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There is much evidence supporting the role of β₂-adrenoceptors (β₂AR) in angiogenesis but the mechanisms underlying their effects have not been elucidated. Hence, we studied post-ischaemic angiogenesis in the hindlimb (HL) of β₂AR knock-out mice (β₂AR-/-) in vivo and explored possible molecular mechanisms in vitro.Femoral artery resection (FAR) was performed in wild-type and β₂AR-/- mice and adaptive responses to chronic HL ischaemia were explored; blood flow was measured by ultrasound and perfusion of dyed beads, bone rarefaction, muscle fibrosis and skin thickness were evaluated by immunoflourescence and morphometric analysis. Intrafemoral delivery of an adenovirus encoding the human β₂AR (ADβ₂AR) was used to reinstate β₂ARs in β₂AR-/- mice. Molecular mechanisms were investigated in mouse-derived aortic endothelial cells (EC) in vitro, focusing on NFκB activation and transcriptional activity.Angiogenesis was severely impaired in β₂AR-/- mice subjected to FAR, but was restored by gene therapy with ADβ₂AR. The proangiogenic responses to a variety of stimuli were impaired in β₂AR-/- EC in vitro. Moreover, removal of β₂ARs impaired the activation of NFκB, a transcription factor that promotes angiogenesis; neither isoprenaline (stimulates βARs) nor TNFα induced NFκB activation in β₂AR(-/-) EC. Interestingly, cAMP response element binding protein (CREB), a transcription factor that counter regulates NFκB, was constitutively increased in β₂AR(-/-) ECs. ADβ₂AR administration restored β₂AR membrane density, reduced CREB activity and reinstated the NFκB response to isoprenaline and TNFα.Our results suggest that β₂ARs control angiogenesis through the tight regulation of nuclear transcriptional activity.

Finding reliable parameters to identify patients with heart failure (HF) that will respond to cardiac resynchronization therapy (CRT) represents a major challenge. We and others have observed post-translational modifications of Ryanodine Receptor (RyR) in several tissues (including skeletal muscle and circulating lymphocytes) of patients with advanced HF. We designed a prospective study to test the hypothesis that RyR1 glycation in circulating lymphocytes could predict CRT responsiveness in patients with non-ischemic HF. We enrolled 94 patients who underwent CRT and 30 individuals without HF, examining RyR1 glycation in peripheral lymphocytes at enrollment and after 1 year. We found that baseline RyR1 glycation independently predicts CRT response at 1 year after adjusting for age, diabetes, QRS duration and morphology, echocardiographic dyssynchrony, and hypertension. Moreover, RyR1 glycation in circulating lymphocytes significantly correlated with pathologic intracellular calcium leak. Taken together, our data show for the first time that RyR1 glycation in circulating lymphocytes represents a novel biomarker to predict CRT responsiveness.

Atherogenesis involves a complex interaction between immune cells and lipids, processes greatly influenced by the vascular smooth muscle cell (VSMC) phenotype. The DNA glycosylase NEIL3 has previously been shown to have a role in atherogenesis, though whether this is due to its ability to repair DNA damage or to other non-canonical functions is not yet clear. Hereby, we investigate the role of NEIL3 in atherogenesis, specifically in VSMC phenotypic modulation, which is critical in plaque formation and stability.Chow diet-fed atherosclerosis-prone ApoeWe show that Neil3 deficiency increases atherosclerotic plaque development without affecting systemic lipids. This observation was associated with a shift in VSMC phenotype towards a proliferating, lipid-accumulating and secretory macrophage-like cell phenotype, without changes in DNA damage. VSMC transdifferentiation in Neil3-deficient mice encompassed increased activity of the Akt signaling pathway, supported by cell experiments showing Akt-dependent proliferation in NEIL3-abrogated human primary aortic VSMCs.Our findings show that Neil3 deficiency promotes atherosclerosis development through non-canonical mechanisms affecting VSMC phenotype involving activation of the Akt signaling pathway.

