Characterization, Pathogenesis, and Clinical Implications of Inflammation‐Related Atrial Myopathy as an Important Cause of Atrial Fibrillation

Abstract Historically, atrial fibrillation has been observed in clinical settings of prolonged hemodynamic stress, eg, hypertension and valvular heart disease. However, recently, the most prominent precedents to atrial fibrillation are metabolic diseases that are associated with adipose tissue inflammation (ie, obesity and diabetes mellitus) and systemic inflammatory disorders (ie, rheumatoid arthritis and psoriasis). These patients typically have little evidence of left ventricular hypertrophy or dilatation; instead, imaging reveals abnormalities of the structure or function of the atria, particularly the left atrium, indicative of an atrial myopathy. The left atrium is enlarged, fibrotic and noncompliant, potentially because the predisposing disorder leads to an expansion of epicardial adipose tissue, which transmits proinflammatory mediators to the underlying left atrium. The development of an atrial myopathy not only leads to atrial fibrillation, but also contributes to pulmonary venous hypertension and systemic thromboembolism. These mechanisms explain why disorders of systemic or adipose tissue inflammation are accompanied an increased risk of atrial fibrillation, abnormalities of left atrium geometry and an enhanced risk of stroke. The risk of stroke exceeds that predicted by conventional cardiovascular risk factors or thromboembolism risk scores used to guide the use of anticoagulation, but it is strongly linked to clinical evidence and biomarkers of systemic inflammation.

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Adipose tissue inflammation and metabolic dysfunction: a clinical perspective

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci-2013-0032 ◽

2013 ◽

Vol 15 (1) ◽

Cited By ~ 2

Author(s):

Charmaine S. Tam ◽

Leanne M. Redman

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Low Grade ◽

Metabolic Dysfunction ◽

Adipose Tissue Inflammation ◽

Tissue Inflammation ◽

Proinflammatory Mediators ◽

Low Grade Inflammation

AbstractObesity is characterized by a state of chronic low-grade inflammation due to increased immune cells, specifically infiltrated macrophages into adipose tissue, which in turn secrete a range of proinflammatory mediators. This nonselective low-grade inflammation of adipose tissue is systemic in nature and can impair insulin signaling pathways, thus, increasing the risk of developing insulin resistance and type 2 diabetes. The aim of this review is to provide an update on clinical studies examining the role of adipose tissue in the development of obesity-associated complications in humans. We will discuss adipose tissue inflammation during different scenarios of energy imbalance and metabolic dysfunction including obesity and overfeeding, weight loss by calorie restriction or bariatric surgery, and conditions of insulin resistance (diabetes, polycystic ovarian syndrome).

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The role of uncoupling protein 2 in macrophages and its impact on obesity-induced adipose tissue inflammation and insulin resistance

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.014868 ◽

2020 ◽

Vol 295 (51) ◽

pp. 17535-17548

Author(s):

Xanthe A. M. H. van Dierendonck ◽

Tiphaine Sancerni ◽

Marie-Clotilde Alves-Guerra ◽

Rinke Stienstra

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Macrophage Activation ◽

Uncoupling Protein ◽

Uncoupling Protein 2 ◽

Adipose Tissue Inflammation ◽

Tissue Inflammation ◽

Obesity And Diabetes ◽

Adipose Tissue Macrophages

The development of a chronic, low-grade inflammation originating from adipose tissue in obese subjects is widely recognized to induce insulin resistance, leading to the development of type 2 diabetes. The adipose tissue microenvironment drives specific metabolic reprogramming of adipose tissue macrophages, contributing to the induction of tissue inflammation. Uncoupling protein 2 (UCP2), a mitochondrial anion carrier, is thought to separately modulate inflammatory and metabolic processes in macrophages and is up-regulated in macrophages in the context of obesity and diabetes. Here, we investigate the role of UCP2 in macrophage activation in the context of obesity-induced adipose tissue inflammation and insulin resistance. Using a myeloid-specific knockout of UCP2 (Ucp2ΔLysM), we found that UCP2 deficiency significantly increases glycolysis and oxidative respiration, both unstimulated and after inflammatory conditions. Strikingly, fatty acid loading abolished the metabolic differences between Ucp2ΔLysM macrophages and their floxed controls. Furthermore, Ucp2ΔLysM macrophages show attenuated pro-inflammatory responses toward Toll-like receptor-2 and -4 stimulation. To test the relevance of macrophage-specific Ucp2 deletion in vivo, Ucp2ΔLysM and Ucp2fl/fl mice were rendered obese and insulin resistant through high-fat feeding. Although no differences in adipose tissue inflammation or insulin resistance was found between the two genotypes, adipose tissue macrophages isolated from diet-induced obese Ucp2ΔLysM mice showed decreased TNFα secretion after ex vivo lipopolysaccharide stimulation compared with their Ucp2fl/fl littermates. Together, these results demonstrate that although UCP2 regulates both metabolism and the inflammatory response of macrophages, its activity is not crucial in shaping macrophage activation in the adipose tissue during obesity-induced insulin resistance.

