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Cellular and Molecular Mechanisms of Cardiovascular and Metabolic Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 21667

Special Issue Editor

Special Issue Information

Dear Colleagues,

Cardiovascular and metabolic diseases including obesity and diabetes are major global health hazards that also represent increasing human and economic burdens. However, the underlying cellular and molecular processes that cause these abnormalities are not fully understood. Therefore, a complete understanding of the cellular and molecular mechanisms involved in the development of cardiovascular and metabolic diseases could help in the introduction of novel strategies for an improved reduction in the risk/predisposition of such diseases in the vulnerable and at-risk populations as well as better-quality treatment. It is envisioned that this Special Issue will bring together contributions from experts around the world to describe recent advances in the different mechanisms that lead to the development of cardiovascular and metabolic diseases. This Special Issue will be uniquely positioned as it will focus on the cellular and molecular mechanisms of cardiovascular disease as well as metabolic diseases including obesity and diabetes. Since cardiovascular and metabolic diseases are linked and can occur concomitantly, an interplay or overlapping of some mechanisms may exist between these pathophysiological conditions, which may be of intrigue and scientific interest. Overall, the information provided in this Special Issue will be of value in the design of novel therapeutic interventions to reduce or reverse cardiovascular and metabolic diseases as well as assist in establishing improved approaches for their prevention.

Dr. Paramjit S. Tappia
Guest Editor

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Keywords

  • cardiovascular diseases
  • metabolic diseases
  • cellular and molecular mechanisms

Published Papers (9 papers)

