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During myocardial infarction, cellular debris is released, causing a sterile inflammation via pattern recognition receptors. These reactions amplify damage and promotes secondary heart failure. The pattern recognition receptor, Toll-like receptor 9 (TLR9) detects immunogenic fragments of endogenous DNA, inducing inflammation by NFκB. The p66ShcA adaptor protein plays an important role in both ischemic myocardial damage and immune responses. We hypothesized that p66ShcA adaptor protein promotes DNA-sensing signaling via the TLR9 pathway after myocardial infarction. TLR9 protein expression increased in cardiac tissue from patients with end-stage heart failure due to ischemic heart disease. Myocardial ischemia in mice in vivo induced gene expression of key TLR9 pathway proteins (MyD88 and Unc93b1). In this model, a functional link between TLR9 and p66ShcA was revealed as; (i) ischemia-induced upregulation of TLR9 protein was abrogated in myocardium of p66ShcA knockout mice; (ii) when p66ShcA was overexpressed in NFkB reporter cells stably expressing TLR9, NFkB-activation increased during stimulation with the TLR9 agonist CpG B; (iii) in cardiac fibroblasts, p66ShcA overexpression caused TLR9 upregulation. Co-immunoprecipitation showed that ShcA proteins and TLR9 may be found in the same protein complex, which was dissipated upon TLR9 stimulation in vivo. A proximity assay confirmed the co-localization of TLR9 and ShcA proteins. The systemic immune response after myocardial ischemia was dampened in p66ShcA knockout mice as interleukin-4, -17 and -22 expression in mononuclear cells isolated from spleens was reduced. In conclusion, p66ShcA adaptor may be an interaction partner and a regulator of the TLR9 pathway post-infarction., Competing Interests: Declaration of competing interest No conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Doxorubicin (DOXO) remains amongst the most commonly used anti-cancer agents for the treatment of solid tumors, lymphomas, and leukemias. However, its clinical use is hampered by cardiotoxicity, characterized by heart failure and arrhythmias, which may require chemotherapy interruption, with devastating consequences on patient survival and quality of life. Although the adverse cardiac effects of DOXO are consolidated, the underlying mechanisms are still incompletely understood. It was previously shown that DOXO leads to proteotoxic cardiomyocyte (CM) death and myocardial fibrosis, both mechanisms leading to mechanical and electrical dysfunction. While several works focused on CMs as the culprits of DOXO-induced arrhythmias and heart failure, recent studies suggest that DOXO may also affect cardiac sympathetic neurons (cSNs), which would thus represent additional cells targeted in DOXO-cardiotoxicity. Confocal immunofluorescence and morphometric analyses revealed alterations in SN innervation density and topology in hearts from DOXO-treated mice, which was consistent with the reduced cardiotropic effect of adrenergic neurons in vivo. Ex vivo analyses suggested that DOXO-induced denervation may be linked to reduced neurotrophic input, which we have shown to rely on nerve growth factor, released from innervated CMs. Notably, similar alterations were observed in explanted hearts from DOXO-treated patients. Our data demonstrate that chemotherapy cardiotoxicity includes alterations in cardiac innervation, unveiling a previously unrecognized effect of DOXO on cardiac autonomic regulation, which is involved in both cardiac physiology and pathology, including heart failure and arrhythmias.

Cell-cell or inter-organ communication allows the exchange of information and messages, which is essential for the coordination of cell/organ functions and the maintenance of homeostasis. It has become evident that dynamic interactions of different cell types play a major role in the heart, in particular during the progression of heart failure, a leading cause of mortality worldwide. Heart failure is associated with compensatory structural and functional changes mostly in cardiomyocytes and cardiac fibroblasts, which finally lead to cardiomyocyte hypertrophy and fibrosis. Intercellular communication within the heart is mediated mostly via direct cell-cell interaction or the release of paracrine signalling mediators such as cytokines and chemokines. However, recent studies have focused on the exchange of genetic information via the packaging into vesicles as well as the crosstalk of lipids and other paracrine molecules within the heart and distant organs, such as kidney and adipose tissue, which might all contribute to the pathogenesis of heart failure. In this review, we discuss emerging communication networks and respective underlying mechanisms which could be involved in cardiovascular disease conditions and further emphasize promising therapeutic targets for drug development., (© 2015 The Authors European Journal of Heart Failure © 2015 European Society of Cardiology.)

