Prevalence and characteristics of known versus newly detected atrial fibrillation in ischemic stroke: a population-based study.

BACKGROUND: Atrial fibrillation (AF) is frequently diagnosed during the acute stage of ischemic (IS), and it may reflect undiagnosed AF before stroke, thus representing a missed opportunity for stroke prevention. This population-based study aimed to assess the prevalence of known AF (KAF) and AF diagnosed early after IS (AFDAS), and to compare clinical and brain/arterial imaging characteristics between patients. METHODS: Among patients with acute IS recorded in the population-based Dijon Stroke Registry, France (2013-2020), we identified those with KAF or AFDAS. AFDAS was considered when AF was diagnosed during the initial work-up based on electrocardiograms, in-hospital continuous electrocardiographic and/or Holter monitoring. Clinical and imaging characteristics on brain CT-scan or angio-CT-scan when available including old parenchymal lesions, arterial territory of the index IS, and aortic arch, cervical and intracranial arteries atheroma were compared between groups (KAF versus AFDAS). Regression logistic models were used to assess factors associated with AFDAS (compared to KAF). RESULTS: Among 1756 IS patients, 550 (31.3%) had AF (mean age: 83.6 ±10.3 years old, 60.5% women), of whom 367 (66.7%) presented with KAF and 183 (33.3%) had AFDAS. In multivariable model, hypertension (OR=0.37; 95% CI: 0.21-0.64, p<0.001), chronic heart failure (OR=0.34; 95% CI: 0.18-0.67, p=0.002), previous stroke (OR=0.42; 95% CI: 0.26-0.67, p<0.001), and preexisting dementia (OR=0.36; 95% CI: 0.21-0.63, p<0.001), were inversely associated with AFDAS, whereas NIHSS score was associated with AFDAS (OR=1.02; 95% CI: 1.00-1.05, p=0.012). CONCLUSIONS: Our findings indicate a more advanced stage of the atrial cardiomyopathy in KAF as compared with AFDAS patients, and may thus contribute to the fact that in these latter patients AF had not been diagnosed prior to stroke. This group of patients undeniably represents a missed opportunity for stroke prevention.

Pre-existing brain damage and association between severity and prior cognitive impairment in ischemic stroke patients.

BACKGROUND: We evaluated whether pre-existing brain damage may explain greater severity in cognitively-impaired patients with ischemic stroke (IS). METHODS: IS patients were retrieved from the population-based registry of Dijon, France. Pre-existing damage (leukoaraiosis, old vascular brain lesions, cortical and central brain atrophy) was assessed on initial CT-scan. Association between prestroke cognitive status defined as no impairment, mild cognitive impairment (MCI), or dementia, and clinical severity at IS onset assessed with the NIHSS score was evaluated using ordinal regression analysis. Mediation analysis was performed to assess pre-existing brain lesions as mediators of the relationship between cognitive status and severity. RESULTS: Among the 916 included patients (mean age 76.8 ± 15.0 years, 54.3% women), those with pre-existing MCI (n = 115, median NIHSS [IQR]: 6 [2-15]) or dementia (n = 147, median NIHSS: 6 [3-15]) had a greater severity than patients without (n = 654, median NIHSS: 3 [1-9]) in univariate analysis (OR=1.69; 95% CI: 1.18-2.42, p = 0.004, and OR=2.06; 95% CI: 1.49-2.84, p < 0.001, respectively). Old cortical lesion (OR=1.53, p = 0.002), central atrophy (OR=1.41, p = 0.005), cortical atrophy (OR=1.90, p < 0.001) and moderate (OR=1.41, p = 0.005) or severe (OR=1.84, p = 0.002) leukoaraiosis were also associated with greater severity. After adjustments, pre-existing MCI (OR=1.52; 95% CI: 1.03-2.26, p = 0.037) or dementia (OR=1.94; 95% CI: 1.32-2.86, p = 0.001) remained associated with higher severity at IS onset, independently of confounding factors including imaging variables. Association between cognitive impairment and severity was not mediated by pre-existing visible brain damages. CONCLUSION: Impaired brain ischemic tolerance in IS patients with prior cognitive impairment could involve other mechanisms than pre-existing visible brain damage.

Lipid Peroxidation and Iron Metabolism: Two Corner Stones in the Homeostasis Control of Ferroptosis.