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Research

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18 pages, 2933 KiB  
Article
The Involvement of Cx43 in JNK1/2-Mediated Endothelial Mechanotransduction and Human Plaque Progression
by Miyuki Tauchi, Kensuke Oshita, Katharina Urschel, Roman Furtmair, Constanze Kühn, Florian M. Stumpfe, Balazs Botos, Stephan Achenbach and Barbara Dietel
Int. J. Mol. Sci. 2023, 24(2), 1174; https://doi.org/10.3390/ijms24021174 - 7 Jan 2023
Cited by 3 | Viewed by 1995
Abstract
Atherosclerotic lesions preferentially develop at bifurcations, characterized by non-uniform shear stress (SS). The aim of this study was to investigate SS-induced endothelial activation, focusing on stress-regulated mitogen-activated protein kinases (MAPK) and downstream signaling, and its relation to gap junction proteins, Connexins (Cxs). Human [...] Read more.
Atherosclerotic lesions preferentially develop at bifurcations, characterized by non-uniform shear stress (SS). The aim of this study was to investigate SS-induced endothelial activation, focusing on stress-regulated mitogen-activated protein kinases (MAPK) and downstream signaling, and its relation to gap junction proteins, Connexins (Cxs). Human umbilical vein endothelial cells were exposed to flow (“mechanical stimulation”) and stimulated with TNF-α (“inflammatory stimulation”). Phosphorylated levels of MAPKs (c-Jun N-terminal kinase (JNK1/2), extracellular signal-regulated kinase (ERK), and p38 kinase (p38K)) were quantified by flow cytometry, showing the activation of JNK1/2 and ERK. THP-1 cell adhesion under non-uniform SS was suppressed by the inhibition of JNK1/2, not of ERK. Immunofluorescence staining and quantitative real-time PCR demonstrated an induction of c-Jun and c-Fos and of Cx43 in endothelial cells by non-uniform SS, and the latter was abolished by JNK1/2 inhibition. Furthermore, plaque inflammation was analyzed in human carotid plaques (n = 40) using immunohistochemistry and quanti-gene RNA-assays, revealing elevated Cx43+ cell counts in vulnerable compared to stable plaques. Cx43+ cell burden in the plaque shoulder correlated with intraplaque neovascularization and lipid core size, while an inverse correlation was observed with fibrous cap thickness. Our results constitute the first report that JNK1/2 mediates Cx43 mechanoinduction in endothelial cells by atheroprone shear stress and that Cx43 is expressed in human carotid plaques. The correlation of Cx43+ cell counts with markers of plaque vulnerability implies its contribution to plaque progression. Full article
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16 pages, 3284 KiB  
Article
Temporal Changes in Extracellular Vesicle Hemostatic Protein Composition Predict Favourable Left Ventricular Remodeling after Acute Myocardial Infarction
by Xiong Chang Lim, Chenyuan Huang, Siti Maryam J. M. Yatim, Suet Yen Chong, Sock Hwee Tan, Xiaoxun Yang, Caryn L. Heldt, Jodi Pedersen, Michael Talanker, Harshvardhan Modh, Matthias G. Wacker, Giorgia Pastorin, Siew Pang Chan, A. Mark Richards, Chris J. Charles, Mark Y. Chan and Jiong-Wei Wang
Int. J. Mol. Sci. 2023, 24(1), 327; https://doi.org/10.3390/ijms24010327 - 25 Dec 2022
Viewed by 1566
Abstract
The subset of plasma extracellular vesicles (EVs) that coprecipitate with low-density lipoprotein (LDL-EVs) carry coagulation and fibrinolysis pathway proteins as cargo. We investigated the association between LDL-EV hemostatic/fibrinolysis protein ratios and post-acute myocardial infarction (post-AMI) left ventricular (LV) remodeling which precedes heart failure. [...] Read more.
The subset of plasma extracellular vesicles (EVs) that coprecipitate with low-density lipoprotein (LDL-EVs) carry coagulation and fibrinolysis pathway proteins as cargo. We investigated the association between LDL-EV hemostatic/fibrinolysis protein ratios and post-acute myocardial infarction (post-AMI) left ventricular (LV) remodeling which precedes heart failure. Protein concentrations of von Willebrand factor (VWF), SerpinC1 and plasminogen were determined in LDL-EVs extracted from plasma samples obtained at baseline (within 72 h post-AMI), 1 month and 6 months post-AMI from 198 patients. Patients were categorized as exhibiting adverse (n = 98) or reverse (n = 100) LV remodeling based on changes in LV end-systolic volume (increased or decreased ≥15) over a 6-month period. Multiple level longitudinal data analysis with structural equation (ML-SEM) model was used to assess predictive value for LV remodeling independent of baseline differences. At