Drug-induced atrial fibrillation. A narrative review of a forgotten adverse effect.

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.

An account on the history of pharmacology in Spain.

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.

Investigative agents for atrial fibrillation: agonists and stimulants, progress and expectations.

INTRODUCTION: Atrial fibrillation (AF) is the most common type of cardiac arrhythmia. Its prevalence has increased due to worldwide populations that are aging in combination with the growing incidence of risk factors associated. Recent advances in our understanding of AF pathophysiology and the identification of nodal players involved in AF-promoting atrial remodeling highlights potential opportunities for new therapeutic approaches. AREAS COVERED: This detailed review summarizes recent developments in the field antiarrhythmic drugs in the field AF. EXPERT OPINION: The current situation is far than optimal. Despite clear unmet needs in drug development in the field of AF treatment, the current development of new drugs is absent. The need for a molecule with absence of cardiac and non-cardiac toxicity in the short and long term is a limitation in the field. Improvement in the understanding of AF genetics, pathophysiology, molecular alterations, big data and artificial intelligence with the objective to provide a personalized AF treatment will be the cornerstone of AF treatment in the coming years.

New pharmacological agents and novel cardiovascular pharmacotherapy strategies in 2023.

Although cardiovascular diseases (CVDs) are the leading cause of death worldwide, their pharmacotherapy remains suboptimal. Thus, there is a clear unmet need to develop more effective and safer pharmacological strategies. In this review, we summarize the most relevant advances in cardiovascular pharmacology in 2023, including the approval of first-in-class drugs that open new avenues for the treatment of atherosclerotic CVD and heart failure (HF). The new indications of drugs already marketed (repurposing) for the treatment of obstructive hypertrophic cardiomyopathy, hypercholesterolaemia, type 2 diabetes, obesity, and HF; the impact of polypharmacy on guideline-directed drug use is highlighted as well as results from negative clinical trials. Finally, we end with a summary of the most important phase 2 and 3 clinical trials assessing the efficacy and safety of cardiovascular drugs under development for the prevention and treatment of CVDs.

Coexistent HCN4 and GATA5 Rare Variants and Atrial Fibrillation in a Large Spanish Family.

BACKGROUND: Familial association of atrial fibrillation (AF) can involve single gene variants related to known arrhythmogenic mechanisms; however, genome-wide association studies often disclose complex genetic variants in familial and nonfamilial AF, making it difficult to relate to known pathogenetic mechanisms. METHODS: The finding of 4 siblings with AF led to studying 47 members of a family. Long-term Holter monitoring (average 298 hours) ruled out silent AF. Whole-exome sequencing was performed, and variants shared by the index cases were filtered and prioritised according to current recommendations. HCN4 currents (IHCN4) were recorded in Chinese hamster ovary cells expressing human p.P1163H or native HCN4 channels with the use of the patch-clamp technique, and topologically associating domain analyses of GATA5 variant were performed. RESULTS: The clinical study diagnosed 2 more AF cases. Five family members carried the heterozygous p.P1163H HCN4 variant, 14 carried the intronic 20,61040536,G,A GATA5 rare variant, and 9 carried both variants (HCN4+GATA5). Five of the 6 AF cases (onset age ranging from 33 to 70 years) carried both variants and 1 carried the GATA5 variant alone. Multivariate analysis showed that the presence of HCN4+GATA5 variants significantly increased AF risk (odds ratio 32.7, 95% confidence interval 1.8-591.4) independently from age, hypertension, and overweight. Functional testing showed that IHCN4 generated by heterozygous p.P1163H were normal. Topologically associating domain analysis suggested that GATA5 could affect the expression of many genes, including those encoding microRNA-1. CONCLUSION: The coincidence of 2 rare gene variants was independently associated with AF, but functional studies do not allow the postulation of the arrhythmogenic mechanisms involved.

