Peroxisome proliferator-activated receptor-α (PPARα), PPARδ and PPARγ are transcription factors that regulate gene expression following ligand activation. PPARα increases cellular fatty acid uptake, ...esterification and trafficking, and regulates lipoprotein metabolism genes. PPARδ stimulates lipid and glucose utilization by increasing mitochondrial function and fatty acid desaturation pathways. By contrast, PPARγ promotes fatty acid uptake, triglyceride formation and storage in lipid droplets, thereby increasing insulin sensitivity and glucose metabolism. PPARs also exert antiatherogenic and anti-inflammatory effects on the vascular wall and immune cells. Clinically, PPARγ activation by glitazones and PPARα activation by fibrates reduce insulin resistance and dyslipidaemia, respectively. PPARs are also physiological master switches in the heart, steering cardiac energy metabolism in cardiomyocytes, thereby affecting pathological heart failure and diabetic cardiomyopathy. Novel PPAR agonists in clinical development are providing new opportunities in the management of metabolic and cardiovascular diseases.
Type 2 diabetes mellitus (T2DM) is a well-recognized independent risk factor for heart failure. T2DM is associated with altered cardiac energy metabolism, leading to ectopic lipid accumulation and ...glucose overload, the exact contribution of these two parameters remaining unclear. To provide new insight into the mechanism driving the development of diabetic cardiomyopathy, we studied a unique model of T2DM: lipodystrophic
(seipin knockout SKO) mice. Echocardiography and cardiac magnetic resonance imaging revealed hypertrophic cardiomyopathy with left ventricular dysfunction in SKO mice, and these two abnormalities were strongly correlated with hyperglycemia. Surprisingly, neither intramyocardial lipid accumulation nor lipotoxic hallmarks were detected in SKO mice.
FFludeoxyglucose positron emission tomography showed increased myocardial glucose uptake. Consistently, the
-GlcNAcylated protein levels were markedly increased in an SKO heart, suggesting a glucose overload. To test this hypothesis, we treated SKO mice with the hypoglycemic sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin and the insulin sensitizer pioglitazone. Both treatments reduced the
-GlcNAcylated protein levels in SKO mice, and dapagliflozin successfully prevented the development of hypertrophic cardiomyopathy. Our data demonstrate that glucotoxicity by itself can trigger cardiac dysfunction and that a glucose-lowering agent can correct it. This result will contribute to better understanding of the potential cardiovascular benefits of SGLT2 inhibitors.
Mitochondrial Dysfunction as an Arrhythmogenic Substrate Montaigne, David, MD, PhD; Marechal, Xavier, PhD; Lefebvre, Philippe, PhD ...
Journal of the American College of Cardiology,
10/2013, Letnik:
62, Številka:
16
Journal Article
Recenzirano
Odprti dostop
Objectives This study sought to provide bedside evidence of the potential link between cardiac mitochondrial dysfunction and arrhythmia as reported in bench studies. Background Atrial fibrillation ...(AF) is a frequent complication of cardiac surgery. Underlying mechanisms of post-operative atrial fibrillation (POAF) remain largely unknown. Because cardiac mitochondrial dysfunction has been reported in clinical conditions with a high risk of POAF, we investigated whether a causal link exists between POAF onset and pre-operative function of cardiac mitochondria. Methods Pre-operative mitochondrial respiration and calcium retention capacity, respiratory complex activity, and myocardial oxidative stress were quantified in right atrial tissue from 104 consecutive patients with metabolic syndrome, in sinus rhythm, and undergoing coronary artery bypass graft surgery. Results In this high-risk population, POAF occurred in 44% of patients. Decreased pre-operative mitochondrial respiration and increased sensitivity to calcium-induced mitochondrial permeability transition pore opening were significantly associated with POAF. Adenosine diphosphate–stimulated mitochondrial respiration supported by palmitoyl- l -carnitine was significantly lower in POAF patients and remained independently associated with AF onset after adjustment for age, body mass index, heart rate, beta-blocker use, and statin medication (multivariate logistic regression coefficient per unit = −0.314 ± 0.144; p = 0.028). Gene expression profile analysis identified a general downregulation of the mitochondria/oxidative phosphorylation gene cluster in pre-operative atrial tissue of patients in whom AF developed. Conclusions Our prospective study identifies an association between pre-operative mitochondrial dysfunction of the atrial myocardium and AF occurrence after cardiac surgery in patients with metabolic disease, providing novel insights into the link between mitochondria and arrhythmias in patients.
