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Purpose of review: The current review aims to present the latest scientific updates on the role of Sortilin in the pathophysiology of hypertension. Recent findings: The main focus of this systematic overview is on the functional contribution of Sortilin to the pathogenesis of hypertension. Sortilin is a glycoprotein mostly known for its actions as a trafficking molecule directing proteins to specific secretory or endocytic compartments of the cell. Emerging evidence indicates that Sortilin is associated with pathological conditions, including inflammation, arteriosclerosis, dyslipidemia, insulin resistance, and vascular calcification. Most recently, Sortilin has been shown to finely control endothelial function and to drive hypertension by modulating sphingolipid/ceramide homeostasis and by triggering oxidative stress. Summary: The latest findings linking Sortilin and hypertension that are herein discussed can inspire novel areas of research which could eventually lead to the discovery of new therapeutic strategies in cardiovascular medicine.

BackgroundAdverse drug reactions (ADRs) remain among the leading causes of therapy-resistant hypertension (TRH) and uncontrolled blood pressure (BP). We have recently reported beneficial results in BP control in patients with TRH adopting an innovative approach, defined as therapeutic concordance, in which trained physicians and pharmacists reach a concordance with patients to make them more involved in the therapeutic decision-making process.MethodsThe main scope of this study was to investigate whether the therapeutic concordance approach could lead to a reduction in ADR occurrence in TRH patients. The study was performed in a large population of hypertensive subjects of the Campania Salute Network in Italy (ClinicalTrials.gov Identifier: NCT02211365).ResultsWe enrolled 4,943 patients who were firstly followed-up for 77.64 ± 34.44 months, allowing us to identify 564 subjects with TRH. Then, 282 of these patients agreed to participate in an investigation to test the impact of the therapeutic concordance approach on ADRs. At the end of this investigation, which had a follow-up of 91.91 ± 54.7 months, 213 patients (75.5%) remained uncontrolled while 69 patients (24.5%, p ConclusionOur findings indicate that the therapeutic concordance approach significantly reduces ADRs in TRH patients.

Background Women have a high risk of frailty independently of age and menopause state. Diabetes and hypertension increase the risk of frailty and cognitive impairment. Metformin has been employed in post-menopausal women and some reports have shown encouraging effects in terms of attenuated frailty. However, the impact on cognitive performance of a recently introduced extended-release formulation of metformin has never been explored. Methods We studied consecutive frail hypertensive and diabetic older women presenting at the ASL (local health authority of the Italian Ministry of Health) Avellino, Italy, from June 2021 to August 2022, who were treated or not with extended-release metformin. We included a control group of frail older males with diabetes and hypertension treated with extended-release metformin and a control group of frail older women with diabetes and hypertension treated with regular metformin. Results A total of 145 patients successfully completed the study. At the end of the 6-month follow-up, we observed a significantly different cognitive performance compared to baseline in the group of frail women treated with extended-release metformin (p: 0.007). Then, we compared the follow-up groups and we observed significant differences between frail women treated vs. untreated (p: 0.041), between treated frail women and treated frail men (p: 0.016), and between women treated with extended-release metformin vs. women treated with regular metformin (p: 0.048). We confirmed the crucial role of extended-release metformin applying a multivariable logistic analysis to adjust for potential confounders. Conclusions We evidenced, for the first time to the best of our knowledge, the favorable effects on cognitive impairment of extended-release metformin in frail women with diabetes and hypertension.

We have recently demonstrated in a double-blind randomized trial the beneficial effects of L-Arginine in patients hospitalized for COVID-19. We hypothesize that one of the mechanisms underlying the favorable effects of L-Arginine is its action on inflammatory cytokines. To verify our hypothesis, we measured longitudinal plasma levels of pro-inflammatory and anti-inflammatory cytokines implied in the pathophysiology of COVID-19 in patients randomized to receive oral L-Arginine or placebo. The study was successfully completed by 169 patients. Patients in the L-Arginine arm had a reduced respiratory support evaluated at 10 and 20 days; moreover, the time to hospital discharge was significantly shorter in the L-Arginine group. The assessment of circulating cytokines revealed that L-Arginine significantly reduced the circulating levels of pro-inflammatory IL-2, IL-6, and IFN-γ and increased the levels of the anti-inflammatory IL-10. Taken together, these findings indicate that adding L-Arginine to standard therapy in COVID-19 patients markedly reduces the need of respiratory support and the duration of in-hospital stay; moreover, L-Arginine significantly regulates circulating levels of pro-inflammatory and anti-inflammatory cytokines.

