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1.
PLoS One ; 15(8): e0236949, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32750067

RESUMO

Heart arrhythmia is a pathological condition where the sequence of electrical impulses in the heart deviates from the normal rhythm. It is often associated with specific channelopathies in cardiac tissue, yet how precisely the changes in ionic channels affect the electrical activity of cardiac cells is still an open question. Even though sodium channel mutations that underlie cardiac syndromes like the Long-Q-T and the Brugada-syndrome are known to affect a number of channel parameters simultaneously, previous studies have predominantly focused on the persistent late component of the sodium current as the causal explanation for an increased risk of heart arrhythmias in these cardiac syndromes. A systematic analysis of the impact of other important sodium channel parameters is currently lacking. Here, we investigate the reduced ten-Tusscher-model for single human epicardium ventricle cells and use mathematical bifurcation analysis to predict the dependence of the cardiac action potential on sodium channel activation and inactivation time-constants and voltage dependence. We show that, specifically, shifts of the voltage dependence of activation and inactivation curve can lead to drastic changes in the action potential dynamics, inducing oscillations of the membrane potential as well as bistability. Our results not only demonstrate a new way to induce multiple co-existing states of excitability (biexcitability) but also emphasize the critical role of the voltage dependence of sodium channel activation and inactivation curves for the induction of heart-arrhythmias.


Assuntos
Potenciais de Ação , Arritmias Cardíacas/fisiopatologia , Modelos Biológicos , Miócitos Cardíacos/fisiologia , Canais de Sódio Disparados por Voltagem/fisiologia , Arritmias Cardíacas/genética , Arritmias Cardíacas/metabolismo , Síndrome de Brugada , Ventrículos do Coração/metabolismo , Humanos , Síndrome do QT Longo , Mutação , Miócitos Cardíacos/metabolismo , Função Ventricular , Canais de Sódio Disparados por Voltagem/genética
2.
PLoS Comput Biol ; 16(8): e1008109, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32797034

RESUMO

In the last decade, there has been tremendous progress in identifying genetic anomalies linked to clinical disease. New experimental platforms have connected genetic variants to mechanisms underlying disruption of cellular and organ behavior and the emergence of proarrhythmic cardiac phenotypes. The development of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) signifies an important advance in the study of genetic disease in a patient-specific context. However, considerable limitations of iPSC-CM technologies have not been addressed: 1) phenotypic variability in apparently identical genotype perturbations, 2) low-throughput electrophysiological measurements, and 3) an immature phenotype which may impact translation to adult cardiac response. We have developed a computational approach intended to address these problems. We applied our recent iPSC-CM computational model to predict the proarrhythmic risk of 40 KCNQ1 genetic variants. An IKs computational model was fit to experimental data for each mutation, and the impact of each mutation was simulated in a population of iPSC-CM models. Using a test set of 15 KCNQ1 mutations with known clinical long QT phenotypes, we developed a method to stratify the effects of KCNQ1 mutations based on proarrhythmic markers. We utilized this method to predict the severity of the remaining 25 KCNQ1 mutations with unknown clinical significance. Tremendous phenotypic variability was observed in the iPSC-CM model population following mutant perturbations. A key novelty is our reporting of the impact of individual KCNQ1 mutant models on adult ventricular cardiomyocyte electrophysiology, allowing for prediction of mutant impact across the continuum of aging. This serves as a first step toward translating predicted response in the iPSC-CM model to predicted response of the adult ventricular myocyte given the same genetic mutation. As a whole, this study presents a new computational framework that serves as a high throughput method to evaluate risk of genetic mutations based-on proarrhythmic behavior in phenotypically variable populations.


Assuntos
Canal de Potássio KCNQ1/genética , Modelos Cardiovasculares , Mutação/genética , Miócitos Cardíacos , Arritmias Cardíacas/genética , Biologia Computacional , Predisposição Genética para Doença/genética , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Miócitos Cardíacos/classificação , Miócitos Cardíacos/citologia
3.
Nihon Yakurigaku Zasshi ; 155(4): 225-229, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32612034

RESUMO

The type 2 ryanodine receptor (RyR2) is a sarcoplasmic reticulum Ca2+ release channel that plays a central role in cardiac excitation-contraction coupling. Abnormal activity of the RyR2 is linked to abnormal Ca2+ signaling in cardiac cells, which often results in cardiac arrhythmias. For example, amino acid mutations in RyR2 have been reported to cause various types of arrhythmias, including catecholaminergic polymorphic ventricular tachycardia (CPVT), idiopathic ventricular fibrillation, and left ventricular non-compaction. At present, the total number of disease-associated RyR2 mutations exceeds 300. In addition, in chronic heart failure, modification of RyR2 by phosphorylation, oxidation or S-nitrosylation may cause abnormal channel activity. Arrhythmogenic mechanisms of these various disorders are not yet fully understood. We have recently established a method to quantitatively evaluate the effects of various arrhythmogenic mutations and modifications on RyR2 channels by using HEK293 expression system. We found that arrhythmogenic mutations in RyR2 are classified into two groups: gain-of-function and loss-of-function of the channel. Since they are indistinguishable in clinical diagnosis, our analysis is very useful for diagnosis and choice of treatment strategies for RyR2-linked arrhythmogenic diseases. This review describes the current advances and issues of research on RyR2 mutation-related arrhythmogenic disorders.