Objectives
This study was conducted in order to evaluate the accuracy of a compressed sensing (CS) real-time single-breath-hold cine sequence for the assessment of left and right ventricular ...functional parameters in daily practice.
Methods
Cardiac magnetic resonance (CMR) cine images were acquired from 100 consecutive patients using both the reference segmented multi-breath-hold steady-state free precession (SSFP) acquisition and a prototype single-breath-hold real-time CS sequence, providing the same slice number, position, and thickness. For both sequences, the left (LV) and right ventricular (RV) ejection fractions (EF) and end-diastolic volumes (EDV) were assessed as well as LV mass (LVM). The visualization of wall-motion disorders (WMD) and signal void related to mitral or tricuspid regurgitation was also analyzed.
Results
The CS sequence mean scan time was 23 ± 6 versus 510 ± 109 s for the multi-breath-hold SSFP sequence (
p
< 0.001). There was an excellent correlation between the two sequences regarding mean LVEF (
r
= 0.995), LVEDV (
r
= 0.997), LVM (
r
= 0.981), RVEF (
r
= 0.979), and RVEDV (
r
= 0.983). Moreover, inter- and intraobserver agreements were very strong with intraclass correlations of 0.96 and 0.99, respectively. On CS images, mitral or tricuspid regurgitation visualization was good (AUC = 0.85 and 0.81, respectively; ROC curve analysis) and wall-motion disorder visualization was excellent (AUC ≥ 0.97).
Conclusion
CS real-time single-breath-hold cine imaging reduces CMR scan duration by almost 20 times in daily practice while providing reliable measurements of both left and right ventricles. There was no clinically relevant information loss regarding valve regurgitation and wall-motion disorder depiction.
Key Points
• Compressed sensing single-breath-hold real-time cine imaging is a reliable sequence in daily practice.
• Fast CS real-time imaging reduces CMR scan time and improves patient workflow.
• There is no clinically relevant information loss with CS regarding heart valve regurgitation or wall-motion disorders.
Scope
Advanced glycation end‐products (AGEs) are endogenously produced and are present in food. Nε‐carboxymethyllysine (CML) is an endothelial activator via the receptor for AGEs (RAGEs) and is a ...major dietary AGE. This work investigated the effects of a CML‐enriched diet and RAGE involvement in aortic aging in mice.
Methods and results
After 9 months of a control diet or CML‐enriched diets (50, 100, or 200 μgCML/g of food), endothelium‐dependent relaxation, RAGE, vascular cell adhesion molecule‐1, and sirtuin‐1 expression, pulse wave velocity and elastin disruption were measured in aortas of wild‐type or RAGE−/− male C57BL/6 mice. Compared to the control diet, endothelium‐dependent relaxation was reduced in the wild‐type mice fed the CML‐enriched diet (200 μgCML/g) (66.8 ± 12.26 vs. 94.3 ± 2.6%, p < 0.01). RAGE and vascular cell adhesion molecule‐1 (p < 0.05) expression were increased in the aortic wall. RAGE−/− mice were protected against CML‐enriched diet‐induced endothelial dysfunction. Compared to control diet, the CML‐enriched diet (200 μgCML/g) increased the aortic pulse wave velocity (86.6 ± 41.1 vs. 251.4 ± 41.1 cm/s, p < 0.05) in wild‐type animals. Elastin disruption was found to a greater extent in the CML‐fed mice (p < 0.05). RAGE‐/− mice fed the CML‐enriched diet were protected from aortic stiffening.
Conclusion
Chronic CML ingestion induced endothelial dysfunction, arterial stiffness and aging in a RAGE‐dependent manner.
