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Cardiotoxicity is a common adverse effect of anticancer drugs (ACDs), including the so-called targeted drugs, and increases morbidity and mortality in patients with cancer. Attention has focused mainly on ACD-induced heart failure, myocardial ischemia, hypertension, thromboembolism, QT prolongation, and tachyarrhythmias. Yet, although an increasing number of ACDs can produce sinus bradycardia (SB), this proarrhythmic effect remains an underappreciated complication, probably because of its low incidence and severity since most patients are asymptomatic. However, SB merits our interest because its incidence increases with the aging of the population and cancer is an age-related disease and because SB represents a risk factor for QT prolongation. Indeed, several ACDs that produce SB also prolong the QT interval. We reviewed published reports on ACD-induced SB from January 1971 to November 2020 using the PubMed and EMBASE databases. Published reports from clinical trials, case reports, and recent reviews were considered. This review describes the associations between ACDs and SB, their clinical relevance, risk factors, and possible mechanisms of onset and treatment. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with an increased morbidity and mortality. There is clinical evidence that an increasing number of cardiovascular and non-cardiovascular drugs, mainly anticancer drugs, can induce AF either in patients with or without pre-existing cardiac disorders, but drug-induced AF (DIAF) has not received the attention that it might deserve. In many cases DIAF is asymptomatic and paroxysmal and patients recover sinus rhythm spontaneously, but sometimes, DIAF persists, and it is necessary to perform a cardioversion. Furthermore, DIAF is not mentioned in clinical guidelines on the treatment of AF. The risk of DIAF increases in elderly and in patients treated with polypharmacy and with risk factors and comorbidities that commonly coexist with AF. This is the case of cancer patients. Under these circumstances ascribing causality of DIAF to a given drug often represents a clinical challenge. We review the incidence, the pathophysiological mechanisms, risk factors, clinical relevance, and treatment of DIAF. Because of the limited information presently available, further research is needed to obtain a deeper insight into DIAF. Meanwhile, it is important that clinicians are aware of the problem that DIAF represents, recognize which drugs may cause DIAF, and consider the possibility that a drug may be responsible for a new-onset AF episode. [Display omitted] [ABSTRACT FROM AUTHOR]

Acute heart failure (AHF) represents a clinical challenge as it encloses a heterogeneous group of syndromes (AHFS) with different pathophysiology, clinical presentations, prognosis and response to therapy. In the last 25 years multiple therapeutic targets have been identified and numerous new drugs were evaluated but, up to now, all failed to demonstrate a consistent benefit on clinical outcomes. Moreover, a repeated finding has been the poor correlation between the encouraging results of preclinical and early clinical trials and the lack of effect on outcomes observed in phase III trials. We review several possible pharmacological reasons that may explain the lack of success to develop new drugs and the pharmacological challenges to overcome in the future to develop new more effective and safer drugs for the treatment of AHFS. [ABSTRACT FROM AUTHOR]

The RAS (renin-angiotensin system) plays a key role in the regulation of blood pressure, fluid and electrolyte homeostasis and cardiovascular and renal structure and function. There is evidence that in addition to the systemic RAS the components of the RAS are expressed in the local milieu of bone, where angiotensin II increases the osteoclastogenesis while inhibit the osteoblastic activity leading to a decrease in bone mineral density. Hypertension and osteoporosis are two common diseases that frequently coexist in the elderly population, and it has been hypothesized that the activation of the local RAS might be involved in the occurrence of both diseases often seen with advancing age. Epidemiological studies have found that RAS inhibitors, including angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, may exert a beneficial effect on bone mineral density, increasing the bone mass and decreasing the risk of bone fractures in patients with osteoporosis and cardiovascular diseases, and might accelerate the fracture healing process. However, both experimental and clinical studies with these RAS inhibitors led to sparse and contradictory results. Thus, in the next future a better understanding on how the components of the local RAS influence bone metabolism and remodeling will allow us to select the best therapeutic strategy for patients with osteoporosis and cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Purpose: The therapeutic index (TI) is the range of doses at which a medication is effective without unacceptable adverse events. Drugs with a narrow TI (NTIDs) have a narrow window between their effective doses and those at which they produce adverse toxic effects. Generic drugs may be substituted for brand-name drugs provided that they meet the recommended bioequivalence (BE) limits. However, an appropriate range of BE for NTIDs is essential to define due to the potential for ineffectiveness or adverse events. Flecainide is an antiarrhythmic agent that has the potential to be considered an NTID. This review aims to evaluate the literature surrounding guidelines on generic substitution for NTIDs and to evaluate the evidence for flecainide to be considered an NTID. Methods: A review of recommendations from various regulatory authorities regarding BE and NTIDs, and publications regarding the NTID characteristics of flecainide, was carried out. Results: Regulatory authorities generally recommend reduced BE limits for NTIDs. Some, but not all, regulatory authorities specify flecainide as an NTID. The literature review demonstrated that flecainide displays NTID characteristics including a steep drug dose-response relationship for safety and efficacy, a need for therapeutic drug monitoring of pharmacokinetic (PK) or pharmacodynamics measures and intra-subject variability in its PK properties. Conclusions: There is much evidence for flecainide to be considered an NTID based on both preclinical and clinical data. A clear understanding of the potential of proarrhythmic effects or lack of efficacy, careful patient selection and regular monitoring are essential for the safe and rational administration of flecainide. [ABSTRACT FROM AUTHOR]

Cardiovascular toxicity is a potential complication of cancer chemotherapy (CC) that increases the morbidity and mortality of cancer patients. Cardiac arrhythmias have been reported as an adverse effect of many chemotherapeutic drugs, including novel targeted therapies. The relationship between chemotherapy and arrhythmias has not been well-established and the proarrhythmogenic mechanisms remain uncertain as they can be the result of a direct electrophysiological effect or of changes in cardiac structure and function, including myocardial ischaemia and heart failure, which create an arrhythmogenic substrate. In this review we summarise available evidence of proarrhythmia induced by CC, discuss the possible mechanisms involved in this adverse effect and emphasise the importance of cardiac monitoring for the early diagnosis, intervention and surveillance of those patients more susceptible to develop proarrhythmia in an attempt to reduce the morbidity and mortality. Oncologists should be fully aware of proarrhythmia and the close collaboration between cardiologists and oncologists would result in a better cardiovascular assessment, risk stratification, cardiac monitoring and treatment during CC and during the follow-up. The final objective is to understand the mechanisms of proarrhythmia and evaluate its real incidence and clinical relevance so as to select the safest and most effective treatment for cancer patients. [ABSTRACT FROM AUTHOR]

Cardiovascular toxicity is a potential complication of cancer chemotherapy (CC) that increases the morbidity and mortality of cancer patients. Cardiac arrhythmias have been reported as an adverse effect of many chemotherapeutic drugs, including novel targeted therapies. The relationship between chemotherapy and arrhythmias has not been well-established and the proarrhythmogenic mechanisms remain uncertain as they can be the result of a direct electrophysiological effect or of changes in cardiac structure and function, including myocardial ischaemia and heart failure, which create an arrhythmogenic substrate. In this review we summarise available evidence of proarrhythmia induced by CC, discuss the possible mechanisms involved in this adverse effect and emphasise the importance of cardiac monitoring for the early diagnosis, intervention and surveillance of those patients more susceptible to develop proarrhythmia in an attempt to reduce the morbidity and mortality. Oncologists should be fully aware of proarrhythmia and the close collaboration between cardiologists and oncologists would result in a better cardiovascular assessment, risk stratification, cardiac monitoring and treatment during CC and during the follow-up. The final objective is to understand the mechanisms of proarrhythmia and evaluate its real incidence and clinical relevance so as to select the safest and most effective treatment for cancer patients. [ABSTRACT FROM AUTHOR]

