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.

Clinical evolution and mortality of critically ill patients with SARS-CoV-2 pneumonia treated with remdesivir in an adult intensive care unit of Paraguay.

BACKGROUND: The health crisis due to Covid-19 led to the search for therapeutics that could improve the evolution of the disease. Remdesivir, an antiviral that interferes with viral replication, was one of the first to be used for the treatment of this pathology. OBJECTIVE: To determine clinical course and mortality of patients with severe SARS-CoV-2 pneumonia treated with remdesivir, in comparison of those who didn't receive the medication. PATIENTS AND METHODS: Retrospective cohort study, with medical records review of COVID-19 patients, between August 2020 and August 2021. The subjects were divided into two groups, those who received remdesivir before or after admission to intensive care and those who didn't. The primary outcome variable was mortality in intensive care. RESULTS: Of 214 subjects included, 109 (50,9%) received remdesivir. The median of days for the drug administration was 8 (2-20), IQR: 3. The bivariate analysis prove that the use of remdesivir was related with lower risk of develop Acute Respiratory Distress Syndrome (ARDS) (p = 0,019; OR: 0,521) and lower requirement of mechanical ventilation (p = 0,006; OR:0,450). Additionally, patients treated with remdesivir develop less kidney injury (p = 0,009; OR: 0,441). There was a total of 82 deaths, 29 (26,6%) in the remdesivir group and 53 (50,5%) in the control group [p < 0,001; OR: 0,356 (0,201-0,630)]. All the risk factors associated with mortality in the bivariate analysis were entered into the multivariate analysis by logistic regression, the use of remdesivir remained associated as an independent protective factor to mortality (p = 0.034; OR: 0.429). CONCLUSION: Critically ill patients with SARS-CoV-2 pneumonia treated with remdesivir had a lower risk of death and need for mechanical ventilation and develop less ARDS as compared to the control group. No differences were found in the presentation of adverse effects.

Mortalidad intrahospitalaria de pacientes con COVID-19 complicados con neumonías bacterianas en asistencia respiratoria mecánica en Cuidados Intensivos de Adultos en un Hospital del Paraguay / In-hospital mortality of patients with COVID-19 complicated by bacterial pneumonia on mechanical ventilation in Adult Intensive Care in a Hospital in Paraguay

Introducción: los pacientes con COVID-19 ingresan en mayor proporción a asistencia respiratoria mecánica, aumentando: el riesgo de neumonía asociada a ventilador (NAV) las tasas de mortalidad, los días de permanencia en las unidades de terapia intensiva (UCI) y los costos sanitarios. Objetivo: determinar la Mortalidad intrahospitalaria de pacientes con COVID-19 complicados con neumonías bacterianas en asistencia respiratoria mecánica en Cuidados Intensivos de Adultos en un Hospital del Paraguay durante los años 2020 a 2021. Metodología: estudio analítico de tipo cohorte retrospectiva. Se registraron variables demográficas, comorbilidades, puntajes en scores de gravedad como el APACHE II al ingreso, la cifra más baja de oxigenación durante la internación expresado por la PaO2 / FIO2, días de ventilación, colocación en decúbito prono, traqueotomía, medidas terapéuticas farmacológicas y no farmacológicas, días de internación, así como las complicaciones y la mortalidad. Resultados: fueron incluidos 214 pacientes, 135 ingresaron a asistencia respiratoria mecánica (ARM) de los cuales 58 (42,9 %) desarrollaron NAV, con edad mediana de 52 años (40-60). Los microorganismos de NAV fueron cocos Gram negativos en 98,3 %, incluyendo Acinetobacter baumanii en 46,5 %, Klebsiella pneumoniae en 22,8 %, Pseudomona aeruginosa en 15,5 % y 5,2 % Stenotrophomona maltofilia. La mortalidad intrahospitalaria fue del 44,8 %. Los menores de 50 años tienen una sobrevida mayor que los mayores (34 días vs 22 días, con p de 0,026). Conclusión: la mortalidad intrahospitalaria fue del 44,8 %. La edad fue un factor de riesgo independiente para la mortalidad en pacientes con NAV, por lo que los profesionales de la salud deben estar atentos a la posibilidad de NAV en pacientes que requieren asistencia respiratoria mecánica, especialmente en pacientes mayores de 50 años.

