Single-tilt tomograms of the dyads in rat ventricular myocytes indicated that type 2 ryanodine receptors (RYR2s) were not positioned in a well-ordered array. Furthermore, the orientation and packing ...strategy of purified type 1 ryanodine receptors in lipid bilayers is determined by the free Mg2+ concentration. These observations led us to test the hypothesis that RYR2s within the mammalian dyad have multiple and complex arrangements.
To determine the arrangement of RYR2 tetramers in the dyads of mammalian cardiomyocytes and the effects of physiologically and pathologically relevant factors on this arrangement.
We used dual-tilt electron tomography to produce en-face views of dyads, enabling a direct examination of RYR2 distribution and arrangement. Rat hearts fixed in situ; isolated rat cardiomyocytes permeabilized, incubated with 1 mmol/L Mg2+, and then fixed; and sections of human ventricle, all showed that the tetramer packing within a dyad was nonuniform containing a mix of checkerboard and side-by-side arrangements, as well as isolated tetramers. Both phosphorylation and 0.1 mmol/L Mg2+ moved the tetramers into a predominantly checkerboard configuration, whereas the 4 mmol/L Mg2+ induced a dense side-by-side arrangement. These changes occurred within 10 minutes of application of the stimuli.
The arrangement of RYR2 tetramers within the mammalian dyad is neither uniform nor static. We hypothesize that this is characteristic of the dyad in vivo and may provide a mechanism for modulating the open probabilities of the individual tetramers.
Puberty is initiated by hormonal changes in the adolescent body that trigger physical and behavioural changes to reach adult maturation. As these changes occur, some adolescents experience concerning ...pubertal symptoms that are associated with dysfunction of the autonomic nervous system. Vasovagal syncope (VVS) and Postural Orthostatic Tachycardia Syndrome (POTS) are common disorders of the autonomic nervous system associated with puberty that are related to orthostatic intolerance and share similar symptoms. Compared to young males, young females have decreased orthostatic tolerance and a higher incidence of VVS and POTS. As puberty is linked to changes in specific sex and non-sex hormones, and hormonal therapy sometimes improves orthostatic symptoms in female VVS patients, it is possible that pubertal hormones play a role in the increased susceptibility of young females to autonomic dysfunction. The purpose of this paper is to review the key hormonal changes associated with female puberty, their effects on the autonomic nervous system, and their potential role in predisposing some adolescent females to cardiovascular autonomic dysfunctions such as VVS and POTS. Increases in pubertal hormones such as estrogen, thyroid hormones, growth hormone, insulin, and insulin-like growth factor 1 promote vasodilatation and decrease blood volume. This may be exacerbated by higher levels of progesterone, which suppresses catecholamine secretion and sympathetic outflow. Abnormal heart rate increases in POTS patients may be exacerbated by pubertal increases in leptin, insulin, and thyroid hormones acting to increase sympathetic nervous system activity and/or catecholamine levels. Given the coincidental timing of female pubertal hormone surges and adolescent onset of VVS and POTS in young women, coupled with the known roles of these hormones in modulating cardiovascular homeostasis, it is likely that female pubertal hormones play a role in predisposing females to VVS and POTS during puberty. Further research is necessary to confirm the effects of female pubertal hormones on autonomic function, and their role in pubertal autonomic disorders such as VVS and POTS, in order to inform the treatment and management of these debilitating disorders.
Background
Orthostatic syncope (transient loss of consciousness when standing—fainting) is common and negatively impacts quality of life. Many patients with syncope report experiencing fatigue, ...sometimes with “brain fog”, which may further impact their quality of life, but the incidence and severity of fatigue in patients with syncope remain unclear. In this systematic review, we report evidence on the associations between fatigue and conditions of orthostatic syncope.
Methods
We performed a comprehensive literature search of four academic databases to identify articles that evaluated the association between orthostatic syncope postural orthostatic tachycardia syndrome (POTS), vasovagal syncope (VVS), orthostatic hypotension (OH) and fatigue. Studies were independently screened using a multi-stage approach by two researchers to maintain consistency and limit bias.