baseline, protein levels of VWF, SerpinC1 and plasminogen in LDL-EVs did not differ between patients with adverse versus reverse LV remodeling. At 1 month post-AMI, protein levels of VWF and SerpinC1 decreased whilst plasminogen increased in patients with adverse LV remodeling. In contrast, VWF and plasminogen decreased whilst SerpinC1 remained unchanged in patients with reverse LV remodeling. Overall, compared with patients with adverse LV remodeling, higher levels of SerpinC1 and VWF but lower levels of plasminogen resulted in higher ratios of VWF:Plasminogen and SerpinC1:Plasminogen at both 1 month and 6 months post-AMI in patients with reverse LV remodeling. More importantly, ratios VWF:Plasminogen (AUC = 0.674) and SerpinC1:Plasminogen (AUC = 0.712) displayed markedly better prognostic power than NT-proBNP (AUC = 0.384), troponin-I (AUC = 0.467) or troponin-T (AUC = 0.389) (p < 0.001) to predict reverse LV remodeling post-AMI. Temporal changes in the ratios of coagulation to fibrinolysis pathway proteins in LDL-EVs outperform current standard plasma biomarkers in predicting post-AMI reverse LV remodeling. Our findings may provide clinical cues to uncover the cellular mechanisms underpinning post-AMI reverse LV remodeling. Full article
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18 pages, 3071 KiB  
Article
Impacts of Telomeric Length, Chronic Hypoxia, Senescence, and Senescence-Associated Secretory Phenotype on the Development of Thoracic Aortic Aneurysm
by Thomas Aschacher, Daniela Geisler, Verena Lenz, Olivia Aschacher, Bernhard Winkler, Anne-Kristin Schaefer, Andreas Mitterbauer, Brigitte Wolf, Florian K. Enzmann, Barbara Messner, Günther Laufer, Marek P. Ehrlich, Martin Grabenwöger and Michael Bergmann
Int. J. Mol. Sci. 2022, 23(24), 15498; https://doi.org/10.3390/ijms232415498 - 7 Dec 2022
Cited by 1 | Viewed by 2049
Abstract
Thoracic aortic aneurysm (TAA) is an age-related and life-threatening vascular disease. Telomere shortening is a predictor of age-related diseases, and its progression is associated with premature vascular disease. The aim of the present work was to investigate the impacts of chronic hypoxia and [...] Read more.
Thoracic aortic aneurysm (TAA) is an age-related and life-threatening vascular disease. Telomere shortening is a predictor of age-related diseases, and its progression is associated with premature vascular disease. The aim of the present work was to investigate the impacts of chronic hypoxia and telomeric DNA damage on cellular homeostasis and vascular degeneration of TAA. We analyzed healthy and aortic aneurysm specimens (215 samples) for telomere length (TL), chronic DNA damage, and resulting changes in cellular homeostasis, focusing on senescence and apoptosis. Compared with healthy thoracic aorta (HTA), patients with tricuspid aortic valve (TAV) showed telomere shortening with increasing TAA size, in contrast to genetically predisposed bicuspid aortic valve (BAV). In addition, TL was associated with chronic hypoxia and telomeric DNA damage and with the induction of senescence-associated secretory phenotype (SASP). TAA-TAV specimens showed a significant difference in SASP-marker expression of IL-6, NF-κB, mTOR, and cell-cycle regulators (γH2AX, Rb, p53, p21), compared to HTA and TAA-BAV. Furthermore, we observed an increase in CD163+ macrophages and a correlation between hypoxic DNA damage and the number of aortic telocytes. We conclude that chronic hypoxia is associated with telomeric DNA damage and the induction of SASP in a diseased aortic wall, promising a new therapeutic target. Full article
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22 pages, 1772 KiB  
Article
Transcriptomic Dysregulation of Inflammation-Related Genes in Leukocytes of Patients with Gestational Diabetes Mellitus (GDM) during and after Pregnancy: Identifying Potential Biomarkers Relevant to Glycemic Abnormality
by Andrzej Zieleniak, Monika Zurawska-Klis, Katarzyna Cypryk, Lucyna Wozniak and Marzena Wojcik
Int. J. Mol. Sci. 2022, 23(23), 14677; https://doi.org/10.3390/ijms232314677 - 24 Nov 2022
Cited by 2 | Viewed by 1549
Abstract
Although the immune system has been implicated in the pathophysiology of gestational diabetes mellitus (GDM) and postpartum abnormal glucose tolerance (AGT), little is known about the transcriptional response of inflammation-related genes linked to metabolic phenotypes of GDM women during and after pregnancy, which [...] Read more.
