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.
Atrial fibrillation (AF) is an increasingly prevalent arrhythmia with significant health and socioeconomic impact. The underlying mechanism of AF is still not well understood. In this study, we ...sought to identify hub genes involved in AF, and explored their functions and underlying mechanisms based on bioinformatics analysis. Five microarray datasets in GEO were used to identify the differentially expressed genes (DEGs) by Robust Rank Aggregation (RRA), and hub genes were screened out using protein-protein interaction (PPI) network. AF model was established using a mixture of acetylcholine and calcium chloride (Ach-CaCl
) by tail vein injection. We totally got 35 robust DEGs that mainly involve in extracellular matrix formation, leukocyte transendothelial migration, and chemokine signaling pathway. Among these DEGs, we identified three hub genes involved in AF, of which CXCL12/CXCR4 axis significantly upregulated in AF patients stands out as one of the most potent targets for AF prevention, and its effect on AF pathogenesis and underlying mechanisms were investigated in vivo subsequently with the specific CXCR4 antagonist AMD3100 (6 mg/kg). Our results demonstrated an elevated transcription and translation of CXCL12/CXCR4 axis in AF patients and mice, accompanied with the anabatic atrial inflammation and fibrosis, thereby providing the substrate for AF maintenance. Blocking its signaling via AMD3100 administration in AF model mice reduced AF inducibility and duration, partly ascribed to decreased atrial inflammation and structural remodeling. Mechanistically, these effects were achieved by reducing the recruitment of CD3+ T lymphocytes and F4/80+ macrophages, and suppressing the hyperactivation of ERK1/2 and AKT/mTOR signaling in atria of AF model mice. In conclusion, this study provides new evidence that antagonizing CXCR4 prevents the development of AF, and suggests that CXCL12/CXCR4 axis may be a potential therapeutic target for AF.
Necroptosis, a novel programmed cell death, plays a critical role in the development of fibrosis, yet its role in atrial fibrillation (AF) remains elusive. Mounting evidence demonstrates that aerobic ...exercise improves AF‐related symptoms and quality of life. Therefore, we explored the role of necroptosis in AF pathogenesis and exercise‐conferred cardioprotection. A mouse AF model was established either by calcium chloride and acetylcholine (CaCl2‐Ach) administration for 3 weeks or high‐fat diet (HFD) feeding for 12 weeks, whereas swim training was conducted 60 min/day, for 3‐week duration. AF susceptibility, heart morphology and function and atrial fibrosis were assessed by electrophysiological examinations, echocardiography and Masson's trichrome staining, respectively. Both CaCl2‐Ach administration and HFD feeding significantly enhanced AF susceptibility (including frequency and duration of episodes), left atrial enlargement and fibrosis. Moreover, protein levels of necroptotic signaling (receptor‐interacting protein kinase 1, receptor‐interacting protein kinase 3, mixed lineage kinase domain‐like protein and calcium/calmodulin‐dependent protein kinase II or their phosphorylated forms) were markedly elevated in the atria of AF mice. However, inhibiting necroptosis with necrostatin‐1 partly attenuated CaCl2‐Ach (or HFD)‐induced fibrosis and AF susceptibility, implicating necroptosis as contributing to AF pathogenesis. Finally, we found 3‐week swim training inhibited necroptotic signaling, consequently decreasing CaCl2‐Ach‐induced AF susceptibility and atrial structural remodeling. Our findings identify necroptosis as a novel mechanism in AF pathogenesis and highlight that aerobic exercise may confer benefits on AF via inhibiting cardiac necroptosis.