Heart failure (HF) represents a leading cause of morbidity and mortality. However, HF trials highlighted many differences between men and women with HF. Thus, women represent approximately a quarter of people with HF with reduced ejection fraction (HFrEF), while they account for over half of those with HF with preserved EF (HFpEF). There are also sex-related differences (SRDs) in the pharmacokinetics, pharmacodynamics and safety profile of some guideline-recommended drugs for the treatment of HF. As compared with men, women with HFrEF are less often treated with guideline-recommended HF drugs, experience more frequent and severe adverse reactions when these drugs are prescribed at the same doses in both sexes, and recent evidence suggests that women might need lower doses than men, bringing into question which are the optimal doses of HF drugs in women and men separately. However, information on SRDs in drug efficacy and safety in patients with HFrEF is very limited due to the underrepresentation of women and the lack of sex-specific evaluations of drug efficacy and safety in HF clinical trials. As a consequence, current clinical guidelines do not provide sex-specific recommendations, even when significant differences exist, at least, in drug safety. The aim of this article is to review the SRDs in the pharmacokinetics, efficacy and safety of guideline-recommended HF drugs and to identify emerging areas of research to improve our understanding of the SRDs, because a better understanding of these differences is the first step to achieve a personalized treatment of HF in women and men. [ABSTRACT FROM AUTHOR]

Despite considerable therapeutic advances, heart failure remains a medical and socioeconomic problem. Thus, there is a compelling need for new drugs that could improve clinical outcomes. In recent years, new potential therapeutic targets that are involved in the pathogenesis of heart failure have been identified, and new drugs are currently under investigation. A repeated finding is that the positive results that have been observed in preclinical studies and Phase II trials are not always confirmed in Phase III studies. This Review analyses the new therapeutic targets (for example, ventricular remodelling, renin-angiotensin-aldosterone system activation, defects in Ca(2+) cycling, and so on), the mechanism of action, efficacy and future perspectives of new drugs that are currently under development for the treatment of heart failure, and the possible explanations for the discrepancy between Phase II and Phase III trials. [ABSTRACT FROM AUTHOR]

Current available data show that about 5 to 40% of coronary patients treated with conventional doses of antithrombotic drugs do not display adequate antiplatelet response. Nowadays, aspirin remains the main antiplatelet therapy. However, a significant number of patients show platelet resistance to aspirin therapy, and recurrent thrombotic events occur. Combined antithrombotic therapies with thienopyridines, such as clopidogrel have been used to resolve this problem. However, clopidogrel treatment has been also associated with wide response variability, and non-responsiveness to clopidogrel also occurs in some patients. Therefore, the main question arising about the antithrombotic therapy is why particular patients do not benefit from the therapy and how they might be identified to improve their treatment. Different hypotheses have been suggested, including genetic factors, platelet heterogeneity, non-compliance and others. However, it is probably that many molecular mechanisms involved in platelet resistance to antithrombotic therapies still remains unknown. New technologies, such as proteomics and genetic, are beginning to show new unknown biological biomarkers and molecular mechanisms which may be associated with platelet antithrombotic drug resistance. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) synthetized by essentially all cardiac cell types plays a key role in the regulation of cardiac function. Recent evidence shows that NO modulates the activity of cardiac ion channels implicated in the genesis of the cardiac action potential and exerts anti-arrhythmic properties under some circumstances. We review the effects of NO on cardiac ion channels and the signalling pathways, including cGMP-dependent (protein kinase G and cGMP-regulated phosphodiesterases) and cGMP-independent mechanisms (S-nitrosylation and direct effects on G proteins) and finally the role of NO in the genesis of cardiac arrhythmias during ischemia–reperfusion, heart failure, long QT syndrome, atrial fibrillation, and sudden cardiac death. [ABSTRACT FROM PUBLISHER]

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (statins) are the most effective and best-tolerated drugs to treat elevated levels of low-density lipoprotein cholesterol (LDL-C). In addition, they exhibit other effects unrelated to their lipid lowering effects (pleiotropic actions). In recent years, experimental and clinical evidence demonstrates that statins exert antiarrhythmic properties, reducing the recurrences of supraventricular and life-threatening ventricular arrhythmias both in patients with and without coronary artery disease (CAD). Thus, statins may constitute a novel therapeutic approach to cardiac arrhythmias. This article reviews the antiarrhythmic properties of statins as well as the possible mechanisms involved, including the lowering of LDL-C levels, the improvement of endothelial dysfunction and autonomic function, the stabilization of the atherosclerotic plaques, the antioxidant, antiinflammatory, antithrombotic and cardioprotective properties and the modulation of transmembrane ion fluxes. [Copyright &y& Elsevier]

Cardiac K+ channels are membrane-spanning proteins that allow the passive movement of K+ ions across the cell membrane along its electrochemical gradient. They regulate the resting membrane potential, the frequency of pacemaker cells and the shape and duration of the cardiac action potential. Additionally, they have been recognized as potential targets for the actions of neurotransmitters and hormones and class III antiarrhythmic drugs that prolong the action potential duration (APD) and refractoriness and have been found effective to prevent/suppress cardiac arrhythmias. In the human heart, K+ channels include voltage-gated channels, such as the rapidly activating and inactivating transient outward current (Ito1), the ultrarapid (IKur), rapid (IKr) and slow (IKs) components of the delayed rectifier current and the inward rectifier current (IK1), the ligand-gated channels, including the adenosine triphosphate-sensitive (IKATP) and the acetylcholine-activated (IKAch) currents and the leak channels. Changes in the expression of K+ channels explain the regional variations in the morphology and duration of the cardiac action potential among different cardiac regions and are influenced by heart rate, intracellular signalling pathways, drugs and cardiovascular disorders. A progressive number of cardiac and noncardiac drugs block cardiac K+ channels and can cause a marked prolongation of the action potential duration (i.e. an acquired long QT syndrome, LQTS) and a distinct polymorphic ventricular tachycardia termed torsades de pointes. In addition, mutations in the genes encoding IKr (KCNH2/KCNE2) and IKs (KCNQ1/KCNE1) channels have been identified in some types of the congenital long QT syndrome. This review concentrates on the function, molecular determinants, regulation and, particularly, on the mechanism of action of drugs modulating the K+ channels present in the sarcolemma of human cardiac myocytes that contribute to the different phases of the cardiac action potential under physiological and pathological conditions. [Copyright &y& Elsevier]