Análisis del tratamiento para mantener el ritmo sinusal en pacientes con fibrilación auricular prescrito en los servicios de urgencias: subanálisis del estudio HERMES-AF / Emergency department prescription of sinus rhythm maintenance therapy for patients treated for atrial fibrillation: a secondary analysis of the HERMES-AF study

Objetivo. El mantenimiento del ritmo sinusal (RS) con fármacos antiarrítmicos (FAA) y/o tratamiento del remodelado (TRM) es parte fundamental en la estrategia de control del ritmo en la fibrilación auricular (FA). Este estudio analiza estas estrategias y su adecuación en los servicios de urgencias hospitalarios (SUH). Método. Análisis secundario del estudio multicéntrico observacional transversal HERMES-AF, desarrollado en 124 SUH representativos del sistema sanitario español en 2011. Se incluyeron pacientes consecutivos con FA que revirtieron a RS y fueron dados de alta desde urgencias. Resultados. Se incluyeron 449 pacientes: 204 (45,4%) ya realizaban tratamiento para mantenimiento del RS. De los 245 restantes se prescribió tratamiento en el SUH a 107 (43,7%): 41 con FAA, 19 TRM y en 47 ambas terapias. En 10 casos (11,8%) la selección del FAA no era acorde a las recomendaciones de las guías. La prescripción de FAA se asoció a FA previa [odds ratio (OR) 2,024, IC 95%: 1,196-3,424, p = 0,009], frecuencia cardiaca > 110 lpm (OR 2,147, IC 95%: 1,034-4,456, p = 0,040) y anticoagulación al alta (OR 1,862, IC 95%: 1,094-3,170, p = 0,022). El TRM se asoció a frecuencia cardiaca > 110 lpm (OR 2,187, IC 95%: 1,005-4,757, p = 0,018). En total, al alta del SUH 311 pacientes (69,2%) recibían tratamiento para mantenimiento del RS (87 con FAA, 117 con TRM y 107 con ambas terapias). Conclusiones. La prescripción de tratamiento para evitar las recurrencias de la FA es insuficiente en los SUH. Extender esta prescripción y mejorar la adecuación del tratamiento antiarrítmico son áreas de mejora de la estrategia de control del ritmo en los SUH.

Background and objective. The maintenance of sinus rhythm by means of antiarrhythmic drugs and/or upstream therapy to counter cardiac remodeling is fundamental to the management of atrial fibrillation (AF). This study aimed to analyze this approach and its appropriateness in the setting of hospital emergency departments. Methods. Secondary analysis of data from the multicenter observational cross-sectional HERMES-AF study carried out in 124 hospitals representative of the Spanish national health service in 2011. Included were consecutive patients with AF restored to sinus rhythm who were discharged home from emergency care. Results. A total of 449 patients were included; 204 (45.4%) were already on sinus rhythm maintenance therapy. Of the 245 remaining patients, 107 (43.67%) were prescribed maintenance treatment in the emergency department, as follows: 41, an antiarrhythmic drug; 19, upstream therapy; and 49, both treatments. The selection of an antiarrhythmic drug did not follow guideline recommendations in 10 patients (11.8%). Antiarrhythmic drug prescription was associated with having had a prior episode of AF (odds ratio [OR], 2.024; 95% CI, 1.196-3.424; P = .009); a heart rate of more than 110 beats/min (OR, 2.147; 95% CI, 1.034-4.456, P = 0.40); and prescription of anticoagulation on discharge (OR, 1.862; 95% CI, 1.094-3.170; P = .022). Upstream therapy prescription was associated only with a heart rate over 110 beats/min (OR, 2.187; 95% CI, 1.005-4.757; P = .018). In total, 311 patients (69.23%) were discharged from the emergency department with sinus rhythm maintenance therapy: 87 with an antiarrhythmic drug, 117 with an upstream therapy, and 107 with both. Conclusions. Treatment to prevent the recurrence of AF is underprescribed in emergency departments. Increasing such prescription and ensuring the appropriateness of antiarrhythmic therapy prescribed are points emergency departments can improve in the interest of better sinus rhythm maintenance.

