PRKAG2 syndrome, a rare hypertrophic cardiomyopathy: a Brazilian long-term follow-up with extracardiac disorders.

OBJECTIVE: This study aimed to provide a long-term follow-up of PRKAG2 syndrome and describe the new phenotypic aspects of the condition. PRKAG2 syndrome is a rare autosomal-dominant glycogen storage disease characterized by cardiac hypertrophy, ventricular pre-excitation, and conduction system disease. Fatal arrhythmias occur frequently. METHODS: A family cohort of 66 participants was recruited. Clinical and genetic analyses were performed. RESULTS: Median age of 36.97±17.28 years, with 69.9% being men. Nineteen subjects carried the deleterious variant p.K290I of the PRKAG2 gene. This group experienced many malignant events, including eight pacemaker implants, three sudden cardiac deaths, five aborted cardiac arrests, four strokes, four premature neonatal deaths, two spontaneous abortions, five forceps deliveries, and 12 cesarean procedures. Extracardiac involvement, such as in neurocognitive and psychiatric disorders, has been observed only in carriers of mutations. Palpitations, Syncope, atrial fibrillation, atrial flutter, sinus pauses, and bradycardia were strongly and significantly associated with major or severe adverse events (sudden cardiac death, aborted cardiac arrest, pacemaker use, stroke, and congestive heart failure). Early diagnosis and intervention through antiarrhythmic drugs, anticoagulation, pacemaker implantation, radiofrequency catheter ablation, and cesarean section surgery improved the symptoms and survival rates. Mutations carriers were advised to avoid pregnancy. CONCLUSION: This study identified that the p.K291I_PRKAG2 mutation is associated with poor prognosis, highlighting the need for early intervention. Further research may uncover the potential connections between intellectual disability, miscarriage, and neonatal death in individuals with this syndrome.

KCNQ1 p.D446E Variant as a Risk Allele for Arrhythmogenic Phenotypes: Electrophysiological Characterization Reveals a Complex Phenotype Affecting the Slow Delayed Rectifier Potassium Current (IKs) Voltage Dependence by Causing a Hyperpolarizing Shift and a Lack of Response to Protein Kinase A Activation.

Genetic testing is crucial in inherited arrhythmogenic channelopathies; however, the clinical interpretation of genetic variants remains challenging. Incomplete penetrance, oligogenic, polygenic or multifactorial forms of channelopathies further complicate variant interpretation. We identified the KCNQ1/p.D446E variant in 2/63 patients with long QT syndrome, 30-fold more frequent than in public databases. We thus characterized the biophysical phenotypes of wildtype and mutant IKs co-expressing these alleles with the ß-subunit minK in HEK293 cells. KCNQ1 p.446E homozygosity significantly shifted IKs voltage dependence to hyperpolarizing potentials in basal conditions (gain of function) but failed to shift voltage dependence to hyperpolarizing potentials (loss of function) in the presence of 8Br-cAMP, a protein kinase A activator. Basal IKs activation kinetics did not differ among genotypes, but in response to 8Br-cAMP, IKs 446 E/E (homozygous) activation kinetics were slower at the most positive potentials. Protein modeling predicted a slower transition of the 446E Kv7.1 tetrameric channel to the stabilized open state. In conclusion, biophysical and modelling evidence shows that the KCNQ1 p.D446E variant has complex functional consequences including both gain and loss of function, suggesting a contribution to the pathogenesis of arrhythmogenic phenotypes as a functional risk allele.

Loss-of-Function FLNC Variants Are Associated With Arrhythmogenic Cardiomyopathy Phenotypes When Identified Through Exome Sequencing of a General Clinical Population.