Assuntos
Arritmias Cardíacas , Cálcio , Canal de Liberação de Cálcio do Receptor de Rianodina , Arritmias Cardíacas/genética , Arritmias Cardíacas/terapia , Cálcio/metabolismo , Células HEK293 , Humanos , Mutação , Canal de Liberação de Cálcio do Receptor de Rianodina/genética
4.
Rev Cardiovasc Med ; 21(2): 205-216, 2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32706209

RESUMO

Sudden cardiac death (SCD) is a rare clinical encounter in pediatrics, but its social impact is immense because of its unpredicted and catastrophic nature in previously healthy individuals. Unlike in adults where the primary cause of SCD is related to ischemic heart disease, the etiology is diverse in young SCD victims. Although certain structural heart diseases may be identified during autopsy in some SCD victims, autopsy-negative SCD is more common in pediatrics, which warrants the diagnosis of sudden arrhythmic death syndrome (SADS) based upon the assumption that the usual heart rhythm is abruptly replaced by lethal ventricular arrhythmia. Despite current advances in molecular genetics, the causes of more than half of SADS cases remain unanswered even after postmortem genetic testing. Moreover, the majority of these deaths occur at rest or during sleep even in the young. Recently, sudden unexpected death in epilepsy (SUDEP) has emerged as another etiology of SCD in children and adults, suggesting critical involvement of the central nervous system (CNS) in SCD. Primary cardiac disorders may not be solely responsible for SCD; abnormal CNS function may also contribute to the unexpected lethal event. In this review article, we provide an overview of the complex pathogenesis of SADS and its diverse clinical presentation in the young and postulate that SADS is, in part, induced by unfortunate miscommunication between the heart and CNS via the autonomic nervous system.


Assuntos
Arritmias Cardíacas/etiologia , Sistema Nervoso Central/fisiopatologia , Morte Súbita Cardíaca/etiologia , Coração/inervação , Morte Súbita Inesperada na Epilepsia/etiologia , Potenciais de Ação , Adolescente , Adulto , Fatores Etários , Animais , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/genética , Arritmias Cardíacas/fisiopatologia , Causas de Morte , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Frequência Cardíaca , Humanos , Lactente , Masculino , Medição de Risco , Fatores de Risco , Adulto Jovem
5.
Am J Physiol Heart Circ Physiol ; 319(3): H557-H570, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32678709

RESUMO

Our objective was to investigate the effect of desmin depletion on the structure and function of the sinoatrial pacemaker complex (SANcl) and its implication in arrhythmogenesis. Analysis of mice and humans (SANcl) indicated that the sinoatrial node exhibits high amounts of desmin, desmoplakin, N-cadherin, and ß-catenin in structures we call "lateral intercalated disks" connecting myocytes side by side. Examination of the SANcl from an arrhythmogenic cardiomyopathy model, desmin-deficient (Des-/-) mouse, by immunofluorescence, ultrastructural, and Western blot analysis showed that the number of these lateral intercalated disks was diminished. Also, electrophysiological recordings of the isolated compact sinoatrial node revealed increased pacemaker systolic potential and higher diastolic depolarization rate compared with wild-type mice. Prolonged interatrial conduction expressed as a longer P wave duration was also observed in Des-/- mice. Upregulation of mRNA levels of both T-type Ca2+ current channels, Cav3.1 and Cav3.2, in the Des-/- myocardium (1.8- and 2.3-fold, respectively) and a 1.9-fold reduction of funny hyperpolarization-activated cyclic nucleotide-gated K+ channel 1 could underlie these functional differences. To investigate arrhythmogenicity, electrocardiographic analysis of Des-deficient mice revealed a major increase in supraventricular and ventricular ectopic beats compared with wild-type mice. Heart rate variability analysis indicated a sympathetic predominance in Des-/- mice, which may further contribute to arrhythmogenicity. In conclusion, our results indicate that desmin elimination leads to structural and functional abnormalities of the SANcl. These alterations may be enhanced by the sympathetic component of the cardiac autonomic nervous system, which is predominant in the desmin-deficient heart, thus leading to increased arrhythmogenesis.NEW & NOTEWORTHY The sinoatrial node exhibits high amounts of desmin and desmoplakin in structures we call "lateral intercalated disks," connecting side-by-side adjacent cardiomyocytes. These structures are diminished in desmin-deficient mouse models. Misregulation of T-type Ca2+ current and hyperpolarization-activated cyclic nucleotide-gated K+ channel 1 was proved along with prolonged interatrial conduction and cardiac autonomic nervous system dysfunction.