Although the immune system has been implicated in the pathophysiology of gestational diabetes mellitus (GDM) and postpartum abnormal glucose tolerance (AGT), little is known about the transcriptional response of inflammation-related genes linked to metabolic phenotypes of GDM women during and after pregnancy, which may be potential diagnostic classifiers for GDM and biomarkers for predicting AGT. To address these questions, gene expression of IL6, IL8, IL10, IL13, IL18, TNFA, and the nuclear factor κB (NFκB)/RELA transcription factor were quantified in leukocytes of 28 diabetic women at GDM diagnosis (GDM group) and 1-year postpartum (pGDM group: 10 women with AGT and 18 normoglycemic women), using a nested RT-PCR method. Control pregnancies with normal glucose tolerance (NGT group; n = 31) were closely matched for maternal age, gestational age, pre-pregnancy BMI, pregnancy weight, and gestational weight gain. Compared with the NGT group, IL8 was downregulated in the GDM group, and IL13 and RELA were upregulated in the pGDM group, whereas IL6, IL10, and IL18 were upregulated in the GDM and pGDM groups. The TNFA level did not change from pregnancy to postpartum. Associations of some cytokines with glycemic measures were detected in pregnancy (IL6 and RELA) and postpartum (IL10) (p < 0.05). Receiver operating characteristic (ROC) curves showed that IL6, IL8, and IL18, if employed alone, can discriminate GDM patients from NGT individuals at GDM diagnosis, with the area under the ROC curves (AUCs) of 0.844, (95% CI 0.736–0.953), 0.771 (95% CI 0.651–0.890), and 0.714 (95% CI 0.582–0.846), respectively. By the logistic regression method, we also identified a three-gene panel (IL8, IL13, and TNFA) for postpartum AGT prediction. This study demonstrates a different transcriptional response of the studied genes in clinically well-characterized women with GDM at GDM diagnosis and 1-year postpartum, and provides novel transcriptomic biomarkers for future efforts aimed at diagnosing GDM and identifying the high risk of postpartum AGT groups. Full article
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20 pages, 8064 KiB  
Article
Targeting the Crosstalk of Immune Response and Vascular Smooth Muscle Cells Phenotype Switch for Arteriovenous Fistula Maturation
by Vikrant Rai, Harbinder Singh and Devendra K. Agrawal
Int. J. Mol. Sci. 2022, 23(19), 12012; https://doi.org/10.3390/ijms231912012 - 10 Oct 2022
Cited by 5 | Viewed by 1990
Abstract
Plaque formation, thrombosis, and embolism are the underlying causes of acute cardiovascular events such as myocardial infarction and stroke while early thrombosis and stenosis are common pathologies for the maturation failure of arteriovenous fistula (AVF). Chronic inflammation is a common underlying pathogenesis mediated [...] Read more.
Plaque formation, thrombosis, and embolism are the underlying causes of acute cardiovascular events such as myocardial infarction and stroke while early thrombosis and stenosis are common pathologies for the maturation failure of arteriovenous fistula (AVF). Chronic inflammation is a common underlying pathogenesis mediated by innate and adaptive immune response involving infiltration of immune cells and secretion of pro- and anti-inflammatory cytokines. Impaired immune cell infiltration and change in vascular smooth muscle cell (VSMC) phenotype play a crucial role in the underlying pathophysiology. However, the change in the phenotype of VSMCs in a microenvironment of immune cell infiltration and increased secretion of cytokines have not been investigated. Since change in VSMC phenotype regulates vessel remodeling after intimal injury, in this study, we investigated the effect of macrophages and pro-inflammatory cytokines, IL-6, IL-1β, and TNF-α, on the change in VSMC phenotype under in vitro conditions. We also investigated the expression of the markers of VSMC phenotypes in arteries with atherosclerotic plaques and VSMCs isolated from control arteries. We found that the inhibition of cytokine downstream signaling may mitigate the effect of cytokines on the change in VSMCs phenotype. The results of this study support that regulating or targeting immune cell infiltration and function might be a therapeutic strategy to mitigate the effects of chronic inflammation to attenuate plaque formation, early thrombosis, and stenosis, and thus enhance AVF maturation. Full article
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18 pages, 1725 KiB  
Article
Type 2 Diabetes Induces a Pro-Oxidative Environment in Rat Epididymis by Disrupting SIRT1/PGC-1α/SIRT3 Pathway
by Antónia Diniz, Marco G. Alves, Emanuel Candeias, Ana I. Duarte, Paula I. Moreira, Branca M. Silva, Pedro F. Oliveira and Luís Rato
