Left atrial strain: A memory of the severity of atrial myocardial stress in atrial fibrillation.

BACKGROUND: Left atrial (LA) strain is a simple marker of LA function. The aim of the study was to evaluate the determinants of atrial cardiomyopathy in AF. METHODS: In this pilot study, we prospectively evaluated clinical, biological, metabolomic and echocardiographic parameters for 85 consecutive patients hospitalized for atrial fibrillation (AF) with restoration of sinus rhythm at 6 months. Eighty-one patients with an analysable LA strain at 6 months were divided into groups according to median reservoir strain:<23.3% (n=40) versus≥23.3% (n=41). RESULTS: Compared to patients with the highest LA strain, patients with lowest LA strain had multiple differences at admission: clinical (older age; more frequent history of AF; more patterns of persistent AF); biological (higher fasting blood glucose levels, glycated haemoglobin, high-sensitivity C-reactive protein, and urea; lower glomerular filtration rate); metabolomic (higher levels of kynurenine, kynurenine/tryptophan, and urea/creatinine; lower levels of arginine and methionine/methionine sulfoxide); and echocardiographic (higher two-dimensional end-systolic LA volume [LAV] indexes; higher three-dimensional end-systolic and end-diastolic LAV and right atrial volume indexes; lower LA and right atrial emptying fractions and three-dimensional right ventricular ejection fraction) (all P<0.05). Area under the receiver operating characteristic curve to predict LA strain alteration at 6 months was highest for a combined score including clinical, biological, metabolomic and echocardiographic variables at admission (area under the receiver operating characteristic curve 0.871; P<0.0001). CONCLUSIONS: LA reservoir strain could be a memory of initial atrial myocardial stress in AF. It can be predicted using a combination of clinical, biological, metabolomic and echocardiographic admission variables.

Targeted delivery of LXR-agonists to atherosclerotic lesions mediated by polydiacetylene micelles.

We report the development of compact and stabilized micelles incorporating a synthetic LXR agonist prodrug for the passive targeting of atherosclerotic lesions and therapeutic intervention. In vivo studies showed that the nanohybrid micelles exhibited favorable pharmacokinetics/biodistribution and were able to upregulate, to some extent, LXR target genes with no alteration of lipid metabolism.

An obesogenic diet increases atherosclerosis through promoting microbiota dysbiosis-induced gut lymphocyte trafficking into the periphery.

Although high-fat diet (HFD)-induced gut microbiota dysbiosis is known to affect atherosclerosis, the underlying mechanisms remain to be fully explored. Here, we show that the progression of atherosclerosis depends on a gut microbiota shaped by an HFD but not a high-cholesterol (HC) diet and, more particularly, on low fiber (LF) intake. Mechanistically, gut lymphoid cells impacted by HFD- or LF-induced microbiota dysbiosis highly proliferate in mesenteric lymph nodes (MLNs) and migrate from MLNs to the periphery, which fuels T cell accumulation within atherosclerotic plaques. This is associated with the induction of mucosal addressin cell adhesion molecule 1 (MAdCAM-1) within plaques and the presence of enterotropic lymphocytes expressing ß7 integrin. MLN resection or lymphocyte deficiency abrogates the pro-atherogenic effects of a microbiota shaped by LF. Our study shows a pathological link between a diet-shaped microbiota, gut immune cells, and atherosclerosis, suggesting that a diet-modulated microbiome might be a suitable therapeutic target to prevent atherosclerosis.

Impaired metabolism predicts coronary artery calcification in women with systemic lupus erythematosus.

BACKGROUND: Patients with systemic lupus erythematosus (SLE) exhibit a high risk for cardiovascular diseases (CVD) which is not fully explained by the classical Framingham risk factors. SLE is characterized by major metabolic alterations which can contribute to the elevated prevalence of CVD. METHODS: A comprehensive analysis of the circulating metabolome and lipidome was conducted in a large cohort of 211 women with SLE who underwent a multi-detector computed tomography scan for quantification of coronary artery calcium (CAC), a robust predictor of coronary heart disease (CHD). FINDINGS: Beyond traditional risk factors, including age and hypertension, disease activity and duration were independent risk factors for developing CAC in women with SLE. The presence of coronary calcium was associated with major alterations of circulating lipidome dominated by an elevated abundance of ceramides with very long chain fatty acids. Alterations in multiple metabolic pathways, including purine, arginine and proline metabolism, and microbiota-derived metabolites, were also associated with CAC in women with SLE. Logistic regression with bootstrapping of lipidomic and metabolomic variables were used to develop prognostic scores. Strikingly, combining metabolic and lipidomic variables with clinical and biological parameters markedly improved the prediction (area under the curve: 0.887, p < 0.001) of the presence of coronary calcium in women with SLE. INTERPRETATION: The present study uncovers the contribution of disturbed metabolism to the presence of coronary artery calcium and the associated risk of CHD in SLE. Identification of novel lipid and metabolite biomarkers may help stratifying patients for reducing CVD morbidity and mortality in SLE. FUNDING: INSERM and Sorbonne Université.