Assuntos
Arritmias Cardíacas/metabolismo , Relógios Biológicos , Desmina/metabolismo , Frequência Cardíaca , Nó Sinoatrial/metabolismo , Potenciais de Ação , Adulto , Animais , Arritmias Cardíacas/genética , Arritmias Cardíacas/patologia , Arritmias Cardíacas/fisiopatologia , Canais de Cálcio Tipo T/metabolismo , Desmina/deficiência , Desmina/genética , Feminino , Humanos , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/metabolismo , Masculino , Camundongos da Linhagem 129 , Camundongos Knockout , Canais de Potássio/metabolismo , Nó Sinoatrial/fisiopatologia , Nó Sinoatrial/ultraestrutura , Sistema Nervoso Simpático/fisiopatologia , Fatores de Tempo
6.
Herzschrittmacherther Elektrophysiol ; 31(4): 394-400, 2020 Dec.
Artigo em Alemão | MEDLINE | ID: mdl-32661562

RESUMO

A variety of arrhythmogenic cardiac diseases such as channelopathies and cardiomyopathies are caused by genetic alterations. In patients with these diseases, malignant arrhythmias or sudden cardiac death frequently manifest already during young adulthood. Early recognition, risk stratification and adequate therapy is therefore essential to avoid sudden cardiac death. This review summarizes the implications of genetic testing for diagnosis, risk stratification and therapy of patients with cardiac channelopathies (long-QT syndrome, short-QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia) and inherited cardiomyopathies (hypertrophic, dilatative or arrhythmogenic right ventricular cardiomyopathy).


Assuntos
Síndrome de Brugada , Canalopatias , Síndrome do QT Longo , Taquicardia Ventricular , Adulto , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/genética , Canalopatias/diagnóstico , Canalopatias/genética , Morte Súbita Cardíaca/prevenção & controle , Humanos , Síndrome do QT Longo/diagnóstico , Síndrome do QT Longo/genética , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/genética , Taquicardia Ventricular/terapia , Adulto Jovem
7.
Cardiovasc Ther ; 2020: 3480276, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32565909

RESUMO

Wenxin Keli (WXKL) is a traditional Chinese medicine drug approved for the treatment of cardiovascular diseases. This study aimed to identify WXKL-targeting genes involved in antiarrhythmic efficacy of WXKL. The Traditional Chinese Medicine Systems Pharmacology (TCMSP) technology platform was used to screen active compounds of WXKL and WXKL-targeting arrhythmia-related genes. A pig model of myocardial ischemia (MI) was established by balloon-expanding the endothelium of the left coronary artery. Pigs were divided into the model group and WXKL group (n = 6). MI, QT interval, heart rate, and arrhythmia were recorded, and the mRNA expression of target genes in myocardial tissues was detected by PCR. Eleven active ingredients of WXKL and eight WXKL-targeting arrhythmia-related genes were screened. Five pathways were enriched, and an "ingredient-gene-path" network was constructed. WXKL markedly decreased the incidence of arrhythmia in the MI pig model (P < 0.05). The QT interval was significantly shortened, and the heart rate was slowed down in the WXKL group compared with the model group (P < 0.05). In addition, the expression of sodium channel protein type 5 subunit alpha (SCN5A) and beta-2 adrenergic receptor (ADRB2) was downregulated, while muscarinic acetylcholine receptor M2 (CHRM2) was upregulated in the WXKL group (P < 0.05). In conclusion, WXKL may shorten the QT interval and slow down the heart rate by downregulating SCN5A and ADRB2 and upregulating CHRM2 during MI. These findings provide novel insight into molecular mechanisms of WXKL in reducing the incidence of ventricular arrhythmia.


Assuntos
Potenciais de Ação/efeitos dos fármacos , Antiarrítmicos/farmacologia , Arritmias Cardíacas/prevenção & controle , Medicamentos de Ervas Chinesas/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Isquemia Miocárdica/tratamento farmacológico , Potenciais de Ação/genética , Animais , Arritmias Cardíacas/genética , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatologia , Modelos Animais de Doenças , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Frequência Cardíaca/genética , Masculino , Medicina Tradicional Chinesa , Isquemia Miocárdica/genética , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/fisiopatologia , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Mapas de Interação de Proteínas , Receptor Muscarínico M2/genética , Receptor Muscarínico M2/metabolismo , Receptores Adrenérgicos beta 2/genética , Receptores Adrenérgicos beta 2/metabolismo , Suínos , Porco Miniatura , Fatores de Tempo
8.
Am J Hum Genet ; 107(1): 111-123, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32533946

