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Idiopathic ventricular fibrillation is diagnosed in survivors of sudden cardiac death that has been caused by ventricular fibrillation without known structural or electrical abnormalities, even after extensive investigation. It is a common cause of sudden death in young adults. Although idiopathic ventricular fibrillation is a diagnosis of exclusion, in many cases only a partial investigation algorithm is performed. The aim of this review is to present a comprehensive diagnostic evaluation algorithm with a focus on diagnostic assessment of inherited arrhythmic syndromes and genetic background.
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Cytopathology induced by methamphetamine (METH) is reminiscent of degenerative disorders such as Parkinson's disease, and it is characterized by membrane organelles arranged in tubulo-vesicular structures. These areas, appearing as clusters of vesicles, have never been defined concerning the presence of specific organelles. Therefore, the present study aimed to identify the relative and absolute area of specific membrane-bound organelles following a moderate dose (100 µM) of METH administered to catecholamine-containing PC12 cells. Organelles and antigens were detected by immunofluorescence, and they were further quantified by plain electron microscopy and in situ stoichiometry. This analysis indicated an increase in autophagosomes and damaged mitochondria along with a decrease in lysosomes and healthy mitochondria. Following METH, a severe dissipation of hallmark proteins from their own vesicles was measured. In fact, the amounts of LC3 and p62 were reduced within autophagy vacuoles compared with the whole cytosol. Similarly, LAMP1 and Cathepsin-D within lysosomes were reduced. These findings suggest a loss of compartmentalization and confirm a decrease in the competence of cell clearing organelles during catecholamine degeneration. Such cell entropy is consistent with a loss of energy stores, which routinely govern appropriate subcellular compartmentalization.
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Autofagosomas , Lisosomas , Metanfetamina , Metanfetamina/farmacología , Animales , Células PC12 , Ratas , Lisosomas/metabolismo , Lisosomas/efectos de los fármacos , Autofagosomas/metabolismo , Autofagosomas/efectos de los fármacos , Autofagia/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Catepsina D/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismoRESUMEN
Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a primary arrhythmia disorder characterized by syncope or sudden cardiac death and typically caused by a gain-of-function of the Ryanodine Receptor Type 2 (RyR2) mutation. Calmodulin is a calcium-binding protein responsible for many intracellular signalling pathways and disruptions in function or regulation may lead to potentially fatal arrhythmias. We present a case of a young patient with CPVT found to have an unusual, potentially causative, Calmodulin 2-a protein coding gene (CALM2) mutation. Case summary: A 21-year-old female with autism was brought to the ED following cardiac arrest. Bidirectional ventricular tachycardia was captured on electrocardiogram. Propranolol was initiated, and patient had no further episodes of ventricular arrhythmia. A subcutaneous implantable cardioverter defibrillator (ICD) was implanted, and further genetics testing was done. Rapid Whole Genome Sequencing (PGnome®-RAPID) resulted heterozygous variant of uncertain significance in CALM2 gene NM_001743.5 for variant c.136G>A. Discussion: To the authors' knowledge, this is the third known record of such mutation in accordance with the International Calmodulin Registry (n = 74). Identification of CALM mutations can help advance the understanding of genetic underpinnings of arrhythmias and underscore necessity of genetic screening and personalized treatment strategies. Subcutaneous ICDs offer a promising therapeutic option while minimizing risks associated with traditional transvenous ICDs.
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BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare and lethal arrhythmia. Ryanodine receptor 2 (RYR2) mutation accounts for â¼60% of CPVT patients which is inherited in an autosomal dominant pattern. OBJECTIVE: This study aimed to identify CPVT-related mutations and clinical characteristics among Taiwanese CPVT patients and compare to other cohorts worldwide. METHODS: Clinical and genetic data were obtained from the Sudden Arrhythmia Death Syndrome Registry in Taiwan (SADS-TW). Forty clinically diagnosed Taiwanese CPVT patients were included. RESULTS: This is the first nationwide CPVT cohort in Taiwan. Among the 29 Taiwanese patients with CPVT-related gene mutations, 55% had RYR2 mutations, a rate similar to other ethnicities. Three out of 12 RYR2 variants were unreported. Exercise-induced symptoms including syncope and cardiac arrest were more frequent in East Asian cohorts (Taiwanese 79%, Japanese 91%), compared to Caucasian cohorts (59%) (p = 0.002). CONCLUSION: The discovery of diverse RYR2 mutations in the Taiwanese CVPT population demonstrates the importance of genetic testing in different ethnicities.