In order to meet its energy requirements, the heart has the intrinsic capability to metabolize a wide range of energy substrates. In normal conditions, the heart favors fatty acids as the main energetic substrate, followed by carbohydrates, ketone bodies, and, lastly, amino acids (1,2). Yet, the myocardium is able to dynamically switch its metabolism according to substrate availability, in order to attempt to guarantee an efficient pumping function in virtually any scenario (2,3). Mechanistically, this phenomenon seems to be possible, as the different substrates available in the heart compete as source of energy, making the final choice essentially based on the relative substrate concentrations. In a seminal Nature article published in 1961, Schipp et al. (4) demonstrated for the first time that increasing fatty acid availability resulted in a marked inhibition of glucose oxidation. Overall, the high flexibility in selecting the most suitable fuel is considered a fingerprint of a healthy myocardium (1). Accordingly, an impaired metabolic flexibility is strongly linked to cardiac damage and dysfunction (2). In the presence of diverse pathological conditions, cardiac metabolism might lose the ability to use some substrates. Whether this phenomenon is deleterious or actually denotes an adaptive response of the myocardium to keep its metabolic rate remains controversial. However, clarifying this aspect is of crucial importance, especially in order to design new therapeutic strategies. In this context, diabetic cardiomyopathy is one of the most critical knots to untie. In diabetes, despite the hyperglycemic status, a reduced capability to use glucose by myocardium has been reported (5,6). However, whether such impairment in glucose oxidization is an adaptive or maladaptive response of the diabetic heart remains to be elucidated. The matter is highly debated, despite recent evidence …

Background The inflammatory response occurring in acute myocardial infarction (AMI) has been proposed as a potential pharmacological target. Sodium-glucose co-transporter 2 inhibitors (SGLT2-I) currently receive intense clinical interest in patients with and without diabetes mellitus (DM) for their pleiotropic beneficial effects. We tested the hypothesis that SGLT2-I have anti-inflammatory effects along with glucose-lowering properties. Therefore, we investigated the link between stress hyperglycemia, inflammatory burden, and infarct size in a cohort of type 2 diabetic patients presenting with AMI treated with SGLT2-I versus other oral anti-diabetic (OAD) agents. Methods In this multicenter international observational registry, consecutive diabetic AMI patients undergoing percutaneous coronary intervention (PCI) between 2018 and 2021 were enrolled. Based on the presence of anti-diabetic therapy at the admission, patients were divided into those receiving SGLT2-I (SGLT-I users) versus other OAD agents (non-SGLT2-I users). The following inflammatory markers were evaluated at different time points: white-blood-cell count, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), neutrophil-to-platelet ratio (NPR), and C-reactive protein. Infarct size was assessed by echocardiography and by peak troponin levels. Results The study population consisted of 583 AMI patients (with or without ST-segment elevation): 98 SGLT2-I users and 485 non-SGLT-I users. Hyperglycemia at admission was less prevalent in the SGLT2-I group. Smaller infarct size was observed in patients treated with SGLT2-I compared to non-SGLT2-I group. On admission and at 24 h, inflammatory indices were significantly higher in non-SGLT2-I users compared to SGLT2-I patients, with a significant increase in neutrophil levels at 24 h. At multivariable analysis, the use of SGLT2-I was a significant predictor of reduced inflammatory response (OR 0.457, 95% CI 0.275–0.758, p = 0.002), independently of age, admission creatinine values, and admission glycemia. Conversely, peak troponin values and NSTEMI occurrence were independent predictors of a higher inflammatory status. Conclusions Type 2 diabetic AMI patients receiving SGLT2-I exhibited significantly reduced inflammatory response and smaller infarct size compared to those receiving other OAD agents, independently of glucose-metabolic control. Our findings are hypothesis generating and provide new insights on the cardioprotective effects of SGLT2-I in the setting of coronary artery disease. Trial Registration: Data are part of the ongoing observational registry: SGLT2-I AMI PROTECT. ClinicalTrials.gov Identifier: NCT 05261867.

Restenosis, defined as the re-narrowing of an arterial lumen after revascularization, represents an increasingly important issue in clinical practice. Indeed, as the number of stent placements has risen to an estimate that exceeds 3 million annually worldwide, revascularization procedures have become much more common. Several investigators have demonstrated that vessels in patients with diabetes mellitus have an increased risk restenosis. Here we present a systematic overview of the effects of diabetes on in-stent restenosis. Current classification and updated epidemiology of restenosis are discussed, alongside the main mechanisms underlying the pathophysiology of this event. Then, we summarize the clinical presentation of restenosis, emphasizing the importance of glycemic control in diabetic patients. Indeed, in diabetic patients who underwent revascularization procedures a proper glycemic control remains imperative.

