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.

Interplay between efferocytosis and atherosclerosis.

In an adult human, billions of cells die and turn over daily. During this process, many apoptotic cells are produced and subsequently cleared by phagocytes - a process termed efferocytosis, which plays a critical role in tissue homeostasis. Efferocytosis is an important mechanism in the control of inflammatory processes. Efficient efferocytosis inhibits accumulation of apoptotic cells/debris and maintains homeostasis before the onset of necrosis (secondary necrosis), which promotes inflammation or injury. During efferocytosis, mitochondrial fission and the oxidative stress process are linked through reactive oxygen species production and oxidative stress control. Autophagy plays an important role in inhibiting inflammation and apoptosis, and in promoting efferocytosis by activated inflammatory cells, particularly neutrophils and macrophages. Autophagy in neutrophils is activated by phagocytosis of pathogens or activation of pattern recognition receptors. Autophagy is essential for major neutrophil functions, including degranulation, reactive oxygen species production, oxidative stress and release of neutrophil extracellular cytokines. Failed efferocytosis is a key mechanism driving the development and progression of chronic inflammatory diseases, including atherosclerosis, cardiometabolic pathology, neurodegenerative disease and cancer. Impairment of efferocytosis in apoptotic macrophages is a determinant of atherosclerosis severity and the vulnerability of plaques to rupture. Recent results suggest that inhibition of efferocytosis in the protection of the myocardium results in reduced infiltration of reparatory macrophages into the tissue, in association with oxidative stress reduction. Activated macrophages play a central role in the development and resolution of inflammation. The resolution of inflammation through efferocytosis is an endogenous process that protects host tissues from prolonged or excessive inflammation. Accordingly, therapeutic strategies that ameliorate efferocytosis control would be predicted to dampen inflammation and improve resolution. Thus, therapies targeting efferocytosis will provide a new means of treating and preventing cardiovascular and metabolic diseases involving the chronic inflammatory state.

Antitumoral Activity of Molecular Hydrogen and Proton in the Treatment of Glioblastoma: An Atypical Pharmacology?

Antioxidants in cancer therapy have been a hot topic in the medical field for 20 years. Antioxidants are able to reduce the risk of cancer formation by neutralizing free radicals. Protons (H+) and molecular hydrogen (H2) interact in the cell and are essential in a wide variety of processes. The antioxidant, anti-inflammatory, and antiapoptotic effects of H2 have been studied in numerous experimental and clinical studies. Experimental data indicate that H2 is an antitumor agent in the treatment of glioblastoma (GBM). In vivo H2 inhalation could suppress the growth of GBM tumors, thereby extending the survival of mice with GBM. The sphere-forming ability of glioma cells was suppressed by hydrogen treatment. In addition, H2 treatment also suppressed the migration, invasion, and colony-forming ability of glioma cells. Proton therapy and proton beam radiotherapy offer some advantages over other modern conformal photon-based therapies when used in the treatment of central nervous system malignancies.

Distribution of atrial cardiomyopathy markers and association with atrial fibrillation detected after ischaemic stroke in the SAFAS study.

BACKGROUND: Atrial cardiomyopathy (AC) is an emerging concept explaining the pathophysiology of cardioembolic strokes in absence of atrial fibrillation (AF). A definition based on the presence of electrical abnormality (P-wave terminal force in lead V1 (PTFV1) >5000 µV×ms), N-Terminal pro-B-type natriuretic peptide (NT pro BNP) >250 pg/mL and/or indexed left atrial diameter (LADI) >3 cm/m² is currently tested in the ARCADIA (AtRial Cardiopathy and Antithrombotic Drugs In prevention After cryptogenic stroke) trial. We set out to estimate the prevalence of AC as defined in the ARCADIA trial, its determinants and its association with AF detected after stroke (AFDAS). METHODS: Stepwise screening for silent Atrial Fibrillation After Stroke (SAFAS) study prospectively included 240 ischaemic stroke patients. AC markers were complete for 192 of them and 9 were not included in this analysis because AF had been diagnosed on admission. RESULTS: A total of 183 patients were analysed, of whom 57% (104 patients) met the AC criteria (79 NT-proBNP, 47 PTFV1, 4 LADI). In the multivariate logistic regression, C reactive protein >3 mg/L (OR (95% CI) 2.60 (1.30 to 5.21), p=0.007) and age (OR (95% CI) 1.07 (1.04 to 1.10), p<0.001) were found to be independently associated with AC. After 6 months of follow-up, AFDAS was detected in 33% of AC patients and in 14% of the remaining ones (p=0.003). However, AC was not independently associated with AFDAS, contrary to left atrial volume index (>34 mL/m2, OR 2.35 (CI 1.09 to 5.06) p=0029). CONCLUSION: AC as defined in ARCADIA is mostly based on NT pro BNP elevation (76% of patients) and is associated with age and inflammation. Moreover, AC was not independently associated with AFDAS at follow-up. The ARCADIA trial, which compares aspirin to apixaban in patients with embolic strokes of undetermined source with AC markers and must, therefore be analysed in the light of these limitations. TRIAL REGISTRATION NUMBER: NCT03570060.