Herbal medicines (HMs) have been traditionally used for the prophylaxis/treatment of cardiovascular diseases (CVDs). Their use is steadily increasing and many patients with CVDs often combine HMs with prescribed cardiovascular medications. Interestingly, up to 70% of patients do not notify cardiologists/physicians the use of HMs and up to 90% of cardiologists/physicians may not routinely inquire them about the use of HMs. There is limited scientific evidence from well-designed clinical trials supporting the efficacy and safety of HMs and because they do not reduce morbidity and mortality are not recommended in clinical guidelines for the prophylaxis/treatment of CVDs. There is also a great deal of confusion about the identification, active constituents and mechanisms of action of HMs; the lack of standardization and quality control (contaminations, adulterations) represent other sources of concern. Furthermore, the widespread perception that unlike prescription drugs HMs are safe is misleading and some HMs can cause clinically relevant adverse events and interactions, particularly when used with narrow therapeutic index prescribed cardiovascular drugs (antiarrhythmics, antithrombotics, digoxin). Cardiologists/physicians can no longer ignore the problem. They must improve their knowledge about the HMs their patients consume to provide the best advice and prevent adverse reactions and drug interactions. This narrative review addresses the putative mechanisms of action, suggested clinical uses and safety of most commonly used HMs, the pivotal role of cardiologists/physicians to protect consumers and the main challenges and gaps in evidence related to the use of HMs in the prophylaxis and treatment of CVDs. Main concerns and challenges to be faced by cardiologists/physicians and patients with cardiovascular diseases that consume herbal medicines. Abbreviations. AE: adverse events. CPG: clinical practice guidelines. CTs: clinical trials. CV: cardiovascular. CVDs: cardiovascular diseases. EMA: European Medicines Agency. FDA: Food and Drug Administration. HDIs: herb-drug interactions. HMs: herbal medicines. RCTs: randomized clinical trials. [Display omitted] • Many patients with cardiovascular diseases (CVDs) combine herbal medicines (HMs) with prescription drugs. • Patients do not notify their use and physicians do not ask about this common practice. • The perception that HMs are safe is misleading as they can produce adverse events and interact with prescribed drugs. • Current scientific evidence does not support the use of HMs for the prevention/treatment of CVDs. • Physicians play a pivotal role in minimizing the risks of HMs. [ABSTRACT FROM AUTHOR]

During the last decade, there has been a tremendous effort to develop different cardiovascular polypills in response to the upsurge in global cardiovascular disease worldwide. The pharmacological development of such a strategy has proven to be extremely complex from a formulation standpoint. Not all drugs are suitable for use in a polypill because of potential drug incompatibilities between them. Candidate agents must be safe, well tolerated, effective, guideline recommended and physiochemically compatible with the other components of the pill. The Fuster-CNIC-Ferrer cardiovascular (CV) polypill has been found to be the first-in-class polypill to be approved and commercialized in Europe and Latinamerican Countries. In this article, we review the pharmacological properties of its three components, including the clinical evidence supporting their use in patients with established cardiovascular disease, their pharmacokinetic properties, adverse effects, drug interactions and contraindications. [ABSTRACT FROM AUTHOR]

ATP-sensitive potassium (KATP) channels composed of Kir6.x and sulfonylurea receptor (SURs) subunits couple cellular metabolism to electrical activity. Cantú syndrome (CS) is a rare disease caused by mutations in the genes encoding Kir6.1 (KCNJ8) and SUR2A (ABCC9) that produce KATP channel hyperactivity due to a reduced channel block by physiological ATP concentrations. We functionally characterized the p.S1054Y SUR2A mutation identified in two CS carriers, who exhibited a mild phenotype although the mutation was predicted as highly pathogenic. We recorded macroscopic and single-channel currents in CHO and HEK-293 cells and measured the membrane expression of the channel subunits by biotinylation assays in HEK-293 cells. The mutation increased basal whole-cell current density and at the single-channel level, it augmented opening frequency, slope conductance, and open probability (Po), and promoted the appearance of multiple conductance levels. p.S1054Y also reduced Kir6.2 and SUR2A expression specifically at the membrane. Overexpression of ankyrin B (AnkB) prevented these gain- and loss-of-function effects, as well as the p.S1054Y-induced reduction of ATP inhibition of currents measured in inside-out macropatches. Yeast two-hybrid assays suggested that SUR2A WT and AnkB interact, while p.S1054Y interaction with AnkB is decreased. The p.E322K Kir6.2 mutation, which prevents AnkB binding to Kir6.2, produced similar biophysical alterations than p.S1054Y. Our results are the first demonstration of a CS mutation whose functional consequences involve the disruption of AnkB effects on KATP channels providing a novel mechanism by which CS mutations can reduce ATP block. Furthermore, they may help explain the mild phenotype associated with this mutation. [ABSTRACT FROM AUTHOR]

Dapagliflozin (dapa) and empagliflozin (empa) are sodium-glucose cotransporter-2 inhibitors (SGLT2is) that reduce morbidity and mortality in heart failure (HF) patients. Sodium and inward rectifier K+ currents (INa and IK1), carried by Nav1.5 and Kir2.1 channels, respectively, are responsible for cardiac excitability, conduction velocity, and refractoriness. In HF patients, Nav1.5 and Kir2.1 expression are reduced, enhancing risk of arrhythmia. Incubation with dapa or empa (24-h,1 µM) significantly increased INa and IK1 densities recorded in human-induced pluripotent stem cell-cardiomyocytes (hiPSC-CMs) using patch-clamp techniques. Dapa and empa, respectively, shifted to more hyperpolarized potentials the INa activation and inactivation curves. Identical effects were observed in Chinese hamster ovary (CHO) cells that were incubated with dapa or empa and transiently expressed human Nav1.5 channels. Conversely, empa but not dapa significantly increased human Kir2.1 currents in CHO cells. Dapa and empa effects on INa and IK1 were also apparent in Ca-calmodulin kinase II-silenced CHO cells. Cariporide, a Na+/H+ exchanger type 1 (NHE1) inhibitor, did not increase INa or IK1 in hiPSC-CMs. Dapa and empa at therapeutic concentrations increased INa and IK1 in healthy human cardiomyocytes. These SGLT2is could represent a new class of drugs with a novel and long-pursued antiarrhythmic mechanism of action. [ABSTRACT FROM AUTHOR]

A response by Juan Tamargo and José López-Sendón to a letter to the editor about their article "Digitalis: A Dangerous Drug in Atrial Fibrillation? An Analysis of the Sportif III and V Data" is presented.

Aims The transcription factor Tbx5 controls cardiogenesis and drives Scn5a expression in mice. We have identified two variants in TBX5 encoding p. D111Y and p. F206L Tbx5, respectively, in two unrelated patients with structurally normal hearts diagnosed with long QT (LQTS) and Brugada (BrS) syndrome. Here, we characterized the consequences of each variant to unravel the underlying disease mechanisms. Methods and results We combined clinical analysis with in vivo and in vitro electrophysiological and molecular techniques in human-induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs), HL-1 cells, and cardiomyocytes from mice trans -expressing human wild-type (WT) or mutant proteins. Tbx5 increased transcription of SCN5A encoding cardiac Nav1.5 channels, while repressing CAMK2D and SPTBN4 genes encoding Ca/calmodulin kinase IIδ (CaMKIIδ) and βIV-spectrin, respectively. These effects significantly increased Na current (INa) in hiPSC-CMs and in cardiomyocytes from mice trans -expressing Tbx5. Consequently, action potential (AP) amplitudes increased and QRS interval narrowed in the mouse electrocardiogram. p. F206L Tbx5 bound to the SCN5A promoter failed to transactivate it, thus precluding the pro-transcriptional effect of WT Tbx5. Therefore, p. F206L markedly decreased INa in hiPSC-CM, HL-1 cells and mouse cardiomyocytes. The INa decrease in p. F206L trans -expressing mice translated into QRS widening and increased flecainide sensitivity. p. D111Y Tbx5 increased SCN5A expression but failed to repress CAMK2D and SPTBN4. The increased CaMKIIδ and βIV-spectrin significantly augmented the late component of INa (INaL) which, in turn, significantly prolonged AP duration in both hiPSC-CMs and mouse cardiomyocytes. Ranolazine, a selective INaL inhibitor, eliminated the QT and QTc intervals prolongation seen in p. D111Y trans -expressing mice. Conclusions In addition to peak INa, Tbx5 critically regulates INaL and the duration of repolarization in human cardiomyocytes. Our original results suggest that TBX5 variants associate with and modulate the intensity of the electrical phenotype in LQTS and BrS patients. [ABSTRACT FROM AUTHOR]