Purpose: We have previously shown that the myocardium of patients with heart failure (HF) is insulin resistant. Chronic beta-adrenergic stimulation has been implicated in insulin resistance in cultured cardiomyocytes in vitro, where sustained noradrenaline stimulation inhibited insulin-modulated glucose uptake. As the failing heart is characterized by increased sympathetic drive, we hypothesized that there is a correlation between pre-synaptic sympathetic function and insulin sensitivity in the myocardium of patients with HF., Methods: Eight patients (aged 67 +/- 7 years) with coronary artery disease and left ventricular dysfunction (ejection fraction 44 +/- 10%) underwent function and viability assessment with cardiovascular magnetic resonance. Myocardial glucose utilization (MGU) was measured using positron emission tomography (PET) with (18)F-fluorodeoxyglucose (FDG). Pre-synaptic noradrenaline re-uptake was measured by calculating [(11)C]meta-hydroxy-ephedrine (HED) volume of distribution (V (d)) with PET. Two groups of healthy volunteers served as controls for the FDG (n = 8, aged 52 +/- 4 years, p < 0.01 vs patients) and HED (n = 8, aged 40 +/- 6 years, p < 0.01 vs patients) data., Results: MGU in patients was reduced in both normal remote (0.44 +/- 0.14 micromol.min(-1).g(-1)) and dysfunctional (0.49 +/- 0.14 micromol.min(-1).g(-1)) segments compared with controls (0.61 +/- 0.7 micromol.min(-1).g(-1); p < 0.001 vs both). HED V (d) was reduced in dysfunctional segments of patients (38.9 +/- 21.2 ml.g(-1)) compared with normal segments (52.2 +/- 19.6 ml.g(-1)) and compared with controls (62.7 +/- 11.3 ml.g(-1)). In patients, regional MGU was correlated with HED V (d)., Conclusion: The results of this study provide novel evidence of a correlation between cardiac sympathetic function and insulin sensitivity, which may represent one of the mechanisms contributing to insulin resistance in failing human hearts.

Aims Increased cardiac sympathetic neuron (SN) activity has been associated with pathologies such as heart failure and hypertrophy, suggesting that cardiac innervation regulates cardiomyocyte trophism. Whether continuous input from the SNs is required for the maintenance of the cardiomyocyte size has not been determined thus far. Methods and results To address the role of cardiac innervation in cardiomyocyte size regulation, we monitored the effect of pharmacological sympathetic denervation in mice on cardiac structure, function, and signalling from 24 h to 30 days in the absence of other pathological stimuli. SN ablation caused an immediate reduction in the cardiomyocyte size with minimal consequences on the resting contractile function. Atrophic remodelling was mediated by the ubiquitin–proteasome system through FOXO-dependent early induction of the muscle-specific E3 ubiquitin ligases Atrogin-1/MAFbx and MuRF1, which was followed by activation of the autophagy–lysosome system. MuRF1 was found to be determinant in denervation atrophy as remodelling did not develop in denervated MuRF1 knock-out (KO) hearts. These effects were caused by decreased basal stimulation of cardiomyocyte β2-adrenoceptor (AR), as atrophy was prevented by treatment of denervated mice with the β2-AR agonist clenbuterol. Consistent with these data, we also observed that β2-AR KO mice showed cardiac atrophy at rest. Conclusion Cardiac SNs are strong regulators of the cardiomyocyte size via β2-AR-dependent repression of proteolysis, demonstrating that the neuro-cardiac axis operates constitutively for the determination of the physiological cardiomyocyte size. These results are of great clinical relevance given the role of β-AR in cardiovascular diseases and their modulation in therapy. [ABSTRACT FROM AUTHOR]