La expresividad variable del síndrome de QT largo de una familia española se explica por la heterocigosis digénica en SCN5A y CACNA1C / Digenic heterozigosity in SCN5A and CACNA1C explains the variable expressivity of the long QT phenotype in a Spanish family

Introducción y objetivos: En 4 miembros de una familia española se identificó una mutación en los canales cardiacos Nav1.5 (p.R1644H) descrita ya y relacionada con el síndrome de QT largo con anterioridad. Sin embargo, solo 1 de los portadores presentaba el intervalo QT prolongado. En los otros 3 individuos se identificó una nueva mutación con cambio de sentido en los canales cardiacos Cav1.2 (p.S1961N). En este trabajo se analizaron las características funcionales de los canales p.S1961N Cav1.2 para averiguar si dicha mutación regula la expresividad del síndrome de QT largo en esta familia. Métodos: La corriente de calcio tipo L (ICaL) se registró mediante la técnica de patch-clamp en células de ovario de hámster chino transfectadas transitoriamente con los canales cardiacos humanos en su forma nativa o mutada. Resultados: La expresión de canales p.S1961N disminuye significativamente la densidad de la ICaL. Al sustituir el ion calcio por bario para suprimir la inactivación dependiente del calcio de los canales Cav1.2, se demostró que la mutación acelera significativamente la inactivación dependiente del voltaje de los canales Cav1.2 y disminuye la constante de tiempo de inactivación. Como consecuencia, la carga total que atraviesa los canales p.S1961N Cav1.2 disminuye significativamente. Los efectos que las mutaciones p.S1961N Cav1.2 y p.R1644H Nav1.5, por separado o en combinación, producen sobre las características de los potenciales de acción (PA) se simularon mediante un modelo matemático de PA ventriculares humanos. Los resultados demuestran que la mutación p.S1961N Cav1.2 abrevia la duración del PA y suprime la prolongación inducida por la mutación p.R1644H de los canales Nav1.5. Conclusiones: La mutación p.S1961N en los canales Cav1.2 disminuye la ICaL, un efecto que podría abreviar la duración de los PA ventriculares humanos. La presencia de esta mutación que disminuye la función de los canales Cav1.2 compensa funcionalmente los efectos producidos por la mutación de los canales Nav1.5 que aumenta su función y prolonga la duración de los PA

Introduction and objectives: A known long QT syndrome-related mutation in Nav1.5 cardiac channels (p.R1644H) was found in 4 members of a Spanish family but only 1 of them showed prolongation of the QT interval. In the other 3 relatives, a novel missense mutation in Cav1.2 cardiac channels was found (p.S1961N). Here, we functionally analyzed p.S1961N Cav1.2 channels to elucidate whether this mutation regulates the expressivity of the long QT syndrome phenotype in this family. Methods: L-type calcium current (ICaL) recordings were performed by using the whole-cell patch-clamp technique in Chinese hamster ovary cells transiently transfected with native and/or p.S1961N Cav1.2 channels. Results: Expression of p.S1961N channels significantly decreased ICaL density. Using Ba as a charge carrier to suppress the Ca-dependent inactivation of Cav1.2 channels, we demonstrated that the mutation significantly accelerates the voltage-dependent inactivation of Cav1.2 channels decreasing the inactivation time constant. As a consequence, the total charge flowing through p.S1961N Cav1.2 channels significantly decreased. The effects of the p.S1961N Cav1.2 and p.R1644H Nav1.5 mutations alone or their combination on the action potential (AP) morphology were simulated using a validated model of the human ventricular AP. The p.S1961N Cav1.2 mutation shortens the AP duration and abrogates the prolongation induced by p.R1644H Nav1.5 channels. Conclusions: The p.S1961N mutation in Cav1.2 channels decreased the ICaL, an effect which might shorten ventricular AP. The presence of the loss-of-function Cav1.2 mutation could functionally compensate the prolonging effects produced by the Nav1.5 gain-of-function mutation

Diferencias de sexo en los beneficios de la anticoagulación en pacientes ancianos con fibrilación auricular: un subanálisis del estudio EMERG-AF / Sex-related differences in benefits of anticoagulation therapy in elderly patients with atrial fibrillation: a subanalysis of the EMERG-AF study