Cognitive impairment is a prevailing event in hypertensive patients and in frail older adults. Endothelial dysfunction has been shown to underlie both hypertension and cognitive dysfunction. Our hypothesis is that L-Arginine, which is known to ameliorate endothelial dysfunction, could counteract cognitive impairment in a high-risk population of hypertensive frail older adults. We designed a clinical trial to verify the effects of 4-weeks oral supplementation of L-Arginine on global cognitive function of hypertensive frail older patients. The study was successfully completed by 35 frail hypertensive elderly patients assigned to L-Arginine and 37 assigned to placebo. At follow-up, we found a significant difference in the Montreal Cognitive Assessment (MoCA) test score between the L-Arginine treated group and placebo (p: 0.0178). Moreover, we demonstrated that L-Arginine significantly attenuates Angiotensin II-induced mitochondrial oxidative stress in human endothelial cells. In conclusion, our findings indicate for the first time that oral L-Arginine supplementation significantly improves cognitive impairment in frail hypertensive older adults.Clinical Trial Registrationwww.ClinicalTrials.gov, identifier: NCT04962841.

Brignole M, Pentimalli F, Palmisano P, et al. AV junction ablation and cardiac resynchronization for patients with permanent atrial fibrillation and narrow QRS: the APAF-CRT mortality trial. Eur Heart J. 2021;42:4731-9. 34453840.

Recent evidence suggests that oxidative stress and endothelial dysfunction play critical roles in the pathophysiology of COVID-19 and Long-COVID. We hypothesized that a supplementation combining L-Arginine (to improve endothelial function) and Vitamin C (to reduce oxidation) could have favorable effects on Long-COVID symptoms.

Ryanodine receptors (RyRs) and inositol 1,4,5-trisphosphate receptors (IP3Rs) are calcium (Ca(2+) ) release channels on the endo/sarcoplasmic reticulum (ER/SR). Here we summarize the latest advances in the field, describing the recently discovered mechanistic roles of intracellular Ca(2+) release channels in the regulation of mitochondrial fitness and endothelial function, providing novel therapeutic options for the treatment of heart failure, hypertension, and diabetes mellitus. This article is protected by copyright. All rights reserved.

In the present article, Wang, Liu, Fu and colleagues report that β2-adrenergic receptor (β2AR) plays a key role in hyperinsulinemia-induced cardiac dysfunction.(1) Overall, the data are very interesting and compelling. However, we noticed that in this paper β2AR-/- mice do not exhibit glucose intolerance; in fact, they seem to have a response to intraperitoneal glucose that is even better than wild-type mice (though a statistical analysis comparing these two groups is not provided). Although surprisingly not reported by the Authors, mounting evidence indicates that the deletion of β2AR has detrimental effects on glucose metabolism.(2-4) Indeed, we have demonstrated that β2AR-/- mice display impaired insulin release and significant glucose intolerance.(2) Muzzin and colleagues found that the ablation of βARs mechanistically underlies impaired glucose homeostasis.(3) Other groups have confirmed these results, also showing that β2AR-/- mice develop diabetic-related microvascular complications (i.e. retinopathy)(4). Nonetheless, the Authors fail to at least discuss previous relevant literature describing the alterations in glucose metabolism observed in β2AR-/- mice and do not accurately circumstantiate their findings. Furthermore, the Authors do not provide any measurement (not in vivo nor in isolated islets) of insulin levels following glucose challenge, showing just baseline serum levels. We believe that for the sake of scientific appropriateness the Readers of Circulation will appreciate a clarification, in particular regarding the fact that pertinent literature in the field has been overlooked.