Regulated cell death (RCD) has a significant impact on development, tissue homeostasis, and the occurrence of various diseases. Among different forms of RCD, ferroptosis is considered as a type of reactive oxygen species (ROS)-dependent regulated necrosis. ROS can react with polyunsaturated fatty acids (PUFAs) of the lipid (L) membrane via the formation of a lipid radical L• and induce lipid peroxidation to form L-ROS. Ferroptosis is triggered by an imbalance between lipid hydroperoxide (LOOH) detoxification and iron-dependent L-ROS accumulation. Intracellular iron accumulation and lipid peroxidation are two central biochemical events leading to ferroptosis. Organelles, including mitochondria and lysosomes are involved in the regulation of iron metabolism and redox imbalance in ferroptosis. In this review, we will provide an overview of lipid peroxidation, as well as key components involved in the ferroptotic cascade. The main mechanism that reduces ROS is the redox ability of glutathione (GSH). GSH, a tripeptide that includes glutamic acid, cysteine, and glycine, acts as an antioxidant and is the substrate of glutathione peroxidase 4 (GPX4), which is then converted into oxidized glutathione (GSSG). Increasing the expression of GSH can inhibit ferroptosis. We highlight the role of the xc- GSH-GPX4 pathway as the main pathway to regulate ferroptosis. The system xc-, composed of subunit solute carrier family members (SLC7A11 and SLC3A2), mediates the exchange of cystine and glutamate across the plasma membrane to synthesize GSH. Accumulating evidence indicates that ferroptosis requires the autophagy machinery for its execution. Ferritinophagy is used to describe the removal of the major iron storage protein ferritin by the autophagy machinery. Nuclear receptor coactivator 4 (NCOA4) is a cytosolic autophagy receptor used to bind ferritin for subsequent degradation by ferritinophagy. During ferritinophagy, stored iron released becomes available for biosynthetic pathways. The dysfunctional ferroptotic response is implicated in a variety of pathological conditions. Ferroptosis inducers or inhibitors targeting redox- or iron metabolism-related proteins and signal transduction have been developed. The simultaneous detection of intracellular and extracellular markers may help diagnose and treat diseases related to ferroptotic damage.

PCSK9 levels do not predict severity and recurrence of cardiovascular events in patients with acute myocardial infarction.

BACKGROUND AND AIMS: It remains unclear whether serum PCSK9 levels can predict the severity of the disease and the risk of future events in patients with coronary artery disease (CAD). We aimed to evaluate the association between PCSK9 levels, metabolic parameters, severity of CAD on coronary angiography (SYNTAX score), and the risk of in-hospital events and at one-year follow-up. METHODS AND RESULTS: From September 2015 to December 2016, serum PCSK9 levels were measured on admission in patients not previously receiving statin therapy, and admitted for an acute myocardial infarction (MI), in an intensive care unit from a university hospital. In a total of 648 patients (mean age: 66 years, 67% male), median PCSK9 was 263 ng/ml, higher for females compared with males (270 vs 256 ng/ml, p = 0.009). Serum PCSK9 was associated with LDL cholesterol (r = 0.083, p = 0.036), total cholesterol (r = 0.136, p = 0.001) and triglycerides (r = 0.137, p = 0.001). A positive association was also observed in the subgroup of patients with CRP >10 mg/L (p < 0.001), but not with NT-proBNP, troponin and creatine kinase. PCSK9 levels were similar whatever the SYNTAX score or the number of significant coronary lesions. PCSK9 levels were not associated with in-hospital events (death, recurrent MI and stroke) and events (cardiovascular death, cardiovascular events, recurrent MI) at one-year follow-up. CONCLUSIONS: In this large cohort of patients hospitalized for acute MI and not previously receiving statin therapy, PCSK9 levels was not associated with the severity or the recurrence of cardiovascular events. The clinical utility of measuring PCSK9 levels for this category of patients therefore appears limited.

GDF15 and Cardiac Cells: Current Concepts and New Insights.