Genetic inhibition of CARD9 accelerates the development of atherosclerosis in mice through CD36 dependent-defective autophagy.

Caspase recruitment-domain containing protein 9 (CARD9) is a key signaling pathway in macrophages but its role in atherosclerosis is still poorly understood. Global deletion of Card9 in Apoe-/- mice as well as hematopoietic deletion in Ldlr-/- mice increases atherosclerosis. The acceleration of atherosclerosis is also observed in Apoe-/-Rag2-/-Card9-/- mice, ruling out a role for the adaptive immune system in the vascular phenotype of Card9 deficient mice. Card9 deficiency alters macrophage phenotype through CD36 overexpression with increased IL-1ß production, increased lipid uptake, higher cell death susceptibility and defective autophagy. Rapamycin or metformin, two autophagy inducers, abolish intracellular lipid overload, restore macrophage survival and autophagy flux in vitro and finally abolish the pro-atherogenic effects of Card9 deficiency in vivo. Transcriptomic analysis of human CARD9-deficient monocytes confirms the pathogenic signature identified in murine models. In summary, CARD9 is a key protective pathway in atherosclerosis, modulating macrophage CD36-dependent inflammatory responses, lipid uptake and autophagy.

Integrated omics approach for the identification of HDL structure-function relationships in PCSK9-related familial hypercholesterolemia.

BACKGROUND: The role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in dyslipidemia may go beyond its immediate effects on low-density lipoprotein receptor (LDL-R) activity. OBJECTIVE: This study aimed to assess PCSK9-derived alterations of high-density lipoprotein (HDL) physiology, which bear a potential to contribute to cardiovascular risk profile. METHODS: HDL was isolated from 33 patients with familial autosomal dominant hypercholesterolemia (FH), including those carrying PCSK9 gain-of-function (GOF) genetic variants (FH-PCSK9, n = 11), together with two groups of dyslipidemic patients employed as controls and carrying genetic variants in the LDL-R not treated (ntFH-LDLR, n = 11) and treated (tFH-LDLR, n = 11) with statins, and 11 normolipidemic controls. Biological evaluations paralleled by proteomic, lipidomic and glycomic analyses were applied to characterize functional and compositional properties of HDL. RESULTS: Multiple deficiencies in the HDL function were identified in the FH-PCSK9 group relative to dyslipidemic FH-LDLR patients and normolipidemic controls, which involved reduced antioxidative, antiapoptotic, anti-thrombotic and anti-inflammatory activities. By contrast, cellular cholesterol efflux capacity of HDL was unchanged. In addition, multiple alterations of the proteomic, lipidomic and glycomic composition of HDL were found in the FH-PCSK9 group. Remarkably, HDLs from FH-PCSK9 patients were systematically enriched in several lysophospholipids as well as in A2G2S2 (GP13) glycan and apolipoprotein A-IV. Based on network analysis of functional and compositional data, a novel mosaic structure-function model of HDL biology involving FH was developed. CONCLUSION: Several metrics of anti-atherogenic HDL functionality are altered in FH-PCSK9 patients paralleled by distinct compositional alterations. These data provide a first-ever overview of the impact of GOF PCSK9 genetic variants on structure-function relationships in HDL.

Abnormal Lipoproteins Trigger Oxidative Stress-Mediated Apoptosis of Renal Cells in LCAT Deficiency.

Familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) is a rare genetic disease caused by the loss of function mutations in the LCAT gene. LCAT deficiency is characterized by an abnormal lipoprotein profile with severe reduction in plasma levels of high-density lipoprotein (HDL) cholesterol and the accumulation of lipoprotein X (LpX). Renal failure is the major cause of morbidity and mortality in FLD patients; the pathogenesis of renal disease is only partly understood, but abnormalities in the lipoprotein profile could play a role in disease onset and progression. Serum and lipoprotein fractions from LCAT deficient carriers and controls were tested for renal toxicity on podocytes and tubular cells, and the underlying mechanisms were investigated at the cellular level. Both LpX and HDL from LCAT-deficient carriers triggered oxidative stress in renal cells, which culminated in cell apoptosis. These effects are partly explained by lipoprotein enrichment in unesterified cholesterol and ceramides, especially in the HDL fraction. Thus, alterations in lipoprotein composition could explain some of the nephrotoxic effects of LCAT deficient lipoproteins on podocytes and tubular cells.

Identification of the specific molecular and functional signatures of pre-beta-HDL: relevance to cardiovascular disease.

While low concentrations of high-density lipoprotein-cholesterol (HDL-C) are widely accepted as an independent cardiovascular risk factor, HDL-C-rising therapies largely failed, suggesting the importance of both HDL functions and individual subspecies. Indeed HDL particles are highly heterogeneous, with small, dense pre-beta-HDLs being considered highly biologically active but remaining poorly studied, largely reflecting difficulties for their purification. We developed an original experimental approach allowing the isolation of sufficient amounts of human pre-beta-HDLs and revealing the specificity of their proteomic and lipidomic profiles and biological activities. Pre-beta-HDLs were enriched in highly poly-unsaturated species of phosphatidic acid and phosphatidylserine, and in an unexpectedly high number of proteins implicated in the inflammatory response, including serum paraoxonase/arylesterase-1, vitronectin and clusterin, as well as in complement regulation and immunity, including haptoglobin-related protein, complement proteins and those of the immunoglobulin class. Interestingly, amongst proteins associated with lipid metabolism, phospholipid transfer protein, cholesteryl ester transfer protein and lecithin:cholesterol acyltransferase were strongly enriched in, or restricted to, pre-beta-HDL. Furthermore, pre-beta-HDL potently mediated cellular cholesterol efflux and displayed strong anti-inflammatory activities. A correlational network analysis between lipidome, proteome and biological activities highlighted 15 individual lipid and protein components of pre-beta-HDL relevant to cardiovascular disease, which may constitute novel diagnostic targets in a pathological context of altered lipoprotein metabolism.

LXR signaling controls homeostatic dendritic cell maturation.

Dendritic cells (DCs) mature in an immunogenic or tolerogenic manner depending on the context in which an antigen is perceived, preserving the balance between immunity and tolerance. Whereas the pathways driving immunogenic maturation in response to infectious insults are well-characterized, the signals that drive tolerogenic maturation during homeostasis are still poorly understood. We found that the engulfment of apoptotic cells triggered homeostatic maturation of type 1 conventional DCs (cDC1s) within the spleen. This maturation process could be mimicked by engulfment of empty, nonadjuvanted lipid nanoparticles (LNPs), was marked by intracellular accumulation of cholesterol, and was highly specific to cDC1s. Engulfment of either apoptotic cells or cholesterol-rich LNPs led to the activation of the liver X receptor (LXR) pathway, which promotes the efflux of cellular cholesterol, and repressed genes associated with immunogenic maturation. In contrast, simultaneous engagement of TLR3 to mimic viral infection via administration of poly(I:C)-adjuvanted LNPs repressed the LXR pathway, thus delaying cellular cholesterol efflux and inducing genes that promote T cell-mediated immunity. These data demonstrate that conserved cellular cholesterol efflux pathways are differentially regulated in tolerogenic versus immunogenic cDC1s and suggest that administration of nonadjuvanted cholesterol-rich LNPs may be an approach for inducing tolerogenic DC maturation.

Enhancer/gene relationships: Need for more reliable genome-wide reference sets.