Int. J. Mol. Sci. 2022, 23(16), 8912; https://doi.org/10.3390/ijms23168912 - 10 Aug 2022
Cited by 4 | Viewed by 2013
Abstract
Diabetes mellitus type 2 (T2DM) has been associated with alterations in the male reproductive tract, especially in the epididymis. Although it is known that T2DM alters epididymal physiology, disturbing mitochondrial function and favoring oxidative stress, the mechanisms remain unknown. Sirtuin 1 (SIRT1), peroxisome [...] Read more.
Diabetes mellitus type 2 (T2DM) has been associated with alterations in the male reproductive tract, especially in the epididymis. Although it is known that T2DM alters epididymal physiology, disturbing mitochondrial function and favoring oxidative stress, the mechanisms remain unknown. Sirtuin 1 (SIRT1), peroxisome proliferators-activated receptor γ coactivator 1α (PGC-1α), and sirtuin 3 (SIRT3) are key regulators of mitochondrial function and inducers of antioxidant defenses. In this study, we hypothesized that the epididymal SIRT1/PGC-1α/SIRT3 axis mediates T2DM-induced epididymis dysfunction by controlling the oxidative profile. Using 7 Goto-Kakizaki (GK) rats (a non-obese model that spontaneously develops T2DM early in life), and 7 age-matched Wistar control rats, we evaluated the protein levels of SIRT1, PGC-1α, and SIRT3, as well as the expression of mitochondrial respiratory complexes. The activities of epididymal glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD), and catalase (CAT) were determined, as well as the epididymal antioxidant capacity. We also evaluated protein nitration, carbonylation, and lipid peroxidation in the epididymis. The T2DM rats presented with hyperglycemia and glucose intolerance. Epididymal levels of SIRT1, PGC-1α, and SIRT3 were decreased, as well as the expression of the mitochondrial complexes II, III, and V, in the T2DM rats. We found a significant decrease in the activities of SOD, CAT, and GPx, consistent with the lower antioxidant capacity and higher protein nitration and lipid peroxidation detected in the epididymis of the T2DM rats. In sum, T2DM disrupted the epididymal SIRT1/PGC-1α/SIRT3 pathway, which is associated with a compromised mitochondrial function. This resulted in a decline of the antioxidant defenses and an increased oxidative damage in that tissue, which may be responsible for the impaired male reproductive function observed in diabetic men. Full article
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14 pages, 1586 KiB  
Article
Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) Deletion but Not Inhibition of Extracellular PCSK9 Reduces Infarct Sizes Ex Vivo but Not In Vivo
by Rolf Schreckenberg, Annemarie Wolf, Tamara Szabados, Kamilla Gömöri, István Adorján Szabó, Gergely Ágoston, Gábor Brenner, Péter Bencsik, Péter Ferdinandy, Rainer Schulz and Klaus-Dieter Schlüter
Int. J. Mol. Sci. 2022, 23(12), 6512; https://doi.org/10.3390/ijms23126512 - 10 Jun 2022
Cited by 4 | Viewed by 1713
Abstract
Hypoxia upregulates PCSK9 expression in the heart, and PCSK9 affects the function of myocytes. This study aimed to investigate the impact of PCSK9 on reperfusion injury in rats and mice fed normal or high-fat diets. Either the genetic knockout of PCSK9 (mice) or [...] Read more.
Hypoxia upregulates PCSK9 expression in the heart, and PCSK9 affects the function of myocytes. This study aimed to investigate the impact of PCSK9 on reperfusion injury in rats and mice fed normal or high-fat diets. Either the genetic knockout of PCSK9 (mice) or the antagonism of circulating PCSK9 via Pep2-8 (mice and rats) was used. Isolated perfused hearts were exposed to 45 min of ischemia followed by 120 min of reperfusion. In vivo, mice were fed normal or high-fat diets (2% cholesterol) for eight weeks prior to coronary artery occlusion (45 min of ischemia) and reperfusion (120 min). Ischemia/reperfusion upregulates PCSK9 expression (rats and mice) and releases it into the perfusate. The inhibition of extracellular PCSK9 does not affect infarct sizes or functional recovery. However, genetic deletion largely reduces infarct size and improves post-ischemic recovery in mice ex vivo but not in vivo. A high-fat diet reduced the survival rate during ischemia and reperfusion, but in a PCSK9-independent manner that was associated with increased plasma matrix metalloproteinase (MMP)9 activity. PCSK9 deletion, but not the inhibition of extracellular PCSK9, reduces infarct sizes in ex vivo hearts, but this effect is overridden in vivo by factors such as MMP9. Full article
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Review