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Progress of treadmill exercise testing in Case 1 Each electrocardiogram shows the maximum load. Before left cardiac sympathetic denervation, polymorphic ventricular tachycardias were observed. After left cardiac sympathetic denervation, no ventricular arrhythmias were induced during exercise.
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INTRODUCTION: We report the case of a 37-year-old male athlete, who developed during exercise atrial and ventricular arrhythmias. No structural heart disease. RESULTS: Invasive programmed ventricular stimulation induced ventricular fibrillation. A heterozygous mutation in the CASQ2 gene (c.775G>T, p.E259X) was found. CONCLUSIONS: The findings in our patient may suggest some increased ventricular excitability using programmed ventricular stimulation in CASQ2 polymorphic ventricular tachycardia patients.
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BACKGROUND: Holter monitoring may raise suspicion of an underlying catecholaminergic polymorphic ventricular tachycardia (CPVT) diagnosis. Although not a primary investigation for CPVT, Holter monitoring is ubiquitously used as a diagnostic tool in the heart rhythm clinic. OBJECTIVES: The objective of this study was to explore Holter monitoring in CPVT diagnosis. METHODS: This retrospective cohort study analyzed off-therapy Holter monitoring from 13 ryanodine receptor 2-positive CPVT and 34 healthy patients from the Canadian Hearts in Rhythm Organization national registry. Using the Edwards method, the ratio of ambient-maximum heart rate during Holter monitoring was correlated with exertion level to separate premature ventricular contractions (PVCs) during periods of adrenergic and nonadrenergic stress. A receiver operating characteristic curve analysis determined the optimal threshold for isolating CPVT-induced PVCs during adrenergic states. RESULTS: PVC burden differed between groups (P = 0.001) but was within population norm, suggesting ambient PVCs are uncommon in CPVT. CPVT patients had higher PVC counts than healthy controls (P = 0.002), with a different distribution based on adrenergic state. The optimal threshold for separating PVCs into periods of adrenergic and nonadrenergic stress in CPVT patients was 76% of the maximum heart rate during the monitoring period. Compared with healthy controls, CPVT patients had a higher PVC count, limited to periods of adrenergic stress, defined by >76% maximum heart rate threshold (P = 0.002; area under the receiver operating characteristic curve: 0.84). Below this threshold, there was no significant PVC difference (P = 0.604). CONCLUSIONS: Holter monitor PVC counts alone are inadequate for CPVT diagnosis, owing to the adrenergic nature of the disease. Quantifying PVC prevalence at a heart rate threshold >76% identified CPVT with moderate sensitivity (69%) and high specificity (94%).
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BACKGROUND: Despite the growing body of evidence supporting the use of angiotensin II (ATII) in distributive shock, its integration into existing treatment algorithms requires careful consideration of factors related to patient comorbidities, hemodynamic parameters, cost-effectiveness, and risk-benefit balance. Moreover, several questions regarding its use in clinical practice warrant further investigations. To address these challenges, a group of Italian intensive care specialists (the panel) developed a consensus process using a modified Delphi technique. METHODS: The panel defined five clinical questions during an online scoping workshop and then provided a short list of statements related to each clinical question based on literature review and clinical experience. A total of 20 statements were collected. Two coordinators screened and selected the final list of statements to be included in the online survey, which consisted of 17 statements. The consensus was reached when ≥ 75% of respondents assigned a score within the 3-point range of 1-3 (disagreement) or 7-9 (agreement). RESULTS: Overall, a consensus on agreement was reached on 13 statements defining the existing gaps in scientific evidence, the possibility of evaluating the addition of drugs with different mechanisms of action for the treatment of refractory shock, the utility of ATII in reducing the catecholamine requirements in the treatment of vasopressor-resistant septic shock, and the effectiveness of ATII in treating patients in whom angiotensin-converting enzyme activity is reduced or pharmacologically blocked. It was widely shared that renin concentration can be used to identify patients who most likely benefit from ATII to restore vascular tone. Thus, the patients who might benefit most from using ATII were defined. Lastly, some potential barriers to the use of ATII were described. CONCLUSIONS: ATII was recognized as a useful treatment to reduce catecholamine requirements in treating vasopressor-resistant septic shock. At the same time, the need for additional clinical trials to further elucidate the efficacy and safety of ATII, as well as investigations into potential mechanisms of action and optimization of treatment protocols in patients with refractory distributive shock, emerged.