BACKGROUND: The FLNC gene has recently garnered attention as a likely cause of arrhythmogenic cardiomyopathy, which is considered an actionable genetic condition. However, the association with disease in an unselected clinical population is unknown. We hypothesized that individuals with loss-of-function variants in FLNC (FLNCLOF) would have increased odds for arrhythmogenic cardiomyopathy-associated phenotypes versus variant-negative controls in the Geisinger MyCode cohort. METHODS: We identified rare, putative FLNCLOF among 171 948 individuals with exome sequencing linked to health records. Associations with arrhythmogenic cardiomyopathy phenotypes from available diagnoses and cardiac evaluations were investigated. RESULTS: Sixty individuals (0.03%; median age 58 years [47-70 interquartile range], 43% male) harbored 27 unique FLNCLOF. These individuals had significantly increased odds ratios for dilated cardiomyopathy (odds ratio, 4.9 [95% CI, 2.6-7.6]; P<0.001), supraventricular tachycardia (odds ratio, 3.2 [95% CI, 1.1-5.6]; P=0.048), and left-dominant arrhythmogenic cardiomyopathy (odds ratio, 4.2 [95% CI, 1.4-7.9]; P=0.03). Echocardiography revealed reduced left ventricular ejection fraction (52±13% versus 57±9%; P=0.001) associated with FLNCLOF. Overall, at least 9% of FLNCLOF patients demonstrated evidence of penetrant disease. CONCLUSIONS: FLNCLOF variants are associated with increased odds of ventricular arrhythmia and dysfunction in an unselected clinical population. These findings support genomic screening of FLNC for actionable secondary findings.

Peculiar Aspects of Patients with Inherited Arrhythmias during the COVID-19 Pandemic. / Peculiaridade dos Pacientes com Arritmias Hereditárias na Pandemia pela COVID-19.

Since December 2019 we have observed the rapid advance of the severe acute respiratory syndrome caused by the new coronavirus (SARS-CoV-2). The impact of the clinical course of a respiratory infection is little known in patients with hereditary arrhythmias, due to the low prevalence of these diseases. Patients who present with infectious conditions may exacerbate hidden or well-controlled primary arrhythmias, due to several factors, such as fever, electrolyte disturbances, drug interactions, adrenergic stress and, eventually, the septic patient's own myocardial damage. The aim of this review is to highlight the main challenges we may encounter during the Covid 19 pandemic, specifically in patients with hereditary arrhythmias, with emphasis on the congenital long QT syndrome (LQTS), Brugada syndrome (SBr), ventricular tachycardia polymorphic catecholaminergic (CPVT) and arrhythmogenic right ventricular cardiomyopathy.

Desde dezembro de 2019, observamos o rápido avanço da síndrome respiratória aguda grave causada pelo coronavírus 2019 (SARS-CoV-2). O impacto da evolução clínica de uma infecção respiratória é pouco conhecido em pacientes portadores de arritmias hereditárias, devido à baixa prevalência dessas doenças. Os pacientes que apresentam quadros infecciosos podem exacerbar arritmias primárias ocultas ou bem controladas, por diversos fatores, tais como febre, distúrbios eletrolíticos, interações medicamentosas, estresse adrenérgico e, eventualmente, o próprio dano miocárdico do paciente séptico. O objetivo desta revisão é destacar os principais desafios que podemos encontrar durante a pandemia pela Covid 19, especificamente nos pacientes com arritmias hereditárias, com destaque para a síndrome do QT longo congênito (SQTL), a síndrome de Brugada (SBr), a taquicardia ventricular polimórfica catecolaminérgica (TVPC) e a cardiomiopatia arritmogênica do ventrículo direito.

Peculiaridade dos pacientes com arritmias hereditárias na pandemia pela COVID-19 / Peculiar aspects of patients with Inherited arrhythmias during the COVID-19 pandemic

Resumo Desde dezembro de 2019, observamos o rápido avanço da síndrome respiratória aguda grave causada pelo coronavírus 2019 (SARS-CoV-2). O impacto da evolução clínica de uma infecção respiratória é pouco conhecido em pacientes portadores de arritmias hereditárias, devido à baixa prevalência dessas doenças. Os pacientes que apresentam quadros infecciosos podem exacerbar arritmias primárias ocultas ou bem controladas, por diversos fatores, tais como febre, distúrbios eletrolíticos, interações medicamentosas, estresse adrenérgico e, eventualmente, o próprio dano miocárdico do paciente séptico. O objetivo desta revisão é destacar os principais desafios que podemos encontrar durante a pandemia pela Covid 19, especificamente nos pacientes com arritmias hereditárias, com destaque para a síndrome do QT longo congênito (SQTL), a síndrome de Brugada (SBr), a taquicardia ventricular polimórfica catecolaminérgica (TVPC) e a cardiomiopatia arritmogênica do ventrículo direito.