Multiple Sclerosis (MS) is an autoimmune demyelinating and neurodegenerative disease of the central nervous system (CNS). Current management strategies suppress or modulate immune function, all with ...consequences and known side effects. They demonstrate a high level of success in limiting new relapses. However, the neurodegenerative process still affects both grey and white matter in the central nervous system. The sigma1 (S1R) ligand-regulated chaperone is implicated in many biological processes in various CNS-targeted diseases, acting on neural plasticity, myelination and neuroinflammation. Among the proteins involved in MS, S1R has therefore emerged as a promising new target. Standard and robust methods have been adopted to analyze the adsorption, distribution, metabolism, excretion (ADME) properties, safety pharmacology and toxicology of a previously synthetized simple benzamide-derived compound with nanomolar affinity for S1R, high selectivity, no cytotoxicity and good metabolic stability. The compound was also characterized as an agonist based on well-validated assays prior to in vivo investigations. Interestingly, we found that the oral administration of this compound resulted in an overall significant reduction in clinical progression in an MS experimental model. This effect is mediated through S1R action. Our results further suggest the potential use of this compound in the treatment of MS.
Abstract Tissue injury causes activation of mesenchymal lineage cells into wound-repairing myofibroblasts (MFs), whose uncontrolled activity ultimately leads to fibrosis. Although this process is ...triggered by deep metabolic and transcriptional reprogramming, functional links between these two key events are not yet understood. Here, we report that the metabolic sensor post-translational modification O -linked β-D-N-acetylglucosaminylation ( O -GlcNAcylation) is increased and required for myofibroblastic activation. Inhibition of protein O -GlcNAcylation impairs archetypal myofibloblast cellular activities including extracellular matrix gene expression and collagen secretion/deposition as defined in vitro and using ex vivo and in vivo murine liver injury models. Mechanistically, a multi-omics approach combining proteomic, epigenomic, and transcriptomic data mining revealed that O- GlcNAcylation controls the MF transcriptional program by targeting the transcription factors Basonuclin 2 (BNC2) and TEA domain transcription factor 4 (TEAD4) together with the Yes-associated protein 1 (YAP1) co-activator. Indeed, inhibition of protein O -GlcNAcylation impedes their stability leading to decreased functionality of the BNC2/TEAD4/YAP1 complex towards promoting activation of the MF transcriptional regulatory landscape. We found that this involves O -GlcNAcylation of BNC2 at Thr 455 and Ser 490 and of TEAD4 at Ser 69 and Ser 99 . Altogether, this study unravels protein O- GlcNAcylation as a key determinant of myofibroblastic activation and identifies its inhibition as an avenue to intervene with fibrogenic processes.
Mitochondrial dysfunction induced by acute cardiac ischemia-reperfusion (IR), may increase susceptibility to arrhythmias by perturbing energetics, oxidative stress production and calcium homeostasis. ...Although changes in mitochondrial morphology are known to impact on mitochondrial function, their role in cardiac arrhythmogenesis is not known. To assess action potential duration (APD) in cardiomyocytes from the Mitofusins-1/2 (Mfn1/Mfn2)-double-knockout (Mfn-DKO) compared to wild-type (WT) mice, optical-electrophysiology was conducted. To measure conduction velocity (CV) in atrial and ventricular tissue from the Mfn-DKO and WT mice, at both baseline and following simulated acute IR, multi-electrode array (MEA) was employed. Intracellular localization of connexin-43 (Cx43) at baseline was evaluated by immunohistochemistry, while Cx-43 phosphorylation was assessed by Western-blotting. Mfn-DKO cardiomyocytes demonstrated an increased APD. At baseline, CV was significantly lower in the left ventricle of the Mfn-DKO mice. CV decreased with simulated-ischemia and returned to baseline levels during simulated-reperfusion in WT but not in atria of Mfn-DKO mice. Mfn-DKO hearts displayed increased Cx43 lateralization, although phosphorylation of Cx43 at Ser-368 did not differ. In summary, Mfn-DKO mice have increased APD and reduced CV at baseline and impaired alterations in CV following cardiac IR. These findings were associated with increased Cx43 lateralization, suggesting that the mitofusins may impact on post-MI cardiac-arrhythmogenesis.
Background
A number of epidemiological studies have suggested an association between metabolic dysfunction-associated fatty liver disease (MAFLD) and the incidence of atrial fibrillation (AF). ...However, the pathogenesis leading to AF in the context of MAFLD remains unclear. We therefore aimed at assessing the impact of MAFLD and liver fibrosis status on left atrium (LA) structure and function.