Introduction: patients with COVID-19 are more likely to require mechanical ventilation, which increases the risk of ventilator-associated pneumonia (VAP), mortality rates, length of stay in intensive care units (ICUs), and healthcare costs. Objective: to determine the in-hospital mortality of patients with COVID-19 complicated by bacterial pneumonia on mechanical ventilation in Adult Intensive Care in a Hospital in Paraguay during the years 2020 to 2021. Methodology: this is a retrospective cohort analytical study. Demographic variables, comorbidities, severity scores such as APACHE II on admission, the worst oxygenation during hospitalization expressed by PaO2/FiO2, days of ventilation, prone position, tracheostomy, pharmacological and non-pharmacological therapeutic measures, days of hospitalization, as well as complications and mortality were recorded. Results: a total of 214 patients were included, 135 were admitted to mechanical ventilation (MRA), of which 58 (42.9%) developed VAP, with a median age of 52 years (40-60). VAP microorganisms were Gram-negative cocci in 98.3%, including Acinetobacter baumanii in 46.5%, Klebsiella pneumoniae in 22.8%, Pseudomona aeruginosa in 15.5%, and Stenotrophomona maltophilia in 5.2%. In-hospital mortality was 44.8%. Those under 50 years of age have a longer survival than those older (34 days vs. 22 days, with p of 0.026). Conclusion: the overall mortality rate was 44.8%. Age was an independent risk factor for mortality in patients with VAP, so healthcare professionals should be aware of the possibility of VAP in patients who require mechanical ventilation, especially in patients over 50 years of age.

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.

Factores asociados a mortalidad en pacientes críticos con COVID-19 en un centro universitario de Paraguay

Introducción: La pandemia por COVID-19 es un problema de salud mundial. Habitualmente cursa con sintomatología leve y 5% de los afectados evoluciona a cuadros graves que requieren de cuidados intensivos. Objetivo: Determinar el perfil clínico, la mortalidad y factores asociados a la misma en pacientes con COVID-19 ingresados al Departamento de Cuidados Intensivos de Adultos, del Hospital de Clínicas de la Facultad de Ciencias Médicas, Universidad Nacional de Asunción, Paraguay, entre agosto de 2020 a agosto de 2021. Pacientes y Método: Se realizó un estudio observacional analítico de corte transverso. Los datos se obtuvieron a partir de las historias clínicas de los pacientes. Resultados: Se incluyeron 214 pacientes críticos entre 21 y 85 años de edad (mediana 54 años), 57,9% del sexo masculino, 85% provenientes del Departamento Central y Asunción. La mortalidad global fue de 38,3%. Se asociaron significativamente con la mortalidad una edad ≥ 60 años, las comorbilidades (diabetes mellitus, cardiopatía, enfermedad renal crónica), los índices de gravedad (APACHE II, SOFA, inicial), procalcitonina elevada, utilización de vasopresor, asistencia respiratoria mecánica y utilización del decúbito prono; así como la presencia de SDRA y el requerimiento de depuración extrarenal. En el análisis multivariado (por regresión logística) los factores de riesgo de mortalidad independientes fueron: la edad mayor de 60 años, la utilización de noradrenalina y depuración extra-renal durante la hospitalización. Conclusión: Nuestra mortalidad es similar a la reportada internacionalmente. Los factores de riesgo de mortalidad identificados muestran una población con mayores posibilidades de un desenlace desfavorable.