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It has been reported that the clinical symptoms of functional dyspepsia (FD) exacerbate upon stress while the gender-related factors have been incompletely understood. This study aims to investigate the role of sex in chronic heterotypic stress (CHS)-induced autonomic and gastric motor dysfunction. For CHS, the rats were exposed to the combination of different stressors for 7 consecutive days. Subsequently, electrocardiography was recorded in anesthetized rats to evaluate heart rate variability (HRV) for the determination of autonomic outflow and sympathovagal balance. Solid gastric emptying (GE) was measured in control and CHS-loaded male and female rats. The immunoreactivities of catecholaminergic cell marker tyrosine hydroxylase (TH), choline acetyltransferase (ChAT), corticotropin releasing factor (CRF), and estrogen receptor (ER-α/ß) were evaluated in medullary and pontine brainstem sections by immunohistochemistry. Compared with the controls, CHS significantly delayed GE in males but not in females. There was no significant sex-related difference in parasympathetic indicator HF under either control or CHS conditions. Sympathetic indicator LF was significantly higher in control females compared to the males. The higher sympathetic output in females was found to be attenuated upon CHS; in contrast, the elevated sympathetic output was detected in CHS-loaded males. No sex- or stress-related effect was observed on ChAT immunoreactivity in the dorsal motor nucleus of N.vagus (DMV). In males, greater number of TH-ir cells was observed in the caudal locus coeruleus (LC), while they were more densely detected in the rostral LC of females. Regardless of sex, CHS elevated immunoreactivity of TH throughout the LC. Under basal conditions, greater number of TH-ir cells was detected in the rostral ventrolateral medulla (RVLM) of females. In contrast, CHS remarkably increased the number of TH-ir cells in the RVLM of males which was found to be decreased in females. There was no sex-related alteration in TH immunoreactivity in the nucleus tractus solitarius (NTS) of control rats, while CHS affected both sexes in a similar manner. Compared with females, CRF immunoreactivity was prominently observed in control males, while both of which were stimulated by CHS. ER-α/ß was found to be co-expressed with TH in the NTS and LC which exhibit no alteration related to either sex or stress status. These results indicate a sexual dimorphism in the catecholaminergic and the CRF system in brainstem which might be involved in the CHS-induced autonomic and visceral dysfunction occurred in males.
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Ratas Sprague-Dawley , Caracteres Sexuales , Estrés Psicológico , Animales , Masculino , Femenino , Estrés Psicológico/metabolismo , Estrés Psicológico/fisiopatología , Ratas , Rombencéfalo/metabolismo , Motilidad Gastrointestinal/fisiología , Catecolaminas/metabolismo , Tirosina 3-Monooxigenasa/metabolismo , Sistema Nervioso Autónomo/fisiopatología , Sistema Nervioso Autónomo/metabolismo , Frecuencia Cardíaca/fisiología , Hormona Liberadora de Corticotropina/metabolismo , Vaciamiento Gástrico/fisiología , Colina O-Acetiltransferasa/metabolismoRESUMEN
Genetic arrhythmia disorders are rare diseases; however, they are a common cause of sudden cardiac death in children, adolescents, and young adults. In principle, a distinction can be made between channelopathies and cardiomyopathies in the context of genetic diseases. This paper focuses on the channelopathies long and short QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia (CPVT). Early diagnosis of these diseases is essential, as drug therapy, behavioral measures, and if necessary, implantation of a cardioverter defibrillator can significantly improve the prognosis and quality of life of patients. This paper highlights the pathophysiological and genetic basis of these channelopathies, describes their clinical manifestations, and comments on the principles of diagnosis, risk stratification and therapy.