Background Diabetes and hypertension are common in older adults and represent established risk factors for frailty. Frailty is a multidimensional condition due to reserve loss and susceptibility to stressors with a high risk of death, hospitalizations, functional and cognitive impairment. Comorbidities such as diabetes and hypertension play a key role in increasing the risk of mortality, hospitalization, and disability. Moreover, frail patients with diabetes and hypertension are known to have an increased risk of cognitive and physical impairment. Nevertheless, no study assessed the correlation between physical and cognitive impairment in frail older adults with diabetes and hypertension. Methods We evaluated consecutive frail older patients with diabetes and hypertension who presented at ASL (local health unit of the Italian Ministry of Health) Avellino, Italy, from March 2021 to October 2021. The inclusion criteria were: a previous diagnosis of diabetes and hypertension with no evidence of secondary causes; age > 65 years; a frailty status; Montreal Cognitive Assessment (MoCA) score Results 179 patients successfully completed the study. We found a strong and significant correlation between MoCA score and 5-m gait speed test (r: 0.877; p Conclusions This is the first study showing a significant correlation between 5-m gait speed test and MoCA score in frail diabetic and hypertensive older adults.

Sortilin has been positively correlated with vascular disorders in humans. No study has yet evaluated the possible direct effect of sortilin on vascular function. We used pharmacological and genetic approaches coupled with study of murine and human samples to unravel the mechanisms recruited by sortilin in the vascular system. Sortilin induced endothelial dysfunction of mesenteric arteries through NADPH oxidase 2 (NOX2) isoform activation, dysfunction that was prevented by knockdown of acid sphingomyelinase (ASMase) or sphingosine kinase 1. In vivo, recombinant sortilin administration induced arterial hypertension in WT mice. In contrast, genetic deletion of sphingosine-1-phosphate receptor 3 (S1P3) and gp91phox/NOX2 resulted in preservation of endothelial function and blood pressure homeostasis after 14 days of systemic sortilin administration. Translating these research findings into the clinical setting, we detected elevated sortilin levels in hypertensive patients with endothelial dysfunction. Furthermore, in a population-based cohort of 270 subjects, we showed increased plasma ASMase activity and increased plasma levels of sortilin, S1P, and soluble NOX2-derived peptide (sNOX2-dp) in hypertensive subjects, and the increase was more pronounced in hypertensive subjects with uncontrolled blood pressure. Our studies reveal what we believe is a previously unrecognized role of sortilin in the impairment of vascular function and in blood pressure homeostasis and suggest the potential of sortilin and its mediators as biomarkers for the prediction of vascular dysfunction and high blood pressure.

microRNAs (miRNA, miRs) play crucial roles in cardiovascular disease regulating numerous processes, including inflammation, cell proliferation, angiogenesis, and cell death. Herein, we present an updated and comprehensive overview of the functional involvement of miRs in the regulation of cardiomyocyte death, a central event in acute myocardial infarction, ischemia/reperfusion, and heart failure. Specifically, in this systematic review we are focusing on necrosis, apoptosis, and autophagy.

T-cell immunoglobulin and mucin domain 1 (TIM-1) has been recently identified as one of the factors involved in the internalization of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in human cells, in addition to angiotensin-converting enzyme 2 (ACE2), transmembrane serine protease 2 (TMPRSS2), neuropilin-1, and others. We hypothesized that specific microRNAs could target TIM-1, with potential implications for the management of patients suffering from coronavirus disease 2019 (COVID-19). By combining bioinformatic analyses and functional assays, we identified miR-142 as a specific regulator of TIM-1 transcription. Since TIM-1 has been implicated in the regulation of endothelial function at the level of the blood-brain barrier (BBB) and its levels have been shown to be associated with stroke and cerebral ischemia-reperfusion injury, we validated miR-142 as a functional modulator of TIM-1 in human brain microvascular endothelial cells (hBMECs). Taken together, our results indicate that miR-142 targets TIM-1, representing a novel strategy against cerebrovascular disorders, as well as systemic complications of SARS-CoV-2 and other viral infections.

Background: Hypertension is common in older adults and its incidence increases with age. We investigated the correlation between physical and cognitive impairment in older adults with frailty and hypertension. Methods: We recruited frail hypertensive older adults during the COVID-19 pandemic, between March 2021 and December 2021. Global cognitive function was assessed through the Montreal Cognitive Assessment (MoCA), physical frailty assessment was performed following the Fried criteria, and all patients underwent physical evaluation through 5-meter gait speed test. Results: We enrolled 203 frail hypertensive older adults and we found a significant correlation between MoCA score and gait speed test (r: 0.495; p