Abstract Hearts of diabetic individuals are susceptible to ischemia/reperfusion (I/R) injury. The RNA-binding protein Quaking (QKI) is known to link intracellular signaling to cellular survival and ...QKI dysregulation may contribute to human diseases. However, the function of QKI in diabetic hearts remains unknown. The current study attempted to identify new molecular mechanisms that potentially contribute to the susceptibility to ischemic injury in diabetic myocardium. Diabetic ob / ob mice or wild-type C57BL/6J mice were subjected to in vivo myocardial I/R. Myocardial infarct size and apoptosis, QKI5 and FoxO1 expression, nitrosative stress (NS) and ER stress were compared. Knockdown of FoxO1 was obtained by intramyocardial injection of FoxO1 specific small interfering RNA (siRNA, 20 μg), and upregulation of QKI5 was acquired by injecting adenovirus encoding-QKI5. Obvious NS stress was observed in the myocardium of ob / ob mice represented by elevated iNOS expression, total NO content and nitrotyrosine content. Administration of 1400W or M40401 partly reduced the caspase-3 activity in ob / ob myocardium encountering I/R ( P < 0.05). Higher ER stress was also observed represented by increased p-PERK, p-eIF2α and expression of CHOP in ob / ob myocardium. ER stress inhibitor did not affect the excessive NS stress, but partially reduced I/R-induced caspase-3 activity in ob / ob hearts ( P < 0.05). FoxO1 was overactivated in ob / ob myocardium, and knockdown of FoxO1 attenuated both levels of NS stress and ER stress ( P < 0.05). Furthermore, QKI5 expression was deficient in ob / ob myocardium. Upregulation of QKI5 diminished FoxO1 expression together with NS and ER stress in ob / ob myocardium, further reducing MI/R injury. Finally, QKI5 overexpression destabilized FoxO1 mRNA in cardiomyocytes. These results suggested that QKI5 deficiency contributed to the overactivation of FoxO1 in ob / ob animals and subsequently magnified nitrosative stress and ER stress, which enhances the ischemic intolerance of diabetic hearts.
Cardiac pacing is an effective therapy for treating patients with bradycardia due to sinus node dysfunction or atrioventricular block. However, traditional right ventricular apical pacing (RVAP) ...causes electric and mechanical dyssynchrony, which is associated with increased risk for atrial arrhythmias and heart failure. Therefore, there is a need to develop a physiological pacing approach that activates the normal cardiac conduction and provides synchronized contraction of ventricles. Although His bundle pacing (HBP) has been widely used as a physiological pacing modality, it is limited by challenging implantation technique, unsatisfactory success rate in patients with wide QRS wave, high pacing capture threshold, and early battery depletion. Recently, the left bundle branch pacing (LBBP), defined as the capture of left bundle branch (LBB) via transventricular septal approach, has emerged as a newly physiological pacing modality. Results from early clinical studies have demonstrated LBBP's feasibility and safety, with rare complications and high success rate. Overall, this approach has been found to provide physiological pacing that guarantees electrical synchrony of the left ventricle with low pacing threshold. This was previously specifically characterized by narrow paced QRS duration, large R waves, fast synchronized left ventricular activation, and correction of left bundle branch block. Therefore, LBBP may be a potential alternative pacing modality for both RVAP and cardiac resynchronization therapy with HBP or biventricular pacing (BVP). However, the technique's widespread adaptation needs further validation to ascertain its safety and efficacy in randomized clinical trials. In this review, we discuss the current knowledge of LBBP.
Moderate exercise decreases the risk for atrial fibrillation (AF), an effect which is probably mediated via exercise-stimulated release of exerkines. β-Aminoisobutyric acid (BAIBA), a novel exerkine, ...has been reported to provide protective benefits against many cardiovascular diseases, yet its role in AF remains elusive. Herein, using a mouse model of obesity-related AF through high-fat diet (HFD) feeding, we found that 12-week drinking administration of BAIBA (170 mg/kg/day) decreased AF susceptibility in obese mice. Atrial remodeling assessment showed that BAIBA attenuated obesity-induced atrial hypertrophy and interstitial fibrosis, thereby ablating the substrate for AF. Of note, to our knowledge, this is the first report of the direct association of BAIBA and hypertrophy. BAIBA has been reported to be a key regulator of glucose and lipid metabolism, and we found that BAIBA alleviated insulin resistance in obese mice. Transcriptional analysis of metabolism-related genes showed that BAIBA increased the transcription of fatty acids metabolism-related genes in the atria of lean mice but not in that of obese mice. Mechanistic investigation showed that BAIBA stimulated AMP-activated protein kinase (AMPK) signaling in the atria of obese mice and palmitic acid (PA)-treated neonatal rat cardiomyocytes (NRCM), whereas inhibition of AMPK via Compound C attenuated BAIBA-conferred cardioprotection against hypertrophy and insulin resistance in PA-treated NRCM. Collectively, BAIBA attenuates AF susceptibility in obese mice via activated AMPK signaling and resultant improvement of insulin sensitivity, thereby providing perspectives on the potential therapeutic role of BAIBA in AF treatment.