Background: The COVID-19 pandemic is a world health issue. Generally, it is with mild and around 5% evolves to a severe disease that requires intensive care. Aim: To determine the clinical profile, mortality and associated factors in COVID-19 patients admitted at the Adult Intensive Care Department at the Hospital de Clinicas, between August 2020 and August 2021. Methods: Cross-section observational analytic study. Data was obtained from clinical charts. Results: 214 patients were included, with an average age of 54 years, 57.9% male. Overall mortality was 38.3%. Factors associated significantly with mortality were: ≥60 years of age, comorbidity (diabetes mellitus, heart disease, chronic renal disease), severity index (APACHE II, initial SOFA), high procalcitonin, use of vasopressor, mechanical respiratory assistance and prone decubitus; as well as the presence of acute respiratory distress syndrome and hemodialysis. Multi varied analysis identified as mortality risk factors: ≥60 years of age, noradrenaline use and hemodialysis. Conclusion: Mortality rate is similar to that reported worldwide. Mortality risk factors identified show a population with higher possibilities for unfavorable outcome.

Coronary artery properties in atherosclerosis: A deep learning predictive model.

In this work an Artificial Neural Network (ANN) was developed to help in the diagnosis of plaque vulnerability by predicting the Young modulus of the core (E core ) and the plaque (E plaque ) of atherosclerotic coronary arteries. A representative in silico database was constructed to train the ANN using Finite Element simulations covering the ranges of mechanical properties present in the bibliography. A statistical analysis to pre-process the data and determine the most influential variables was performed to select the inputs of the ANN. The ANN was based on Multilayer Perceptron architecture and trained using the developed database, resulting in a Mean Squared Error (MSE) in the loss function under 10-7, enabling accurate predictions on the test dataset for E core and E plaque . Finally, the ANN was applied to estimate the mechanical properties of 10,000 realistic plaques, resulting in relative errors lower than 3%.

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.

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.

Empagliflozin and Dapagliflozin Increase Na+ and Inward Rectifier K+ Current Densities in Human Cardiomyocytes Derived from Induced Pluripotent Stem Cells (hiPSC-CMs).

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.

Hypertrophic cardiomyopathy: an up-to-date snapshot of the clinical drug development pipeline.

INTRODUCTION: Hypertrophic cardiomyopathy (HCM) is a complex cardiac disease with highly variable phenotypic expression and clinical course most often caused by sarcomeric gene mutations resulting in left ventricular hypertrophy, fibrosis, hypercontractility, and diastolic dysfunction. For almost 60 years, HCM has remained an orphan disease and still lacks a disease-specific treatment. AREAS COVERED: This review summarizes recent preclinical and clinical trials with repurposed drugs and new emerging pharmacological and gene-based therapies for the treatment of HCM. EXPERT OPINION: The off-label drugs routinely used alleviate symptoms but do not target the core pathophysiology of HCM or prevent or revert the phenotype. Recent advances in the genetics and pathophysiology of HCM led to the development of cardiac myosin adenosine triphosphatase inhibitors specifically directed to counteract the hypercontractility associated with HCM-causing mutations. Mavacamten, the first drug specifically developed for HCM successfully tested in a phase 3 trial, represents the major advance for the treatment of HCM. This opens new horizons for the development of novel drugs targeting HCM molecular substrates which hopefully modify the natural history of the disease. The role of current drugs in development and genetic-based approaches for the treatment of HCM are also discussed.

Cancer Chemotherapy-Induced Sinus Bradycardia: A Narrative Review of a Forgotten Adverse Effect of Cardiotoxicity.

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.

Sex-related differences in the pharmacological treatment of heart failure.

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.

Tbx5 variants disrupt Nav1.5 function differently in patients diagnosed with Brugada or Long QT Syndrome.

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 ßIV-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 ßIV-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.

Zfhx3 Transcription Factor Represses the Expression of SCN5A Gene and Decreases Sodium Current Density (INa).

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.

The pharmacotherapeutic management of hyperkalemia in patients with cardiovascular disease.