This document is a reply to a letter from Benndorff and DiFrancesco regarding the reliability of human HCN4 single-channel recordings using the cell-attached configuration in expression systems. The authors of the reply thank Benndorff and DiFrancesco for their interest and comment on the differences between their recordings and others reported in different cell types. They explain that they were rigorous in their experimental design and used CHO cells instead of HEK-293 cells to avoid interference from endogenous K channels. They also discuss the disparities in experimental conditions and the species-dependent nature of HCN4 channels. The authors conclude by reinforcing the validity of their single-channel experiments. [Extracted from the article]

Here we present an account on the history of pharmacology in Spain. Pharmacology as an independent science in Europe began with the creation of university chairs. Of particular relevance was the appointment in 1872 of Osswald Shmiedeberg as chairman of an Institute of Pharmacology at the University of Strassbourg, Germany. Teófilo Hernando pioneered in Spain the new emerging pharmacology at the beginning of the XX Century. He made a posdoctoral stay in the laboratory of Schmiedeberg, working on digitalis. In 1912 he won the chair of "Materia Médica y Arte de Recetar" at "Universidad Central of Madrid" (today, "Universidad Complutense de Madrid", UCM). He soon decided to transform such subject to the emerging modern pharmacology, with the teaching of experimental pharmacology in the third course of medical studies and clinical therapeutics (today clinical pharmacology) in the sixth course. This was the status of pharmacology in 1920, supporting the view that Hernando was a pioneer of clinical pharmacology. However, the Spanish Civil War and the II Word War interropted this division of preclinical and clinical pharmacology; only in the 1980's was clinical pharmacolgy partially developed in Spain. From a scientific point of view, Hernando directly trained various young pharmacologists that extended the new science to various Spanish universities. Some of his direct disciples were Benigno Lorenzo Velázquez, Francisco García Valdecasas, Rafael Méndez, Tomás Alday, Gabriel Sánchez de la Cuesta, Dámaso Gutiérrez or Ramón P é rez-Cirera. One of the central research subject was the analysis of the effects of digitalis on the cat and frog heart. In the initiation of the 1970 s pharmacologists trained by those Hernando's students grew throughout various universities and the "Consejo Superior de Investigaciones Científicas" (CSIC). And hence, in 1972 the "Sociedad Española de Farmacología" (SEF) emerged. Later on, in the 1990's the "Sociedad Española de Farmacología Clínica (SEFC) also emerged. The relationship between the two societies is still weak. Out of the vast scope of the pharmacological sciences, Spanish pharmacologists have made relevant contributions in two areas namely, neuropsychopharmacology and cardiovacular pharmacology. Nonetheless, in other areas such as smooth muscle, gastroenterology, pharmacogenetics and hepatic toxicity, Spanish pharmacologists have also made relevant contributions. A succint description of such contributions is made. Finally, some hints on perspectives for the further development of preclinical and clinical pharmacology in Spain, are offered. [ABSTRACT FROM AUTHOR]

Proteomics and Atrial Appendages. Introduction: The objective was to compare by proteomics the expression of proteins associated with the cytoskeleton, energetic metabolism, and cardiac cytoprotection between left atrial appendages (LAA) and right atrial appendages (RAA) obtained from patients with mitral valve disease both in sinus rhythm (SR, n = 6) and in permanent atrial fibrillation (AF, n = 11). Methods and Results: Samples from RAA and LAA were obtained from the same patient. Proteins were separated in 2-dimensional electrophoresis and identified by mass spectrometry. LAA from SR patients upexpressed α-actin isotype 1 and desmin isotypes 3 and 5 with respect to RAA. In LAA from AF patients were upexpressed cardiac α-actin isotypes 1 and 2, tropomyosin α- and β-chains, and myosin light chain embryonic muscle/atrial isoform with respect to LAA from SR patients. In RAA from AF patients also upexpressed different cytoskeleton associated proteins with respect to RAA from SR patients. Different energetic metabolism-associated proteins were upexpressed in LAA and RAA from AF with respect those from SR patients. In AF patients, the expression of proteins associated with cardiac cytoprotection such as gluthatione-S-transferase, heat shock protein (Hsp) 27, and different Hsp60 isotypes, were higher in RAA but not in LAA with respect to the corresponding appendages in SR patients. Conclusions: For each individual patient RAA and LAA showed a similar level of proteins expressed associated with cytoskeleton, energetic metabolism, and cardiac cytoprotection. There were more differences in the level of proteins associated with the above-mentioned mechanisms between the atrial appendages from AF with respect to SR patients, which may open new targets for drugs. (J Cardiovasc Electrophysiol, Vol. 21, pp. 859-868, August 2010) [ABSTRACT FROM AUTHOR]

Choosing an antiplatelet strategy in patients with non-ST segment elevation acute coronary syndrome (NSTE-ACS) at high bleeding risk (HBR), undergoing post-percutaneous coronary intervention (PCI), is complex. We used a unique open-source approach (crowdsourcing) to document if practices varied across a small, global cross-section of antiplatelet prescribers in the post-PCI setting. Five-hundred and fifty-nine professionals from 70 countries (the 'crowd') completed questionnaires containing single- or multi-option and free form questions regarding antiplatelet clinical practice in post-PCI NSTE-ACS patients at HBR. A threshold of 75% defined 'agreement'. There was strong agreement favouring monotherapy with either aspirin or a P2Y 12 inhibitor following initial DAPT, within the first year (94%). No agreement was reached on the optimal duration of DAPT or choice of monotherapy: responses were in equipoise for shorter (≤3 months, 51%) or longer (≥6 months, 46%) duration, and monotherapy choice (45% aspirin; 53% P2Y 12 inhibitor). Most respondents stated use of guideline-directed tools to assess risk, although clinical judgement was preferred by 32% for assessing bleeding risk and by 46% for thrombotic risk. The crowdsourcing methodology showed potential as a tool to assess current practice and variation on a global scale and to achieve a broad demographic representation. These preliminary results indicate a high degree of variation with respect to duration of DAPT, monotherapy drug of choice following DAPT and how thrombotic and bleeding risk are assessed. Further investigations should concentrate on interrogating practice variation between key demographic groups. • Antiplatelet choice is complex in NSTE-ACS patients at high bleeding risk. • Practice is expected to vary and may deviate from guidelines. • A crowdsourcing approach was used to assess current practices. • We noted high practice variation across a global cohort of prescribers. • Crowdsourcing may be an effective tool to monitor practice variation. [ABSTRACT FROM AUTHOR]