Differences in cells' functions arise from differential activity of regulatory elements, including enhancers. Enhancers are cis-regulatory elements that cooperate with promoters through transcription factors to activate the expression of one or several genes by getting physically close to them in the 3D space of the nucleus. There is increasing evidence that genetic variants associated with common diseases are enriched in enhancers active in cell types relevant to these diseases. Identifying the enhancers associated with genes and conversely, the sets of genes activated by each enhancer (the so-called enhancer/gene or E/G relationships) across cell types, can help understanding the genetic mechanisms underlying human diseases. There are three broad approaches for the genome-wide identification of E/G relationships in a cell type: 1) genetic link methods or eQTL, 2) functional link methods based on 1D functional data such as open chromatin, histone mark or gene expression and 3) spatial link methods based on 3D data such as HiC. Since 1) and 3) are costly, the current strategy is to develop functional link methods and to use data from 1) and 3) as reference to evaluate them. However, there is still no consensus on the best functional link method to date, and method comparison remain seldom. Here, we compared the relative performances of three recent methods for the identification of enhancer-gene links, TargetFinder, Average-Rank, and the ABC model, using the three latest benchmarks from the field: a reference that combines 3D and eQTL data, called BENGI, and two genetic screening references, called CRiFF and CRiSPRi. Overall, none of the three methods performed best on the three references. CRiFF and CRISPRi reference sets are likely more reliable, but CRiFF is not genome-wide and CRiFF and CRISPRi are mostly available on the K562 cancer cell line. The BENGI reference set is genome-wide but likely contains many false positives. This study therefore calls for new reliable and genome-wide E/G reference data rather than new functional link E/G identification methods.

Liver RBFOX2 regulates cholesterol homeostasis via Scarb1 alternative splicing in mice.

RNA alternative splicing (AS) expands the regulatory potential of eukaryotic genomes. The mechanisms regulating liver-specific AS profiles and their contribution to liver function are poorly understood. Here, we identify a key role for the splicing factor RNA-binding Fox protein 2 (RBFOX2) in maintaining cholesterol homeostasis in a lipogenic environment in the liver. Using enhanced individual-nucleotide-resolution ultra-violet cross-linking and immunoprecipitation, we identify physiologically relevant targets of RBFOX2 in mouse liver, including the scavenger receptor class B type I (Scarb1). RBFOX2 function is decreased in the liver in diet-induced obesity, causing a Scarb1 isoform switch and alteration of hepatocyte lipid homeostasis. Our findings demonstrate that specific AS programmes actively maintain liver physiology, and underlie the lipotoxic effects of obesogenic diets when dysregulated. Splice-switching oligonucleotides targeting this network alleviate obesity-induced inflammation in the liver and promote an anti-atherogenic lipoprotein profile in the blood, underscoring the potential of isoform-specific RNA therapeutics for treating metabolism-associated diseases.

Mathematical Modelling of Material Transfer to High-Density Lipoprotein (HDL) upon Triglyceride Lipolysis by Lipoprotein Lipase: Relevance to Cardioprotective Role of HDL.

High-density lipoprotein (HDL) contributes to lipolysis of triglyceride-rich lipoprotein (TGRL) by lipoprotein lipase (LPL) via acquirement of surface lipids, including free cholesterol (FC), released upon lipolysis. According to the reverse remnant-cholesterol transport (RRT) hypothesis recently developed by us, acquirement of FC by HDL is reduced at both low and extremely high HDL concentrations, potentially underlying the U-shaped relationship between HDL-cholesterol and cardiovascular disease. Mechanisms underlying impaired FC transfer however remain indeterminate. We developed a mathematical model of material transfer to HDL upon TGRL lipolysis by LPL. Consistent with experimental observations, mathematical modelling showed that surface components of TGRL, including FC, were accumulated in HDL upon lipolysis. The modelling successfully reproduced major features of cholesterol accumulation in HDL observed experimentally, notably saturation of this process over time and appearance of a maximum as a function of HDL concentration. The calculations suggested that the both phenomena resulted from competitive fluxes of FC through the HDL pool, including primarily those driven by FC concentration gradient between TGRL and HDL on the one hand and mediated by lecithin-cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) on the other hand. These findings provide novel opportunities to revisit our view of HDL in the framework of RRT.

Normal HDL Cholesterol Efflux and Anti-Inflammatory Capacities in Type 2 Diabetes Despite Lipidomic Abnormalities.