Results
Our initial search identified 2797 articles, of which 13 met our inclusion criteria (POTS
n
= 10; VVS
n
= 1; OH
n
= 1; VVS and POTS
n
= 1). Fatigue scores were significantly higher in patients with orthostatic syncope than healthy controls, and were particularly severe in those with POTS. Fatigue associated with orthostatic syncope disorders spanned multiple domains, with each dimension contributing equally to increased fatigue. “Brain fog” was an important symptom of POTS, negatively affecting productivity and cognition. Finally, fatigue was negatively associated with mental health in patients with POTS.
Conclusion
In conditions of orthostatic syncope, fatigue is prevalent and debilitating, especially in patients with POTS. The consideration of fatigue in patients with orthostatic disorders is essential to improve diagnosis and management of symptoms, thus improving quality of life for affected individuals.
Permanent junctional reciprocating tachycardia (PJRT) is an uncommon form of supraventricular tachycardia in children. Treatment of this arrhythmia has been considered difficult because of a high ...medication failure rate and risk of cardiomyopathy. Outcomes in the current era of interventional treatment with catheter ablation have not been published.
To describe the presentation and clinical course of PJRT in children.
This is a retrospective review of 194 pediatric patients with PJRT managed at 11 institutions between January 2000 and December 2010.
The median age at diagnosis was 3.2 months, including 110 infants (57%; aged <1 year). PJRT was incessant in 47%. The ratio of RP interval to cycle length was higher with incessant than with nonincessant tachycardia. Tachycardia-induced cardiomyopathy was observed in 18%. Antiarrhythmic medications were used for initial management in 76%, while catheter ablation was used initially in only 10%. Medications achieved complete resolution in 23% with clinical benefit in an additional 47%. Overall, 140 patients underwent 175 catheter ablation procedures with a success rate of 90%. There were complications in 9% with no major complications reported. Patients were followed for a median of 45.1 months. Regardless of treatment modality, normal sinus rhythm was present in 90% at last follow-up. Spontaneous resolution occurred in 12% of the patients.
PJRT in children is frequently incessant at the time of diagnosis and may be associated with tachycardia-induced cardiomyopathy. Antiarrhythmic medications result in complete control in few patients. Catheter ablation is effective, and serious complications are rare.
Abstract Pediatric syncope is a common problem that peaks in adolescence, for which there are few data or evidence-based consensus on investigation and management. This document offers guidance for ...practical evaluation/management of pediatric patients (age < 19 years) with syncope encountered in the acute or primary care setting. The writing committee used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. Most syncope is vasovagal, which is benign and does not require extensive investigation. This Position Statement presents recommendations to encourage an efficient and cost-effective disposition for the many patients with a benign cause of syncope, and highlights atypical or concerning clinical findings associated with other causes of transient loss of consciousness. The prodrome and the circumstances around which the event occurred are the most important aspects of the history. Syncope occurring midexertion suggests a cardiac etiology. A family history, which includes sudden death in the young or from unknown causes or causes that might be suspected to be other than natural can be a red flag. The electrocardiogram is the most frequently ordered test, but the yield is low and the test is not cost-effective when applied broadly to a population of patients with syncope. We recommend an electrocardiogram when the history is not suggestive of vasovagal syncope and there are features suggestive of a cardiac cause like absence of a prodrome, midexertional event, family history of early-life sudden death or heart disease, abnormal physical examination, or new medication with potential cardiotoxicity. For most patients with syncope, medical testing is not required and lifestyle modifications without medications suffice to prevent recurrences.
Sudden cardiac death (SCD) is a rare and devastating event in children and remains a leading cause of death in young athletes. Channelopathies and cardiomyopathies, in particular long QT syndrome ...(LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), hypertrophic cardiomyopathy (HCM), and arrhythmogenic cardiomyopathy (ACM) are associated with exercise-related SCD. Implantable cardioverter-defibrillators (ICDs) are often placed for secondary prevention for athletes with cardiomyopathy or channelopathy. There remains concern regarding the safety of return to participation with an ICD in place. Guidelines have historically recommended that patients with inherited heart rhythm disorders be restricted from competitive sports participation. Increasing evidence suggests a lower risk of exercise-related cardiac events in young athletes with inherited heart rhythm disorders. In this review, we highlight current knowledge, evolving guidelines, and present a multidisciplinary approach involving shared decision-making and appropriate planning for safe sports participation of children with inherited heart rhythm disorders.