Synapse-Associated Protein 97 (SAP97) is an anchoring protein that in cardiomyocytes targets to the membrane and regulates Na+ and K+ channels. Here we compared the electrophysiological effects of native (WT) and p.P888L SAP97, a common polymorphism. Currents were recorded in cardiomyocytes from mice trans-expressing human WT or p.P888L SAP97 and in Chinese hamster ovary (CHO)-transfected cells. The duration of the action potentials and the QT interval were significantly shorter in p.P888L-SAP97 than in WT-SAP97 mice. Compared to WT, p.P888L SAP97 significantly increased the charge of the Ca-independent transient outward (Ito,f) current in cardiomyocytes and the charge crossing Kv4.3 channels in CHO cells by slowing Kv4.3 inactivation kinetics. Silencing or inhibiting Ca/calmodulin kinase II (CaMKII) abolished the p.P888L-induced Kv4.3 charge increase, which was also precluded in channels (p.S550A Kv4.3) in which the CaMKII-phosphorylation is prevented. Computational protein-protein docking predicted that p.P888L SAP97 is more likely to form a complex with CaMKII than WT. The Na+ current and the current generated by Kv1.5 channels increased similarly in WT-SAP97 and p.P888L-SAP97 cardiomyocytes, while the inward rectifier current increased in WT-SAP97 but not in p.P888L-SAP97 cardiomyocytes. The p.P888L SAP97 polymorphism increases the Ito,f, a CaMKII-dependent effect that may increase the risk of arrhythmias. [ABSTRACT FROM AUTHOR]

Long QT syndrome (LQTS) exhibits great phenotype variability among family members carrying the same mutation, which can be partially attributed to genetic factors. We functionally analyzed the KCNH2 (encoding for Kv11.1 or hERG channels) and TBX20 (encoding for the transcription factor Tbx20) variants found by next-generation sequencing in two siblings with LQTS in a Spanish family of African ancestry. Affected relatives harbor a heterozygous mutation in KCNH2 that encodes for p.T152HfsX180 Kv11.1 (hERG). This peptide, by itself, failed to generate any current when transfected into Chinese hamster ovary (CHO) cells but, surprisingly, exerted "chaperone-like" effects over native hERG channels in both CHO cells and mouse atrial-derived HL-1 cells. Therefore, heterozygous transfection of native (WT) and p.T152HfsX180 hERG channels generated a current that was indistinguishable from that generated by WT channels alone. Some affected relatives also harbor the p.R311C mutation in Tbx20. In human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), Tbx20 enhanced human KCNH2 gene expression and hERG currents (IhERG) and shortened action-potential duration (APD). However, Tbx20 did not modify the expression or activity of any other channel involved in ventricular repolarization. Conversely, p.R311C Tbx20 did not increase KCNH2 expression in hiPSC-CMs, which led to decreased IhERG and increased APD. Our results suggest that Tbx20 controls the expression of hERG channels responsible for the rapid component of the delayed rectifier current. On the contrary, p.R311C Tbx20 specifically disables the Tbx20 protranscriptional activity over KCNH2. Therefore, TBX20 can be considered a KCNH2-modifying gene. [ABSTRACT FROM AUTHOR]

The article presents the 2016 European Society of Cardiology (ESC) position paper on cancer treatments and cardiovascular toxicity. Topics discussed include the cardiovascular complications of cancer therapy, strategies to prevent cardiovascular complications of cancer therapy, and long-term surveillance programmes for cancer survivors.

Bacterial endotoxin lipopolysaccharide (LPS) activates inflammatory pathways, induces cytokine expression in the endothelium, augments reactive oxygen species (ROS) production in the vascular wall, and induces endothelial dysfunction. The aim of the present study was to analyze the effects of peroxisome proliferator-activated receptor (PPAR)β/δ activation on LPS-induced inflammation, oxidative stress and endothelial dysfunction and to determine whether uncoupling protein-2 (UCP2) plays a role in these effects. In vivo , the PPARβ/δ agonist GW0742 treatment prevented the LPS-induced reduction in aortic relaxation, the increase in vascular ROS production, the upregulation of NOX1, NOX2, p47 phox , and p22 phox mRNA levels, and the endoplasmic reticulum (ER) stress markers in mice. We show that in mouse aortic endothelial cells (MAECs), GW0742 prevented the decreased A23187-stimulated nitric oxide (NO) production, and the increased intracellular ROS levels caused by exposure to LPS in vitro . The PPARβ/δ antagonist GSK0660 abolished all these in vivo and in vitro protective effects induced by GW0742. This agonist also restored the reduced expression of UCP2 and mitofusin-2 induced by LPS. The effects of GW0742 on NO and ROS production in MAEC exposed to LPS were abolished by the UCP2 inhibitor genipin or by siRNA targeting UCP-2. Genipin also suppressed the expressional changes on NADPH oxidase and ER stress markers induced by GW0742. In conclusion, PPARβ/δ activation restored the LPS-induced endothelial dysfunction by upregulation of UCP2, with the subsequent alleviation of ER stress and NADPH oxidase activity, thus reducing intracellular ROS production and increasing NO bioavailability. [ABSTRACT FROM AUTHOR]

Aims Cardiac excitability and refractoriness are largely determined by the function and number of inward rectifier K+ channels (Kir2.1-2.3), which are differentially expressed in the atria and ventricles, and Nav1.5 channels. We have focused on how Nav1.5 and Kir2.x function within a macromolecular complex by elucidating the molecular determinants that govern Nav1.5/Kir2.x reciprocal modulation. Methods and results The results demonstrate that there is an unexpected 'internal' PDZ-like binding domain located at the N-terminus of the Nav1.5 channel that mediates its binding to a1-syntrophin. Nav1.5 N-terminal domain, by itself (the 132 aa peptide) (Nter), exerts a 'chaperone-like' effect that increases sodium (INa) and inward rectifier potassium (IK1) currents by enhancing the expression of Nav1.5, Kir2.1, and Kir2.2 channels as demonstrated in Chinese hamster ovary (CHO) cells and in rat cardiomyocytes. Site-directed mutagenesis analysis demonstrates that the Nter chaperone-like effect is determined by Serine 20. Nav1.5-Kir2.x reciprocal positive interactions depend on a specific C-terminal PDZ-binding domain sequence (SEI), which is present in Kir2.1 and Kir2.2 channels but not in Kir2.3. Therefore, in human atrial myocytes, the presence of Kir2.3 isoforms precludes reciprocal IK1-INa density modulation. Moreover, results in rat and human atrial myocytes demonstrate that binding to a1-syntrophin is necessary for the Nav1.5-Kir2.x-positive reciprocal modulation. Conclusions The results demonstrate the critical role of the N-terminal domain of Nav1.5 channels in Nav1.5-Kir2.x-reciprocal interactions and suggest that the molecular mechanisms controlling atrial and ventricular cellular excitability may be different. [ABSTRACT FROM AUTHOR]

Aims Atrial fibrillation (AF) produces rapid changes in the electrical properties of the atria (electrical remodelling) that promote its own recurrence. In chronic AF (CAF) patients, up-regulation of the slow delayed rectifier K+ current (Iks) and down-regulation of the voltage-gated Ca2+ current (ICa,L) are hallmarks of electrical remodelling and critically contribute to the abbreviation of action potential duration and atrial refractory period. Recent evidences suggested that Pitx2c, a bicoid-related homeodomain transcription factor involved in directing cardiac asymmetric morphogenesis, could play a role in atrial remodelling. However, its effects on Iks and ICa,L are unknown. Methods and results Real-time quantitative polymerase chain reaction analysis showed that Pitx2c mRNA expression was significantly higher in human atrial myocytes from CAF patients than those from sinus rhythm patients. The expression of Pitx2c was positively and negatively correlated with Iks and ICa,L densities, respectively. Expression of Pitx2c in HL-1 cells increased Iks density and reduced ICa,L density. Luciferase assays demonstrated that Pitx2c increased transcriptional activity of KCNQ1 and KCNE1 genes. Conversely, its effects on ICa,L could be mediated by the atrial natriuretic peptide. Conclusion Our results demonstrated for the first time that CAF increases Pitx2c expression in isolated human atrial myocytes and suggested that this transcription factor could contribute to the CAF-induced Iks increase and ICa,L reduction observed in humans. [ABSTRACT FROM AUTHOR]