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22 pages, 1302 KiB  
Review
Nonalcoholic Fatty Liver Disease and Chronic Kidney Disease: Epidemiology, Pathogenesis, and Clinical and Research Implications
by Amedeo Lonardo, Alessandro Mantovani, Giovanni Targher and Gyorgy Baffy
Int. J. Mol. Sci. 2022, 23(21), 13320; https://doi.org/10.3390/ijms232113320 - 1 Nov 2022
Cited by 26 | Viewed by 4077
Abstract
Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease worldwide, affecting up to ~30% of adult populations. NAFLD defines a spectrum of progressive liver conditions ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma, [...] Read more.
Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease worldwide, affecting up to ~30% of adult populations. NAFLD defines a spectrum of progressive liver conditions ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma, which often occur in close and bidirectional associations with metabolic disorders. Chronic kidney disease (CKD) is characterized by anatomic and/or functional renal damage, ultimately resulting in a reduced glomerular filtration rate. The physiological axis linking the liver and kidneys often passes unnoticed until clinically significant portal hypertension, as a major complication of cirrhosis, becomes apparent in the form of ascites, refractory ascites, or hepatorenal syndrome. However, the extensive evidence accumulated since 2008 indicates that noncirrhotic NAFLD is associated with a higher risk of incident CKD, independent of obesity, type 2 diabetes, and other common renal risk factors. In addition, subclinical portal hypertension has been demonstrated to occur in noncirrhotic NAFLD, with a potential adverse impact on renal vasoregulation. However, the mechanisms underlying this association remain unexplored to a substantial extent. With this background, in this review we discuss the current evidence showing a strong association between NAFLD and the risk of CKD, and the putative biological mechanisms underpinning this association. We also discuss in depth the potential pathogenic role of the hepatorenal reflex, which may be triggered by subclinical portal hypertension and is a poorly investigated but promising research topic. Finally, we address emerging pharmacotherapies for NAFLD that may also beneficially affect the risk of developing CKD in individuals with NAFLD. Full article
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21 pages, 1165 KiB  
Review
Metabolic Inflexibility as a Pathogenic Basis for Atrial Fibrillation
by Xinghua Qin, Yudi Zhang and Qiangsun Zheng
Int. J. Mol. Sci. 2022, 23(15), 8291; https://doi.org/10.3390/ijms23158291 - 27 Jul 2022
Cited by 9 | Viewed by 3866
Abstract
Atrial fibrillation (AF), the most common sustained arrhythmia, is closely intertwined with metabolic abnormalities. Recently, a metabolic paradox in AF pathogenesis has been suggested: under different forms of pathogenesis, the metabolic balance shifts either towards (e.g., obesity and diabetes) or away from (e.g., [...] Read more.
Atrial fibrillation (AF), the most common sustained arrhythmia, is closely intertwined with metabolic abnormalities. Recently, a metabolic paradox in AF pathogenesis has been suggested: under different forms of pathogenesis, the metabolic balance shifts either towards (e.g., obesity and diabetes) or away from (e.g., aging, heart failure, and hypertension) fatty acid oxidation, yet they all increase the risk of AF. This has raised the urgent need for a general consensus regarding the metabolic changes that predispose patients to AF. “Metabolic flexibility” aptly describes switches between substrates (fatty acids, glucose, amino acids, and ketones) in response to various energy stresses depending on availability and requirements. AF, characterized by irregular high-frequency excitation and the contraction of the atria, is an energy challenge and triggers a metabolic switch from preferential fatty acid utilization to glucose metabolism to increase the efficiency of ATP produced in relation to oxygen consumed. Therefore, the heart needs metabolic flexibility. In this review, we will briefly discuss (1) the current understanding of cardiac metabolic flexibility with an emphasis on the specificity of atrial metabolic characteristics; (2) metabolic heterogeneity among AF pathogenesis and metabolic inflexibility as a common pathological basis for AF; and (3) the substrate-metabolism mechanism underlying metabolic inflexibility in AF pathogenesis. Full article
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