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•BAIBA attenuated obesity-induced atrial structural remodeling and AF susceptibility.•Providing direct evidence linking BAIBA and its anti-hypertrophic effect.•AMPK signaling is critical for BAIBA-mediated attenuation of AF susceptibility in obese mice.
Aerobic exercise confers sustainable protection against cardiac hypertrophy and heart failure (HF). Nitric oxide synthase (NOS) and nitric oxide (NO) are known to play an important role in ...exercise-mediated cardioprotection, but the mechanism of NOS/NO stimulation during exercise remains unclear. The aim of this study is to determine the role of β3-adrenergic receptors (β3-ARs), NOS activation, and NO metabolites (nitrite and nitrosothiols) in the sustained cardioprotective effects of aerobic exercise. An HF model was constructed by transverse aortic constriction (TAC). Animals were treated with either moderate aerobic exercise by swimming for 9 weeks and/or the β3-AR-specific inhibitor SR59230A at 0.1 mg/kg/hour one day after TAC operation. Myocardial fibrosis, myocyte size, plasma catecholamine (CA) level, cardiac function and geometry were assessed using Masson's trichrome staining, FITC-labeled wheat germ agglutinin staining, enzyme-linked immuno sorbent assay (ELISA) and echocardiography, respectively. Western blot analysis was performed to elucidate the expression of target proteins. The concentration of myocardial NO production was evaluated using the nitrate reductase method. Myocardial oxidative stress was assessed by detecting the concentration of myocardial super oxidative dismutase (SOD), malonyldialdehyde (MDA), and reactive oxygen species (ROS). Aerobic exercise training improved dilated left ventricular function and partially attenuated the degree of cardiac hypertrophy and fibrosis in TAC mice. Moreover, the increased expression of β3-AR, activation of neuronal NOS (nNOS), and production of NO were detected after aerobic exercise training in TAC mice. However, selective inhibition of β3-AR by SR59230A abolished the upregulation and activation of nNOS induced NO production. Furthermore, aerobic exercise training decreased the myocardial ROS and MDA contents and increased myocardial levels of SOD; both effects were partially attenuated by SR59230A. Our study suggested that aerobic exercise training could improve cardiac systolic function and alleviate LV chamber dilation, cardiac fibrosis and hypertrophy in HF mice. The mechanism responsible for the protective effects of aerobic exercise is associated with the activation of the β3-AR-nNOS-NO pathway.
Abstract
Background
Atrial fibrillation (AF) is the most common type of cardiac arrhythmia. Nonetheless, the accurate diagnosis of this condition continues to pose a challenge when relying on ...conventional diagnostic techniques. Cell death is a key factor in the pathogenesis of AF. Existing investigations suggest that cuproptosis may also contribute to AF. This investigation aimed to identify a novel diagnostic gene signature associated with cuproptosis for AF using ensemble learning methods and discover the connection between AF and cuproptosis.
Results
Two genes connected to cuproptosis, including solute carrier family 31 member 1 (SLC31A1) and lipoic acid synthetase (LIAS), were selected by integration of random forests and eXtreme Gradient Boosting algorithms. Subsequently, a diagnostic model was constructed that includes the two genes for AF using the Light Gradient Boosting Machine (LightGBM) algorithm with good performance (the area under the curve value > 0.75). The microRNA-transcription factor-messenger RNA network revealed that homeobox A9 (HOXA9) and Tet methylcytosine dioxygenase 1 (TET1) could target SLC31A1 and LIAS in AF. Functional enrichment analysis indicated that cuproptosis might be connected to immunocyte activities. Immunocyte infiltration analysis using the CIBERSORT algorithm suggested a greater level of neutrophils in the AF group. According to the outcomes of Spearman’s rank correlation analysis, there was a negative relation between SLC31A1 and resting dendritic cells and eosinophils. The study found a positive relationship between LIAS and eosinophils along with resting memory CD4
+
T cells. Conversely, a negative correlation was detected between LIAS and CD8
+
T cells and regulatory T cells.