Endothelial dysfunction is a key hallmark of hypertension, which is a leading risk factor for cognitive decline in older adults with or without frailty. Similarly, hyperglycemia is known to impair endothelial function and is a predictor of severe cardiovascular outcomes, independent of the presence of diabetes. On these grounds, we designed a study to assess the effects of high-glucose and metformin on brain microvascular endothelial cells (ECs) and on cognitive impairment in frail hypertensive patients. We tested the effects of metformin on high-glucose-induced cell death, cell permeability, and generation of reactive oxygen species in vitro, in human brain microvascular ECs. To investigate the consequences of hyperglycemia and metformin in the clinical scenario, we recruited frail hypertensive patients and we evaluated their Montreal Cognitive Assessment (MoCA) scores, comparing them according to the glycemic status (normoglycemic vs. hyperglycemic) and the use of metformin. We enrolled 376 patients, of which 209 successfully completed the study. We observed a significant correlation between MoCA score and glycemia. We found that hyperglycemic patients treated with metformin had a significantly better MoCA score than hyperglycemic patients treated with insulin (18.32 ± 3.9 vs. 14.94 ± 3.8, p &lt, 0.001). Our in vitro assays confirmed the beneficial effects of metformin on human brain microvascular ECs. To our knowledge, this is the first study correlating MoCA score and glycemia in frail and hypertensive older adults, showing that hyperglycemia aggravates cognitive impairment.

International audience; Patients with heart failure (HF) have augmented vascular tone, which increases cardiac workload, impairing ventricular output and promoting further myocardial dysfunction. The molecular mechanisms underlying the maladaptive vascular responses observed in HF are not fully understood. Vascular smooth muscle cells (VSMCs) control vasoconstriction via a Ca2+-dependent process, in which the type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) on the sarcoplasmic reticulum (SR) plays a major role. To dissect the mechanistic contribution of intracellular Ca2+ release to the increased vascular tone observed in HF, we analyzed the remodeling of IP3R1 in aortic tissues from patients with HF and from controls. VSMC IP3R1 channels from patients with HF and HF mice were hyperphosphorylated by both serine and tyrosine kinases. VSMCs isolated from IP3R1VSMC-/- mice exhibited blunted Ca2+ responses to angiotensin II (ATII) and norepinephrine compared with control VSMCs. IP3R1VSMC-/- mice displayed significantly reduced responses to ATII, both in vivo and ex vivo. HF IP3R1VSMC-/- mice developed significantly less afterload compared with HF IP3R1fl/fl mice and exhibited significantly attenuated progression toward decompensated HF and reduced interstitial fibrosis. Ca2+-dependent phosphorylation of the MLC by MLCK activated VSMC contraction. MLC phosphorylation was markedly increased in VSMCs from patients with HF and HF mice but reduced in VSMCs from HF IP3R1VSMC-/- mice and HF WT mice treated with ML-7. Taken together, our data indicate that VSMC IP3R1 is a major effector of increased vascular tone, which contributes to increased cardiac afterload and decompensation in HF.

Background Despite primary percutaneous coronary intervention (PPCI) is generally considered the best therapy in older frail adults with ST-segment elevation myocardial infarction (STEMI), the incidence of re-hospitalization for cardiovascular diseases remains significant in these patients. Aims We hypothesized that thrombus aspiration (TA) before PPCI could be a useful treatment for reducing mortality and rehospitalizations in frail patients undergoing PPCI for STEMI. Methods We conducted a study comparing PPCI alone vs TA + PPCI in frail STEMI patients. We examined a cohort of consecutive frail patients aged ≥ 65 years with first STEMI treated with PPCI between February 2008 and July 2015 at the Department of Cardiology of the “Cardarelli” Hospital in Naples, Italy. Results The study was completed by 389 patients (PPCI: 195, TA + PPCI: 194). At 1-month follow-up, the rate of death from any cause was 7.0% in patients treated with PPCI alone vs 3.0% in patients treated with TA + PPCI (p 0.036), whereas death from cardiovascular causes was 6.0% in the PPCI group vs 3.0% in the TA + PPCI group (p 0.028). Equally important, the rate of re-hospitalization due to heart failure was 7.5% in the PPCI group vs 4.0% in TA + PPCI group (p 0.025) and the rate of re-hospitalization due to acute coronary syndrome was 10.0% in the PPCI group vs 4.5% in the TA + PPCI group (p 0.016). Conclusion These results indicate the importance of TA in the treatment of STEMI in a group of high-risk patients such as elderly with frailty.