OBJECTIVE: To assess whether, in type 2 diabetes (T2D) patients, lipidomic abnormalities in high-density lipoprotein (HDL) are associated with impaired cholesterol efflux capacity and anti-inflammatory effect, 2 pro-atherogenic abnormalities. DESIGN AND METHODS: This is a secondary analysis of the Lira-NAFLD study, including 20 T2D patients at T0 and 25 control subjects. Using liquid chromatography/tandem mass spectrometry, we quantified 110 species of the main HDL phospholipids and sphingolipids. Cholesterol efflux capacity was measured on THP-1 macrophages. The anti-inflammatory effect of HDL was measured as their ability to inhibit the tumor necrosis factor α (TNFα)-induced expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular cell adhesion molecule-1 (ICAM-1) on human vascular endothelial cells (HUVECs). RESULTS: The cholesterol-to-triglyceride ratio was decreased in HDL from T2D patients compared with controls (-46%, P = 0.00008). As expressed relative to apolipoprotein AI, the amounts of phosphatidylcholines, sphingomyelins, and sphingosine-1-phosphate were similar in HDL from T2D patients and controls. Phosphatidylethanolamine-based plasmalogens and ceramides (Cer) were, respectively, 27% (P = 0.038) and 24% (P = 0.053) lower in HDL from T2D patients than in HDL from controls, whereas phosphatidylethanolamines were 41% higher (P = 0.026). Cholesterol efflux capacity of apoB-depleted plasma was similar in T2D patients and controls (36.2 ±â€…4.3 vs 35.5 ±â€…2.8%, P = 0.59). The ability of HDL to inhibit the TNFα-induced expression of both VCAM-1 and ICAM-1 at the surface of HUVECs was similar in T2D patients and controls (-70.6 ±â€…16.5 vs -63.5 ±â€…18.7%, P = 0.14; and -62.1 ±â€…13.2 vs -54.7 ±â€…17.7%, P = 0.16, respectively). CONCLUSION: Despite lipidomic abnormalities, the cholesterol efflux and anti-inflammatory capacities of HDL are preserved in T2D patients.

Proprotein convertase PCSK9 affects expression of key surface proteins in human pancreatic beta cells via intracellular and extracellular regulatory circuits.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is involved in the degradation of the low-density lipoprotein receptor. PCSK9 also targets proteins involved in lipid metabolism (very low-density lipoprotein receptor), immunity (major histocompatibility complex I), and viral infection (cluster of differentiation 81). Recent studies have also indicated that PCSK9 loss-of-function mutations are associated with an increased incidence of diabetes; however, the expression and function of PCSK9 in insulin-producing pancreatic beta cells remain unclear. Here, we studied PCSK9 regulation and function by performing loss- and gain-of-function experiments in the human beta cell line EndoC-ßH1. We demonstrate that PCSK9 is expressed and secreted by EndoC-ßH1 cells. We also found that PCSK9 expression is regulated by cholesterol and sterol regulatory element-binding protein transcription factors, as previously demonstrated in other cell types such as hepatocytes. Importantly, we show that PCSK9 knockdown using siRNA results in deregulation of various elements of the transcriptome, proteome, and secretome, and increases insulin secretion. We also observed that PCSK9 decreases low-density lipoprotein receptor and very low-density lipoprotein receptor levels via an extracellular signaling mechanism involving exogenous PCSK9, as well as levels of cluster of differentiation 36, a fatty acid transporter, through an intracellular signaling mechanism. Finally, we found that PCSK9 regulates the cell surface expression of PDL1 and HLA-ABC, proteins involved in cell-lymphocyte interaction, also via an intracellular mechanism. Collectively, these results highlight PCSK9 as a regulator of multiple cell surface receptors in pancreatic beta cells.

The critical role of the TB5 domain of fibrillin-1 in endochondral ossification.

Mutations in the fibrillin-1 (FBN1) gene are responsible for the autosomal dominant form of geleophysic dysplasia (GD), which is characterized by short stature and extremities, thick skin and cardiovascular disease. All known FBN1 mutations in patients with GD are localized within the region encoding the transforming growth factor-ß binding protein-like 5 (TB5) domain of this protein. Herein, we generated a knock-in mouse model, Fbn1Y1698C by introducing the p.Tyr1696Cys mutation from a patient with GD into the TB5 domain of murine Fbn1 to elucidate the specific role of this domain in endochondral ossification. We found that both Fbn1Y1698C/+ and Fbn1Y1698C/Y1698C mice exhibited a reduced stature reminiscent of the human GD phenotype. The Fbn1 point mutation introduced in these mice affected the growth plate formation owing to abnormal chondrocyte differentiation such that mutant chondrocytes failed to establish a dense microfibrillar network composed of FBN1. This original Fbn1 mutant mouse model offers new insight into the pathogenic events underlying GD. Our findings suggest that the etiology of GD involves the dysregulation of the extracellular matrix composed of an abnormal FBN1 microfibril network impacting the differentiation of the chondrocytes.

Phosphatidylserine enhances anti-inflammatory effects of reconstituted HDL in macrophages via distinct intracellular pathways.

