated a placebo-subtracted average weight loss of 17% in its phase 3 trial, with roughly one in three participants achieving ≥25% weight loss.⁴⁰ Only GLP-1 receptor agonists (GLP-1RA) have been investigated in relation to inflammation and have demonstrated the most robust data for CVD benefits.

GLP-1RAs have been shown to reduce inflammatory markers and improve cardiovascular outcomes in patients with T2D. Liraglutide 1.8mg (Victoza), approved for T2D, has shown reduction in leptin levels and CRP but no consistent reduction in TNF alpha in patients with T2D.^19-22 The LEADER and SUSTAIN-6 trials have proven significant reductions in major adverse cardiovascular events (MACE) in those with T2D.^23,24 A prespecified meta-analysis of seven SURPASS trials found a hazard ratio of 0.80 for tirzepatide vs. placebo with regards to 4-point MACE (cardiovascular death, myocardial infarction, stroke and hospitalized unstable angina).²⁵ We await the results of the SELECT trial (NCT03574597) which will evaluate the effect of semaglutide 2.4mg once weekly for the treatment of obesity on cardiovascular outcomes in high-risk patients without T2D and SURPASS-CVOT (NCT04255433) which will evaluate the effect of tirzepatide once weekly on cardiovascular outcomes in patients with T2D.

Metabolic Surgery:

Individuals with BMI of ≥ 40 kg/m² or ≥ 35 kg/m² with comorbidities are eligible for bariatric surgery. Metabolic surgery is a subset of bariatric surgery whose mechanism of action includes hormonal changes vs. restriction alone (e.g., Roux-en-Y gastric bypass and sleeve gastrectomy vs. gastric band). Metabolic surgery remains the gold standard for weight loss and improvement in multiple obesity-related comorbidities. All forms of metabolic surgery have been shown to reduce leptin and CRP levels but no consistent reduction in TNFα, which suggests that other factors may continue to drive TNFα levels beyond weight loss, post-surgically.⁶ Many observational studies have shown that metabolic surgery is associated with a reduction in cardiovascular events in patients with obesity both with and without T2D and improved life expectancy.^26-31

Summary

Obesity is a state of chronic low-grade inflammation that is present both centrally and peripherally. This inflammatory state leads to a thrombogenic environment, and glucose and fatty acid dysregulation leading to the development of cardiometabolic diseases including atherosclerosis and coronary artery disease. A comprehensive medical approach to the management of obesity with lifestyle modification, pharmacotherapy, and/or metabolic surgery shows improvement in inflammatory markers, cardiometabolic markers and risk reduction of cardiovascular events.

References

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Disclosures: Dr. Mohini Aras has no financial relationships to disclose. Dr. Beverly Tchang has earned consulting fees from Gelesis Inc and 2nd MD. Dr. Louis Aronne reports receiving consulting fees from/and serving on advisory boards for Allurion, Altimmune, Atria, Gelesis, Jamieson Wellness, Janssen Pharmaceuticals, Jazz Pharmaceuticals, Novo Nordisk, Pfizer, Optum, Eli Lilly, Senda Biosciences and Versanis; receiving research funding from Allurion, Astra Zeneca, Gelesis, Janssen Pharmaceuticals, Novo Nordisk and Eli Lilly; having equity interests in Allurion, ERX Pharmaceuticals, Gelesis, Intellihealth, Jamieson Wellness and Myos Corp; and serving on a board of directors for ERX Pharmaceuticals, Intellihealth and Jamieson Wellness.