Conclusions
This study successfully constructed a cuproptosis-related diagnostic model for AF based on the LightGBM algorithm and validated its diagnostic efficacy. Cuproptosis may be regulated by HOXA9 and TET1 in AF. Cuproptosis might interact with infiltrating immunocytes in AF.
Apolipoprotein (Apo) A1 and Apo B are strongly associated with the risk of atherosclerotic cardiovascular disease (ASCVD). However, the relationship between the Apo B/A1 ratio and the morphology of ...coronary vulnerable plaques has not been fully elucidated in patients with ASCVD.
A total of 320 patients with ASCVD undergoing percutaneous coronary intervention were enrolled and assigned into acute coronary syndrome (ACS) or chronic coronary syndrome (CCS) group. The morphology of culprit plaque was analyzed by intravascular optical coherence tomography. Association between the Apo B/A1 ratio and coronary vulnerable plaques were evaluated using logistic regression models and receiver operator characteristic (ROC) curve analyses.
The Apo B/A1 ratio was higher in ACS patients than CCS patients (0.77 ± 0.28 vs. 0.64 ± 0.22, P < 0.001) and it was also higher in patients with plaque rupture, erosion or thrombus than those without culprit plaques. The high Apo B/A1 ratio was associated with high percent of vulnerable plaques compared with low ratio group. The Apo B/A1 ratio was negatively related to fibrous cap thickness in lipid-rich plaque (r = - 0.228, P = 0.043). Univariate and multivariate logistic regression analyses revealed that the Apo B/A1 ratio was an independent factor of plaque rupture, erosion, and thrombus. The area under the ROC curve of the Apo B/A1 ratio for plaque rupture, erosion, and thrombus were 0.632, 0.624, and 0.670 respectively (P < 0.001 for all), which were higher than that of low-density lipoprotein cholesterol.
The Apo B/A1 ratio is an independent predictor for plaque rupture, erosion, and thrombus in patients with ASCVD.
It is well known that insulin possesses a cardioprotective effect and that insulin resistance is closely related to cardiovascular diseases. Peroxynitrite (ONOO(-)) formation may trigger ...oxidative/nitrative stress and represent a major cytotoxic effect in heart diseases. This study was designed to investigate whether insulin attenuates ONOO(-) generation and oxidative/nitrative stress in acute myocardial ischemia/reperfusion (MI/R). Adult male rats were subjected to 30 min of myocardial ischemia and 3 h of reperfusion. Rats randomly received vehicle, insulin, or insulin plus wortmannin. Arterial blood pressure and left ventricular pressure were monitored throughout the experiment. Insulin significantly improved cardiac functions and reduced myocardial infarction, apoptotic cell death, and blood creatine kinase/lactate dehydrogenase levels following MI/R. Myocardial ONOO(-) formation was significantly attenuated after insulin treatment. Moreover, insulin resulted in a significant increase in Akt and endothelial nitric oxide (NO) synthase (eNOS) phosphorylation, NO production, and antioxidant capacity in ischemic/reperfused myocardial tissue. On the other hand, insulin markedly reduced MI/R-induced inducible NOS (iNOS) and gp91(phox) expression in cardiac tissue. Inhibition of insulin signaling with wortmannin not only blocked the cardioprotection of insulin but also markedly attenuated insulin-induced antioxidative/antinitrative effect. Furthermore, the suppression on ONOO(-) formation by either insulin or an ONOO(-) scavenger uric acid reduced myocardial infarct size in rats subjected to MI/R. We concluded that insulin exerts a cardioprotective effect against MI/R injury by blocking ONOO(-) formation. Increased physiological NO production (via eNOS phosphorylation) and superoxide anion reduction contribute to the antioxidative/antinitrative effect of insulin, which can be reversed by inhibiting phosphatidylinositol 3'-kinase. These results provide important novel information on the mechanisms of cardiovascular actions of insulin.
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