Introduction: Diabetes and cardiovascular disease are important health concerns in United States and worldwide. However, while the increased risk of cardiovascular disease and heart failure (HF) in diabetic patients has been established, the reciprocal relationship, i.e. the augmented risk of glucose intolerance and type 2 diabetes mellitus (TD2M) in patients with cardiovascular disorders, has been evidenced in the clinical scenario but the underlying mechanisms remain essentially unclear. Hypothesis: HF causes pancreatic beta cell dysfunction via endoplasmic reticulum (ER) stress and impairment of mitochondrial dynamics. Methods/Results: In this study we focused on the beta cell function in a murine model of post-ischemic HF, obtained via ligation of the coronary artery. The HF group exhibited glucose intolerance and impaired glucose-stimulated insulin release, with no major differences in islet architecture when comparing HF and SHAM. Islets isolated from HF mice displayed upregulation of common markers of ER stress, including BiP and spliced XBP. Ultrastructural analysis revealed significant mitochondrial dysmorphology (fragmented cristae, swelling, and outer membrane disruption) in HF beta cells. We also found significantly altered mitochondrial dynamics in ex vivo experiments in HF vs SHAM, including reduced glucose-stimulated and glutamine/leucine-stimulated ATP production, impaired oxygen consumption rate (measured at Seahorse), decreased mtDNA/nDNA, aconitase activity, and NADPH following glucose stimulation, alongside with augmented generation of reactive oxygen species. Strikingly, we demonstrate that during HF beta cells display decreased intracellular calcium stores, and mitochondria exhibit a significantly reduced glucose-stimulated uptake of calcium, known activator of three matrix dehydrogenases in the tricarboxylic acid (aka Krebs) cycle. Moreover, the expression of mitochondrial calcium uniporter (MCU) was decreased in HF islets. Conclusions: Taken together, our in vivo and ex vivo findings establish that HF induces beta cell failure, characterized by mitochondrial dysfunction, ER stress, and overall impaired fuel-stimulated insulin release.

Angiogenesis is a crucial component of lung pathophysiology, not only in cancer but also in other disorders, such as chronic obstructive pulmonary disease (COPD). In COPD angiogenesis is definitely able to control and orchestrate the progression of airway remodeling. Herein, we provide several remarkable translational aspects of angiogenesis in COPD, exploring both basic and clinical research in this field. Indeed, we present a number of pro- and anti-angiogenic factors, which can be also used as potential biomarkers to monitor disease progression.

Calcium (Ca2+) release from intracellular stores plays a key role in the regulation of skeletal muscle contraction. The type 1 ryanodine receptors (RyR1) is the major Ca2+ release channel on the sarcoplasmic reticulum (SR) of myocytes in skeletal muscle and is required for excitation–contraction (E–C) coupling. This article explores the role of RyR1 in the skeletal muscle physiology and pathophysiology.

The number of papers dealing with new modus operandi or new biological functions of non-coding RNAs published in recent years has indeed exploded. A simple search for ‘non-coding RNA’ in Pubmed on 10 June 2015 yielded 128,649 articles, half of which were published in the last 10 years [1]. Every researcher in this field knows that he has something to learn and can discover new ideas, new concepts or new tools from studies made in models others than the ones used in its lab. The Scientific board of Non-Coding RNA publishes here its first Journal Club and highlights, in about hundred words, a selection of the most interesting papers published recently. We hope we will tease your curiosity and encourage you to read full papers outside of your research area that you may not have read otherwise. [...]

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

Please note that in the published editorial [1], affiliations 1, and 8 contained errors.[...].

Chest pain may be due benign diseases but often suggests an association with coronary artery disease, which justifies a quick search for medical care. However, some people have anxiety disorder with symptoms that resemble clearly an acute coronary syndrome. More specifically, during a panic attack an abrupt feeling of fear accompanied by symptoms such as breathlessness, palpitations and chest pain, makes patients believe they have a heart attack and confuse physicians about the diagnosis. The association between panic disorder and coronary artery disease has been extensively studied in recent years and, although some studies have shown anxiety disorders coexisting or increasing the risk of heart disease, one causal hypothesis is still missing. The aim of this systematic review is to present the various ways in which the scientific community has been investigating the relation between chest pain, panic disorder and coronary artery disease.

In this study, we investigated the significance of β(2)-adrenergic receptor (β(2)AR) in age-related impaired insulin secretion and glucose homeostasis. We characterized the metabolic phenotype of β(2)AR-null C57Bl/6N mice (β(2)AR(-/-)) by performing in vivo and ex vivo experiments. In vitro assays in cultured INS-1E β-cells were carried out in order to clarify the mechanism by which β(2)AR deficiency affects glucose metabolism. Adult β(2)AR(-/-) mice featured glucose intolerance, and pancreatic islets isolated from these animals displayed impaired glucose-induced insulin release, accompanied by reduced expression of peroxisome proliferator-activated receptor (PPAR)γ, pancreatic duodenal homeobox-1 (PDX-1), and GLUT2. Adenovirus-mediated gene transfer of human β(2)AR rescued these defects. Consistent effects were evoked in vitro both upon β(2)AR knockdown and pharmacologic treatment. Interestingly, with aging, wild-type (β(2)AR(+/+)) littermates developed impaired insulin secretion and glucose tolerance. Moreover, islets from 20-month-old β(2)AR(+/+) mice exhibited reduced density of β(2)AR compared with those from younger animals, paralleled by decreased levels of PPARγ, PDX-1, and GLUT2. Overexpression of β(2)AR in aged mice rescued glucose intolerance and insulin release both in vivo and ex vivo, restoring PPARγ/PDX-1/GLUT2 levels. Our data indicate that reduced β(2)AR expression contributes to the age-related decline of glucose tolerance in mice.