Chronic stable angina is a common and progressive disease which has a major impact on patient quality of life and imposes a high financial and medical burden on society. Given the range of agents now available, optimal medical therapy – which according to guidelines is the preferred option in the majority of patients with low-risk disease – offers the opportunity for effective control. However, recent studies suggest that management remains suboptimal in up to a third of patients and that physicians often underestimate the extent to which angina continues to limit patients' lives. A higher frequency of angina also relates directly to increased healthcare costs. These factors suggest the need for the development and implementation of appropriate guidelines, for tools to encourage the regular, systematic assessment of the management of chronic stable angina patients, and for improved means of communication between doctors and patients. Neither physicians nor their patients need to accept that a certain level of angina symptoms is unavoidable. [ABSTRACT FROM AUTHOR]

Aims We hypothesize that some drugs, besides flecainide, increase the inward rectifier current (IK1) generated by Kir2.1 homotetramers (IKir2.1) and thus, exhibit pro- and/or antiarrhythmic effects particularly at the ventricular level. To test this hypothesis, we analysed the effects of propafenone, atenolol, dronedarone, and timolol on Kir2.x channels. Methods and results Currents were recorded with the patch-clamp technique using whole-cell, inside-out, and cell-attached configurations. Propafenone (0.1 nM–1 µM) did not modify either IK1 recorded in human right atrial myocytes or the current generated by homo- or heterotetramers of Kir2.2 and 2.3 channels recorded in transiently transfected Chinese hamster ovary cells. On the other hand, propafenone increased IKir2.1 (EC50 = 12.0 ± 3.0 nM) as a consequence of its interaction with Cys311, an effect which decreased inward rectification of the current. Propafenone significantly increased mean open time and opening frequency at all the voltages tested, resulting in a significant increase of the mean open probability of the channel. Timolol, which interacted with Cys311, was also able to increase IKir2.1. On the contrary, neither atenolol nor dronedarone modified IKir2.1. Molecular modelling of the Kir2.1–drugs interaction allowed identification of the pharmacophore of drugs that increase IKir2.1. Conclusions Kir2.1 channels exhibit a binding site determined by Cys311 that is responsible for drug-induced IKir2.1 increase. Drug binding decreases channel affinity for polyamines and current rectification, and can be a mechanism of drug-induced pro- and antiarrhythmic effects not considered until now. [ABSTRACT FROM AUTHOR]

Objective: To analyse if platelet responsiveness to aspirin (ASA) may be associated with a different ability of platelets to generate nitric oxide (NO). Patients/Methods: Platelets were obtained from 50 patients with stable coronary ischemia and were divided into ASA-sensitive (n = 26) and ASA-resistant (n = 24) using a platelet functionality test (PFA-100). Results: ASA-sensitive platelets tended to release more NO (determined as nitrite + nitrate) than ASA-resistant platelets but it did not reach statistical significance. Protein expression of nitric oxide synthase 3 (NOS3) was higher in ASA-sensitive than in ASA-resistant platelets but there were no differences in the platelet expression of nitric oxide synthase 2 (NOS2) isoform. The highest NOS3 expression in ASA-sensitive platelets was independent of the presence of T-to-C mutation at nucleotide position −786 (T−786→C) in the NOS3-coding gene. However, platelet content of phosphorylated NOS3 at Serine (Ser)1177, an active form of NOS3, was higher in ASA-sensitive than in ASA-resistant platelets. The level of platelet NOS3 Ser1177 phosphorylation was positively associated with the closure time in the PFA-100 test. In vitro, collagen failed to stimulate the aggregation of ASA-sensitive platelets, determined by lumiaggregometry, and it was associated with a significant increase (p = 0.018) of NOS3 phosphorylation at Ser1177. On the contrary, collagen stimulated the aggregation of ASA-resistant platelets but did not significantly modify the platelet content of phosphorylated NOS3 Ser1177. During collagen stimulation the release of NO from ASA-sensitive platelets was significantly enhanced but it was not modified in ASA-resistant platelets. Conclusions: Functional platelet responsiveness to ASA was associated with the platelet content of phosphorylated NOS3 at Ser1177. [ABSTRACT FROM AUTHOR]

Aims We analysed the chronic effects of the peroxisome proliferator-activated receptor β/δ (PPAR-β) agonist GW0742 on the renin-independent hypertension induced by deoxycorticosterone acetate (DOCA)-salt. Methods and results Rats were treated for 5 weeks with: control-vehicle, control-GW0742 (5 or 20 mg kg−1 day−1), DOCA-vehicle, DOCA-GW0742 (5 or 20 mg kg−1 day−1), DOCA-GSK0660 (1 mg kg−1 day−1), and DOCA-GSK0660-GW0742. Rats receiving DOCA-vehicle showed increased systolic blood pressure, left ventricular and kidney weight indices, endothelin-1 (ET-1), and malondialdehyde plasma levels, urinary iso-PGF2α excretion, impaired endothelium-dependent relaxation to acetylcholine, and contraction to ET-1 when compared with controls. Aortic reactive oxygen species content, NADPH oxidase activity, and p47phox, p22phox, NOX-4, glutathione peroxidase 1, hemeoxygenase-1, and preproET-1 expression were increased, whereas catalase and regulators of G protein-coupled signalling proteins (RGS)5 expression were decreased in the DOCA-vehicle group. GW0742 prevented the development of hypertension in a dose-dependent manner but the reduction of renal and cardiac hypertrophy, systemic and vascular oxidative stress markers, and improvement of endothelial dysfunction were only observed after the higher dose. GW0742, at 20 mg kg−1 day−1, attenuated ET-1 contraction by increasing RGS5 expression and restored the intracellular redox balance by reducing NADPH-oxidase activity, and by increasing the antioxidant genes expression. The PPAR-β antagonist GSK0660 prevented all vascular changes induced by GW0742 but not its antihypertensive effects. Conclusion Vascular protective effects of GW0742 operate via PPAR-β by interference with the ET-1 signalling as a result of increased expression of RGS5 and up-regulation of antioxidant genes and via PPAR-β-independent mechanisms to decrease blood pressure. [ABSTRACT FROM AUTHOR]

The ZFHX3 and SCN5A genes encode the zinc finger homeobox 3 (Zfhx3) transcription factor (TF) and the human cardiac Na+ channel (Nav1.5), respectively. The effects of Zfhx3 on the expression of the Nav1.5 channel, and in cardiac excitability, are currently unknown. Additionally, we identified three Zfhx3 variants in probands diagnosed with familial atrial fibrillation (p.M1260T) and Brugada Syndrome (p.V949I and p.Q2564R). Here, we analyzed the effects of native (WT) and mutated Zfhx3 on Na+ current (INa) recorded in HL-1 cardiomyocytes. ZFHX3 mRNA can be detected in human atrial and ventricular samples. In HL-1 cardiomyocytes, transfection of Zfhx3 strongly reduced peak INa density, while the silencing of endogenous expression augmented it (from −65.9 ± 8.9 to −104.6 ± 10.8 pA/pF; n ≥ 8, p < 0.05). Zfhx3 significantly reduced the transcriptional activity of human SCN5A, PITX2, TBX5, and NKX25 minimal promoters. Consequently, the mRNA and/or protein expression levels of Nav1.5 and Tbx5 were diminished (n ≥ 6, p < 0.05). Zfhx3 also increased the expression of Nedd4-2 ubiquitin-protein ligase, enhancing Nav1.5 proteasomal degradation. p.V949I, p.M1260T, and p.Q2564R Zfhx3 produced similar effects on INa density and time- and voltage-dependent properties in WT. WT Zfhx3 inhibits INa as a result of a direct repressor effect on the SCN5A promoter, the modulation of Tbx5 increasing on the INa, and the increased expression of Nedd4-2. We propose that this TF participates in the control of cardiac excitability in human adult cardiac tissue. [ABSTRACT FROM AUTHOR]