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Obesity and Breast Cancer: A Case of Inflamed Adipose Tissue

Cancers ◽

10.3390/cancers12061686 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1686 ◽

Cited By ~ 3

Author(s):

Ryan Kolb ◽

Weizhou Zhang

Keyword(s):

Breast Cancer ◽

Adipose Tissue ◽

Molecular Mechanisms ◽

Breast Cancer Incidence ◽

Menopausal Status ◽

Epidemiological Data ◽

Adipose Tissue Inflammation ◽

Tissue Inflammation ◽

Cancer Subtypes ◽

Increased Risk

Obesity is associated with an increased risk of estrogen receptor-positive breast cancer in postmenopausal women and a worse prognosis for all major breast cancer subtypes regardless of menopausal status. While the link between obesity and the pathogenesis of breast cancer is clear, the molecular mechanism of this association is not completely understood due to the complexity of both obesity and breast cancer. The aim of this review is to highlight the association between obesity and breast cancer and discuss the literature, which indicates that this association is due to chronic adipose tissue inflammation. We will discuss the epidemiological data for the association between breast cancer incidence and progression as well as the potential molecular mechanisms for this association. We will focus on the role of inflammation within the adipose tissue during the pathogenesis of breast cancer. A better understanding of how obesity and adipose tissue inflammation affects the pathogenesis of breast cancer will lead to new strategies to reduce breast cancer risk and improve patient outcomes for obese patients.

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CTRP7 deletion attenuates obesity-linked glucose intolerance, adipose tissue inflammation, and hepatic stress

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00344.2016 ◽

2017 ◽

Vol 312 (4) ◽

pp. E309-E325 ◽

Cited By ~ 18

Author(s):

Pia S. Petersen ◽

Xia Lei ◽

Risa M. Wolf ◽

Susana Rodriguez ◽

Stefanie Y. Tan ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Glucose Metabolism ◽

Resistance Index ◽

Activity Level ◽

Low Grade ◽

Adipose Tissue Inflammation ◽

Tissue Inflammation ◽

Metabolic Role ◽

Obesity And Diabetes

Chronic low-grade inflammation and cellular stress are important contributors to obesity-linked metabolic dysfunction. Here, we uncover an immune-metabolic role for C1q/TNF-related protein 7 (CTRP7), a secretory protein of the C1q family with previously unknown function. In obese humans, circulating CTRP7 levels were markedly elevated and positively correlated with body mass index, glucose, insulin, insulin resistance index, hemoglobin A1c, and triglyceride levels. Expression of CTRP7 in liver was also significantly upregulated in obese humans and positively correlated with gluconeogenic genes. In mice, Ctrp7 expression was differentially modulated in various tissues by fasting and refeeding and by diet-induced obesity. A genetic loss-of-function mouse model was used to determine the requirement of CTRP7 for metabolic homeostasis. When fed a control low-fat diet, male or female mice lacking CTRP7 were indistinguishable from wild-type littermates. In obese male mice consuming a high-fat diet, however, CTRP7 deficiency attenuated insulin resistance and enhanced glucose tolerance, effects that were independent of body weight, metabolic rate, and physical activity level. Improved glucose metabolism in CTRP7-deficient mice was associated with reduced adipose tissue inflammation, as well as decreased liver fibrosis and cellular oxidative and endoplasmic reticulum stress. These results provide a link between elevated CTRP7 levels and impaired glucose metabolism, frequently associated with obesity. Inhibiting CTRP7 action may confer beneficial metabolic outcomes in the setting of obesity and diabetes.

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Visceral adipose tissue, inflammation and fibrosis in patients with atrial fibrillation and metabolic syndrome

Atherosclerosis ◽

10.1016/j.atherosclerosis.2018.06.522 ◽

2018 ◽

Vol 275 ◽

pp. e172-e173

Author(s):

V. Ionin ◽

E. Zaslavskaya ◽

Y. Ma ◽

A. Morozov ◽

E. Polyakova ◽

...