Long QT syndrome confers susceptibility to ventricular arrhythmia, predisposing to syncope, seizures, and sudden death. While rare globally, long QT syndrome is ≈15× more common in First Nations of ...Northern British Columbia largely because of a known mutation in
. However, 2 large multigenerational families were affected, but negative for the known mutation.
Long QT syndrome panel testing was carried out in the index case of each family, and clinical information was collected. Cascade genotyping was performed. Biochemical and myocyte-based assays were performed to evaluate the identified gene variant for loss-of-function activity. Index cases in these 2 families harbored a novel
c.1937C>T variant (p.S646F). An additional 16 carriers were identified, including 2 with structural heart disease: one with cardiomyopathy resulting in sudden death and the other with congenital heart disease. For all carriers of this variant, the average QTc was 475 ms (±40). Although ankyrin-B p.S646F is appropriately folded and expressed in bacteria, the mutant polypeptide displays reduced expression in cultured H9c2 cells and aberrant localization in primary cardiomyocytes. Furthermore, myocytes expressing ankyrin-B p.S646F lack normal membrane targeting of the ankyrin-binding partner, the Na/Ca exchanger. Thus, ankyrin-B p.S646F is a loss-of-function variant.
We identify the first disease-causing
variant localized to the membrane-binding domain resulting in reduced ankyrin-B expression and abnormal localization. Further study is warranted on the potential association of this variant with structural heart disease given the role of
in targeting and stabilization of key structural and signaling molecules in cardiac cells.
Abstract Current survival rates for complex forms of congenital heart disease (CHD) are excellent, allowing for an ever-growing population of adult survivors. Previous interventions and complex ...physiology, including the systemic right ventricle and single ventricle circulations, predispose these patients to heart failure and arrhythmias. The relationship between arrhythmias and heart failure in CHD is complex: cause and effect are not always readily separated. Therefore, the assessment and management of these patients requires an understanding of the relationship between the 2, with careful review of risk factors and arrhythmia substrates. Several forms of CHD predispose to arrhythmias even in the absence of surgical intervention because of abnormalities of the conduction system and intrinsic structural malformations. Surgical interventions might result in sinus node dysfunction and propensity for supraventricular and ventricular arrhythmias. Arrhythmias are important risk factors for sudden death in the CHD population. Device therapies directed at maintaining chronotropic competence, cardiac resynchronization, and preventing sudden death are increasingly used. These challenges unique to CHD underscore recommendations for such complex patients to be referred to specialized centres with expertise in managing CHD and its complications. In this review, we explore the complex interplay between arrhythmogenesis, CHD, and heart failure.
This retrospective study sought to determine the safety and effectiveness of flecainide in children with normal hearts and those with congenital heart disease (CHD) or cardiomyopathy (CMO). Baseline ...and follow-up data at two pediatric cardiology sites were queried (2000–2015); a total of 175 patients (20 with CHD and two with CMO) receiving flecainide were assessed. When comparing patients with CHD to those with normal hearts, patients with CHD were younger at diagnosis (median age 19 days; IQR 3–157.5 days vs normal heart patients median age 21 days; IQR 7–172 days,
p
= 0.4) and severe cardiac dysfunction was more prevalent (30% in CHD patients vs 8% in normal heart patients,
p
= 0.009). Treatment duration did not differ between the two groups (CHD patients median duration 52 weeks; IQR 27–91.5 weeks vs normal heart patients median duration 55 weeks; IQR 32–156 weeks,
p
= 0.5). Cardiac dysfunction resulting in flecainide discontinuation occurred in two patients (1%), one with CHD and one without. Three patients experienced proarrhythmia (2%) and there were no cardiac arrests during follow-up. There was one death in this cohort in a patient with severe CHD and an RSV infection (<1%). Arrhythmia control did not differ between the groups (90% in CHD patients vs 77% in normal heart patients,
p
= 0.2). Flecainide was well tolerated in this cohort, with fewer than 3% discontinuing medication due to flecainide-associated adverse events. Contrary to adult studies, there was no difference in the incidence of adverse events between patients with normal hearts and patients with CHD. Flecainide is a safe and effective antiarrhythmic medication, even for children with underlying CHD.
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