Introduction: Patients with cardiovascular diseases (CVD) are at increased risk of hyperkalemia, particularly when treated with renin-angiotensin-aldosterone inhibitors (RAASIs). Because the occurrence or fear of hyperkalemia, RAASIs are frequently down-titrated or discontinued in patients with CVD, with consequent worse outcomes than patients who remain on maximum doses.Areas covered: This article reviews potassium homeostasis, epidemiology, risk factors, and outcomes of hyperkalemia, and efficacy and safety of the drugs used for acute and chronic treatment of hyperkalemia. A literature search was carried out using the PubMed and guidelines for the management of hyperkalemia.Expert opinion: The emergency treatment of hyperkalemia is not supported by high-quality evidence and clinical trials did not report drug effects on clinical outcomes. Two potassium binders, patiromer and sodium zirconium cyclosilicate, represent a new approach in the treatment of chronic hyperkalemia as they may allow the titration and maintenance of guidelines-recommended doses of RAASIs in patients with CVD who otherwise would not tolerate them due to the risk of hyperkalemia.Further studies are needed to evaluate the safety and efficacy of drug therapy and support the development of guidelines for acute and chronic hyperkalemia.

A rare HCN4 variant with combined sinus bradycardia, left atrial dilatation, and hypertrabeculation/left ventricular noncompaction phenotype.

INTRODUCTION AND OBJECTIVES: HCN4 variants have been reported to cause combined sick sinus syndrome (SSS) and left ventricular noncompaction (LVNC) cardiomyopathy. This relationship has been proven in few cases and no previous patients have associated left atrial dilatation (LAD). Our objective was to study a familial disorder characterized by SSS, LAD, and hypertrabeculation/LVNC and to identify the underlying genetic and electrophysiological characteristics. METHODS: A family with SSS and LVNC underwent a clinical, genetic, and electrophysiological assessment. They were studied via electrocardiography, Holter recording, echocardiography, and exercise stress tests; cardiac magnetic resonance imaging was additionally performed in affected individuals. Genetic testing was undertaken with targeted next-generation sequencing, as well as a functional study of the candidate variant in Chinese hamster ovary cells. RESULTS: Twelve members of the family had sinus bradycardia, associated with complete criteria of LVNC in 4 members and hypertrabeculation in 6 others, as well as LAD in 9 members. A HCN4 c.1123C>T;(p.R375C) variant was present in heterozygosis in all affected patients and absent in unaffected individuals. Electrophysiological analyses showed that the amplitude and densities of the HCN4 currents (IHCN4) generated by mutant p.R375C HCN4 channels were significantly lower than those generated by wild-type channels. CONCLUSIONS: The combined phenotype of SSS, LAD, and LVNC is associated with the heritable HCN4 c.1123C>T;(p.R375C) variant. HCN4 variants should be included in the genetic diagnosis of LVNC cardiomyopathy and of patients with familial forms of SSS, as well as of individuals with sinus bradycardia and LAD.

The p.P888L SAP97 polymorphism increases the transient outward current (Ito,f) and abbreviates the action potential duration and the QT interval.

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.

Childhood-only epilepsy with generalized tonic-clonic seizures: A well-defined epileptic syndrome.

PURPOSE: The aim of this study was to analyze patients whose only manifestation of epilepsy were generalized tonic-clonic seizures (GTCS) during childhood and discuss its validity as separate syndrome of childhood. METHODS: We included children with at least two unprovoked GTCS between 3 and 11 years of age, no other seizure types at diagnosis, normal psychomotor development and neurological examination, an EEG with normal background and paroxysms of generalized spikes and waves with a frequency 2.5 Hz or above, and an unknown cause for epilepsy. Only patients with a follow-up >2 years were included. RESULTS: Over a 12-year period (2005-2017) 26 patients met the inclusion criteria of epilepsy with GTCS only. Mean age at onset was 5 years. The seizures occurred while awake in 16 patients, on awakening in two, and during sleep in eight patients. The duration of seizures was around 3 min. Generalized spike-and-wave discharges were observed in all patients when awake and during sleep in eight and 26 patients, respectively. Nineteen responded well to valproic acid or levetiracetam. Two patients who received clobazam initially did not respond well; however, a switch to valproic acid resulted in excellent seizure control. Antiepileptic treatment was discontinued in sixteen patients who remained seizure free over a period of 2-9 years of follow-up. CONCLUSION: Epilepsy with GTCS alone in childhood is a type of epilepsy; however, it may be considered as a well-defined epileptic syndrome. Patients responded well to valproic acid or levetiracetam.