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 non-familial 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 (298 hours average) ruled out silent AFWhole-exome sequencing was performed and variants shared by the index cases were filtered and prioritized according to current recommendations. HCN4 currents (IHCN4) were recorded in Chinese hamster ovary cells expressing human p.P1163H and/or native Hcn4 channels using the patch-clamp technique and topologically associated domain analysis of GATA5 variant carriers were performed. RESULTS: The clinical study diagnosed 2 more AF cases. Five family members carried the heterozygous p.P1163H, HCN4 variant, 14 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 33-70 years) carried both variants and one the GATA5 variant alone. Multivariate analysis showed that the presence of HCN4+GATA5 variants significantly and independently increased AF risk [OR=32.740 (1.812-591.408)] and not age, hypertension or 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 two rare gene variants was independently associated with AF, but functional studies do not allow the postulation of the arrhythmogenic mechanism(s) involved.

New pharmacological agents and novel cardiovascular pharmacotherapy strategies in 2023.

Although cardiovascular diseases 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 cardiovascular disease and heart failure. The new indications of drugs already marketed (repurposing) for the treatment of obstructive hypertrophic cardiomyopathy, hypercholesterolemia, type 2 diabetes, obesity and heart failure, 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 cardiovascular diseases.

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.

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.

A gain-of-function HCN4 mutant in the HCN domain is responsible for inappropriate sinus tachycardia in a Spanish family.

In a family with inappropriate sinus tachycardia (IST), we identified a mutation (p.V240M) of the hyperpolarization-activated cyclic nucleotide-gated type 4 (HCN4) channel, which contributes to the pacemaker current (If) in human sinoatrial node cells. Here, we clinically study fifteen family members and functionally analyze the p.V240M variant. Macroscopic (IHCN4) and single-channel currents were recorded using patch-clamp in cells expressing human native (WT) and/or p.V240M HCN4 channels. All p.V240M mutation carriers exhibited IST that was accompanied by cardiomyopathy in adults. IHCN4 generated by p.V240M channels either alone or in combination with WT was significantly greater than that generated by WT channels alone. The variant, which lies in the N-terminal HCN domain, increased the single-channel conductance and opening frequency and probability of HCN4 channels. Conversely, it did not modify the channel sensitivity for cAMP and ivabradine or the level of expression at the membrane. Treatment with ivabradine based on functional data reversed the IST and the cardiomyopathy of the carriers. In computer simulations, the p.V240M gain-of-function variant increases If and beating rate and thus explains the IST of the carriers. The results demonstrate the importance of the unique HCN domain in HCN4, which stabilizes the channels in the closed state.

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)

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

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. CONCLUSION: ED anticoagulant prescription for elderly patients with atrial fibrillation is safe and contributes to a reduction in mortality. Women in this age group benefited more than men from starting anticoagulation during the acute phase in the ED.

OBJETIVO: 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. METODO: 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. CONCLUSIONES: La prescripción de ACO en los SU a pacientes mayores con FA es segura y contribuye a reducir la mortalidad. En este grupo etario, las mujeres se benefician más que los hombres de iniciar la ACO en la fase aguda.

Triglycerides revisited: is hypertriglyceridaemia a necessary therapeutic target in cardiovascular disease?

Despite the atherosclerotic cardiovascular disease (ASCVD) risk reduction achieved by low-density lipoprotein cholesterol (LDL-C) lowering therapy, residual ASCVD risk still exists. Previous epidemiological studies have suggested high plasma triglyceride (TG) levels as a risk factor or risk marker for ASCVD independent of LDL-C levels. In this review, we highlighted the underlying pathophysiology of hypertriglyceridaemia, the mechanistic action of therapeutic agents, the interpretation of conflicting results on recent clinical trials, and the present options for primary and secondary prevention. The benefits of fibrates-induced reduction in TG and increase in high-density lipoprotein cholesterol might outweigh the disadvantages of increasing LDL-C levels in primary prevention. In secondary CVD prevention, using eicosapentaenoic acid without docosahexaenoic acid, in addition to statins, will be beneficial. This comprehensive review may prove useful for the development of novel approaches that target hypertriglyceridaemia in future.

New pharmacological agents and novel cardiovascular pharmacotherapy strategies in 2022.