INTRODUCTION: Inositol 1,4,5-trisphosphate receptors (IP3Rs) are intracellular calcium (Ca(2+)) release channels located on the endoplasmic/sarcoplasmic reticulum. The availability of the structure of the ligand-binding domain of IP3Rs has enabled the design of compatible ligands, but the limiting step remains their actual effectiveness in a biological context. AREAS COVERED: This article summarizes the compelling literature on both agonists and antagonists targeting IP3Rs, emphasizing their strengths and limitations. The main challenges toward the discovery and development of IP3 receptor modulators are also described. EXPERT OPINION: Despite significant progress in recent years, the pharmacology of IP3R still has major drawbacks, especially concerning the availability of specific antagonists. Moreover, drugs specifically targeting the three different subtypes of IP3R are especially needed.

Heart failure and cardiovascular disorders represent the leading cause of death in diabetic patients. Here we present a systematic review of the main mechanisms underlying the development of diabetic cardiomyopathy. We also provide an excursus on the relative contribution of cardiomyocytes, fibroblasts, endothelial and smooth muscle cells to the pathophysiology of heart failure in diabetes. After having described the preclinical tools currently available to dissect the mechanisms of this complex disease, we conclude with a section on the most recent updates of the literature on clinical management.

l-Arginine is involved in many different biological processes and recent reports indicate that it could also play a crucial role in the coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Herein, we present an updated systematic overview of the current evidence on the functional contribution of L-Arginine in COVID-19, describing its actions on endothelial cells and the immune system and discussing its potential as a therapeutic tool, emerged from recent clinical experimentations.

Excessive BK (bradykinin) stimulation is responsible for the exaggerated permeabilization of the endothelium in angioedema. However, the molecular mechanisms underlying these responses have not been investigated. BK receptors are Gq-protein-coupled receptors phosphorylated by GRK2 (G protein-coupled receptor kinase 2) with a hitherto unknown biological and pathophysiological significance. In the present study, we sought to identify the functional role of GRK2 in angioedema through the regulation of BK signaling. We found that the accumulation of cytosolic Ca 2+ in endothelial cells induced by BK was sensitive to GRK2 activity, as it was significantly augmented by inhibiting the kinase. Accordingly, permeabilization and NO production induced by BK were enhanced, as well. In vivo, mice with reduced GRK2 levels in the endothelium (Tie2-CRE/GRK2 fl+/fl − ) exhibited an increased response to BK in terms of vascular permeability and extravasation. Finally, patients with reduced GRK2 levels displayed a severe phenotype of angioedema. Taken together, these findings establish GRK2 as a novel pivotal regulator of BK signaling with an essential role in the pathophysiology of vascular permeability and angioedema.

Glucagon-like peptide-1 (GLP-1) has been shown to potentiate glucose-stimulated insulin secretion binding GLP-1 receptor on pancreatic &beta, cells. &beta, arrestin 1 (&beta, ARR1) is known to regulate the desensitization of GLP-1 receptor. Mounting evidence indicates that microRNAs (miRNAs, miRs) are fundamental in the regulation of &beta, cell function and insulin release. However, the regulation of GLP-1/&beta, ARR1 pathways by miRs has never been explored. Our hypothesis is that specific miRs can modulate the GLP-1/&beta, ARR1 axis in &beta, cells. To test this hypothesis, we applied a bioinformatic approach to detect miRs that could target &beta, ARR1, we identified hsa-miR-7-5p (miR-7) and we validated the specific interaction of this miR with &beta, ARR1. Then, we verified that GLP-1 was indeed able to regulate the transcription of miR-7 and &beta, ARR1, and that miR-7 significantly regulated GLP-1-induced insulin release and cyclic AMP (cAMP) production in &beta, cells. Taken together, our findings indicate, for the first time, that miR-7 plays a functional role in the regulation of GLP-1-mediated insulin release by targeting &beta, ARR1. These results have a decisive clinical impact given the importance of drugs modulating GLP-1 signaling in the treatment of patients with type 2 diabetes mellitus.

BackgroundHypertension is the most frequent co-morbidity in patients with covid-19 infection, and we might speculate that a specific blood group could play a key role in the clinical outcome of hypertensive patients with covid-19.MethodsIn this prospective study, we compared 0 vs. non-0 blood group in hypertensive patients with covid-19 infection. In these patients, we evaluated inflammatory and thrombotic status, cardiac injury, and death events.ResultsPatients in non-0 (n = 92) vs. 0 blood group (n = 72) had significantly different values of activated pro-thrombin time, D-dimer, and thrombotic indexes as Von Willebrand factor and Factor VIII (p p ConclusionsTaken together, our data indicate that non-0 covid-19 hypertensive patients have significantly higher values of pro-thrombotic indexes, as well as higher rate of cardiac injury and deaths compared to 0 patients. Moreover, AB0 blood type influences worse prognosis in hypertensive patients with covid-19 infection.