Plasma growth differentiation factor - 8 / Myostatin level as prognostic biomarker of patients with ischemic stroke and acute revascularization therapy. PARADISE study.

BACKGROUND: Identifying biological markers of ischemic stroke (IS) is an important research approach to develop innovative therapeutic strategies. This study aimed to assess the association between plasma Growth Differentiation Factor-8 (GDF-8)/Myostatin levels and outcome of IS patients. METHODS: Consecutive patients with acute IS treated with either intravenous thrombolysis and/or mechanical thrombectomy at Dijon University Hospital, France were prospectively included. Clinical variables were recorded, and plasma GDF-8 was collected just after the revascularization procedure. Primary endpoint was functional outcome at 3 months assessed by the modified Rankin Scale (mRS) score. Secondary endpoints included mRS scores at 6 and 12 months, and overall mortality over 1-year of follow-up. RESULTS: Among the 173 included patients (median age: 76 years, Interquartile range (IQR): 66-85; 49% women), median plasma GDF-8 levels at admission were significantly lower in those with a poor outcome at 3 months defined as a mRS score > 2 (2073 (IQR: 1564-2757) pg/mL versus 1471 (1192-2241) pg/mL, p < 0.001). Lower GDF-8 levels at admission were associated with higher 3-months mRS score in multivariable ordinal logistic regression analysis (OR = 0.9995; 95% CI: 0.9991-0.9999, p = 0.011). The association was also observed with 6- and 12-month mRS scores. Although mortality was higher in patients with lower GDF-8 levels, the association was not significant in multivariable Cox analysis. CONCLUSION: Lower plasma GDF-8 levels were associated with a poorer functional outcome in IS patients treated with acute revascularization therapy. Underlying pathophysiological mechanisms involving GDF-8 in post-stroke outcome remain to be elucidated.

The long-lasting shadow of litter size in rodents: litter size is an underreported variable that strongly determines adult physiology.

BACKGROUND/PURPOSE: Litter size is a biological variable that strongly influences adult physiology in rodents. Despite evidence from previous decades and recent studies highlighting its major impact on metabolism, information about litter size is currently underreported in the scientific literature. Here, we urge that this important biological variable should be explicitly stated in research articles. RESULTS/CONCLUSION: Below, we briefly describe the scientific evidence supporting the impact of litter size on adult physiology and outline a series of recommendations and guidelines to be implemented by investigators, funding agencies, editors in scientific journals, and animal suppliers to fill this important gap.

Stress: Eight Decades after Its Definition by Hans Selye: "Stress Is the Spice of Life".

July 1936: Hans Selye describes in 74 lines in the prestigious journal Nature a new concept: Stress [...].

Growth differentiation factor 11: A proangiogenic drug as a potential antiaging regulating molecule.

Organs and tissues are subjected to numerous alterations during aging, as a result of complex biochemical changes. Aging is certainly associated with the accumulation of "antiaging" and "proaging" factors in the systemic circulation. The effects of young blood on rejuvenation of regenerative capacity suggest the existence of multiple "proyouthful" factors, such as growth differentiation factor 11 (GDF11), in the young blood of animals. GDF11 is a member of the transforming growth factor beta (TGFß) superfamily of cytokines, and appears to be a critical rejuvenation factor in aging organs. In the context of aging, GDF11 promotes vascular and neural plasticity of the central nervous system. Parabiosis, the surgical linking of circulations between old and young mice, was employed to identify GDF11 as an antihypertrophic factor that appears to rejuvenate the aging murine heart. Current theories suggest that GDF11 in young blood has beneficial effects on cognitive and cardiovascular functions and wound healing. The cellular mechanisms of GDF11 in cardiovascular, neurological, skin and skeletal muscle diseases are not clearly defined, but evidence indicates that it may function as a proneurogenic and proangiogenic drug. GDF11 binds and activates specific receptor complexes, which transmit signals by two procedures: the TGFß-Smad pathway and the bone morphogenic protein (BMP)-Smad pathway. GDF11 is perhaps only the first in a series of circulating molecules that will be found to influence the aging of different tissues, and it may be a potential candidate for therapeutic intervention against angiogenesis-related disorders.