Growth and differentiation factor 15 (GDF15) belongs to the transforming growth factor-ß (TGF-ß) superfamily of proteins. Glial-derived neurotrophic factor (GDNF) family receptor α-like (GFRAL) is an endogenous receptor for GDF15 detected selectively in the brain. GDF15 is not normally expressed in the tissue but is prominently induced by "injury". Serum levels of GDF15 are also increased by aging and in response to cellular stress and mitochondrial dysfunction. It acts as an inflammatory marker and plays a role in the pathogenesis of cardiovascular diseases, metabolic disorders, and neurodegenerative processes. Identified as a new heart-derived endocrine hormone that regulates body growth, GDF15 has a local cardioprotective role, presumably due to its autocrine/paracrine properties: antioxidative, anti-inflammatory, antiapoptotic. GDF15 expression is highly induced in cardiomyocytes after ischemia/reperfusion and in the heart within hours after myocardial infarction (MI). Recent studies show associations between GDF15, inflammation, and cardiac fibrosis during heart failure and MI. However, the reason for this increase in GDF15 production has not been clearly identified. Experimental and clinical studies support the potential use of GDF15 as a novel therapeutic target (1) by modulating metabolic activity and (2) promoting an adaptive angiogenesis and cardiac regenerative process during cardiovascular diseases. In this review, we comment on new aspects of the biology of GDF15 as a cardiac hormone and show that GDF15 may be a predictive biomarker of adverse cardiac events.

Influence of Pre-Existing Mild Cognitive Impairment and Dementia on Post-Stroke Mortality. The Dijon Stroke Registry.

OBJECTIVE: We assessed the association between pre-stroke cognitive status and 90-day case-fatality. METHODS: Patients with ischemic stroke (IS) or spontaneous intracerebral hemorrhage (ICH) were prospectively identified among residents of Dijon, France, between 2013 and 2015, using a population-based registry. Association between pre-stroke cognitive status and case-fatality at 90 days was evaluated using Cox regression. RESULTS: Seven hundred sixty-two patients were identified, and information about pre-stroke cognitive status was obtained for 716 (92.6%) of them, including 603 IS (84.2%) and 113 ICH (15.8%). Before stroke, 99 (13.8%) patients had mild cognitive impairment (MCI) and 98 (13.7%) had dementia. Patients with cognitive impairment were older, had a higher prevalence of several risk factors, more severe stroke, more frequent ICH, and less admission to stroke unit. Case-fatality rate at 90 days was 11.7% in patients without cognitive impairment, 32.3% in MCI patients, and 55.1% in patients with dementia. In multivariable analyses, pre-existing MCI (hazard ratio [HR] 2.22, 95% CI 1.21-4.05, p = 0.009) and dementia (HR 4.35, 95% CI 2.49-7.61, p < 0.001) were both associated with 90-day case-fatality. CONCLUSION: Pre-stroke MCI and dementia were both associated with increased mortality. These associations were not fully explained by baseline characteristics, pre-stroke dependency, stroke severity or patient management, and underlying reasons need to be investigated.

The Crosstalk of Adipose-Derived Stem Cells (ADSC), Oxidative Stress, and Inflammation in Protective and Adaptive Responses.

The potential use of stem cell-based therapies for the repair and regeneration of various tissues and organs is a major goal in repair medicine. Stem cells are classified by their potential to differentiate into functional cells. Compared with other sources, adipose-derived stem cells (ADSCs) have the advantage of being abundant and easy to obtain. ADSCs are considered to be tools for replacing, repairing, and regenerating dead or damaged cells. The capacity of ADSCs to maintain their properties depends on the balance of complex signals in their microenvironment. Their properties and the associated outcomes are in part regulated by reactive oxygen species, which mediate the oxidation-reduction state of cells as a secondary messenger. ADSC therapy has demonstrated beneficial effects, suggesting that secreted factors may provide protection. There is evidence that ADSCs secrete a number of cytokines, growth factors, and antioxidant factors into their microenvironment, thus regulating intracellular signaling pathways in neighboring cells. In this review, we introduce the roles of ADSCs in the protection of cells by modulating inflammation and immunity, and we develop their potential therapeutic properties.

Programming of Cardiovascular Dysfunction by Postnatal Overfeeding in Rodents.

Nutritional environment in the perinatal period has a great influence on health and diseases in adulthood. In rodents, litter size reduction reproduces the effects of postnatal overnutrition in infants and reveals that postnatal overfeeding (PNOF) not only permanently increases body weight but also affects the cardiovascular function in the short- and long-term. In addition to increased adiposity, the metabolic status of PNOF rodents is altered, with increased plasma insulin and leptin levels, associated with resistance to these hormones, changed profiles and levels of circulating lipids. PNOF animals present elevated arterial blood pressure with altered vascular responsiveness to vasoactive substances. The hearts of overfed rodents exhibit hypertrophy and elevated collagen content. PNOF also induces a disturbance of cardiac mitochondrial respiration and produces an imbalance between oxidants and antioxidants. A modification of the expression of crucial genes and epigenetic alterations is reported in hearts of PNOF animals. In vivo, a decreased ventricular contractile function is observed during adulthood in PNOF hearts. All these alterations ultimately lead to an increased sensitivity to cardiac pathologic challenges such as ischemia-reperfusion injury. Nevertheless, caloric restriction and physical exercise were shown to improve PNOF-induced cardiac dysfunction and metabolic abnormalities, drawing a path to the potential therapeutic correction of early nutritional programming.