RESUMO

Partial or complete loss-of-function variants in SCN5A are the most common genetic cause of the arrhythmia disorder Brugada syndrome (BrS1). However, the pathogenicity of SCN5A variants is often unknown or disputed; 80% of the 1,390 SCN5A missense variants observed in at least one individual to date are variants of uncertain significance (VUSs). The designation of VUS is a barrier to the use of sequence data in clinical care. We selected 83 variants: 10 previously studied control variants, 10 suspected benign variants, and 63 suspected Brugada syndrome-associated variants, selected on the basis of their frequency in the general population and in individuals with Brugada syndrome. We used high-throughput automated patch clamping to study the function of the 83 variants, with the goal of reclassifying variants with functional data. The ten previously studied controls had functional properties concordant with published manual patch clamp data. All 10 suspected benign variants had wild-type-like function. 22 suspected BrS variants had loss of channel function (<10% normalized peak current) and 22 variants had partial loss of function (10%-50% normalized peak current). The previously unstudied variants were initially classified as likely benign (n = 2), likely pathogenic (n = 10), or VUSs (n = 61). After the patch clamp studies, 16 variants were benign/likely benign, 45 were pathogenic/likely pathogenic, and only 12 were still VUSs. Structural modeling identified likely mechanisms for loss of function including altered thermostability and disruptions to alpha helices, disulfide bonds, or the permeation pore. High-throughput patch clamping enabled reclassification of the majority of tested VUSs in SCN5A.


Assuntos
Canal de Sódio Disparado por Voltagem NAV1.5/genética , Arritmias Cardíacas/genética , Síndrome de Brugada/genética , Linhagem Celular , Feminino , Variação Genética , Genótipo , Células HEK293 , Ensaios de Triagem em Larga Escala/métodos , Humanos , Masculino , Fenótipo
9.
Nat Commun ; 11(1): 2542, 2020 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-32439900

RESUMO

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.


Assuntos
Arritmias Cardíacas/genética , Eletrocardiografia , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Arritmias Cardíacas/fisiopatologia , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/fisiopatologia , Endofenótipos , Feminino , Expressão Gênica , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Herança Multifatorial , Locos de Características Quantitativas/genética
10.
Adv Clin Exp Med ; 29(4): 423-429, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32330377

RESUMO

BACKGROUND: Coronary artery disease (CAD) and its ultimate consequence - myocardial infarction (MI) - are major causes of sudden cardiac death (SCD). Previous studies have demonstrated the role of genetic polymorphisms in the risk of SCD and ventricular arrhythmia (VA) during MI. OBJECTIVES: To investigate the association between single nucleotide polymorphisms (SNPs) of genes implicated in congenital cardiac arrhythmias and the risk of developing VA in the context of MI. MATERIAL AND METHODS: We performed a case-control study in which we genotyped 4 SNPs (rs11708996, rs10428132, rs9388451, and rs2200733) in 469 subjects using amplification refractory mutation system (ARMS) and a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). These SNPs are located in the SCN5A, SCN10A, HEY2, and PITX2 genes, respectively. We first compared 70 patients who had developed VA in the context of MI with 141 healthy controls; next, we compared VA patients with 258 MI patients who did not develop VA during a 1-year follow up. The statistical analyses were adjusted for sex and age. RESULTS: Compared to the controls, 2 polymorphisms were significantly associated with the development of VA during MI, located in SCN5A rs11708996 (p = 0.001) and SCN10A rs10428132 (p = 0.001). Similar results were found when comparing VA cases with patients without VA. No associations of HEY2 and PITX2 polymorphisms were observed. CONCLUSIONS: Our results suggest that the rs11708996 and rs10428132 polymorphisms of the SCN5A and SCN10A genes may contribute to an elevated risk of developing VA in the context of MI. The associated alleles or genotypes may be used to predict the risk, and thus prevent eventual SCD.


Assuntos
Arritmias Cardíacas/genética , Infarto do Miocárdio/complicações , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Canal de Sódio Disparado por Voltagem NAV1.8/genética , Polimorfismo de Nucleotídeo Único/genética , Estudos de Casos e Controles , Humanos , Fatores de Risco
11.
PLoS One ; 15(4): e0231056, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32302318