GDF15 : A modulator of immunity and a predictive biomarker of cardiovascular events : A strategy in COVID-19.

In the recently published manuscript entitled "GDF15 a rising modulator of immunity and a strategy in Coronavirus disease 2019 (COVID-19) in relationship with iron metabolism" and we examined the potential properties of Growth and differentiation factor 15 (GDF15) as an emerging modulator of immunity in COVID-19. We commented new aspects of the biology of GDF15 and investigated the potential value of GDF15 as a biomarker. Is GDF15 a biomarker of the inflammatory process and oxidative stress state? Recently, it was reported that 1500 clinical trials related to COVID-19 have been registered, but none have yet found an optimal strategy. In these conditions, more clinical studies are needed before any of these agents can be considered antiviral agents.

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.

Multimodal Approach for the Prediction of Atrial Fibrillation Detected After Stroke: SAFAS Study.

Background: Intensive screening for atrial fibrillation (AF) has led to a better recognition of this cause in stroke patients. However, it is currently debated whether AF Detected After Stroke (AFDAS) has the same pathophysiology and embolic risk as prior-to-stroke AF. We thus aimed to systematically approach AFDAS using a multimodal approach combining clinical, imaging, biological and electrocardiographic markers. Methods: Patients without previously known AF admitted to the Dijon University Hospital (France) stroke unit for acute ischemic stroke were prospectively enrolled. The primary endpoint was the presence of AFDAS at 6 months, diagnosed through admission ECG, continuous electrocardiographic monitoring, long-term external Holter during the hospital stay, or implantable cardiac monitor if clinically indicated after discharge. Results: Of the 240 included patients, 77 (32%) developed AFDAS. Compared with sinus rhythm patients, those developing AFDAS were older, more often women and less often active smokers. AFDAS patients had higher blood levels of NT-proBNP, osteoprotegerin, galectin-3, GDF-15 and ST2, as well as increased left atrial indexed volume and lower left ventricular ejection fraction. After multivariable analysis, galectin-3 ≧ 9 ng/ml [OR 3.10; 95% CI (1.03-9.254), p = 0.042], NT-proBNP ≧ 290 pg/ml [OR 3.950; 95% CI (1.754-8.892, p = 0.001], OPG ≥ 887 pg/ml [OR 2.338; 95% CI (1.015-5.620), p = 0.046) and LAVI ≥ 33.5 ml/m2 [OR 2.982; 95% CI (1.342-6.625), p = 0.007] were independently associated with AFDAS. Conclusion: A multimodal approach combining imaging, electrocardiography and original biological markers resulted in good predictive models for AFDAS. These results also suggest that AFDAS is probably related to an underlying atrial cardiopathy. Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [NCT03570060].

Effect of acute iron infusion on insulin secretion: A randomized, double-blind, placebo-controlled trial.

Background: Chronic exposure to high iron levels increases diabetes risk partly by inducing oxidative stress, but the consequences of acute iron administration on beta cells are unknown. We tested whether the acute administration of iron for the correction of iron deficiency influenced insulin secretion and the production of reactive oxygen species. Methods: Single-center, double-blinded, randomized controlled trial conducted between June 2017 and March 2020. 32 women aged 18 to 47 years, displaying symptomatic iron deficiency without anaemia, were recruited from a community setting and randomly allocated (1:1) to a single infusion of 1000 mg intravenous ferric carboxymaltose (iron) or saline (placebo). The primary outcome was the between group mean difference from baseline to day 28 in first and second phase insulin secretion, assessed by a two-step hyperglycaemic clamp. All analyses were performed by intention to treat. This trial was registered in ClinicalTrials.gov NCT03191201. Findings: Iron infusion did not affect first and second phase insulin release. For first phase, the between group mean difference from baseline to day 28 was 0 µU × 10 min/mL [95% CI, -22 to 22, P = 0.99]. For second phase, it was -5 µUx10min/mL [95% CI, -161 to 151; P = 0.95] at the first plateau of the clamp and -249 µUx10min/mL [95% CI, -635 to 137; P = 0.20] at the second plateau. Iron infusion increased serum ascorbyl/ascorbate ratio, a marker of plasma oxidative stress, at day 14, with restoration of normal ratio at day 28 relative to placebo. Finally, high-sensitive C-reactive protein levels remained similar among groups. Interpretation: In iron deficient women without anaemia, intravenous administration of 1000 mg of iron in a single sitting did not impair glucose-induced insulin secretion despite a transient increase in the levels of circulating reactive oxygen species. Funding: The Swiss National Science Foundation, University of Lausanne and Leenaards, Raymond-Berger and Placide Nicod Foundations.