Keyword(s):

Atrial Fibrillation ◽

Metabolic Syndrome ◽

Adipose Tissue ◽

Visceral Adipose Tissue ◽

Adipose Tissue Inflammation ◽

Tissue Inflammation ◽

Visceral Adipose

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Abstract 17226: Increased Risk of Heart Failure Associated With Left Atrial Remodeling Without Known Atrial Fibrillation

Circulation ◽

10.1161/circ.138.suppl_1.17226 ◽

2018 ◽

Vol 138 (Suppl_1) ◽

Author(s):

Jodi Edwards ◽

Jiming Fang ◽

Jeff S Healey ◽

Kathy Yip ◽

Lisa Mielniczuk ◽

...

Keyword(s):

Heart Failure ◽

Atrial Fibrillation ◽

Left Atrial ◽

Left Ventricular ◽

Administrative Databases ◽

Risk Scores ◽

Atrial Remodeling ◽

Left Atrial Remodeling ◽

Lv Dysfunction ◽

Increased Risk

Background: Atrial fibrillation (AF) significantly increases risk for heart failure (HF) and independently increases mortality and adverse in-hospital outcomes in HF patients. Validated clinical risk scores (ARC2H) can predict HF in patients with AF, but are limited in application as AF is frequently clinically silent or undetected. However, AF may be preceded by significant preclinical remodeling (left atrial enlargement (LAE) or excessive atrial ectopy (EAE)). Whether LAE and EAE are associated with HF prior to AF is unclear. Method(s): We analyzed consecutive adults >65 years with outpatient echocardiography or Holter at 11 Ontario community cardiology clinics (2010-2017). Exclusions were history of AF, anticoagulation, pacemaker/ICD/ILR, and prosthetic valve. Using linked administrative databases, we assessed 5-year rates of HF (primary) and incident AF and death (secondary) associated with LAE and EAE and among subgroups (M vs. F; <75 vs. >75; CHADS-VASC 0-2 vs. 3-6). Competing risks cox proportional hazards estimated adjusted hazard of HF for severe LAE: >47mm (M);>52mm (F)) or increased APBs/hour (EAE: >30) or both LAE and EAE, adjusting for age, vascular comorbidities and left ventricular (LV) dysfunction. Results: In 28,261 adults (mean 73+/-6 years), direct age-adjusted survival was reduced for those with severe LAE and EAE. 5-year rates of HF were increased for severe (8.8%) vs. moderate (3.5%) and mild (1.4%) LAE and for those with excessive (3.8%) vs. normal (2.5%) ectopy. For both LAE and EAE, those >75 and with a CHADS score 3-6 showed marked increases in HF at 5 years compared to <75 (LAE: 10.6% vs. 7.9%; EAE: 4.3% vs. 1.9%) and CHADS score 0-2 (LAE:21.4% vs. 6.6%; EAE: 8.9% vs. 2.4%). Severe LAE increased hazard of HF 2-fold (HR=2.07; p<.0001), and incident AF over 3-fold (HR= 3.43; p<.0001) and EAE increased hazard of HF (HR=1.31; p<.0001) and incident AF (HR=1.13; p<.0001). Those with both LAE and EAE showed an over 3-fold increased hazard of HF (HR=3.28; p<.0014). Conclusions: Severe LAE and EAE without known AF are associated with increased risk of HF and AF after adjusting for LV dysfunction, particularly for those >75 and with high vascular burden. These data have implications for risk stratification, AF screening, and trials for HF prevention in individuals with left atrial remodeling.

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Obesity and Cancer Mechanisms: Tumor Microenvironment and Inflammation

Journal of Clinical Oncology ◽

10.1200/jco.2016.67.4283 ◽

2016 ◽

Vol 34 (35) ◽

pp. 4270-4276 ◽

Cited By ~ 163

Author(s):

Neil M. Iyengar ◽

Ayca Gucalp ◽

Andrew J. Dannenberg ◽

Clifford A. Hudis

Keyword(s):