RESUMO

Transverse and axial tubules (TATS) are an essential ingredient of the excitation-contraction machinery that allow the effective coupling of L-type Calcium Channels (LCC) and ryanodine receptors (RyR2). They form a regular network in ventricular cells, while their presence in atrial myocytes is variable regionally and among animal species We have studied the effect of variations in the TAT network using a bidomain computational model of an atrial myocyte with variable density of tubules. At each z-line the t-tubule length is obtained from an exponential distribution, with a given mean penetration length. This gives rise to a distribution of t-tubules in the cell that is characterized by the fractional area (F.A.) occupied by the t-tubules. To obtain consistent results, we average over different realizations of the same mean penetration length. To this, in some simulations we add the effect of a network of axial tubules. Then we study global properties of calcium signaling, as well as regional heterogeneities and local properties of sparks and RyR2 openings. In agreement with recent experiments in detubulated ventricular and atrial cells, we find that detubulation reduces the calcium transient and synchronization in release. However, it does not affect sarcoplasmic reticulum (SR) load, so the decrease in SR calcium release is due to regional differences in Ca2+ release, that is restricted to the cell periphery in detubulated cells. Despite the decrease in release, the release gain is larger in detubulated cells, due to recruitment of orphaned RyR2s, i.e, those that are not confronting a cluster of LCCs. This probably provides a safeguard mechanism, allowing physiological values to be maintained upon small changes in the t-tubule density. Finally, we do not find any relevant change in spark properties between tubulated and detubulated cells, suggesting that the differences found in experiments could be due to differential properties of the RyR2s in the membrane and in the t-tubules, not incorporated in the present model. This work will help understand the effect of detubulation, that has been shown to occur in disease conditions such as heart failure (HF) in ventricular cells, or atrial fibrillation (AF) in atrial cells.


Assuntos
Canais de Cálcio Tipo L/genética , Sinalização do Cálcio/genética , Miócitos Cardíacos/fisiologia , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Potenciais de Ação/fisiologia , Animais , Arritmias Cardíacas/genética , Arritmias Cardíacas/fisiopatologia , Fibrilação Atrial/genética , Fibrilação Atrial/fisiopatologia , Cálcio/metabolismo , Acoplamento Excitação-Contração/fisiologia , Átrios do Coração/metabolismo , Átrios do Coração/fisiopatologia , Humanos , Mamíferos , Sarcolema/genética , Sarcolema/fisiologia , Retículo Sarcoplasmático/genética , Retículo Sarcoplasmático/fisiologia , Ovinos
12.
Heart Rhythm ; 17(9): 1456-1462, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32244059

RESUMO

Ever since the first case was reported at the end of 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the associated coronavirus disease 2019 (COVID-19) has become a serious threat to public health globally in short time. At this point in time, there is no proven effective therapy. The interactions with concomitant disease are largely unknown, and that may be particularly pertinent to inherited arrhythmia syndrome. An arrhythmogenic effect of COVID-19 can be expected, potentially contributing to disease outcome. This may be of importance for patients with an increased risk of cardiac arrhythmias, either secondary to acquired conditions or comorbidities or consequent to inherited syndromes. Management of patients with inherited arrhythmia syndromes such as long QT syndrome, Brugada syndrome, short QT syndrome, and catecholaminergic polymorphic ventricular tachycardia in the setting of the COVID-19 pandemic may prove particularly challenging. Depending on the inherited defect involved, these patients may be susceptible to proarrhythmic effects of COVID-19-related issues such as fever, stress, electrolyte disturbances, and use of antiviral drugs. Here, we describe the potential COVID-19-associated risks and therapeutic considerations for patients with distinct inherited arrhythmia syndromes and provide recommendations, pending local possibilities, for their monitoring and management during this pandemic.


Assuntos
Arritmias Cardíacas/genética , Arritmias Cardíacas/terapia , Betacoronavirus , Infecções por Coronavirus/complicações , Pneumonia Viral/complicações , Arritmias Cardíacas/virologia , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/terapia , Humanos , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/terapia , Síndrome
13.
PLoS Pathog ; 16(3): e1008379, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32160269

RESUMO

Chagas Disease (CD) is one of the leading causes of heart failure and sudden death in Latin America. Treatments with antioxidants have provided promising alternatives to ameliorate CD. However, the specific roles of major reactive oxygen species (ROS) sources, including NADPH-oxidase 2 (NOX2), mitochondrial-derived ROS and nitric oxide (NO) in the progression or resolution of CD are yet to be elucidated. We used C57BL/6 (WT) and a gp91PHOX knockout mice (PHOX-/-), lacking functional NOX2, to investigate the effects of ablation of NOX2-derived ROS production on the outcome of acute chagasic cardiomyopathy. Infected PHOX-/- cardiomyocytes displayed an overall pro-arrhythmic phenotype, notably with higher arrhythmia incidence on ECG that was followed by higher number of early afterdepolarizations (EAD) and 2.5-fold increase in action potential (AP) duration alternans, compared to AP from infected WT mice. Furthermore, infected PHOX-/- cardiomyocytes display increased diastolic [Ca2+], aberrant Ca2+ transient and reduced Ca2+ transient amplitude. Cardiomyocyte contraction is reduced in infected WT and PHOX-/- mice, to a similar extent. Nevertheless, only infected PHOX-/- isolated cardiomyocytes displayed significant increase in non-triggered extra contractions (appearing in ~75% of cells). Electro-mechanical remodeling of infected PHOX-/-cardiomyocytes is associated with increase in NO and mitochondria-derived ROS production. Notably, EADs, AP duration alternans and in vivo arrhythmias were reverted by pre-incubation with nitric oxide synthase inhibitor L-NAME. Overall our data show for the first time that lack of NOX2-derived ROS promoted a pro-arrhythmic phenotype in the heart, in which the crosstalk between ROS and NO could play an important role in regulating cardiomyocyte electro-mechanical function during acute CD. Future studies designed to evaluate the potential role of NOX2-derived ROS in the chronic phase of CD could open new and more specific therapeutic strategies to treat CD and prevent deaths due to heart complications.