Involvement of Oxidative Stress in Protective Cardiac Functions of Calprotectin.

Calprotectin (CLP) belonging to the S-100 protein family is a heterodimeric complex (S100A8/S100A9) formed by two binding proteins. Upon cell activation, CLP stored in neutrophils is released extracellularly in response to inflammatory stimuli and acts as damage-associated molecular patterns (DAMPs). S100A8 and S100A9 possess both anti-inflammatory and anti-bacterial properties. The complex is a ligand of the toll-like receptor 4 (TLR4) and receptor for advanced glycation end (RAGE). At sites of infection and inflammation, CLP is a target for oxidation due to its co-localization with neutrophil-derived oxidants. In the heart, oxidative stress (OS) responses and S100 proteins are closely related and intimately linked through pathophysiological processes. Our review summarizes the roles of S100A8, S100A9 and CLP in the inflammation in relationship with vascular OS, and we examine the importance of CLP for the mechanisms driving in the protection of myocardium. Recent evidence interpreting CLP as a critical modulator during the inflammatory response has identified this alarmin as an interesting drug target.

Mitochondrial-derived peptides: New markers for cardiometabolic dysfunction.

Great attention is being paid to the evaluation of new markers in blood circulation for the estimation of tissue metabolism disturbance. This endogenous disturbance may contribute to the onset and progression of cardiometabolic disease. In addition to their role in energy production and metabolism, mitochondria play a main function in cellular mechanisms, including apoptosis, oxidative stress and calcium homeostasis. Mitochondria produce mitochondrial-derived peptides that mediate the transcriptional stress response by translocating into the nucleus and interacting with deoxyribonucleic acid. This class of peptides includes humanin, mitochondrial open reading frame of the 12S ribosomal ribonucleic acid type c (MOTS-c) and small humanin-like peptides. Mitochondrial-derived peptides are regulators of metabolism, exerting cytoprotective effects through antioxidative stress, anti-inflammatory responses and antiapoptosis; they are emerging biomarkers reflecting mitochondrial function, and the circulating concentration of these proteins can be used to diagnose cardiometabolic dysfunction. The aims of this review are: (1) to describe the emerging role for mitochondrial-derived peptides as biomarkers; and (2) to discuss the therapeutic application of these peptides.

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.

Assessment of Clinical Scales for Detection of Large Vessel Occlusion in Ischemic Stroke Patients from the Dijon Stroke Registry.

(1) Background: The limited availability of thrombectomy-capable stroke centres raises questions about pre-hospital triage of patients with suspected stroke (IS) due to large vessel occlusion (LVO). Aims: This study aimed to evaluate the diagnostic accuracy of clinical stroke severity scales available for LVO detection. (2) Methods: Patients with IS were prospectively identified among residents of Dijon, France, using a population-based registry (2013-2017). Clinical signs and arterial imaging data were collected. LVO was defined as an occlusion site affecting the terminal intracranial internal carotid artery, the M1 segment of the middle cerebral artery (MCA), or the basilar artery (restricted definition). A wide definition of LVO also included the M2 segment of the MCA. For each of the 16 evaluated scales, a receiver operator characteristic (ROC) analysis was performed, and the c-statistic representing the area under the ROC curve was evaluated to assess discrimination for predicting LVO. (3) Results: 971 patients were registered, including 123 patients (12.7%) with an LVO according to the restricted definition. The c-statistic for LVO detection ranged between 0.66 and 0.80 according to the different scales, with a sensibility varying from 70% to 98% and a specificity from 33% to 86%. According to the wide definition of LVO (174 patients, 17.9%), the c-statistic was slightly lower, ranging between 0.64 and 0.79. The sensitivity was 59% to 93%, and the specificity was 34% to 89%. (4) Conclusion: The clinical scales failed to combine a high sensitivity and a high specificity to detect LVO. Further studies are needed to determine the best strategy for pre-hospital triage of IS patients.