Anti-Aging Effects of GDF11 on Skin.

Human skin is composed of three layers: the epidermis, the dermis, and the hypodermis. The epidermis has four major cell layers made up of keratinocytes in varying stages of progressive differentiation. Skin aging is a multi-factorial process that affects every phase of its biology and function. The expression profiles of inflammation-related genes analyzed in resident immune cells demonstrated that these cells have a strong ability to regenerate adult skin stem cells and to produce endogenous substances such as growth differentiation factor 11 (GDF11). GDF11 appears to be the key to progenitor proliferation and/or differentiation. The preservation of youthful phenotypes has been tied to the presence of GDF11 in different human tissues, and, in the skin, this factor inhibits inflammatory responses. The protective role of GDF11 depends on a multi-factorial process implicating various types of skin cells such as keratinocytes, fibroblasts and inflammatory cells. GDF11 should be further studied for the purpose of developing novel therapies for the treatment of skin diseases.

Mitochondrial SLC25 Carriers: Novel Targets for Cancer Therapy.

The transfer of metabolites through the mitochondrial membranes is a vital process that is highly controlled and regulated by the inner membrane. A variety of metabolites, nucleotides, and cofactors are transported across the inner mitochondrial membrane (IMM) by a superfamily of membrane transporters which are known as the mitochondrial carrier family (MCF) or the solute carrier family 25 (SLC25 protein family). In humans, the MCF has 53 members encoded by nuclear genes. Members of the SLC25 family of transporters, which is the largest group of solute carriers, are also known as mitochondrial carriers (MCs). Because MCs are nuclear-coded proteins, they must be imported into the IMM. When compared with normal cells, the mitochondria of cancer cells exhibit significantly increased transmembrane potentials and a number of their transporters are altered. SLC25 members were identified as potential biomarkers for various cancers. The objective of this review is to summarize what is currently known about the involvement of mitochondrial SLC25 carriers in associated diseases. This review suggests that the SLC25 family could be used for the development of novel points of attack for targeted cancer therapy.

The Role of Osteoprotegerin in Vascular Calcification and Bone Metabolism: The Basis for Developing New Therapeutics.

Osteoporosis (OP) and cardiovascular diseases (CVD) are both important causes of mortality and morbidity in aging patients. There are common mechanisms underlying the regulation of bone remodeling and the development of smooth muscle calcification; a temporal relationship exists between osteoporosis and the imbalance of mineral metabolism in the vessels. Vascular calcification appears regulated by mechanisms that include both inductive and inhibitory processes. Multiple factors are implicated in both bone and vascular metabolism. Among these factors, the superfamily of tumor necrosis factor (TNF) receptors including osteoprotegerin (OPG) and its ligands has been established. OPG is a soluble decoy receptor for receptor activator of nuclear factor-kB ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL). OPG binds to RANKL and TRAIL, and inhibits the association with their receptors, which have been labeled as the receptor activator of NF-kB (RANK). Sustained release of OPG from vascular endothelial cells (ECs) has been demonstrated in response to inflammatory proteins and cytokines, suggesting that OPG/RANKL/RANK system plays a modulatory role in vascular injury and inflammation. For the development of potential therapeutic strategies targeting vascular calcification, critical consideration of the implications for bone metabolism must be taken into account to prevent potentially detrimental effects to bone metabolism.

The Role of Osteoprotegerin and Its Ligands in Vascular Function.

The superfamily of tumor necrosis factor (TNF) receptors includes osteoprotegerin (OPG) and its ligands, which are receptor activators of nuclear factor kappa-B ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL). The OPG/RANKL/RANK system plays an active role in pathological angiogenesis and inflammation as well as cell survival. It has been demonstrated that there is crosstalk between endothelial cells and osteoblasts during osteogenesis, thus establishing a connection between angiogenesis and osteogenesis. This OPG/RANKL/RANK/TRAIL system acts on specific cell surface receptors, which are then able to transmit their signals to other intracellular components and modify gene expression. Cytokine production and activation of their receptors induce mechanisms to recruit monocytes and neutrophils as well as endothelial cells. Data support the role of an increased OPG/RANKL ratio as a possible marker of progression of endothelial dysfunction in metabolic disorders in relationship with inflammatory marker levels. We review the role of the OPG/RANKL/RANK triad in vascular function as well as molecular mechanisms related to the etiology of vascular diseases. The potential therapeutic strategies may be very promising in the future.