Lipopolysaccharides (LPS) is emerging as a novel risk factor for cardiovascular events (CVEs). Furthermore, in vitro evidence suggested that LPS may elicit proprotein convertase subtilisin/kexin 9 (PCSK9) expression, but their relationship in vivo has not been investigated.We conducted a post-hoc analysis of a prospective, single centre cohort study of 907 patients with non-valvular atrial fibrillation (AF). At baseline, PCSK9, LPS and NADPH oxidase (sNox2-dp) were measured. PCSK9 and LPS were correlated with the incidence of CVEs.Median PCSK9 and LPS were 1200 [900-1970] and 49.9 [15.0-108.2] pg/ml, respectively. LPS and PCSK9 were significantly correlated (rS 0.378, p 0.001). Logistic regression analysis showed that LPS was associated with PCSK9 above the median (odds ratio [OR] 1.727 95% confidence interval [CI] 1.147-2.600 p = 0.009). Other factors associated with PCSK9 above the median were sNox2-dp (OR 1.759 C.I. 95% 1.167-2.650, p = 0.007), use of antiplatelet drugs (OR 0.437 95%CI 0.219-0.871 p = 0.017) and high adherence to Mediterranean diet (OR 0.737 95%CI 0.643-0.845 p = 0.001). Olive oil (OR 0.376 95%CI 0.185-0.763, p = 0.001) and wine (OR 0.460 95%CI 0.289-0.733 p = 0.007) were negatively associated with PCSK9. Patients with concomitant high PCSK9 and LPS (LPS ≥88 pg/ml and PCSK9 ≥1570 pg/ml) had an increased risk of CVEs compared to those with low levels (LPS24.3 pg/ml and PCSK91000 pg/ml, Log-Rank test, p = 0.022).This study demonstrated, for the first time in vivo, that circulating levels of PCSK9 and LPS are associated with a mechanism possibly involving NADPH oxidase activation. Patients with concomitant increase of PCSK9 and LPS showed a higher risk of CVEs.

The membrane of most cells in the body is surrounded by a dynamically regulated, highly-hydrated fibrous meshwork of carbohydrates, known as pericellular matrix or glycocalyx. Its main constituents are several glycoconjugates (see nomenclature and definitions in Box 1), including glycolipids, the polysaccharide heparan sulfate (HS) linked to proteoglycan core proteins (e.g. glypican, syndecan, betaglycan), the polysaccharide hyaluronan and proteins bound to these polysaccharides. Box 1 Nomenclature and definitions Glycoconjugates: Various types of compounds consisting of carbohydrates covalently linked with other types of chemical constituent. Glycolipids: lipids with a carbohydrate attached by a covalent glycosidic bond. The carbohydrate portion may be a single monosaccharide or a linear or branched chain. Glycoproteins: proteins containing oligosaccharide chains (glycans) covalently attached to amino acid side-chains; the carbohydrate portion consists of short chains, often branched. Proteoglycans: proteins that are heavily glycosylated; the protein portion of the molecule represents only a small portion of the total molecular weight; the carbohydrate portion consists of long unbranched repeating disaccharide units (glycosaminoglycans, a.k.a. mucopolysaccharides). The three major classes of proteoglycans, characterized by their side chains, are the heparan sulfate proteoglycans, chondroitin sulfate proteoglycans, and keratan sulfate proteoglycans. Polysaccharides: polymeric carbohydrate molecules composed of relatively long chains of monosaccharide units bound together by glycosidic linkages. Lipopolysaccharides: large molecules consisting of a lipid and a polysaccharide composed of O-antigen, outer core, and inner core joined by a covalent bond; they are typically found in the outer membrane of Gram-negative BACTERIA. They are also known as lipoglycans and endotoxins. Peptidoglycans: polymers consisting of a mino acids and specific sugars — alternating residues of β-(1,4) l inked N-acetylglucosamine (NAG) and N-acetylmuramic acid NAM) — that form a mesh-like layer outside the plasma membrane of most BACTERIA; they are also known as mureins.

Heart failure (HF) disease progression is related to numerous adaptive processes including cardiac fibrosis, hypertrophy and apoptosis by activation of the ‘fetal’ gene program and downregulation of mRNA signatures, suggesting the importance of molecular mechanisms that suppress mRNA steady-state levels. miRNAs (miRs) are small, noncoding RNAs that bind mRNAs at their 3′-UTRs, leading to mRNA degradation or inhibition of protein translation. Several miRs are unregulated in response to cellular stress and can modify cellular functions such as proliferation, differentiation and programmed death; these miRs are also regulated in cardiac disease. Cardiac resynchronization therapy improves cardiac performance and myocardial mechanical efficiency. . In this updated critical appraisal we report on the main miRs that play a key role in response to cardiac resynchronization therapy (i.e., responder vs nonresponder HF patients), focusing on the miR-mediated modulation of cardiac angiogenesis, apoptosis, fibrosis and membrane ionic currents.