Cardiovascular diseases (CVD) remain the leading cause of death worldwide and pharmacotherapy of most of them is suboptimal. Thus, there is a clear unmet clinical need to develop new pharmacological strategies with greater efficacy and better safety profiles. In this review, we summarize the most relevant advances in cardiovascular pharmacology in 2022 including the approval of first-in-class drugs that open new avenues for the treatment of obstructive hypertrophic cardiomyopathy (mavacamten), type 2 diabetes mellitus (tirzepatide), and heart failure (HF) independent of left ventricular ejection fraction (sodium-glucose cotransporter 2 inhibitors). We also dealt with fixed dose combination therapies repurposing different formulations of "old" drugs with well-known efficacy and safety for the treatment of patients with acute decompensated HF (acetazolamide plus loop diuretics), atherosclerotic cardiovascular disease (moderate-dose statin plus ezetimibe), Marfan syndrome (angiotensin receptor blockers plus ß-blockers), and secondary cardiovascular prevention (i.e. low-dose aspirin, ramipril and atorvastatin), thereby filling existing gaps in knowledge, and opening new avenues for the treatment of CVD. Clinical trials confirming the role of dapagliflozin in patients with HF and mildly reduced or preserved ejection fraction, long-term evolocumab to reduce the risk of cardiovascular events, vitamin K antagonists for stroke prevention in patients with rheumatic heart disease-associated atrial fibrillation, antibiotic prophylaxis in patients at high risk for infective endocarditis before invasive dental procedures, and vutrisiran for the treatment of hereditary transthyretin-related amyloidosis with polyneuropathy were also reviewed. Finally, we briefly discuss recent clinical trials suggesting that FXIa inhibitors may have the potential to uncouple thrombosis from hemostasis and attenuate/prevent thromboembolic events with minimal disruption of hemostasis.

Ivabradine for controlling heart rate in permanent atrial fibrillation: A translational clinical trial.

BACKGROUND: Pharmacological options for rate control in atrial fibrillation are scarce. Ivabradine was postulated to reduce the ventricular rate in this setting. OBJECTIVES: The objectives of this study were to evaluate the mechanism of inhibition of atrioventricular conduction produced by ivabradine and to determine its efficacy and safety in atrial fibrillation. METHODS: The effects of ivabradine on atrioventricular node and ventricular cells were studied by in vitro whole-cell patch-clamp experiments and mathematical simulation of human action potentials. In parallel, a multicenter, randomized, open-label, phase III clinical trial compared ivabradine with digoxin for uncontrolled permanent atrial fibrillation despite ß-blocker or calcium channel blocker treatment. RESULTS: Ivabradine 1 µM inhibited "funny" current and rapidly activating delayed rectifier potassium channel current by 28.9% and 22.8%, respectively (P < .05). The sodium channel current and L-type calcium channel current were reduced only at 10 µM. Ivabradine slowed the firing frequency of a modeled human atrioventricular node action potential by 10.6% and induced a minimal prolongation of ventricular action potential. Thirty-five (51.5%) patients were randomized to ivabradine and 33 (49.5%) to digoxin. The mean daytime heart rate decreased by 11.6 beats/min (-11.5%) in the ivabradine arm (P = .02) vs 19.6 (-20.6%) in the digoxin arm (P < .001), although the noninferiority margin of efficacy was not met (Z = -1.95; P = .97). The primary safety end point occurred in 3 patients (8.6%) on ivabradine and in 8 (24.2%) on digoxin (P = .10). CONCLUSION: Ivabradine produced a moderate rate reduction in patients with permanent atrial fibrillation. The inhibition of funny current in the atrioventricular node seems to be the main mechanism responsible for this reduction. Compared with digoxin, ivabradine was less effective, was better tolerated, and had a similar rate of serious adverse events.

Herbal medicines for the treatment of cardiovascular diseases: Benefits and risks - A narrative review.

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.

EHRA expert consensus document on the management of arrhythmias in frailty syndrome, endorsed by the Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), Latin America Heart Rhythm Society (LAHRS), and Cardiac Arrhythmia Society of Southern Africa (CASSA).

There is an increasing proportion of the general population surviving to old age with significant chronic disease, multi-morbidity, and disability. The prevalence of pre-frail state and frailty syndrome increases exponentially with advancing age and is associated with greater morbidity, disability, hospitalization, institutionalization, mortality, and health care resource use. Frailty represents a global problem, making early identification, evaluation, and treatment to prevent the cascade of events leading from functional decline to disability and death, one of the challenges of geriatric and general medicine. Cardiac arrhythmias are common in advancing age, chronic illness, and frailty and include a broad spectrum of rhythm and conduction abnormalities. However, no systematic studies or recommendations on the management of arrhythmias are available specifically for the elderly and frail population, and the uptake of many effective antiarrhythmic therapies in these patients remains the slowest. This European Heart Rhythm Association (EHRA) consensus document focuses on the biology of frailty, common comorbidities, and methods of assessing frailty, in respect to a specific issue of arrhythmias and conduction disease, provide evidence base advice on the management of arrhythmias in patients with frailty syndrome, and identifies knowledge gaps and directions for future research.