Over the past century, understanding the mechanisms underlying muscle fatigue and weakness has been the focus of much investigation. However, the dominant theory in the field, that lactic acidosis causes muscle fatigue, is unlikely to tell the whole story. Recently, dysregulation of sarcoplasmic reticulum (SR) Ca(2+) release has been associated with impaired muscle function induced by a wide range of stressors, from dystrophy to heart failure to muscle fatigue. Here, we address current understandings of the altered regulation of SR Ca(2+) release during chronic stress, focusing on the role of the SR Ca(2+) release channel known as the type 1 ryanodine receptor. [ABSTRACT FROM AUTHOR]

During the classic "fight-or-flight" stress response, sympathetic nervous system activation leads to catecholamine release, which increases heart rate and contractility, resulting in enhanced cardiac output. Catecholamines bind to β-adrenergic receptors, causing cAMP generation and activation of PKA, which phosphorylates multiple targets in cardiac muscle, including the cardiac ryanodine receptor/calcium release channel (RyR2) required for muscle contraction. PKA phosphorylation of RyR2 enhances channel activity by sensitizing the channel to cytosolic calcium (Ca²+). Here, we found that mice harboring RyR2 channels that cannot be PKA phosphorylated (referred to herein as RyR2-S2808A+/+ mice) exhibited blunted heart rate and cardiac contractile responses to catecholamines (isoproterenol). The isoproterenol-induced enhancement of ventricular myocyte Ca²+ transients and fractional shortening (contraction) and the spontaneous beating rate of sinoatrial nodal cells were all blunted in RyR2-S2808A+/+ mice. The blunted cardiac response to catecholamines in RyR2-S2808A+/+ mice resulted in impaired exercise capacity. RyR2-S2808A+/+ mice were protected against chronic catecholaminergic-induced cardiac dysfunction. These studies identify what we believe to be new roles for PKA phosphorylation of RyR2 in both the heart rate and contractile responses to acute catecholaminergic stimulation. [ABSTRACT FROM AUTHOR]

Objectives: This research was designed to assess the effect of type 2 diabetes mellitus (T2DM) on myocardial glucose utilization in patients with heart failure secondary to coronary artery disease. Background: Patients with T2DM and coronary artery disease have an increased morbidity and mortality compared with patients with coronary artery disease without diabetes that may relate to a reduction in the ability of the myocardium to utilize glucose. Methods: Myocardial blood flow and glucose utilization were assessed during a hyperinsulinemic clamp by 18F-flurodeoxyglucose and positron emission tomography in 54 patients (19 with T2DM) with multivessel coronary artery disease and heart failure. In a subgroup of 18 patients, myocardial biopsies were obtained during coronary bypass surgery to assess glucose transporter (GLUT4) distribution and protein concentration, and compared with myocardium from transplant donor hearts. Results: Myocardial blood flow was similar in patients without diabetes and those with T2DM. Myocardial glucose utilization was lower in patients with T2DM (0.34 ± 0.16 vs. 0.47 ± 0.24 μmol·min−1·g−1, p = 0.0002) despite comparable plasma insulin concentrations and a higher blood glucose concentration. Extraction of glucose by the myocardium was reduced in patients with T2DM (7.1 ± 3.1% vs. 13.5 ± 5.2%, p < 0.01). Myocardial GLUT4 protein was similar in patients with and without T2DM (p = 0.75). Conclusions: Patients with coronary artery disease and heart failure exhibit myocardial insulin resistance, and this is greater in those with T2DM. This may limit the ability of the myocardium in patients with T2DM to withstand ischemia and may contribute to the increased cardiovascular morbidity and mortality in such patients. [Copyright &y& Elsevier]