Assuntos
Arritmias Cardíacas/metabolismo , Sinalização do Cálcio , Cardiomiopatia Chagásica/metabolismo , Miócitos Cardíacos/metabolismo , Óxido Nítrico/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Doença Aguda , Animais , Arritmias Cardíacas/genética , Arritmias Cardíacas/patologia , Arritmias Cardíacas/fisiopatologia , Cálcio/metabolismo , Cardiomiopatia Chagásica/genética , Cardiomiopatia Chagásica/patologia , Cardiomiopatia Chagásica/fisiopatologia , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Knockout , Miócitos Cardíacos/patologia , NADPH Oxidase 2/genética , NADPH Oxidase 2/metabolismo
14.
Artigo em Inglês | MEDLINE | ID: mdl-32196358

RESUMO

Synapse-associated protein 97 (SAP97) is a scaffolding protein crucial for the functional expression of several cardiac ion channels and therefore proper cardiac excitability. Alterations in the functional expression of SAP97 can modify the ionic currents underlying the cardiac action potential and consequently confer susceptibility for arrhythmogenesis. In this study, we generated a murine model for inducible, cardiac-targeted Sap97 ablation to investigate arrhythmia susceptibility and the underlying molecular mechanisms. Furthermore, we sought to identify human SAP97 (DLG1) variants that were associated with inherited arrhythmogenic disease. The murine model of cardiac-specific Sap97 ablation demonstrated several ECG abnormalities, pronounced action potential prolongation subject to high incidence of arrhythmogenic afterdepolarizations and notable alterations in the activity of the main cardiac ion channels. However, no DLG1 mutations were found in 40 unrelated cases of genetically elusive long QT syndrome (LQTS). Instead, we provide the first evidence implicating a gain of function in human DLG1 mutation resulting in an increase in Kv4.3 current (Ito) as a novel, potentially pathogenic substrate for Brugada syndrome (BrS). In conclusion, DLG1 joins a growing list of genes encoding ion channel interacting proteins (ChIPs) identified as potential channelopathy-susceptibility genes because of their ability to regulate the trafficking, targeting, and modulation of ion channels that are critical for the generation and propagation of the cardiac electrical impulse. Dysfunction in these critical components of cardiac excitability can potentially result in fatal cardiac disease.NEW & NOTEWORTHY The gene encoding SAP97 (DLG1) joins a growing list of genes encoding ion channel-interacting proteins (ChIPs) identified as potential channelopathy-susceptibility genes because of their ability to regulate the trafficking, targeting, and modulation of ion channels that are critical for the generation and propagation of the cardiac electrical impulse. In this study we provide the first data supporting DLG1-encoded SAP97's candidacy as a minor Brugada syndrome susceptibility gene.


Assuntos
Arritmias Cardíacas/metabolismo , Proteína 1 Homóloga a Discs-Large/metabolismo , Coração/fisiopatologia , Miocárdio/metabolismo , Animais , Arritmias Cardíacas/genética , Arritmias Cardíacas/fisiopatologia , Proteína 1 Homóloga a Discs-Large/genética , Humanos , Camundongos , Camundongos Knockout , Miócitos Cardíacos/metabolismo
15.
Sci Rep ; 10(1): 5554, 2020 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-32221364