GDF15: an emerging modulator of immunity and a strategy in COVID-19 in association with iron metabolism.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic of respiratory and cardiovascular diseases, known as coronavirus disease 2019 (COVID-19). SARS-CoV-2 encodes the structural proteins spike (S), envelope (E), membrane (M), and nucleocapsid (N). The receptor-binding domain on the surface subunit S1 is responsible for attachment of the virus to angiotensin (Ang)-converting enzyme 2 (ACE2), which is highly expressed in host cells. The cytokine storm observed in patients with COVID-19 contributes to the endothelial vascular dysfunction, which can lead to acute respiratory distress syndrome, multiorgan failure, alteration in iron homeostasis, and death. Growth and differentiation factor 15 (GDF15), which belongs to the transforming growth factor-ß (TGF-ß) superfamily of proteins, has a pivotal role in the development and progression of diseases because of its role as a metabolic regulator. In COVID-19, GDF15 activity increases in response to tissue damage. GDF15 appears to be a strong predictor of poor outcomes in patients critically ill with COVID-19 and acts as an 'inflammation-induced central mediator of tissue tolerance' via its metabolic properties. In this review, we examine the potential properties of GDF15 as an emerging modulator of immunity in COVID-19 in association with iron metabolism. The virus life cycle in host cell provides potential targets for drug therapy.

Association between Serum Osteoprotegerin Levels and Severity of Coronary Artery Disease in Patients with Acute Myocardial Infarction.

BACKGROUND: Osteoprotegerin (OPG), a glycoprotein of the tumour necrosis factor (TNF) superfamily, is one of the main biomarkers for vascular calcification. AIM: We aimed to evaluate the association between serum OPG levels and extent of coronary lesions in patients with acute myocardial infarction (MI). METHODS: Consecutive patients hospitalized for an acute MI who underwent coronary angiography were included. SYNTAX score was calculated to assess the severity of coronary artery disease. The population was analysed in low (5 (3-6)), medium (11 (9-13)) and high (20 (18-23)) tertiles of SYNTAX score. RESULTS: Among the 378 patients included, there was a gradual increase in age, rate of diabetes, anterior wall location, and a reduction in left ventricular ejection fraction across the SYNTAX tertiles. OPG levels significantly increased across the tertiles (962 (782-1497), 1240 (870-1707), and 1464 (1011-2129) pg/mL, respectively (p < 0.001)). In multivariate analysis, OPG [OR(CI95%): 2.10 (1.29-3.49) 0.003], were associated with the high SYNTAX group, beyond hypercholesterolemia, CV history and reduced glomerular filtration rate. CONCLUSION: We found an association between OPG levels and coronary lesions complexity patients with acute MI.

The emerging role of miRNA-132/212 cluster in neurologic and cardiovascular diseases: Neuroprotective role in cells with prolonged longevity.

miRNA-132/212 are small regulators of gene expression with a function that fulfills a vital function in diverse biological processes including neuroprotection of cells with prolonged longevity in neurons and the cardiovascular system. In neurons, miRNA-132 appears to be essential for controlling differentiation, development, and neural functioning. Indeed, it also universally promotes axon evolution, nervous migration, plasticity as well, it is suggested to be neuroprotective against neurodegenerative diseases. Moreover, miRNA-132/212 disorder leads to neural developmental perturbation, and the development of degenerative disorders covering Alzheimer's, Parkinson's, and epilepsy's along with psychiatric perturbations including schizophrenia. Furthermore, the cellular mechanisms of the miRNA-132/212 have additionally been explored in cardiovascular diseases models. Also, the miRNA-132/212 family modulates cardiac hypertrophy and autophagy in cardiomyocytes. The protective and effective clinical promise of miRNA-132/212 in these systems is discussed in this review. To sum up, the current progress in innovative miRNA-based therapies for human pathologies seems of extreme concern and reveals promising novel therapeutic strategies.

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.