Abstract: Human cardiac inward rectifier current (I K1) is generated by Kir2.x channels. Inhibition of I K1 could offer a useful antiarrhythmic strategy against fibrillatory arrhythmias. Therefore, elucidation of Kir2.x channels pharmacology, which still remains elusive, is mandatory. We characterized the electrophysiological and molecular basis of the inhibition produced by the antiarrhythmic propafenone of the current generated by Kir2.x channels (I Kir2.x) and the I K1 recorded in human atrial myocytes. Wild type and mutated human Kir2.x channels were transiently transfected in CHO and HEK-293 cells. Macroscopic and single-channel currents were recorded using the patch-clamp technique. At concentrations >1μM propafenone inhibited I Kir2.x the order of potency being Kir2.3∼ I K1 >Kir2.2>Kir2.1 channels. Blockade was irrespective of the extracellular K+ concentration whereas markedly increased when the intracellular K+ concentration was decreased. Propafenone decreased inward rectification since at potentials positive to the K+ equilibrium potential propafenone-induced block decreased in a voltage-dependent manner. Importantly, propafenone favored the occurrence of subconductance levels in Kir2.x channels and decreased phosphatidylinositol 4,5-bisphosphate (PIP2)-channel affinity. Blind docking and site-directed mutagenesis experiments demonstrated that propafenone bound Kir2.x channels at the cytoplasmic domain, close to, but not in the pore itself, the binding site involving two conserved Arg residues (residues 228 and 260 in Kir2.1). Our results suggested that propafenone incorporated into the cytoplasmic domain of the channel in such a way that it decreased the net negative charge sensed by K+ ions and polyamines which, in turn, promotes the appearance of subconductance levels and the decrease of PIP2 affinity of the channels. [Copyright &y& Elsevier]

Aims β-adrenergic stimulation has profound influence in the genesis and maintenance of atrial fibrillation (AF). However, the effects of β-Adrenoceptor stimulation on repolarizing currents and action potential (AP) characteristics in human atrial myocytes from left (LAA) and right atrial appendages (RAA) obtained from sinus rhythm (SR) and chronic atrial fibrillation (CAF) patients have not been compared yet. Methods and results Currents and APs were recorded using whole-cell patch-clamp in RAA and LAA myocytes from SR and CAF patients. Isoproterenol concentration-dependently decreased the Ca2+-independent 4-aminopyridine-sensitive component of the transient outward current (Ito1) and the inward rectifying current (IK1). CAF significantly enhanced this inhibition, this effect being more marked in the left than in the right atria. CAF dramatically enhanced β-Adrenoceptor-mediated increase in the slow component of the delayed rectifier current (IKs), whose density was already markedly increased by CAF. Conversely, the ultrarapid component of the delayed rectifier current (IKur) of both SR and CAF myocytes was insensitive to low isoproterenol concentrations. As a consequence, stimulation of β1-Adrenoceptors in SR myocytes lengthened, whereas in CAF myocytes shortened, the AP duration. Quantitative PCR revealed that CAF up-regulated β1-Adrenoceptor expression, preferentially in the left atria. Conclusion The present results demonstrate that CAF increases the effects of β1-Adrenoceptor stimulation on repolarizing currents by means of a chamber-specific up-regulation of the receptors. This, together with the ion channel derangements produced by CAF, could contribute to the long-term stabilization of the arrhythmia by shortening the AP duration. [ABSTRACT FROM AUTHOR]

Abstract: Endothelial dysfunction plays a key role in the pathogenesis of diabetic vascular disease. Herein, we have analyzed if the peroxisome proliferator-activated receptor-β/-δ (PPARβ/δ) agonist GW0742 exerts protective effects on endothelial function in type 1 diabetic rats. The rats were divided into 4 groups: control, control-treated (GW0742, 5mgkg−1 day−1 for 5 weeks), diabetic (streptozotocin injection), and diabetic-treated. GW0742 administration in diabetic rats did not alter plasma glucose, systolic blood pressure, or heart rate, but reduced plasma triglyceride levels. The vasodilatation induced by acetylcholine was decreased in aortas from diabetic rats. GW0742 restored endothelial function, increasing eNOS phosphorylation. Superoxide production, NADPH oxidase activity, and mRNA expression of prepro endothelin-1, p22phox, p47phox, and NOX-1 were significantly higher in diabetic aortas, and GW0742 treatment prevented these changes. In addition, GW0742 prevented the endothelial dysfunction and the upregulation of prepro endothelin-1and p47phox after the in vitro incubation of aortic rings with high glucose and these effects were prevented by the PPARβ/δ antagonist GSK0660. PPARβ/δ activation restores endothelial function in type 1 diabetic rats. This effect seems to be related to an increase in nitric oxide bioavailability as a result of reduced NADPH oxidase-driven superoxide production and downregulation of prepro endothelin-1. [Copyright &y& Elsevier]

J. Neurochem. (2012) 121, 314-325. Abstract Stroke patients have a high risk of vascular recurrence. Biomarkers related to vascular recurrence, however, remain to be identified. The aim of the study was to identify, through proteomic analysis, plasma biomarkers associated with vascular recurrence within one year after the first ischemic stroke. This is a substudy ( n = 134) of a large prospective multicenter study of post-stroke patients with an ischemic stroke. Plasma samples were obtained at inclusion. Among the identified proteins, only plasma levels of desmoplakin I were associated with protection against a new vascular event (Odds ratio: 0.64; 95% CI: 0.46-0.89; p = 0.009) after adjustment for hypercholesterolemia, statins and previous atherothrombotic stroke subtype. A greater number of patients without vascular recurrence had been treated with statins within three months of the recent ischemic stroke. Only patients who had been taking statins for 3 months after the ischemic stroke and did not suffer vascular recurrence over a follow-up year, have higher levels of desmoplakin I at the time of inclusion (Odds ratio 0.49; 95% CI: 0.28-0.86; p = 0.013). Increased desmoplakin I levels, determined within 1-3 months of the first ischemic stroke, could be a biomarker for statin responsiveness against a new vascular event in post-ischemic stroke patients taking statins early (1-3 months) after the ischemic stroke. [ABSTRACT FROM AUTHOR]