RESUMO

We hypothesized that some molecular pathways might interact to initiate the process of nervous tissue destruction, promoting cardiac autonomic neuropathy (CAN) in the course of diabetes type 1 (T1D). The study group consisted of 60 T1D patients (58.33% women/41.67% men), on standard therapy. The control group consisted of twenty healthy volunteers recruited in accordance with age, gender and body weight. The presence of CAN was documented by the Ewing test method (ProSciCard apparatus). A microarray data analysis was performed using Gene Spring version 13. The microarray results for selected genes were confirmed by real-time PCR (qRT-PCR), using specific TaqMan Gene Expression Assays. Plasma IL-6 content was measured by an enzyme-linked immunosorbent assay (ELISA). The p < 0.05 value was considered as statistically significant. The microarray analysis, confirmed by qRTPCR, showed significant up-regulation of autophagy, quantity of mitochondria, quality regulatory genes (mTOR, GABARAPL2) apoptosis, ER-stress and inflammation (NFKB1, IL1b, IL1R1, SOD1), in T1D when compared to the control group. A significantly higher IL-6 protein level was observed in T1D patients, in comparison to the control group. We concluded that the observed changes in gene expression and activation of intracellular pathways give a coherent picture of the important role of oxidative stress in inflammation and the activation of apoptosis in the pathomechanism of DM. The significance of the inflammatory process, confirmed by the increased level of the inflammation biomarker IL-6 in the pathomechanisms of CAN was shown even in patients with properly treated T1D.


Assuntos
Arritmias Cardíacas/genética , Diabetes Mellitus Tipo 1/genética , Neuropatias Diabéticas/genética , Perfilação da Expressão Gênica , Sistema de Condução Cardíaco/fisiopatologia , Adulto , Arritmias Cardíacas/etiologia , Autofagia/genética , Biomarcadores , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/terapia , Estresse do Retículo Endoplasmático/genética , Feminino , Humanos , Inflamação/genética , Interleucina-6/sangue , Interleucina-6/genética , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Estresse Oxidativo/genética , Reação em Cadeia da Polimerase em Tempo Real , Adulto Jovem
16.
Life Sci ; 250: 117546, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32184125

RESUMO

AIM: The enzyme 3-phosphoinositide-dependent protein kinase-1 (PDK1) is associated with cardiac and pathological remodeling and ion channel function regulation. However, whether it regulates hyperpolarization-activated cyclic nucleotide-modulated channels (HCNs) remains unclear. MAIN METHODS: In the atrial myocytes of heart-specific PDK1 "knockout" mouse model and neonatal mice, protein kinase B (AKT)-related inhibitors or agonists as well as knockdown or overexpression plasmids were used to study the relationship between PDK1 and HCNs. KEY FINDINGS: HCN1 expression and AKT phosphorylation at the Thr308 site were significantly decreased in atrial myocytes after PDK1 knockout or inhibition; in contrast, HCN2 and HCN4 levels were significantly increased. Also, a similar trend of HCNs expression has been observed in cultured atrial myocytes after PDK1 inhibition, as further demonstrated via immunofluorescence and patch-clamp experiments. Moreover, these results of PDK1 overexpression indicate an opposite trend compared with the previous experimental results. However, the results of PDK1 inhibition or overexpression could be reversed by activating or inhibiting AKT, respectively. SIGNIFICANCE: These results indicate that the PDK1-AKT signaling pathway is involved in the regulation of HCN mRNA transcription, protein expression, HCN current density, and cell membrane location.


Assuntos
Proteínas Quinases Dependentes de 3-Fosfoinositídeo/metabolismo , Regulação Enzimológica da Expressão Gênica , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/metabolismo , Canais de Potássio/metabolismo , Transdução de Sinais , Proteínas Quinases Dependentes de 3-Fosfoinositídeo/genética , Animais , Arritmias Cardíacas/genética , Arritmias Cardíacas/metabolismo , Células Cultivadas , Feminino , Deleção de Genes , Átrios do Coração/citologia , Masculino , Camundongos , Camundongos Knockout , Células Musculares/citologia , Técnicas de Patch-Clamp , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Tirosina/metabolismo
18.
Can J Cardiol ; 36(4): 584-587, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32007350

RESUMO

Genetic testing is playing an ever-expanding role in cardiovascular care and is becoming part of the "toolkit" for the cardiovascular clinician. In patients with inherited arrhythmias, genetic testing can confirm a suspected diagnosis, establish a diagnosis in unexplained cases, and help facilitate cascade family screening. Many inherited arrhythmia syndromes are monogenic diseases arising from a single pathogenic variant involved in the structure and function of cardiac ion channels or structural proteins. As such, "arrhythmia gene panels" will often cast a wide net for such heritable diseases. However, challenges may arise when genetic testing results are ambiguous, or when genetic testing results (genotype) and clinical phenotypes do not match. In cases of "genotype-phenotype matching," genetic results complement the clinical phenotype and genetic testing can be used in diagnosis, family screening, and occasionally prognostication. It becomes more challenging when genetic results are negative or noncontributory and "contradict" the clinical phenotype. "Genotype mismatches" can also occur when genotype-positive patients have no clinical phenotype, or when genetic testing results point towards a completely different disease than the clinical phenotype. We discuss an approach to genetic testing and review the challenges that may arise when interpreting genetic testing results. Genetic testing has opened a wealth of opportunities in the diagnosis, management, and cascade screening of inherited arrhythmia syndromes, but has also opened a "Pandora's box" of challenges. Genetic results should be interpreted with caution and in a multidisciplinary clinic, with support from genetic counsellors and an expert with a focused interest in cardiovascular genetics.