Excitation-contraction (EC) coupling denotes the conversion of electric stimulus in mechanic output in contractile cells. Several studies have demonstrated that calcium (Ca2+) plays a pivotal role in this process. Here we present a comprehensive and updated description of the main systems involved in cardiac Ca2+ handling that ensure a functional EC coupling and their pathological alterations, mainly related to heart failure.

Catheter ablation (CA) is a procedure commonly used to restore sinus rhythm in patients with atrial fibrillation (AF). However, AF recurrence after CA remains a relevant clinical issue. We tested the effects of an oral anti-oxidant treatment (α-lipoic acid, ALA) on AF recurrence post-CA. Patients with paroxysmal AF have been enrolled in a randomized, prospective, double blind, controlled placebo trial. Following CA, patients have been randomly assigned to receive ALA oral supplementation (ALA group) or placebo (control group), and evaluated at baseline and after a 12-month follow-up: 73 patients completed the 12-month follow-up (ALA: 33; control: 40). No significant difference has been detected between the two groups at baseline. Strikingly, one year after CA, ALA therapy significantly reduced serum markers of inflammation. However, there was no significant difference in AF recurrence events at follow-up when comparing ALA to placebo group. Multivariate analysis revealed that the only independent prognostic risk factor for AF recurrence post-CA is age. In conclusion, ALA therapy reduces serum levels of common markers of inflammation in ablated patients. Nevertheless, ALA does not prevent AF recurrence after an ablative treatment.

Aim: Telemonitoring (TM) is a safe and efficient monitoring system for internal cardioverter defibrillator device (ICD) recipients. TM has been used to track info on the clinical status of heart failure patients treated by ICD and/or cardiac resynchronisation therapy defibrillator (CRT-D). The aim of this study was to investigate the impact of TM on clinical outcomes in a population of CRT-D patients with heart failure. Methods: In a multicentre, randomised study, patients with chronic heart failure, New York Heart Association (NYHA) functional class II or III, left bundle branch block, severe left ventricle ejection fraction reduction (LVEF < 35%) have been identified and screened. Results: One hundred and ninety-one patients have been randomised to receive either a CRT-D with TM or a CRT-D with traditional ambulatory monitoring (control group) and completed the 12-month study follow-up. Primary endpoints were all cause death, cardiac death and hospital admission for heart failure. Secondary endpoints were atrial fibrillation, sustained episodes, non-sustained and self terminated ventricular tachyarrhythmia, sustained ventricular tachycardia, and ventricular fibrillation, ICD shocks and percentage of CRT-D responder patients. Univariate analysis identified the following factors predicting hospitalisation: TM, age, chronic kidney disease, hypercholesterolaemia, LVEF and NYHA class. At multivariate analysis, TM was the only factor predicting heart failure hospitalisation (hazard ratio 0.6, 0.42–0.79, 95% CI, p = 0.002), without affecting overall mortality and cardiac deaths events. Conclusions: Taken together, our data indicate the importance of TM in predicting heart failure hospitalisation in patients treated with CRT-D.

Background The purpose of this study was to investigate the impact of metabolic syndrome (MS) on outcome of catheter ablation (CA) for treatment of frequent premature ventricular contraction beats (PVCs) originating from right ventricular outflow tract (RVOT), left ventricular outflow tract (LVOT) or coronary cusps (CUSPs), in patients with normal ventricular systolic function and absence of cardiac structural disease. Methods In this multicentre prospective study we evaluated 90 patients with frequent PVCs originating from RVOT (n = 68), LVOT (n = 19) or CUSPs (n = 3), treated with CA. According to baseline diagnosis they were divided in patients with MS (n = 24) or without MS (n = 66). The study endpoint was a composite of recurrence of acute or delayed outflow tract ventricular arrhythmia: acute spontaneous or inducible outflow tract ventricular arrhythmia recurrence or recurrence of outflow tract PVCs in holter monitoring at follow up. Results Patients with MS compared to patients without MS showed a higher acute post-procedural recurrence of outflow tract PVCs (n = 8, 66.6%, vs. n = 6, 9.0%, p = 0.005). At a mean follow up of 35 (17-43) months survival free of recurrence of outflow tract PVCs was lower in patients with baseline MS compared to patients without MS diagnosis (log-rank test, p