Abstract Since December 2019 we have observed the rapid advance of the severe acute respiratory syndrome caused by the new coronavirus (SARS-CoV-2). The impact of the clinical course of a respiratory infection is little known in patients with hereditary arrhythmias, due to the low prevalence of these diseases. Patients who present with infectious conditions may exacerbate hidden or well-controlled primary arrhythmias, due to several factors, such as fever, electrolyte disturbances, drug interactions, adrenergic stress and, eventually, the septic patient's own myocardial damage. The aim of this review is to highlight the main challenges we may encounter during the Covid 19 pandemic, specifically in patients with hereditary arrhythmias, with emphasis on the congenital long QT syndrome (LQTS), Brugada syndrome (SBr), ventricular tachycardia polymorphic catecholaminergic (CPVT) and arrhythmogenic right ventricular cardiomyopathy.

Clinical Spectrum of SCN5A Channelopathy in Children with Primary Electrical Disease and Structurally Normal Hearts.

Sodium voltage-gated channel α subunit 5 (SCN5A)-mutations may cause an array of arrhythmogenic syndromes most frequently as an autosomal dominant trait, with incomplete penetrance, variable expressivity and male predominance. In the present study, we retrospectively describe a group of Mexican patients with SCN5A-disease causing variants in whom the onset of symptoms occurred in the pediatric age range. The study included 17 patients with clinical diagnosis of primary electrical disease, at least one SCN5A pathogenic or likely pathogenic mutation and age of onset <18 years, and all available first- and second-degree relatives. Fifteen patients (88.2%) were male, and sixteen independent variants were found (twelve missense, three truncating and one complex inframe deletion/insertion). The frequency of compound heterozygosity was remarkably high (3/17, 17.6%), with early childhood onset and severe disease. Overall, 70.6% of pediatric patients presented with overlap syndrome, 11.8% with isolated sick sinus syndrome, 11.8% with isolated Brugada syndrome (BrS) and 5.9% with isolated type 3 long QT syndrome (LQTS). A total of 24/45 SCN5A mutation carriers were affected (overall penetrance 53.3%), and penetrance was higher in males (63.3%, 19 affected/30 mutation carriers) than in females (33.3%, 5 affected/15 carriers). In conclusion, pediatric patients with SCNA-disease causing variants presented mainly as overlap syndrome, with predominant loss-of-function phenotypes of sick sinus syndrome (SSS), progressive cardiac conduction disease (PCCD) and ventricular arrhythmias.

Systematic Review: Models of Changes in Gene Expression of MTOR, MURF-1, and MAFBX in Rats and Mice.

INTRODUCTION: Various pathologies and lifestyle factors, such as nutritional factors and physical exercises, can alter the gene expression of proteins related to synthesis and degradation. AIM: We performed a systematic review of atrophy models, cancer models, burn models, sepsis models, cardiac insufficiency models, amino acid supplementation models, protein supplementation models, and miscellaneous models that have altered the gene expression of MTOR, MURF-1, or MAFBX in rats and mice. MATERIALS AND METHODS: We searched the literature in the following databases: Medline, Scielo.org, Scielo.br, Redib, Lilacs, and the Periodicos Capes. RESULTS: We selected 56 articles for this review. DISCUSSION: Several conditions can alter the gene expression of muscle proteins under conditions that stimulate muscle degradation pathways. Therefore, treatments must normalize the expression of the degradation pathways and potentiate the synthesis pathways so the muscular tissue confers an increase in functional capacity and thus, survival in diseased patients. Therefore, the reversal of the mechanisms that promote its depletion must be achieved. CONCLUSION: Identification of the atrophic mechanisms present in pathologies and other conditions of muscular disuse in the scientific literature is fundamental for the adoption of clinical strategies to prevent protein degradation and to promote the maintenance and/or increase of muscle tissue. Such strategies include physical exercise, protein supplementation, and/or pharmacological applications, aimed toward restoring the fullness of functional capacity.