Objetivos: Analizar los beneficios y seguridad a largo plazo de la anticoagulación oral (ACO) prescrita en los servicios de urgencias (SU) a pacientes mayores con fibrilación auricular (FA) y las diferencias en función del sexo. Método: Se trata de un análisis post-hoc del estudio EMERG-AF. Se incluyeron pacientes consecutivos $ 75 años, que consultaron en 62 SU por FA. Se recogieron datos clínicos y ACO. La variable principal estuvo compuesta por muerte, tromboembolia o sangrado mayor en 1 año. Resultados: Se incluyeron 690 pacientes, 386 mujeres (55,9%). Al alta, 575 pacientes (83,3%) estaban con ACO. En 96 de ellos se inició en el SU. Tras 1 año, la variable principal sucedió en 158 pacientes (22,9%): 118 (17,1%) fallecieron, 22 (2,7%) tuvieron una complicación tromboembólica y 34 (4,9%) una hemorragia mayor. Tras ajustar por las principales características clínicas, la ACO se asoció a una reducción en la variable principal (HR: 0,372, IC 95%: 0,236-0,587, p < 0,001), pero no se asoció con la hemorragia mayor. En las mujeres, la ACO se asoció con una reducción en la variable principal (HR: 0,372, IC 95%: 0,236-0,587, p < 0,001) y una menor mortalidad (HR: 0,281, IC 95%: 0,168-0,469, p < 0,001), incluidos pacientes con nueva prescripción y en aquellos dados de alta. Esta asociación no alcanzó significación en los hombres. (AU)

Objectives: To analyze the long-term benefits and safety of oral anticoagulation therapy prescribed in emergency departments for elderly patients with atrial fibrillation, and to detect any sex-related differences present. Material and methods: Post-hoc analysis of data compiled by the EMERG-AF group (Spanish acronym for Emergency Department Stroke Prophylaxis and Guidelines Implementation in Atrial Fibrillation). Consecutive patients aged 75 years or older with atrial fibrillation who were treated in 62 EDs were included. We recorded clinical data and anticoagulants prescribed. Patients were followed for 1 year. The main outcome variable was a composite of death, thromboembolism, or major bleeding within 1 year. Results: Data for 690 patients were registered; 386 (55.9%) were women. At discharge, 575 patients (83.3%) were on anticoagulants; therapy was started in the ED for 96 of them. A total of 158 patients (22.9%) had experienced at least 1 component of the main outcome within 1 year: 118 (17.1%) died, 22 (2.7%) had thromboembolic complications, and 34 (4.9%) had major bleeding. After adjustment for main clinical characteristics, hazard ratios (HRs) showed that anticoagulation therapy was associated with a reduction in the composite outcome (HR, 0.372; 95% CI, 0.236-0.587; P .001) but not specifically with major bleeding overall. When data for women were analyzed separately, anticoagulant therapy was again associated with a reduction in the composite outcome (HR, 0.372; 95% CI, 0.236-0.587; P .001) and also with death (HR, 0.281; 95% CI, 0.168-0.469; P .001), even in patients with anticoagulant prescriptions initiated on discharge from the ED. These associations did not reach statistical significance in men. (AU)

Edoxabán. Propiedades farmacocinéticas y farmacodinámicas / Edoxaban: Pharmacodynamic and Pharmacokinetic Properties

El edoxabán es un inhibidor potente, directo, selectivo y reversible del factor Xa de la coagulación. Por su mecanismo de acción, prolonga los tiempos de protrombina y de tromboplastina parcial activada e inhibe la actividad anti-factor Xa. En modelos in vitro e in vivo, el edoxabán es más efectivo como antitrombótico que el fondaparinux. Por vía oral, alcanza rápidamente (1-2 h) concentraciones plasmáticas máximas y su efecto máximo en diversos biomarcadores antitrombóticos (tiempos de protrombina y de tromboplastina parcial activada, actividad anti-factor Xa). El edoxabán (15-150 mg una vez al día) presenta un perfil farmacocinético lineal. Se absorbe bien por vía oral (biodisponibilidad del 62%) pero, a diferencia de otros inhibidores del factor Xa, se une poco a proteínas plasmáticas y no se biotransforma a través del citocromo P3A4, se elimina por vía biliar y renal y tiene una semivida de 10-14 h, lo que permite su administración una vez al día. La exposición al edoxabán es independiente de la edad, el sexo o la raza, pero aumenta al disminuir el peso y la función renal del paciente (AU)