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Arritmias Cardíacas , Síndrome de Brugada , Canalopatías , Humanos , Arritmias Cardíacas/genética , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/terapia , Arritmias Cardíacas/fisiopatología , Canalopatías/genética , Canalopatías/diagnóstico , Canalopatías/terapia , Síndrome de Brugada/genética , Síndrome de Brugada/diagnóstico , Síndrome de Brugada/fisiopatología , Síndrome de Brugada/terapia , Taquicardia Ventricular/genética , Taquicardia Ventricular/terapia , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/fisiopatología , Adolescente , Niño , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/diagnóstico , Síndrome de QT Prolongado/terapia , Síndrome de QT Prolongado/fisiopatología , Muerte Súbita Cardíaca/prevención & control , Muerte Súbita Cardíaca/etiología , Adulto , Desfibriladores Implantables , ElectrocardiografíaRESUMEN
Cardiac ryanodine receptor (RyR2) gain-of-function mutations cause catecholaminergic polymorphic ventricular tachycardia (CPVT). Conversely, RyR2 loss-of-function mutations cause a new disease entity, termed calcium release deficiency syndrome (CRDS), which may include RYR2-related long QT syndrome (LQTS). Importantly, unlike CPVT, patients with CRDS do not always exhibit exercise- or epinephrine-induced ventricular arrhythmias, which precludes a diagnosis of CRDS. Here we report a boy and his father, who both experienced exercise-induced cardiac events and harbor the same RYR2 E4107A variant. In the boy, an exercise stress test (EST) and epinephrine provocation test (EPT) did not induce any ventricular arrhythmias. QTc was slightly prolonged (QTc: 474 ms), and an EPT induced QTc prolongation (QTc-baseline: 466 ms, peak: 532 ms, steady-state: 527 ms). In contrast, in his father, QTc was not prolonged (QTc: 417 ms), and neither an EST nor EPT induced QTc prolongation. However, an EST induced multifocal premature ventricular contraction (PVC) bigeminy and bidirectional PVC couplets. Thus, they exhibited distinct clinical phenotypes: the boy exhibited LQTS (or CRDS) phenotype, whereas his father exhibited CPVT phenotype. These findings suggest that, in addition to the altered RyR2 function, other unidentified factors, such as other genetic, epigenetic, and environmental factors, and aging, may be involved in the diverse phenotypic manifestations. Considering that a single RYR2 variant can cause both CPVT and LQTS (or CRDS) phenotypes, in cascade screening of patients with CPVT and CRDS, an EST and EPT are not sufficient and genetic analysis is required to identify individuals who are at increased risk for life-threatening arrhythmias.
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Síndrome de QT Prolongado , Fenotipo , Canal Liberador de Calcio Receptor de Rianodina , Taquicardia Ventricular , Humanos , Canal Liberador de Calcio Receptor de Rianodina/genética , Masculino , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/diagnóstico , Taquicardia Ventricular/genética , Taquicardia Ventricular/diagnóstico , Electrocardiografía , Linaje , Adulto , Prueba de Esfuerzo , MutaciónRESUMEN
Arrhythmias account for over 300,000 annual deaths in the United States, and approximately half of all deaths are associated with heart disease. Mechanisms underlying arrhythmia risk are complex; however, work in humans and animal models over the past 25 years has identified a host of molecular pathways linked with both arrhythmia substrates and triggers. This chapter will focus on select arrhythmia pathways solved by linking human clinical and genetic data with animal models.