Reactive oxygen species and nitric oxide imbalances lead to in vivo and in vitro arrhythmogenic phenotype in acute phase of experimental Chagas disease.

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.

Genetic susceptibility in pharmacodynamic and pharmacokinetic pathways underlying drug induced arrhythmia and sudden unexplained deaths

Abstract Drug-induced arrhythmia is an adverse drug reaction that can be potentially fatal since it is mostly related to drug-induced QT prolongation, a known risk factor for Torsade de Pointes and sudden cardiac death (SCD). Several risk factors have been described in association to these drug-induced events, such as preexistent cardiac disease and genetic variation. Our objective was to study the genetic susceptibility in pharmacodynamic and pharmacokinetic pathways underlying suspected drug-induced arrhythmias and sudden unexplained deaths in 32 patients. The genetic component in the pharmacodynamic pathway was studied by analyzing 96 genes associated with higher risk of SCD through massive parallel sequencing. Pharmacokinetic mediated genetic susceptibility was investigated by studying the genes encoding cytochrome P450 enzymes using medium-throughput genotyping. Pharmacodynamic analysis showed three probably pathogenic variants and 45 variants of uncertain significance in 28 patients, several of them previously described in relation to mild or late onset cardiomyopathies. These results suggest that genetic variants in cardiomyopathy genes, in addition to those related with channelopathies, could be relevant to drug-induced cardiotoxicity and contribute to the arrhythmogenic phenotype. Pharmacokinetic analysis showed three patients that could have an altered metabolism of the drugs they received involving CYP2C19 and/or CYP2D6, probably contributing to the arrhythmogenic phenotype. The study of genetic variants in both pharmacodynamic and pharmacokinetic pathways may be a useful strategy to understand the multifactorial mechanism of drug-induced events in both clinical practice and forensic field. However, it is necessary to comprehensively study and evaluate the contribution of the genetic susceptibility to drug-induced cardiotoxicity. (AU)

Ablation of phospholamban rescues reperfusion arrhythmias but exacerbates myocardium infarction in hearts with Ca2+/calmodulin kinase II constitutive phosphorylation of ryanodine receptors.

AIMS: Abnormal Ca2+ release from the sarcoplasmic reticulum (SR), associated with Ca2+-calmodulin kinase II (CaMKII)-dependent phosphorylation of RyR2 at Ser2814, has consistently been linked to arrhythmogenesis and ischaemia/reperfusion (I/R)-induced cell death. In contrast, the role played by SR Ca2+ uptake under these stress conditions remains controversial. We tested the hypothesis that an increase in SR Ca2+ uptake is able to attenuate reperfusion arrhythmias and cardiac injury elicited by increased RyR2-Ser2814 phosphorylation. METHODS AND RESULTS: We used WT mice, which have been previously shown to exhibit a transient increase in RyR2-Ser2814 phosphorylation at the onset of reperfusion; mice with constitutive pseudo-phosphorylation of RyR2 at Ser2814 (S2814D) to exacerbate CaMKII-dependent reperfusion arrhythmias and cardiac damage, and phospholamban (PLN)-deficient-S2814D knock-in (SDKO) mice resulting from crossbreeding S2814D with phospholamban knockout deficient (PLNKO) mice. At baseline, S2814D and SDKO mice had structurally normal hearts. Moreover none of the strains were arrhythmic before ischaemia. Upon cardiac I/R, WT, and S2814D hearts exhibited abundant arrhythmias that were prevented by PLN ablation. In contrast, PLN ablation increased infarct size compared with WT and S2814D hearts. Mechanistically, the enhanced SR Ca2+ sequestration evoked by PLN ablation in SDKO hearts prevented arrhythmogenic events upon reperfusion by fragmenting SR Ca2+ waves into non-propagated and non-arrhythmogenic events (mini-waves). Conversely, the increase in SR Ca2+ sequestration did not reduce but rather exacerbated I/R-induced SR Ca2+ leak, as well as mitochondrial alterations, which were greatly avoided by inhibition of RyR2. These results indicate that the increase in SR Ca2+ uptake is ineffective in preventing the enhanced SR Ca2+ leak of PLN ablated myocytes from either entering into nearby mitochondria and/or activating additional CaMKII pathways, contributing to cardiac damage. CONCLUSION: Our results demonstrate that increasing SR Ca2+ uptake by PLN ablation can prevent the arrhythmic events triggered by CaMKII-dependent phosphorylation of RyR2-induced SR Ca2+ leak. These findings underscore the benefits of increasing SERCA2a activity in the face of SR Ca2+ triggered arrhythmias. However, enhanced SERCA2a cannot prevent but rather exacerbates I/R cardiac injury.