Edoxaban is a potent, selective, direct, reversible inhibitor of coagulation factor Xa. Because of its mechanism of action, edoxaban prolongs the prothrombin time and the activated partial thromboplastin time and reduces anti-factor-Xa activity. In both in vitro and in vivo models, edoxaban is a more effective antithrombotic than fondaparinux. Given orally, the drug rapidly (i.e. in 1-2 hours) reaches its peak plasma concentration and achieves its maximum effect on various antithrombotic biomarkers (e.g. prothrombin time, activated partial thromboplastin time and anti-factor-Xa activity). Edoxaban (15-150 mg once daily) has a linear pharmacokinetic profile. It is readily absorbed when given orally (the bioavailability is 62%), but, unlike other factor-Xa inhibitors, it exhibits only poor binding to plasma proteins and is not biotransformed via CYP3A4. It is eliminated by biliary and renal routes and has a half-life of 10-14 hours, which enables edoxaban to be administered once daily. Exposure to the drug is independent of age, sex and ethnicity, but increases as the patient’s weight and renal function decrease (AU)

Tratamiento farmacológico de la obesidad / Pharmacological approaches in obesity treatment

La obesidad es la enfermedad metabólica más prevalente y un factor de riesgo para la aparición de enfermedades cardiovasculares razón por la que debe ser tratada. El tratamiento farmacológico debe entenderse como una medida coadyuvante de los cambios en el estilo de vida que constituyen el primer escalón del tratamiento, estando indicado tan sólo en pacientes obesos y en pacientes con sobrepeso que presentan patologías asociadas (p.ej., hipertensión arterial, diabetes tipo 2 o dislipemias) en los que la dieta y el ejercicio durante los 2-3 meses anteriores han sido inefectivas. Debemos tener presente que los fármacos no curan la obesidad, su efecto a largo plazo es modesto, pueden producir reacciones adversas (a veces graves) y que la interrupción del tratamiento conduce a un rápido aumento del peso corporal En este capítulo analizaremos el tratamiento farmacológico de la obesidad, analizando los objetivos del mismo, las barreras que lo dificultan y la evidencia que avala los fármacos que actualmente han sido aceptados tanto por la Food and Drug Administration de los Estados Unidos y la European Medicines Agency (AU)

Obesity is the most prevalent metabolic disease and a risk factor for cardiovascular diseases and, therefore, it should be treated. Drug treatment should be understood as an adjunctive measure of changes in lifestyle that are the first step of treatment, being indicated only in obese patients and in overweight patients with associated cardiovascular diseases (eg, hypertension, type 2 diabetes or dyslipidemia) when diet and exercise during the previous 2-3 months have been found ineffective. We must remember that drugs do not cure obesity, its long-term effect is modest, they can produce adverse reactions (sometimes severe) and discontinuation of treatment leads to a rapid gain in body weight This chapter discusses the pharmacological treatment obesity, analyses the main objectives of drug therapy, the barriers that hinder the treatment and the evidence supporting the drugs at the present time accepted by the Food and drug Administration and the European medicines Agency (AU)

Farmacología clínica de la ranolazina, un nuevo fármaco en el tratamiento de la angina crónica estable / Clinical pharmacology of ranolazine, a novel compound for treating chronic stable angina

La ranolazina es un derivado piperazínico con un nuevo mecanismo de acción que ha sido aprobado para su uso en combinación en pacientes con angina crónica estable. La isquemia miocárdica aumenta la corriente tardía de entrada de Na+ en las células cardiacas (INaL) e incrementa la concentración de sodio intracelular ([Na+ ] i ), lo que, a su vez, activa el modo inverso del intercambiador Na+ -Ca2+ y aumenta la concentración de calcio intracelular ([Ca2+] i ). Este aumento en Na+ i y Ca2+ i conduce a una disfunción mecánica (aumenta la presión diastólica y reduce la contractilidad y el aporte coronario de O2 ), eléctrica (produce arritmias) y mitocondrial (aumenta las demandas miocárdicas de O2 y reducción de la formación de adenosintrifosfato). La ranolazina inhibe selectivamente la INaL, reduce la acumulación intracelular de Na+ y la posterior de Ca2+ inducido por el Na+ , así como las anomalías mecánicas, eléctricas y metabólicas en el miocardio isquémico o insuficiente. En ensayos clínicos controlados realizados en pacientes con angina crónica estable, la ranolazina ejerce acciones antianginosas y antiisquémicas y, en pacientes con síndrome coronario agudo, ejerce acciones antiarrítmicas. Además, reduce la glucohemoglobina en pacientes coronarios diabéticos y mejora la función ventricular en pacientes con cardiopatía isquémica o insuficiencia cardiaca crónica. La ranolazina es un fármaco bien tolerado cuyos efectos adversos más comunes son náuseas, mareos, astenia y estreñimiento. Por todo lo anterior, la ranolazina representa una alternativa segura y eficaz en pacientes con angina crónica estable con síntomas no controlados o que no toleran los fármacos antianginosos convencionales (AU)