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Arritmias Cardíacas , Modelos Animales de Enfermedad , Animales , Humanos , Arritmias Cardíacas/genética , Arritmias Cardíacas/fisiopatología , Arritmias Cardíacas/metabolismo , Transducción de Señal/genéticaRESUMEN
BACKGROUND: Energy drinks potentially can trigger life-threatening cardiac arrhythmias. It has been postulated that the highly stimulating and unregulated ingredients alter heart rate, blood pressure, cardiac contractility, and cardiac repolarization in a potentially proarrhythmic manner. OBJECTIVE: The purpose of this study was to describe our experience regarding sudden cardiac arrest (SCA) occurring in proximity to energy drink consumption in patients with underlying genetic heart diseases. METHODS: The electronic medical records of all SCA survivors with proven arrhythmias referred to the Mayo Clinic Windland Smith Rice Genetic Heart Rhythm Clinic for evaluation were reviewed to identify those who consumed an energy drink before their event. Patient demographics, clinical characteristics, documented energy drink consumption, and temporal relationship of energy drink consumption to SCA were obtained. RESULTS: Among 144 SCA survivors, 7 (5%; 6 female; mean age at SCA 29 ± 8 years) experienced an unexplained SCA associated temporally with energy drink consumption. Of these individuals, 2 had long QT syndrome and 2 had catecholaminergic polymorphic ventricular tachycardia; the remaining 3 were diagnosed with idiopathic ventricular fibrillation. Three patients (43%) consumed energy drinks regularly. Six patients (86%) required a rescue shock, and 1 (14%) was resuscitated manually. All SCA survivors have quit consuming energy drinks and have been event-free since. CONCLUSION: Overall, 5% of SCA survivors experienced SCA in proximity to consuming an energy drink. Although larger cohort studies are needed to elucidate the incidence/prevalence and quantify its precise risk, it seems prudent to sound an early warning on this potential risk.
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Muerte Súbita Cardíaca , Bebidas Energéticas , Humanos , Femenino , Masculino , Bebidas Energéticas/efectos adversos , Adulto , Muerte Súbita Cardíaca/etiología , Muerte Súbita Cardíaca/epidemiología , Estudios Retrospectivos , Adulto Joven , Incidencia , Electrocardiografía , Factores de Riesgo , Taquicardia Ventricular/etiología , Taquicardia Ventricular/fisiopatología , Taquicardia Ventricular/epidemiología , Síndrome de QT Prolongado/fisiopatología , Síndrome de QT Prolongado/inducido químicamenteRESUMEN
Inherited forms of cardiac arrhythmias mostly are rare diseases (prevalence <1:2000) and considered to be either "primary electrical heart disorders" due to the absence of structural heart abnormalities or "cardiac ion channel disorders" due to the myocellular structures involved. Precise knowledge of the electrocardiographic features of these diseases and their genetic classification will enable early disease recognition and prevention of cardiac events including sudden cardiac death.The genetic background of these diseases is complex and heterogeneous. In addition to the predominant "private character" of a mutation in each family, locus heterogeneity involving many ion channel genes for the same familial arrhythmia syndrome is typical. Founder pathogenic variants or mutational hot spots are uncommon. Moreover, phenotypes may vary and overlap even within the same family and mutation carriers. For the majority of arrhythmias, the clinical phenotype of an ion channel mutation is restricted to cardiac tissue, and therefore, the disease is nonsyndromic.Recent and innovative methods of parallel DNA analysis (so-called next-generation sequencing, NGS) will enhance further mutation and other variant detection as well as arrhythmia gene identification.