La autopsia molecular en la muerte súbita cardiaca / Molecular autopsy in sudden cardiac death

Resumen Actualmente hay un porcentaje importante de autopsias que quedan sin un diag nóstico concluyente del fallecimiento, especialmente cuando este evento letal se produce súbitamente. El análisis genético se ha ido incorporando recientemente al campo de la medicina forense, sobre todo en aquellos pacientes que han fallecido de forma repentina, y donde no se identifica causa concluyente del fallecimiento tras una autopsia médico-legal completa. En estos casos las enfermedades eléctricas primarias son las principales responsables del fallecimiento. Hasta la fecha se han descrito más de 40 genes asociados a afecciones arritmogénicas causantes de muerte súbita cardiaca. Las principales enfermedades arritmogénicas son el síndrome de QT largo y la taquicardia ventricular; estudios genéticos post-mortem no solo permiten llevar a cabo un diagnóstico de la causa del fallecimiento, sino que también permiten una traslación clínica hacia los familiares, focalizado en la identificación precoz de individuos en riesgo de síncope, así como adopción de medidas terapéuticas personalizadas para la prevención de un episodio arrítmico letal.

Abstract Currently, there are a significant percentage of autopsies left without a conclusive diagnosis of death, especially when this lethal event occurs suddenly. Genetic analysis has been recently incorporated into the field of forensic medicine, especially in patients with sudden death and where no conclusive cause of death is identified after a complete medical- legal autopsy. Inherited arrhythmogenic diseases are the main cause of death in these cases. To date, more than 40 genes have been associated with arrhythmogenic disease, and causing sudden cardiac death has been described. The main arrhythmogenic diseases are Long QT Syndrome, Catecholaminergic Polymorphic Ventricular Tachycardia, Brugada Syndrome, and Short QT Syndrome. These post-mortem genetic studies, not only allow a diagnosis of the cause of death, but also allow a clinical translation in relatives, focusing on the early identification of individuals at risk of syncope, as well as adopting personalised therapeutic measures for the prevention of a lethal arrhythmic episode.

SERCA is critical to control the Bowditch effect in the heart.

The Bowditch effect or staircase phenomenon is the increment or reduction of contractile force when heart rate increases, defined as either a positive or negative staircase. The healthy and failing human heart both show positive or negative staircase, respectively, but the causes of these distinct cardiac responses are unclear. Different experimental approaches indicate that while the level of Ca2+ in the sarcoplasmic reticulum is critical, the molecular mechanisms are unclear. Here, we demonstrate that Drosophila melanogaster shows a negative staircase which is associated to a slight but significant frequency-dependent acceleration of relaxation (FDAR) at the highest stimulation frequencies tested. We further showed that the type of staircase is oppositely modified by two distinct SERCA mutations. The dominant conditional mutation SERCAA617T induced positive staircase and arrhythmia, while SERCAE442K accentuated the negative staircase of wild type. At the stimulation frequencies tested, no significant FDAR could be appreciated in mutant flies. The present results provide evidence that two individual mutations directly modify the type of staircase occurring within the heart and suggest an important role of SERCA in regulating the Bowditch effect.

[Molecular autopsy in sudden cardiac death]. / La autopsia molecular en la muerte súbita cardiaca.

Currently, there are a significant percentage of autopsies left without a conclusive diagnosis of death, especially when this lethal event occurs suddenly. Genetic analysis has been recently incorporated into the field of forensic medicine, especially in patients with sudden death and where no conclusive cause of death is identified after a complete medical-legal autopsy. Inherited arrhythmogenic diseases are the main cause of death in these cases. To date, more than 40 genes have been associated with arrhythmogenic disease, and causing sudden cardiac death has been described. The main arrhythmogenic diseases are Long QT Syndrome, Catecholaminergic Polymorphic Ventricular Tachycardia, Brugada Syndrome, and Short QT Syndrome. These post-mortem genetic studies, not only allow a diagnosis of the cause of death, but also allow a clinical translation in relatives, focusing on the early identification of individuals at risk of syncope, as well as adopting personalised therapeutic measures for the prevention of a lethal arrhythmic episode.