Flecainide is a class Ic antiarrhythmic agent that has an important role as part of rhythm control strategies in patients with atrial fibrillation (AF). Early clinical data on the use of flecainide showed an increase in arrhythmias and mortality compared with placebo in patients with a previous myocardial infarction and asymptomatic or mildly symptomatic ventricular arrhythmias. These findings only apply to a specific group of patients with left ventricular dysfunction and ischaemic heart disease, but had a negative impact on the use of class Ic antiarrhythmics across all indications and patient groups. The aim of this review was to evaluate the available safety data for flecainide in the literature and to assess its current use in patients with AF. Current European guidelines now recommend the use of flecainide in carefully selected groups of patients with AF who do not have structural heart disease. This includes for the cardioversion of recent-onset AF, pretreatment prior to direct current cardioversion, out-of-hospital acute oral therapy ('pill-in-the-pocket' approach) and for the ongoing maintenance of sinus rhythm. Potential cardiac adverse effects of flecainide include proarrhythmia, conduction abnormalities and negative inotropic effects. Dizziness is the most frequent non-cardiac side effect, followed by blurred vision and difficulty focusing; these are almost all mild, transient and tolerable. Data from recent clinical trials in patients with supraventricular arrhythmias suggest that flecainide has a good tolerability profile in groups of appropriately selected patients. Caution is required when using flecainide in patients with renal dysfunction, and there are a number of drug interactions, but these are well documented and manageable. Overall, flecainide is a good choice for the pharmacological management of AF. It has a good safety record and low incidence of adverse effects, rare end-organ toxicity and a low risk of ventricular proarrhythmia. To ensure that the benefits of treatment outweigh any potential risks, careful patient selection and monitoring is required. [ABSTRACT FROM AUTHOR]

Background: Chronic oral quercetin reduces blood pressure and restores endothelial dysfunction in hypertensive animals. However, quercetin (aglycone) is usually not present in plasma, because it is rapidly metabolized into conjugated, mostly inactive, metabolites. The aim of the study is to analyze whether deconjugation of these metabolites is involved in the blood pressure lowering effect of quercetin. Methodology/Principal Findings: We have analyzed the effects on blood pressure and vascular function in vitro of the conjugated metabolites of quercetin (quercetin-3-glucuronide, Q3GA; isorhamnetin-3-glucuronide, I3GA; and quercetin-3'- sulfate, Q3'S) in spontaneously hypertensive rats (SHR). Q3GA and I3GA (1 mg/kg i.v.), but not Q3'S, progressively reduced mean blood pressure (MBP), measured in conscious SHR. The hypotensive effect of Q3GA was abolished in SHR treated with the specific inhibitor of β-glucuronidase, saccharic acid 1,4-lactone (SAL, 10 mg/ml). In mesenteric arteries, unlike quercetin, Q3GA had no inhibitory effect in the contractile response to phenylephrine after 30 min of incubation. However, after 1 hour of incubation Q3GA strongly reduced this contractile response and this effect was prevented by SAL. Oral administration of quercetin (10 mg/Kg) induced a progressive decrease in MBP, which was also suppressed by SAL. Conclusions: Conjugated metabolites are involved in the in vivo antihypertensive effect of quercetin, acting as molecules for the plasmatic transport of quercetin to the target tissues. Quercetin released from its glucuronidated metabolites could be responsible for its vasorelaxant and hypotensive effect. [ABSTRACT FROM AUTHOR]

Abstract: Flavanol-rich diets have been reported to exert beneficial effects in preventing cardiovascular diseases, such as hypertension. We studied the effects of chronic treatment with epicatechin on blood pressure, endothelial function, and oxidative status in deoxycorticosterone acetate (DOCA)-salt-induced hypertension. Rats were treated for 5weeks with (−)-epicatechin at 2 or 10mg kg−1 day−1. The high dose of epicatechin prevented both the increase in systolic blood pressure and the proteinuria induced by DOCA-salt. Plasma endothelin-1 and malondialdehyde levels and urinary iso-prostaglandin F2α excretion were increased in animals of the DOCA-salt group and reduced by the epicatechin 10mg kg−1 treatment. Aortic superoxide levels were enhanced in the DOCA-salt group and abolished by both doses of epicatechin. However, only epicatechin at 10mg kg−1 reduced the rise in aortic nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and p47phox and p22phox gene overexpression found in DOCA-salt animals. Epicatechin increased the transcription of nuclear factor-E2-related factor-2 (Nrf2) and Nrf2 target genes in aortas from control rats. Epicatechin also improved the impaired endothelium-dependent relaxation response to acetylcholine and increased the phosphorylation of both Akt and eNOS in aortic rings. In conclusion, epicatechin prevents hypertension, proteinuria, and vascular dysfunction. Epicatechin also induced a reduction in ET-1 release, systemic and vascular oxidative stress, and inhibition of NADPH oxidase activity. [Copyright &y& Elsevier]

RWPs (red wine polyphenols) exert antihypertensive effects and improve endothelial function by reducing the plasma levels of ET-1 (endothelin-1) and the subsequent vascular production of O2•- (superoxide anion). Our present study was designed to evaluate whether RWPs act directly in the vascular wall improving endothelial dysfunction and O2•- production induced by ET-1 and to analyse the compounds responsible for these protective effects. We incubated rat isolated aortic rings in the presence or absence of ET-1 (10 nM) and RWPs (10-4 to 10-2 g/l) or catechin (0.2 μM), epicatechin (10 μM) and resveratrol (0.1 μM). ET-1 reduced the relaxant responses to acetylcholine, increased intracellular O2•- production, NADPH oxidase activity and protein expression of NADPH oxidase subunit p47phox. All these changes were prevented by RWPs. The preventive effects of RWPs were unaffected by co-incubation with either ICI-182780, an ER (oestrogen receptor) antagonist, or GW9662, a PPARγ (peroxisome-proliferator-activated receptor γ) antagonist. RWPs inhibited the phosphorylation of the mitogen-activated protein kinase, ERK1/2 (extracellular signal-regulated kinase 1/2), a key regulator of p47phox expression in response to ET-1. When the isolated polyphenols were tested, at the concentrations found in 10-2 g/l RWPs, only epicatechin prevented endothelial dysfunction and all biochemical changes induced by ET-1 in the vascular wall. Taken together, these results indicate that RWPs prevent ET-1-induced vascular O2•- production by reducing overexpression of p47phox and the subsequent increased NADPH oxidase activity, leading to improvement in endothelial function. The effects of RWPs appear to be independent of ER and PPARγ activation and are related to ERK1/2 inhibition. [ABSTRACT FROM AUTHOR]

Abstract: ET-1 induces vascular O2 − production via activation of NADPH oxidase. We have investigated whether c-Src and MAPKs activation are involved in ET-1-induced vascular oxidative response. At 2h, ET-1 induced an increase in NADPH oxidase-driven O2 − production in rat isolated aortic rings, which was completely suppressed in PP2 (c-Src inhibitor)-pretreated rings, whereas PP3 (inactive analogue of PP2) was without effect. ET-1 increased the levels of phospho-c-Src, the active form of c-Src, and the phosphorylation of cortactin, a Src-specific substrate. Both c-Src and cortactin phosphorylation induced by ET-1 were prevented by PP2. The increased expression of p47phox, the main cytosolic subunit of NADPH oxidase, induced by ET-1 was also prevented by PP2. The increased vascular O2 − production and p47phox up-regulation induced by ET-1 was only inhibited in aortic rings coincubated with the ERK1/2 inhibitor, PD98059; being without effects both the p38 MAPK inhibitor, SB203580, and JNK inhibitor, SP600125. Aortic rings incubation with ET-1 increased the phosphorylation of ERK1/2. This effect was suppressed by coincubation with PP2 showing that this event is down-stream of c-Src activation. In conclusion, ET-1 induces NADPH oxidase-driven O2 − generation through increase of p47phox protein expression. The signalling pathway for this effect involves c-Src activation and ERK1/2 phosphorylation. [ABSTRACT FROM AUTHOR]