Sex and gender differences in the treatment of arterial hypertension.

INTRODUCTION: Arterial hypertension represents the leading modifiable risk factor for all-cause death and early development of cardiovascular disease in women. Current clinical guidelines for the treatment of hypertension noted that women respond to antihypertensive drugs similarly to men and, therefore, treatment recommendations remain the same for both sexes. However, clinical evidence suggests the existence of sex- and gender-related differences (SGRD) in the prevalence, pathophysiology, pharmacodynamics (efficacy and safety) and pharmacokinetics of antihypertensive drugs. AREAS COVERED: This review summarizes SGRD in the prevalence of hypertension, hypertension-mediated organ damage and blood pressure control, prescription patterns, and pharmacokinetics/ pharmacodynamics and doses of antihypertensive drugs. EXPERT OPINION: There is limited information on SGRD in antihypertensive drug efficacy because of the underrepresentation of women in randomized clinical trials and, more important, because few trials reported results stratified by sex or performed sex-specific analyses. However, there are SGRD in hypertension-mediated organ damage, drug pharmacokinetics and, particularly, in drug safety. Prospective trials specifically designed to better understand the basis for SGRD in the pathophysiology of hypertension and in the efficacy and safety of antihypertensive drugs are needed to achieve a more personalized treatment of hypertension and hypertension-mediated organ damage in women.

An Updated Review on the Role of Non-dihydropyridine Calcium Channel Blockers and Beta-blockers in Atrial Fibrillation and Acute Decompensated Heart Failure: Evidence and Gaps.

PURPOSE: The 2021 European Society of Cardiology guidelines on acute and chronic heart failure (HF) recommend that non-dihydropyridine calcium channel blockers (NDCC) should be avoided in patients with HF with reduced ejection fraction. It also emphasizes that beta-blockers only be initiated in clinically stable, euvolemic patients. Despite these recommendations, NDCC and beta-blockers are often still employed in patients with AF with rapid ventricular response and acute decompensated HF. The relative safety and efficacy of these therapies in this setting is unclear. METHODS: To address the question of the safety and efficacy of NDCC and beta-blockers for acute rate control in decompensated HF, we provide a perspective on the literature of NDCC and beta-blockers in chronic HF with reduced and preserved ejection fraction and AF, including trials on the management of AF with rapid ventricular response with and without HF. RESULTS: Robust data demonstrates mortality benefits when beta-blockers are used in patients with chronic HF with reduced ejection fraction. The data that inform the contraindication of NDCC in HF with reduced ejection fraction are outdated and were not primarily designed to address the efficacy and safety of rate control of AF in patients with HF. Several studies indicate that for acute rate control, NDCC and beta-blockers are both efficacious therapies, especially in the setting of tachycardia-induced cardiomyopathy. CONCLUSION: Future studies are needed to assess the safety and efficacy of beta-blockers and NDCC in both acute and chronic AF with HF with reduced and preserved ejection fraction.

A Cantú syndrome mutation produces dual effects on KATP channels by disrupting ankyrin B regulation.

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.

Treatment of hypertriglyceridaemia with icosapent ethyl in patients with high/very high cardiovascular risk. Consensus document of the Sociedad Española de Cardiología [Spanish Society of Cardiology] and the Sociedad Española de Diabetes [Spanish Diabetes Society].

The Working Groups of Cardiovascular Pharmacotherapy of the Sociedad Española de Cardiología and Cardiovascular Disease of the Sociedad Española de Diabetes have prepared a consensus document on the treatment of hypertriglyceridaemia in patients with high/very-high-cardiovascular risk with icosapent ethyl, a highly purified and stable eicosapentaenoic acid ethyl ester. This document is necessary since there are differences among the three main omega-3 fatty acids and there is large-scale clinical evidence with icosapent ethyl that demonstrates that in addition to its efficacy in lowering triglyceridaemia, it reduces the risk of cardiovascular events in both patients with atherosclerotic cardiovascular disease and in those with type 2 diabetes, with a good safety profile. The number needed to treat to avoid a major cardiovascular event is analysed, comparing it with other pivotal studies of pharmacological intervention in cardiovascular prevention, and an estimate of the Spanish population likely to be treated with ethyl icosapent is carried out. These recommendations are of interest to all clinicians who manage patients with lipid metabolism disorders, cardiovascular disease and diabetes.