[The difficulties and needs of families of children in remission from a childhood cancer]. / Difficultés et besoins des familles d'enfants en rémission d'un cancer pédiatrique.

Childhood cancer causes immense upheaval for the child and his or her family. The end of the treatments constitutes a transition period which brings with it numerous other problems. It is essential to take into account the difficulties expressed by families and to envisage areas of action to help and support them.

Ischemic Stroke Increases Heart Vulnerability to Ischemia-Reperfusion and Alters Myocardial Cardioprotective Pathways.

Background and Purpose- For years, the relationship between cardiac and neurological ischemic events has been limited to overlapping pathophysiological mechanisms and common risk factors. However, acute stroke may induce dramatic changes in cardiovascular function. The aim of this study was to evaluate how prior cerebrovascular lesions affect myocardial function and signaling in vivo and ex vivo and how they influence cardiac vulnerability to ischemia-reperfusion injury. Methods- Cerebral embolization was performed in adult Wistar male rats through the injection of microspheres into the left or right internal carotid artery. Stroke lesions were evaluated by microsphere counting, tissue staining, and assessment of neurological deficit 2 hours, 24 hours, and 7 days after surgery. Cardiac function was evaluated in vivo by echocardiography and ex vivo in isolated perfused hearts. Heart vulnerability to ischemia-reperfusion injury was investigated ex vivo at different times post-embolization and with varying degrees of myocardial ischemia. Left ventricles (LVs) were analyzed with Western blotting and quantitatve real-time polymerase chain reaction. Results- Our stroke model produced large cerebral infarcts with severe neurological deficit. Cardiac contractile dysfunction was observed with an early but persistent reduction of LV fractional shortening in vivo and of LV developed pressure ex vivo. Moreover, after 20 or 30 minutes of global cardiac ischemia, recovery of contractile function was poorer with impaired LV developed pressure and relaxation during reperfusion in both stroke groups. Following stroke, circulating levels of catecholamines and GDF15 (growth differentiation factor 15) increased. Cerebral embolization altered nitro-oxidative stress signaling and impaired the myocardial expression of ADRB1 (adrenoceptor ß1) and cardioprotective Survivor Activating Factor Enhancement signaling pathways. Conclusions- Our findings indicate that stroke not only impairs cardiac contractility but also worsens myocardial vulnerability to ischemia. The underlying molecular mechanisms of stroke-induced myocardial alterations after cerebral embolization remain to be established, insofar as they may involve the sympathetic nervous system and nitro-oxidative stress.

Regenerative Capacity of Endogenous Factor: Growth Differentiation Factor 11; a New Approach of the Management of Age-Related Cardiovascular Events.

Aging is a complicated pathophysiological process accompanied by a wide array of biological adaptations. The physiological deterioration correlates with the reduced regenerative capacity of tissues. The rejuvenation of tissue regeneration in aging organisms has also been observed after heterochronic parabiosis. With this model, it has been shown that exposure to young blood can rejuvenate the regenerative capacity of peripheral tissues and brain in aged animals. An endogenous compound called growth differentiation factor 11 (GDF11) is a circulating negative regulator of cardiac hypertrophy, suggesting that raising GDF11 levels could potentially treat or prevent cardiac diseases. The protein GDF11 is found in humans as well as animals. The existence of endogenous regulators of regenerative capacity, such as GDF11, in peripheral tissues and brain has now been demonstrated. It will be important to investigate the mechanisms with therapeutic promise that induce the regenerative effects of GDF11 for a variety of age-related diseases.

Cutting edge: IL-1α is a crucial danger signal triggering acute myocardial inflammation during myocardial infarction.