Body Mass Index ◽

Adipose Tissue ◽

Tumor Growth ◽

Body Mass ◽

Low Grade ◽

Adipose Tissue Inflammation ◽

Tissue Inflammation ◽

The Metabolic Syndrome ◽

Increased Risk ◽

Adipose Inflammation

Purpose There is growing evidence that inflammation is a central and reversible mechanism through which obesity promotes cancer risk and progression. Methods We review recent findings regarding obesity-associated alterations in the microenvironment and the local and systemic mechanisms through which these changes support tumor growth. Results Locally, hyperadiposity is associated with altered adipose tissue function, adipocyte death, and chronic low-grade inflammation. Most individuals who are obese harbor inflamed adipose tissue, which resembles chronically injured tissue, with immune cell infiltration and remodeling. Within this distinctly altered local environment, several pathophysiologic changes are found that may promote breast and other cancers. Consistently, adipose tissue inflammation is associated with a worse prognosis in patients with breast and tongue cancers. Systemically, the metabolic syndrome, including dyslipidemia and insulin resistance, occurs in the setting of adipose inflammation and operates in concert with local mechanisms to sustain the inflamed microenvironment and promote tumor growth. Importantly, adipose inflammation and its protumor consequences can be found in some individuals who are not considered to be obese or overweight by body mass index. Conclusion The tumor-promoting effects of obesity occur at the local level via adipose inflammation and associated alterations in the microenvironment, as well as systemically via circulating metabolic and inflammatory mediators associated with adipose inflammation. Accurately characterizing the obese state and identifying patients at increased risk for cancer development and progression will likely require more precise assessments than body mass index alone. Biomarkers of adipose tissue inflammation would help to identify high-risk populations. Moreover, adipose inflammation is a reversible process and represents a novel therapeutic target that warrants further study to break the obesity-cancer link.

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The nuclear retinoid‐related orphan receptor RORα controls adipose tissue inflammation in patients with morbid obesity and diabetes

International Journal of Obesity ◽

10.1038/s41366-021-00787-5 ◽

2021 ◽

Author(s):

Rebeca Ortega ◽

Luisa Hueso ◽

Esther Benito ◽

Joaquín Ortega ◽

Miguel Civera ◽

...

Keyword(s):

Morbid Obesity ◽

Adipose Tissue ◽

Orphan Receptor ◽

Adipose Tissue Inflammation ◽

Tissue Inflammation ◽

Obesity And Diabetes

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Increased GIP signaling induces adipose inflammation via a HIF-1α-dependent pathway and impairs insulin sensitivity in mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00418.2014 ◽

2015 ◽

Vol 308 (5) ◽

pp. E414-E425 ◽

Cited By ~ 34

Author(s):

Shu Chen ◽

Fumiaki Okahara ◽

Noriko Osaki ◽

Akira Shimotoyodome

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Adipose Tissue Inflammation ◽

Obese Mice ◽

Plasminogen Activator Inhibitor 1 ◽

Tissue Inflammation ◽

Obesity And Diabetes ◽

Gut Hormone

Glucose-dependent insulinotropic polypeptide (GIP) is a gut hormone secreted in response to dietary fat and glucose. The blood GIP level is elevated in obesity and diabetes. GIP stimulates proinflammatory gene expression and impairs insulin sensitivity in cultured adipocytes. In obesity, hypoxia within adipose tissue can induce inflammation. The aims of this study were 1) to examine the proinflammatory effect of increased GIP signaling in adipose tissues in vivo and 2) to clarify the association between GIP and hypoxic signaling in adipose tissue inflammation. We administered GIP intraperitoneally to misty (lean) and db/db (obese) mice and examined adipose tissue inflammation and insulin sensitivity. We also examined the effects of GIP and hypoxia on expression of the GIP receptor (GIPR) gene and proinflammatory genes in 3T3-L1 adipocytes. GIP administration increased monocyte chemoattractant protein-1 (MCP-1) expression and macrophage infiltration into adipose tissue and increased blood glucose in db/db mice. GIPR and hypoxia-inducible factor-1α (HIF-1α) expressions were positively correlated in the adipose tissue in mice. GIPR expression increased dramatically in differentiated adipocytes. GIP treatment of adipocytes increased MCP-1 and interleukin-6 (IL-6) production. Adipocytes cultured either with RAW 264 macrophages or under hypoxia expressed more GIPR and HIF-1α, and GIP treatment increased gene expression of plasminogen activator inhibitor 1 and IL-6. HIF-1α gene silencing diminished both macrophage- and hypoxia-induced GIPR expression and GIP-induced IL-6 expression in adipocytes. Thus, increased GIP signaling plays a significant role in adipose tissue inflammation and thereby insulin resistance in obese mice, and HIF-1α may contribute to this process.

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