Grape pomace reduced reperfusion arrhythmias in rats with a high-fat-fructose diet.

Metabolic syndrome (MetS) is a risk factor for sudden cardiac death in humans, but animal models are needed for the study of this association. Grape pomace (GP), obtained from the winemaking process, contains phenolic compounds with potential cardioprotective effects. The aim of this study was to evaluate if a high-fat-fructose (HFF) diet facilitates the occurrence of arrhythmias during the reperfusion, and if a GP supplementation could counteract these effects. Wistar rats were fed with control (Ctrl), HFF diet and HFF plus GP (1 g kg-1 day-1) for six weeks. The HFF diet induces characteristic features of MetS (higher systolic blood pressure, dyslipidemia and insulin resistance) which was attenuated by GP supplementation. In addition, HFF induced increased reperfusion arrhythmias that were reduced upon GP supplementation. GP also reduced the non-phosphorylated form of connexin-43 (Cx43) while enhancing heart p-AKT and p-eNOS protein levels and reducing Nox4 levels enhanced by the HFF diet, indicating that GP may increase NO bioavailability in the heart. We found a murine model of MetS with increased arrhythmogenesis and translational value. Furthermore, GP prevents diet-induced heart dysfunction and metabolic alterations. These results highlight the potential utilization of winemaking by-products containing significant amounts of bioactive compounds to prevent/attenuate MetS-associated cardiovascular pathologies.

A diagnostic approach for neurodegeneration with brain iron accumulation: clinical features, genetics and brain imaging.

Neurodegeneration with brain iron accumulation (NBIA) represents a heterogeneous and complex group of inherited neurodegenerative diseases, characterized by excessive iron accumulation, particularly in the basal ganglia. Common clinical features of NBIA include movement disorders, particularly parkinsonism and dystonia, cognitive dysfunction, pyramidal signs, and retinal abnormalities. The forms of NBIA described to date include pantothenase kinase-associated neurodegeneration (PKAN), phospholipase A2 associated neurodegeneration (PLAN), neuroferritinopathy, aceruloplasminemia, beta-propeller protein-associated neurodegeneration (BPAN), Kufor-Rakeb syndrome, mitochondrial membrane protein-associated neurodegeneration (MPAN), fatty acid hydroxylase-associated neurodegeneration (FAHN), coenzyme A synthase protein-associated neurodegeneration (CoPAN) and Woodhouse-Sakati syndrome. This review is a diagnostic approach for NBIA cases, from clinical features and brain imaging findings to the genetic etiology.

A diagnostic approach for neurodegeneration with brain iron accumulation: clinical features, genetics and brain imaging / Uma orientação diagnóstica para neurodegeneração com acúmulo cerebral de ferro: aspectos clínicos, genéticos e de neuroimagem

ABSTRACT Neurodegeneration with brain iron accumulation (NBIA) represents a heterogeneous and complex group of inherited neurodegenerative diseases, characterized by excessive iron accumulation, particularly in the basal ganglia. Common clinical features of NBIA include movement disorders, particularly parkinsonism and dystonia, cognitive dysfunction, pyramidal signs, and retinal abnormalities. The forms of NBIA described to date include pantothenase kinase-associated neurodegeneration (PKAN), phospholipase A2 associated neurodegeneration (PLAN), neuroferritinopathy, aceruloplasminemia, beta-propeller protein-associated neurodegeneration (BPAN), Kufor-Rakeb syndrome, mitochondrial membrane protein-associated neurodegeneration (MPAN), fatty acid hydroxylase-associated neurodegeneration (FAHN), coenzyme A synthase protein-associated neurodegeneration (CoPAN) and Woodhouse-Sakati syndrome. This review is a diagnostic approach for NBIA cases, from clinical features and brain imaging findings to the genetic etiology.