Drugs currently approved to coat stents used in percutaneous coronary interventions do not discriminate between proliferating vascular smooth muscle cells (VSMCs) and endothelial cells (ECs). This lack of discrimination delays reendothelialization and vascular healing, increasing the risk of late thrombosis following angioplasty. We developed a microRNA-based (miRNA-based) approach to inhibit proliferative VSMCs, thus preventing restenosis, while selectively promoting reendothelialization and preserving EC function. We used an adenoviral (Ad) vector that encodes cyclin-dependent kinase inhibitor p27(Kip1) (p27) with target sequences for EC-specific miR-126-3p at the 3' end (Ad-p27-126TS). Exogenous p27 overexpression was evaluated in vitro and in a rat arterial balloon injury model following transduction with Ad-p27-126TS, Ad-p27 (without miR-126 target sequences), or Ad-GFP (control). In vitro, Ad-p27-126TS protected the ability of ECs to proliferate, migrate, and form netw! orks. At 2 and 4 weeks after injury, Ad-p27-126TS-treated animals exhibited reduced restenosis, complete reendothelialization, reduced hypercoagulability, and restoration of the vasodilatory response to acetylcholine to levels comparable to those in uninjured vessels. By incorporating miR-126-3p target sequences to leverage endogenous EC-specific miR-126, we overexpressed exogenous p27 in VSMCs, while selectively inhibiting p27 overexpression in ECs. Our proof-of-principle study demonstrates the potential of using a miRNA-based strategy as a therapeutic approach to specifically inhibit vascular restenosis while preserving EC function.

The mTOR signaling pathway integrates inputs from a variety of upstream stimuli to regulate diverse cellular processes including proliferation, growth, survival, motility, autophagy, protein synthesis and metabolism. The mTOR pathway is dysregulated in a number of human pathologies including cancer, diabetes, obesity, autoimmune disorders, neurological disease and aging. Ongoing clinical trials testing mTOR-targeted treatments number in the hundreds and underscore its therapeutic potential. To date mTOR inhibitors are clinically approved to prevent organ rejection, to inhibit restenosis after angioplasty, and to treat several advanced cancers. In this review we discuss the continuously evolving field of mTOR pharmacogenomics, as well as highlight the emerging efforts in identifying diagnostic and prognostic markers, including miRNAs, in order to assess successful therapeutic responses.

The type 2 ryanodine receptor (RyR2) is a Ca2+ release channel on the endoplasmic reticulum (ER) of several types of cells, including cardiomyocytes and pancreatic β cells. In cardiomyocytes, RyR2-dependent Ca2+ release is critical for excitation-contraction coupling; however, a functional role for RyR2 in β cell insulin secretion and diabetes mellitus remains controversial. Here, we took advantage of rare RyR2 mutations that were identified in patients with a genetic form of exercise-induced sudden death (catecholaminergic polymorphic ventricular tachycardia [CPVT]). As these mutations result in a "leaky" RyR2 channel, we exploited them to assess RyR2 channel function in β cell dynamics. We discovered that CPVT patients with mutant leaky RyR2 present with glucose intolerance, which was heretofore unappreciated. In mice, transgenic expression of CPVT-associated RyR2 resulted in impaired glucose homeostasis, and an in-depth evaluation of pancreatic islets and β cells from these animals revealed intracellular Ca2+ leak via oxidized and nitrosylated RyR2 channels, activated ER stress response, mitochondrial dysfunction, and decreased fuel-stimulated insulin release. Additionally, we verified the effects of the pharmacological inhibition of intracellular Ca2+ leak in CPVT-associated RyR2-expressing mice, in human islets from diabetic patients, and in an established murine model of type 2 diabetes mellitus. Taken together, our data indicate that RyR2 channels play a crucial role in the regulation of insulin secretion and glucose homeostasis.

The importance of diet in the pathophysiology of metabolic syndrome is well acknowledged and may be crucial in the determination of cardiovascular risk and the development of cardiovascular complications. The contributions presented here provide an updated systematic overview examining in detail the functional role of different diets and dietary components in maintaining glucose homeostasis and prevention of long-term complications.