Assuntos
Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/genética , Testes Genéticos/métodos , Feminino , Genótipo , Humanos , Masculino , Linhagem , Fenótipo
19.
Cardiology ; 145(3): 136-147, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32007997

RESUMO

INTRODUCTION: Ventricular arrhythmia is the most important risk factor for sudden cardiac death (SCD) after acute myocardial infarction (MI) worldwide. However, the molecular mechanisms underlying these arrhythmias are complex and not completely understood. OBJECTIVE: Here, we evaluated whether caveolin-3 (Cav3), the structural protein of caveolae, plays an important role in the therapeutic strategy for ventricular arrhythmias. METHODS: A model of cardiac-specific overexpression of Cav3 was established to evaluate the incidence of ventricular arrhythmias after MI in mice. Ca2+ imaging was employed to detect the propensity of adult murine cardiomyocytes to generate arrhythmias, and immunoprecipitation and immunofluorescence were used to determine the relationship of proteins. Additionally, qRT-PCR and western blotting were used to detect the mRNA and protein expression. RESULTS: We found that cardiac-specific overexpression of Cav3 delivered by a recombinant adeno-associated viral vector reduced the incidence of ventricular arrhythmias and SCD after MI in mice. Ca2+ imaging and western blotting revealed that overexpression of Cav3 reduced diastolic spontaneous Ca2+ waves by inhibiting the hyperphosphorylation of ryanodine receptor-2 (RyR2) at Ser2814, rather than at Ser2808, compared to in rAAV-red fluorescent protein control mice. Furthermore, we demonstrated that Cav3-regulated RYR2 hyperphosphorylation relied on plakophilin-2 in hypoxia-stimulated cultured cardiomyocytes by western blotting, immunoprecipitation, and immunofluorescence in vitro. CONCLUSIONS: Our results suggested a novel role for Cav3 in the prevention of ventricular arrhythmias, thereby identifying a new target for preventing SCD after MI.


Assuntos
Arritmias Cardíacas/metabolismo , Caveolina 3/metabolismo , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Animais , Arritmias Cardíacas/genética , Arritmias Cardíacas/mortalidade , Cálcio/metabolismo , Caveolina 3/genética , Morte Súbita Cardíaca/etiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/mortalidade , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Fosforilação , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Serina/metabolismo , Remodelação Ventricular
20.
Biochem Biophys Res Commun ; 524(2): 431-438, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32007269

RESUMO

AIMS: Ca2+/calmodulin-dependent protein kinase II (CaMKII) has been shown to induce aberrant Ca2+ release from the cardiac ryanodine receptor (RyR2) in various diseased hearts. However, the precise pathogenic mechanism remains to be elucidated. Here, we investigated the effect of dantrolene (DAN): a RyR2 stabilizer on local Ca2+ release, cardiac function, and lethal arrhythmia in CaMKIIδc transgenic (TG) mice. METHODS AND RESULTS: The TG mice showed an increase in left ventricular end-diastolic diameter (LVEDD) and left ventricular end-systolic diameter (LVESD) with a reduction in LV fractional shortening (LVFS). The phosphorylation levels of Ser2814 in RyR2 and Thr287 in CaMKII increased in TG mice. In TG cardiomyocytes, peak cell shortening (CS) decreased, and the frequency of spontaneous Ca2+ transients (sCaTs) increased. Endogenous RyR2-associated calmodulin (CaM) markedly decreased in TG cardiomyocytes. After chronic DAN treatment for 1 month, LVESD (but not LVEDD) decreased with an increase in LVFS. In the chronic DAN-treated cardiomyocytes, CS increased, sCaTs decreased, and the endogenous CaM binding to RyR2 normally restored. The phosphorylation levels of Ser2814 in RyR2 and Thr287 in CaMKII remained elevated even after DAN treatment. Moreover, in TG mice, chronic DAN treatment prevented sustained ventricular tachycardia induced by epinephrine. CONCLUSIONS: Defective association of CaM with RyR2 is most likely to be involved in the pathogenesis of CaMKII-mediated cardiac dysfunction and lethal arrhythmia.


Assuntos
Arritmias Cardíacas/prevenção & controle , Arritmias Cardíacas/fisiopatologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Coração/fisiopatologia , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Animais , Arritmias Cardíacas/genética , Arritmias Cardíacas/metabolismo , Cálcio/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Células Cultivadas , Dantroleno/uso terapêutico , Técnicas de Introdução de Genes , Coração/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Relaxantes Musculares Centrais/uso terapêutico , Fosforilação/efeitos dos fármacos , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Regulação para Cima/efeitos dos fármacos
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