Ranolazine is a piperazine derivative that has a novel mechanism of action and which has been approved as add-on therapy for patients with chronic stable angina. Myocardial ischemia increases the late inward sodium ion (Na+ ) current in cardiac cells (INaL) and raises the intracellular sodium concentration (Na+ i ), which in turn activates the reverse mode of the sodium-calcium (Na+ - Ca2+) exchanger and increases the intracellular calcium concentration (Ca2+ i ). This increase in Na+ i and Ca2+ i leads to mechanical dysfunction (i.e. diastolic pressure increases, and contractility and myocardial oxygen supply decrease), electrical dysfunction (i.e. the induction of arrhythmias) and mitochondrial dysfunction (i.e. myocardial oxygen demand increases and the rate of ATP formation decreases). Ranolazine selectively inhibits the increase in INaL, reduces intracellular Na+ accumulation and the subsequent Ca2+ accumulation induced by Na+ , and decreases mechanical, electrical and metabolic dysfunction in the ischemic or failing myocardium. Controlled clinical trials have shown that ranolazine has both antianginal and anti-ischemic effects in patients with chronic stable angina, and an antiarrhythmic effect in patients with acute coronary syndrome. Moreover, ranolazine reduces the glycosylated hemoglobin level in diabetic patients with coronary heart disease and improves ventricular function in patients with ischemic heart disease or chronic heart failure. Ranolazine is well tolerated, with the most common adverse effects being nausea, dizziness, asthenia and constipation. For these reasons, ranolazine is a safe and effective option for patients with chronic stable angina whose symptoms are not under control or who can not tolerate conventional anti-anginal drugs (AU)

Estimulación vagal y remodelado eléctrico auricular / No disponible

No disponible

Fisiopatología de la prorrenina y la renina. Cincuenta años en busca de los inhibidores directos de la renina. Sus ventajas y sus limitaciones / Physiopathology of prorenin and renin. Fifty years in search of direct renin inhibitors. Their benefits and limitations

La renina es la enzima que limita la síntesis de angiotensina II y la activación del sistema renina-angiotensina (SRA), por lo que desde hace más de 50 años se ha intentado desarrollar fármacos activos por vía oral capaces de inhibir directamente la renina. Recientemente se ha demostrado que prorrenina y renina son moléculas activas que interactúan con un receptor específico, (P)RR, y que su estimulación activa diversas vías de señalización independientes de las activadas por la angiotensina II. Aliskiren, el primer inhibidor directo de la renina (IDR) no peptídico, activo por vía oral, ha mostrado eficacia y seguridad en el tratamiento de la hipertensión arterial. Este artículo revisa el desarrollo de los IDR, el papel fisiopatológico de la prorrenina y la renina, la estructura y las vías de señalización acopladas a la activación del (P)RR, el mecanismo de acción y las posibles diferencias, ventajas y/o desventajas de los IDR con respecto a otros fármacos que inhiben el SRA, como los inhibidores de la enzima de conversión y los antagonistas de los receptores AT1 (AU)