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Arritmias Cardíacas , Predisposición Genética a la Enfermedad , Mutación , Humanos , Arritmias Cardíacas/genética , Arritmias Cardíacas/fisiopatología , Predisposición Genética a la Enfermedad/genética , Canales Iónicos/genética , Fenotipo , ElectrocardiografíaRESUMEN
In this case report, we describe a 14-year-old patient with a novel RyR2 gene mutation (c.6577G > T/p.Val2193Leu), identified through a comprehensive review of medical history, examination findings, and follow-up data. The pathogenic potential of this mutation, which results in the loss of some interatomic forces and compromises the closure of the RyR2 protein pore leading to calcium leakage, was analyzed using the I-TASSER Suite to predict the structural changes in the protein. This mutation manifested clinically as co-morbid catecholaminergic polymorphic ventricular tachycardia (CPVT) and benign epilepsy with centrotemporal spikes (BECTS), a combination not previously documented in the same patient. While seizures were successfully managed with levetiracetam, the patient's exercise-induced syncope episodes could not be controlled with metoprolol, highlighting the complexity and challenge in managing CPVT associated with this novel RyR2 variation.
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Mutación , Canal Liberador de Calcio Receptor de Rianodina , Taquicardia Ventricular , Humanos , Canal Liberador de Calcio Receptor de Rianodina/genética , Taquicardia Ventricular/genética , Taquicardia Ventricular/tratamiento farmacológico , Adolescente , Masculino , Epilepsia Rolándica/genética , Epilepsia Rolándica/tratamiento farmacológico , ElectrocardiografíaRESUMEN
BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) may cause sudden cardiac death (SCD) despite medical therapy. Therefore, implantable cardioverter-defibrillators (ICDs) are commonly advised. However, there is limited data on the outcomes of ICD use in children. OBJECTIVE: The purpose of this study was to compare the risk of arrhythmic events in pediatric patients with CPVT with and without an ICD. METHODS: We compared the risk of SCD in patients with RYR2 (ryanodine receptor 2) variants and phenotype-positive symptomatic CPVT patients with and without an ICD who were younger than 19 years and had no history of sudden cardiac arrest at phenotype diagnosis. The primary outcome was SCD; secondary outcomes were composite end points of SCD, sudden cardiac arrest, or appropriate ICD shocks with or without arrhythmic syncope. RESULTS: The study included 235 patients, 73 with an ICD (31.1%) and 162 without an ICD (68.9%). Over a median follow-up of 8.0 years (interquartile range 4.3-13.4 years), SCD occurred in 7 patients (3.0%), of whom 4 (57.1%) were noncompliant with medications and none had an ICD. Patients with ICD had a higher risk of both secondary composite outcomes (without syncope: hazard ratio 5.85; 95% confidence interval 3.40-10.09; P < .0001; with syncope: hazard ratio 2.55; 95% confidence interval 1.50-4.34; P = .0005). Thirty-one patients with ICD (42.5%) experienced appropriate shocks, 18 (24.7%) inappropriate shocks, and 21 (28.8%) device-related complications. CONCLUSION: SCD events occurred only in patients without an ICD and mostly in those not on optimal medical therapy. Patients with an ICD had a high risk of appropriate and inappropriate shocks, which may be reduced with appropriate device programming. Severe ICD complications were common, and risks vs benefits of ICDs need to be considered.
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Functional magnetic resonance imaging (fMRI) suggests that the hypoxic ventilatory response is facilitated by the AMP-activated protein kinase (AMPK), not at the carotid bodies, but within a subnucleus (Bregma -7.5 to -7.1 mm) of the nucleus tractus solitarius that exhibits right-sided bilateral asymmetry. Here, we map this subnucleus using cFos expression as a surrogate for neuronal activation and mice in which the genes encoding the AMPK-α1 (Prkaa1) and AMPK-α2 (Prkaa2) catalytic subunits were deleted in catecholaminergic cells by Cre expression via the tyrosine hydroxylase promoter. Comparative analysis of brainstem sections, relative to controls, revealed that AMPK-α1/α2 deletion inhibited, with right-sided bilateral asymmetry, cFos expression in and thus activation of a neuronal cluster that partially spanned three interconnected anatomical nuclei adjacent to the area postrema: SolDL (Bregma -7.44 mm to -7.48 mm), SolDM (Bregma -7.44 mm to -7.48 mm) and SubP (Bregma -7.48 mm to -7.56 mm). This approximates the volume identified by fMRI. Moreover, these nuclei are known to be in receipt of carotid body afferent inputs, and catecholaminergic neurons of SubP and SolDL innervate aspects of the ventrolateral medulla responsible for respiratory rhythmogenesis. Accordingly, AMPK-α1/α2 deletion attenuated hypoxia-evoked increases in minute ventilation (normalised to metabolism), reductions in expiration time, and increases sigh frequency, but increased apnoea frequency during hypoxia. The metabolic response to hypoxia in AMPK-α1/α2 knockout mice and the brainstem and spinal cord catecholamine levels were equivalent to controls. We conclude that within the brainstem an AMPK-dependent, hypoxia-responsive subnucleus partially spans SubP, SolDM and SolDL, namely SubSol-HIe, and is critical to coordination of active expiration, the hypoxic ventilatory response and defence against apnoea.