Phosphatidylserine (PS) is a minor phospholipid constituent of high-density lipoprotein (HDL) that exhibits potent anti-inflammatory activity. It remains indeterminate whether PS incorporation can enhance anti-inflammatory effects of reconstituted HDL (rHDL). Human macrophages were treated with rHDL containing phosphatidylcholine alone (PC-rHDL) or PC and PS (PC/PS-rHDL). Interleukin (IL)-6 secretion and expression was more strongly inhibited by PC/PS-rHDL than PC-rHDL in both tumor necrosis factor (TNF)-α- and lipopolysaccharide (LPS)-stimulated macrophages. siRNA experiments revealed that the enhanced anti-inflammatory effects of PC/PS-rHDL required scavenger receptor class B type I (SR-BI). Furthermore, PC/PS-rHDL induced a greater increase in Akt1/2/3 phosphorylation than PC-rHDL. In addition, PC/PS but not PC-rHDL decreased the abundance of plasma membrane lipid rafts and p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation. Finally, when these rHDL formulations were administered to dyslipidemic low-density lipoprotein (LDL)-receptor knockout mice fed a high-cholesterol diet, circulating IL-6 levels were significantly reduced only in PC/PS-rHDL-treated mice. In parallel, enhanced Akt1/2/3 phosphorylation by PC/PS-rHDL was observed in the mouse aortic tissue using immunohistochemistry. We concluded that the incorporation of PS into rHDLs enhanced their anti-inflammatory activity by modulating Akt1/2/3- and p38 MAPK-mediated signaling through SR-BI in stimulated macrophages. These data identify PS as a potent anti-inflammatory component capable of enhancing therapeutic potential of rHDL-based therapy.

Macrophage SR-B1 in atherosclerotic cardiovascular disease.

PURPOSE OF REVIEW: Scavenger receptor class B type 1 (SR-B1) promotes atheroprotection through its role in HDL metabolism and reverse cholesterol transport in the liver. However, evidence indicates that SR-B1 may impact atherosclerosis through nonhepatic mechanisms. RECENT FINDINGS: Recent studies have brought to light various mechanisms by which SR-B1 affects lesional macrophage function and protects against atherosclerosis. Efferocytosis is efficient in early atherosclerotic lesions. At this stage, and beyond its role in cholesterol efflux, SR-B1 promotes free cholesterol-induced apoptosis of macrophages through its control of apoptosis inhibitor of macrophage (AIM). At more advanced stages, macrophage SR-B1 binds and mediates the removal of apoptotic cells. SR-B1 also participates in the induction of autophagy which limits necrotic core formation and increases plaque stability. SUMMARY: These studies shed new light on the atheroprotective role of SR-B1 by emphasizing its essential contribution in macrophages during atherogenesis as a function of lesion stages. These new findings suggest that macrophage SR-B1 is a therapeutic target in cardiovascular disease.

Transcriptomic and Lipidomic Mapping of Macrophages in the Hub of Chronic Beta-Adrenergic-Stimulation Unravels Hypertrophy-, Proliferation-, and Lipid Metabolism-Related Genes as Novel Potential Markers of Early Hypertrophy or Heart Failure.

Sympathetic nervous system overdrive with chronic release of catecholamines is the most important neurohormonal mechanism activated to maintain cardiac output in response to heart stress. Beta-adrenergic signaling behaves first as a compensatory pathway improving cardiac contractility and maladaptive remodeling but becomes dysfunctional leading to pathological hypertrophy and heart failure (HF). Cardiac remodeling is a complex inflammatory syndrome where macrophages play a determinant role. This study aimed at characterizing the temporal transcriptomic evolution of cardiac macrophages in mice subjected to beta-adrenergic-stimulation using RNA sequencing. Owing to a comprehensive bibliographic analysis and complementary lipidomic experiments, this study deciphers typical gene profiles in early compensated hypertrophy (ECH) versus late dilated remodeling related to HF. We uncover cardiac hypertrophy- and proliferation-related transcription programs typical of ECH or HF macrophages and identify lipid metabolism-associated and Na+ or K+ channel-related genes as markers of ECH and HF macrophages, respectively. In addition, our results substantiate the key time-dependent role of inflammatory, metabolic, and functional gene regulation in macrophages during beta-adrenergic dependent remodeling. This study provides important and novel knowledge to better understand the prevalent key role of resident macrophages in response to chronically activated beta-adrenergic signaling, an effective diagnostic and therapeutic target in failing hearts.