Myocardial infarction (MI) induces a sterile inflammatory response that contributes to adverse cardiac remodeling. The initiating mechanisms of this response remain incompletely defined. We found that necrotic cardiomyocytes released a heat-labile proinflammatory signal activating MAPKs and NF-κB in cardiac fibroblasts, with secondary production of cytokines. This response was abolished in Myd88(-/-) fibroblasts but was unaffected in nlrp3-deficient fibroblasts. Despite MyD88 dependency, the response was TLR independent, as explored in TLR reporter cells, pointing to a contribution of the IL-1 pathway. Indeed, necrotic cardiomyocytes released IL-1α, but not IL-1ß, and the immune activation of cardiac fibroblasts was abrogated by an IL-1R antagonist and an IL-1α-blocking Ab. Moreover, immune responses triggered by necrotic Il1a(-/-) cardiomyocytes were markedly reduced. In vivo, mice exposed to MI released IL-1α in the plasma, and postischemic inflammation was attenuated in Il1a(-/-) mice. Thus, our findings identify IL-1α as a crucial early danger signal triggering post-MI inflammation.

La transition de l'enfant atteint de cancer, regard des familles.

THE TRANSITION OF CHILDREN AFFECTED BY CANCER, THE FAMILY PERSPECTIVE.: During serious diseases in childhood such as cancer, the journey of the families is staged in information and transition times, which are essential stages for rebuilding family life. Support, orientation and proposals for a way forward are necessary for patients or their families not to be left in destructive isolation. Support actions for patients and their loved ones are implemented, particularly by associations.

Diabetes, oxidative stress and therapeutic strategies.

BACKGROUND: Diabetes has emerged as a major threat to health worldwide. SCOPE OF REVIEW: The exact mechanisms underlying the disease are unknown; however, there is growing evidence that excess generation of reactive oxygen species (ROS), largely due to hyperglycemia, causes oxidative stress in a variety of tissues. Oxidative stress results from either an increase in free radical production, or a decrease in endogenous antioxidant defenses, or both. ROS and reactive nitrogen species (RNS) are products of cellular metabolism and are well recognized for their dual role as both deleterious and beneficial species. In type 2 diabetic patients, oxidative stress is closely associated with chronic inflammation. Multiple signaling pathways contribute to the adverse effects of glucotoxicity on cellular functions. There are many endogenous factors (antioxidants, vitamins, antioxidant enzymes, metal ion chelators) that can serve as endogenous modulators of the production and action of ROS. Clinical trials that investigated the effect of antioxidant vitamins on the progression of diabetic complications gave negative or inconclusive results. This lack of efficacy might also result from the fact that they were administered at a time when irreversible alterations in the redox status are already under way. Another strategy to modulate oxidative stress is to exploit the pleiotropic properties of drugs directed primarily at other targets and thus acting as indirect antioxidants. MAJOR CONCLUSIONS: It appears important to develop new compounds that target key vascular ROS producing enzymes and mimic endogenous antioxidants. GENERAL SIGNIFICANCE: This strategy might prove clinically relevant in preventing the development and/or retarding the progression of diabetes associated with vascular diseases.

Paradoxically, iron overload does not potentiate doxorubicin-induced cardiotoxicity in vitro in cardiomyocytes and in vivo in mice.

Doxorubicin (DOX) is known to induce serious cardiotoxicity, which is believed to be mediated by oxidative stress and complex interactions with iron. However, the relationship between iron and DOX-induced cardiotoxicity remains controversial and the role of iron chelation therapy to prevent cardiotoxicity is called into question. Firstly, we evaluated in vitro the effects of DOX in combination with dextran-iron on cell viability in cultured H9c2 cardiomyocytes and EMT-6 cancer cells. Secondly, we used an in vivo murine model of iron overloading (IO) in which male C57BL/6 mice received a daily intra-peritoneal injection of dextran-iron (15mg/kg) for 3weeks (D0-D20) and then (D21) a single sub-lethal intra-peritoneal injection of 6mg/kg of DOX. While DOX significantly decreased cell viability in EMT-6 and H9c2, pretreatment with dextran-iron (125-1000µg/mL) in combination with DOX, paradoxically limited cytotoxicity in H9c2 and increased it in EMT-6. In mice, IO alone resulted in cardiac hypertrophy (+22%) and up-regulation of brain natriuretic peptide and ß-myosin heavy-chain (ß-MHC) expression, as well as an increase in cardiac nitro-oxidative stress revealed by electron spin resonance spectroscopy. In DOX-treated mice, there was a significant decrease in left-ventricular ejection fraction (LVEF) and an up-regulation of cardiac ß-MHC and atrial natriuretic peptide (ANP) expression. However, prior IO did not exacerbate the DOX-induced fall in LVEF and there was no increase in ANP expression. IO did not impair the capacity of DOX to decrease cancer cell viability and could even prevent some aspects of DOX cardiotoxicity in cardiomyocytes and in mice.