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Proteínas Quinasas Activadas por AMP , Apnea , Hipoxia , Núcleo Solitario , Animales , Núcleo Solitario/metabolismo , Hipoxia/metabolismo , Ratones , Proteínas Quinasas Activadas por AMP/metabolismo , Proteínas Quinasas Activadas por AMP/genética , Apnea/metabolismo , Apnea/fisiopatología , Masculino , Ratones Endogámicos C57BL , RespiraciónRESUMEN
Inherited arrhythmia syndromes (IASs) can cause life-threatening arrhythmias and are responsible for a significant proportion of sudden cardiac deaths (SCDs). Despite progress in the development of devices to prevent SCDs, the precise molecular mechanisms that induce detrimental arrhythmias remain to be fully investigated, and more effective therapies are desirable. In the present study, we screened a large-scale randomly mutagenized mouse library by electrocardiography to establish a disease model of IASs and consequently found one pedigree that exhibited spontaneous ventricular arrhythmias (VAs) followed by SCD within 1 y after birth. Genetic analysis successfully revealed a missense mutation (p.I4093V) of the ryanodine receptor 2 gene to be a cause of the arrhythmia. We found an age-related increase in arrhythmia frequency accompanied by cardiomegaly and decreased ventricular contractility in the Ryr2I4093V/+ mice. Ca2+ signaling analysis and a ryanodine binding assay indicated that the mutant ryanodine receptor 2 had a gain-of-function phenotype and enhanced Ca2+ sensitivity. Using this model, we detected the significant suppression of VA following flecainide or dantrolene treatment. Collectively, we established an inherited life-threatening arrhythmia mouse model from an electrocardiogram-based screen of randomly mutagenized mice. The present IAS model may prove feasible for use in investigating the mechanisms of SCD and assessing therapies.
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Taquicardia Ventricular , Ratones , Animales , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Arritmias Cardíacas/genética , Flecainida , Mutación Missense , Muerte Súbita Cardíaca , MutaciónRESUMEN
Background: Ryanodine receptor 2 (RYR2) gene mutation causing catecholaminergic polymorphic ventricular tachycardia (CPVT) is one of the identified causes of sudden death in adults and children. Case Description: We report a case of RYR2 gene mutation presented with cardiac arrest and recurrent syncopal attack with accidental finding of cardiac tumour. For the systematic review, we used four databases (Scopus, PubMed, Ovid and Google Scholar) to search articles with the terms "RYR2 gene mutation" and "catecholaminergic polymorphic ventricular tachycardia (CPVT)". Fourteen studies were chosen and reviewed together with our reported patient. Most of the patients presented initially with syncopal attack and developed cardiac arrest later. Some of them presented with both syncopal attack and seizures precipitated by exercise or stress. We found that 43.8% of patients shared similar variants or coding effects in RYR2 gene mutation. Demographically, the mean age at presentation is 11 years old with 53% of reported cases were male. Conclusions: Refractory arrhythmias cardiac arrest not responding to adrenaline should raise the suspicion towards RYR2 gene mutations. Recognition of this condition is important as it affects the outcome of resuscitation. Untimely diagnosis of RYR2 gene mutations with appropriate use of pharmacological agents during resuscitation is important to ensure a better outcome.