Heart failure (HF) and type 2 diabetes mellitus (T2DM) exhibit a well-established interrelationship and a growing prevalence, in particular in elderly people. Cardiac resynchronization therapy (CRT) has been shown to improve myocardial function in patients with HF and cardiac dyssynchrony. However, reports on CRT in diabetic elderly patients are limited and controversial. Therefore, the aim of the present study was to investigate the functional role of T2DM on the effectiveness of CRT at advanced age. In this single-center prospective study, we enrolled 72 HF patients over 75 years old with and without T2DM who underwent CRT implant. Detailed clinical and instrumental data, including cardiac ultrasound analysis, 6-min walk test, and quality-of-life evaluation, were collected at baseline and at 1-year follow-up. At the time of implantation, 44.4 % of patients had T2DM, of which 62.5 % were well controlled with diet and hypoglycemic drugs and 37.5 % were treated by insulin therapy. After 1 year, CRT improved myocardial ventricular geometry and functional capacity in a comparable proportion of diabetic and non-diabetic patients alongside with a similar amelioration in the functional status. Taken together, our findings demonstrate that diabetic patients >75 years old exhibit a response to CRT that is comparable to non-diabetic subjects.

Patients with concomitant diabetes mellitus (DM) and prior stroke (PS) were excluded from European approval of alteplase in stroke. We examined the influence of DM and PS on the outcomes of patients who received thrombolytic therapy (T; data from Safe Implementation of Thrombolysis in Stroke-International Stroke Thrombolysis Register) compared to nonthrombolyzed controls (C; data from Virtual International Stroke Trials Archive).We selected ischemic stroke patients on whom we held data on age, baseline NIH Stroke Scale score (NIHSS), and 90-day modified Rankin Scale score (mRS). We compared the distribution of mRS between T and C by Cochran-Mantel-Haenszel (CMH) test and proportional odds logistic regression, after adjustment for age and baseline NIHSS, in patients with and without DM, PS, or the combination. We report odds ratios (OR) for improved distribution of mRS with 95% confidence interval (CI) and CMH p value.Data were available for 29,500 patients: 5,411 (18.5%) had DM, 5,019 had PS (17.1%), and 1,141 (5.5%) had both. Adjusted mRS outcomes were better for T vs C among patients with DM (OR 1.45 [1.30-1.62], n = 5,354), PS (OR 1.55 [1.40-1.72], n = 4,986), or concomitant DM and PS (OR 1.23 [0.996-1.52], p = 0.05, n = 1,136), all CMH p0.0001. These are comparable to outcomes between T and C among patients with neither DM nor PS: OR = 1.53 (1.42-1.63), p0.0001, n = 19,339. There was no interaction on outcome between DM and PS with alteplase treatment (tissue plasminogen activator × DM × PS, p = 0.5). Age ≤80 years or80 years did not influence our findings.Outcomes from thrombolysis are better than the controls among patients with DM, PS, or both. We find no statistical justification for the exclusion of these patients from receiving thrombolytic therapy.

To the Editor In a recent issue of Heart , Steffel et al 1 showed in an elegant retrospective study that patients with an exceptionally good echocardiographic response to cardiac resynchronisation therapy (CRT) are highly likely to experience a favourable outcome after CRT. …

We read with great interest the paper by Carluccio et al. ([1][1]) regarding the impact of left ventricular (LV) remodeling on the response to cardiac resynchronization therapy (CRT). In this elegant study, the authors performed a comprehensive assessment of LV function, showing that extensive LV

Adrenergic stimulation of the heart engages cAMP and phosphoinositide second messenger signaling cascades. Cardiac phosphoinositide 3-kinase p110 gamma participates in these processes by sustaining beta-adrenergic receptor internalization through its catalytic function and by controlling phosphodiesterase 3B (PDE3B) activity via an unknown kinase-independent mechanism. We have discovered that p110 gamma anchors protein kinase A (PKA) through a site in its N-terminal region. Anchored PKA activates PDE3B to enhance cAMP degradation and phosphorylates p110 gamma to inhibit PIP3 production. This provides local feedback control of PIP3 and cAMP signaling events. In congestive heart failure, p110 gamma is upregulated and escapes PKA-mediated inhibition, contributing to a reduction in beta-adrenergic receptor density. Pharmacological inhibition of p110 gamma normalizes beta-adrenergic receptor density and improves contractility in failing hearts.