Methods
Patients with a Fatty Liver Index (FLI) >60 and the presence of metabolic comorbidities were classified as MAFLD+. In MAFLD+ patients, liver fibrosis severity was defined using the non-alcoholic fatty liver disease (NAFLD) Fibrosis Score (NFS), as follows: MAFLD w/o fibrosis (NFS ≦ −1.455), MAFLD w/indeterminate fibrosis (−1.455 < NFS < 0.675), and MAFLD w/fibrosis (NFS ≧ 0.675). In the first cohort of patients undergoing AF ablation, the structural and functional impact on LA of MAFLD was assessed by LA strain analysis and endocardial voltage mapping. Histopathological assessment of atrial fibrosis was performed in the second cohort of patients undergoing cardiac surgery. Finally, the impact of MAFLD on AF recurrence following catheter ablation was assessed.
Results
In the AF ablation cohort (NoMAFLD n = 123; MAFLD w/o fibrosis n = 37; MAFLD indeterm. fibrosis n = 75; MAFLD w/severe fibrosis n = 10), MAFLD patients with high risk of F3–F4 liver fibrosis presented more LA low-voltage areas as compared to patients without MAFLD (16.5 10.25; 28 vs 5.0 1; 11 low-voltage areas p = 0.0115), impaired LA reservoir function assessed by peak left atrial longitudinal strain (19.7% ± 8% vs 8.9% ± 0.89% p = 0.0268), and increased LA volume (52.9 ± 11.7 vs 43.5 ± 18.0 ml/m
2
p = 0.0168). Accordingly, among the MAFLD patients, those with a high risk of F3–F4 liver fibrosis presented a higher rate of AF recurrence during follow-up (p = 0.0179). In the cardiac surgery cohort (NoMAFLD n = 12; MAFLD w/o fibrosis n = 5; MAFLD w/fibrosis n = 3), an increase in histopathological atrial fibrosis was observed in MAFLD patients with a high risk of F3–F4 liver fibrosis (p = 0.0206 vs NoMAFLD; p = 0.0595 vs MAFLD w/o fibrosis).
Conclusion
In conclusion, we found that liver fibrosis scoring in MAFLD patients is associated with adverse atrial remodeling and AF recurrences following catheter ablation. The impact of the management of MAFLD on LA remodeling and AF ablation outcomes should be assessed in dedicated studies.
Modifications in left atrial (LA) flow velocities after left atrial appendage (LAA) exclusion have been shown in animal and ex vivo models. In a substudy of PROTECT AF (Percutaneous Closure of the ...Left Atrial Appendage Versus Warfarin Therapy for Prevention of Stroke in Patients With Atrial Fibrillation), an objective improvement in quality of life was observed after LAA closure.
The purpose of this study was to investigate the impact of LAA closure on LA transport function.
Comprehensive transthoracic echocardiography evaluation (2-dimensional 2D/3-dimensional 3D, 2D speckle tracking) was prospectively performed before and after LAA closure (at discharge and 45 days after procedure) in 33 patients.
LAA closure was associated with a significant improvement in LA reservoir function at discharge and 45 days after the procedure with (1) increased maximum LA volume index, (2) increased 2D-LA reservoir volume and expansion index, and (3) increased 2D speckle tracking-derived peak atrial longitudinal strain (PALS) (27.9 ± 14 and 26 ± 12.6 vs 21.7 ± 10.7%, P <.0001). LAA closure was also associated with a significant improvement in LA contractile function with (1) increased LA ejection fraction and (2) increased speckle tracking-derived peak atrial contraction strain (PACS) in sinus rhythm patients (19.1 ± 6.8 and 18.1 ± 5.4 vs 14.4 ± 6.4%, P = .0006). Conversely, the slope of the relation between PACS and PALS remained unchanged (0.5 ± 0.27 and 0.53 ± 0.3 vs 0.5 ± 0.25, P = .99), thus arguing for an improvement in LA contractile function secondary to a Frank-Starling effect rather than a modification in its intrinsic contractility.
LAA closure was associated with an improvement in LA mechanical function. These changes appeared to be related to a modification in loading conditions, that is, a Frank-Starling effect.
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