RESUMO A neurodegeneração com acúmulo cerebral de ferro (sigla em inglês NBIA) representa um grupo heterogêneo e complexo de doenças neurodegenerativas hereditárias, caracterizada pelo acúmulo cerebral de ferro, especialmente nos núcleos da base. O quadro clínico das NBIAs em geral inclui distúrbios do movimento, particularmente parkinsonismo e distonia, disfunção cognitiva, sinais piramidais e anormalidades da retina. As formas de NBIA descritas até o momento incluem neurodegeneração associada a pantothenase kinase (PKAN), neurodegeneração associada a phospholipase A2 (PLAN), neuroferritinopatia, aceruloplasminemia, neurodegeneração associada a beta-propeller protein (BPAN), síndrome de Kufor-Rakeb, neurodegeneração associada a mitochondrial membrane protein (MPAN), neurodegeneração associada a “fatty acid hydroxylase” (FAHN), neurodegeneração associada a coenzyme A synthase protein (CoPAN) e síndrome de Woodhouse-Sakati. Esta revisão é uma orientação para o diagnóstico das NBIAs, partindo das características clínicas e achados de neuroimagem, até a etiologia genética.

Tiaogan Qingxin Granule treatment increases myocardial connexin 43 expression in a rat model of arrhythmia.

Myocardial ischemia-induced arrhythmia, especially ventricular arrhythmia, is the main reason for sudden cardiac death. Therefore, ischemic ventricular arrhythmia-targeted treatments are urgently needed. The mechanism of Tiaogan Qingxin Granule in premature ventricular beat (PVB) treatment was explored in arrhythmic rats pretreated with Tiaogan Qingxin Granule. Sprague-Dawley rats (N = 40) were randomly divided into 4 groups: sham-operated, arrhythmia model, Wenxin Granule, and Tiaogan Qingxin Granule. The ischemic arrhythmia model was established by ligating the left anterior descending coronary artery. The Tiaogan Qingxin Granule group was treated intragastrically for 7 days before surgery. Sham-operated rats underwent thoracotomy without coronary artery ligation. Myocardial infarction rate was measured using the triphenyltetrazolium chloride method and Cx43 expression was quantified by western blotting. Compared to the arrhythmia model group, the Tiaogan Qingxin Granule group showed a significant reduction in the myocardial infarct size and myocardial infarction rate (P < 0.01). Cx43 expression in the left ventricular myocardial tissues was significantly lower in the arrhythmia model group than in the sham-operated group (P < 0.01), but significantly higher in the Tiaogan Qingxin Granule group (P < 0.01). Intergroup difference in the relative Cx43 expression between the Tiaogan Qingxin Granule and Wenxin Granule groups was not significant (P > 0.05). Thus, Tiaogan Qingxin Granule reduced the myocardial infarct size, lowered the myocardial infarction rate, and increased Cx43 expression, possibly by increasing blood supply to the cardiac muscles. In conclusion, Tiaogan Qingxin Granule may be useful for treating ischemic PVB.

Phospholamban ablation rescues the enhanced propensity to arrhythmias of mice with CaMKII-constitutive phosphorylation of RyR2 at site S2814.