Renin is an enzyme that limits angiotensin-II synthesis and activates the renin-angiotensin system (RAS). Therefore, for almost 50 years, multiple attempts were made to develop orally active direct renin inhibitors (DRIs). Recently, it has been demonstrated that both prorenin and renin are active molecules that interact with a specific receptor, (P)RR, and that stimulation of this receptor leads to the activation of signal transduction pathways independent of angiotensin-II activity. Aliskiren, the first non-peptide orally active DRI, has been found to be safe and effective in the treatment of hypertension. The present article reviews the development of DRIs, the pathophysiological roles of prorenin and renin, the structure of and the signal transduction pathways involved in activation of the (P)RR, and the mechanisms of action of, the possible differences between, and the comparative advantages and disadvantages of DRIs and other RAS inhibitors, mainly angiotensin-converting enzyme inhibitors and angiotensin AT1 receptor blockers (AU)

Red cardiovascular HERACLES / The HERACLES cardiovascular network

En 2002, un grupo de investigadores en electrofisiología celular, cardiología, genética de poblaciones, epidemiología, proteómica, biología molecular, bioinformática y estadística decidió afrontar el reto de analizar los mecanismos y la genética de la hipertensión arterial (HTA). Se identificaron mecanismos relacionados con la regulación de la función de la musculatura lisa arterial por canales iónicos. La Red HERACLES (Hipertensión Esencial: Red de Análisis de Canales iónicos de la musculatura Lisa arterial y su Explotación terapéutica Sistemática) fue calificada con mención Excelente en la evaluación de 2005, y se ha consolidado con la incorporación de nuevos grupos en la convocatoria 2007. Las actividades de la red se enmarcan en la transferencia de conocimiento del bedside-to-bench, así como su inversa, bench-to-bedside. Los objetivos actuales de la red son: a) estudio de canales de K+ dependientes de Ca2+, canales catiónicos TRP y canales de Cl- dependientes de Ca2+ que participan en la fisiología vascular; b) estudio de los mapas de expresión proteínica en plasma y tejido cardiovascular y su relevancia en el tratamiento farmacológico; c) estudios del efecto de los flavonoides en el transporte iónico y la respuesta al estrés oxidativo, y d) identificación de marcadores biológicos de riesgo, pronóstico y respuesta al tratamiento en fenotipos de HTA extremos. Nuestro proyecto incluye un conjunto de líneas de investigación coordinadas con programas horizontales basados en plataformas centrales, que las sirven. La red ha publicado más de 60 manuscritos (disponibles en: http://www.redheracles.net) y ha recibido financiación para más de 90 proyectos en convocatorias competitivas nacionales y 6 internacionales, y un Biobanco ADN (AU)

In 2002, a group of researchers in the fields of cell electrophysiology, cardiology, population genetics, epidemiology, proteomics, molecular biology, bioinformatics and statistics decided to take up the challenge of investigating the mechanisms and genetics of arterial hypertension (AH). Mechanisms related to ion channel regulation of arterial smooth muscle function were identified. The HERACLES (Hipertensión Esencial: Red de Análisis de Canales iónicos de la musculatura Lisa arterial y su Explotación terapéutica Sistemática) network was honored with a distinguished mention in the 2005 evaluation, and was strengthened by the incorporation of new research groups in 2007. The work of the HERACLES network is characterized as much by the transfer of knowledge «from bedside to bench» as by its converse: «from bench to bedside». The current objectives of the HERACLES network are: a) to study the Ca2+-dependent K+ channels, the transient receptor potential (TRP) cation channels, and the Ca2+-dependent Cl- channels that are involved in vascular physiology; b) to study protein expression maps in plasma and cardiovascular tissue and their significance for drug treatment; c) to study the effect of flavonoids onion transport and responses to oxidative stress, and d) to identify biomarkers of risk, prognosis, and treatment responses in extreme AH phenotypes. Our project includes a number of lines of research coordinated within cross-sectional programs based on centralized facilities, which are used by them. The HERACLES network has published more than 60 articles (available from: http://www.redheracles.net), funding has been received for more than 90 projects in competitive submissions to Spanish and six international bodies, and there is a DNA Biobank (AU)

Evaluación y tratamiento de la hipertensión arterial en España. Documento de consenso / No disponible

No disponible

Documento de consenso sobre bloqueadores de los receptores betaadrenérgicos y consumo de cocaína. Respuesta / Expert consensus document on beta-adrenergic receptor blockers and cocaine use. Response

No disponible

No disponible