KEY POINTS: Mice with Ca(2+) -calmodulin-dependent protein kinase (CaMKII) constitutive pseudo-phosphorylation of the ryanodine receptor RyR2 at Ser2814 (S2814D(+/+) mice) exhibit a higher open probability of RyR2, higher sarcoplasmic reticulum (SR) Ca(2+) leak in diastole and increased propensity to arrhythmias under stress conditions. We generated phospholamban (PLN)-deficient S2814D(+/+) knock-in mice by crossing two colonies, S2814D(+/+) and PLNKO mice, to test the hypothesis that PLN ablation can prevent the propensity to arrhythmias of S2814D(+/+) mice. PLN ablation partially rescues the altered intracellular Ca(2+) dynamics of S2814D(+/+) hearts and myocytes, but enhances SR Ca(2+) sparks and leak on confocal microscopy. PLN ablation diminishes ventricular arrhythmias promoted by CaMKII phosphorylation of S2814 on RyR2. PLN ablation aborts the arrhythmogenic SR Ca(2+) waves of S2814D(+/+) and transforms them into non-propagating events. A mathematical human myocyte model replicates these results and predicts the increase in SR Ca(2+) uptake required to prevent the arrhythmias induced by a CaMKII-dependent leaky RyR2. ABSTRACT: Mice with constitutive pseudo-phosphorylation at Ser2814-RyR2 (S2814D(+/+) ) have increased propensity to arrhythmias under ß-adrenergic stress conditions. Although abnormal Ca(2+) release from the sarcoplasmic reticulum (SR) has been linked to arrhythmogenesis, the role played by SR Ca(2+) uptake remains controversial. We tested the hypothesis that an increase in SR Ca(2+) uptake is able to rescue the increased arrhythmia propensity of S2814D(+/+) mice. We generated phospholamban (PLN)-deficient/S2814D(+/+) knock-in mice by crossing two colonies, S2814D(+/+) and PLNKO mice (SD(+/+) /KO). SD(+/+) /KO myocytes exhibited both increased SR Ca(2+) uptake seen in PLN knock-out (PLNKO) myocytes and diminished SR Ca(2+) load (relative to PLNKO), a characteristic of S2814D(+/+) myocytes. Ventricular arrhythmias evoked by catecholaminergic challenge (caffeine/adrenaline) in S2814D(+/+) mice in vivo or programmed electric stimulation and high extracellular Ca(2+) in S2814D(+) /(-) hearts ex vivo were significantly diminished by PLN ablation. At the myocyte level, PLN ablation converted the arrhythmogenic Ca(2+) waves evoked by high extracellular Ca(2+) provocation in S2814D(+/+) mice into non-propagated Ca(2+) mini-waves on confocal microscopy. Myocyte Ca(2+) waves, typical of S2814D(+/+) mice, could be evoked in SD(+/+) /KO cells by partially inhibiting SERCA2a. A mathematical human myocyte model replicated these results and allowed for predicting the increase in SR Ca(2+) uptake required to prevent the arrhythmias induced by a Ca(2+) -calmodulin-dependent protein kinase (CaMKII)-dependent leaky RyR2. Our results demonstrate that increasing SR Ca(2+) uptake by PLN ablation can prevent the arrhythmic events triggered by SR Ca(2+) leak due to CaMKII-dependent phosphorylation of the RyR2-S2814 site and underscore the benefits of increasing SERCA2a activity on SR Ca(2+) -triggered arrhythmias.

Arritmias genéticas: como investigar e como tratar? / Inherited arrhythmias: how to investigate and how to treat?

As arritmias hereditárias são responsáveis por uma proporção significante de mortes cardíacas súbitas em indivíduos jovens aparentemente saudáveis. As canalopatias, como síndrome de Brugada, síndrome do QT longo/curto e taquicardia ventricular polimórfica catecolaminérgica, contribuem com essa incidência e não são marcadas por anomalias estruturais. A cardiomiopatia genética, como cardiomiopatia arritmogênica doventrículo direito e cardiomiopatia hipertrófica, também são causas de morte súbita por arritmia. Novos consensos têm sido publicados para orientar melhor as ferramentas dediagnóstico, os escores de estratificação e o tratamento. Os testes genéticos têm papel importante no diagnóstico, na estratificação de risco e no tratamento de pacientes e de suas famílias. Os avanços da genética molecular nas duas últimas décadas revelaram a base genética subjacente da doença, e podem levar a tratamentos mais personalizados...

Inherited arrhythmias account for a significant proportion of sudden cardiac deaths in apparently healthy and young individuals. Ion channelopathies such as Brugada syndrome, long/short QT syndrome and catecholaminergic polymorphic ventricular tachycardiacontribute to this incidence and are marked by no structural abnormalities. Genetic cardiomyopathy such as Right Ventricular Arrhythmogenic Cardiomyopathy and HypertrophicCardiomyopathy are also causes of arrhythmogenic sudden death. New consensuses are published to better guide the diagnostic tools, stratification scores and treatment. Genetic testing plays somehow an important role in the diagnosis, risk-stratification and treatment of patients and family members. Molecular genetic advances in the last 2 decades have revealed the underlying genetic basis and these may lead to a personalized medicine...