Abstract Background Sudden arrhythmic death syndrome (SADS) describes a sudden death with negative autopsy and toxicological analysis. Cardiac genetic disease is a likely etiology. Objectives This ...study investigated the clinical utility and combined yield of post-mortem genetic testing (molecular autopsy) in cases of SADS and comprehensive clinical evaluation of surviving relatives. Methods We evaluated 302 expertly validated SADS cases with suitable DNA (median age: 24 years; 65% males) who underwent next-generation sequencing using an extended panel of 77 primary electrical disorder and cardiomyopathy genes. Pathogenic and likely pathogenic variants were classified using American College of Medical Genetics (ACMG) consensus guidelines. The yield of combined molecular autopsy and clinical evaluation in 82 surviving families was evaluated. A gene-level rare variant association analysis was conducted in SADS cases versus controls. Results A clinically actionable pathogenic or likely pathogenic variant was identified in 40 of 302 cases (13%). The main etiologies established were catecholaminergic polymorphic ventricular tachycardia and long QT syndrome (17 6% and 11 4%, respectively). Gene-based rare variants association analysis showed enrichment of rare predicted deleterious variants in RYR2 (p = 5 × 10-5 ). Combining molecular autopsy with clinical evaluation in surviving families increased diagnostic yield from 26% to 39%. Conclusions Molecular autopsy for electrical disorder and cardiomyopathy genes, using ACMG guidelines for variant classification, identified a modest but realistic yield in SADS. Our data highlighted the predominant role of catecholaminergic polymorphic ventricular tachycardia and long QT syndrome, especially the RYR2 gene, as well as the minimal yield from other genes. Furthermore, we showed the enhanced utility of combined clinical and genetic evaluation.
Objective
Persons with epilepsy have an increased mortality including a high risk of sudden unexplained death (SUD), also referred to as sudden unexpected death in epilepsy (SUDEP). We aimed to ...evaluate the risk of SUDEP in comparison to other causes of death and the risk of SUD in persons with and without epilepsy.
Methods
We undertook a retrospective population‐based cohort study of all Danish citizens with and without epilepsy aged 1–49 years during 2007–2009. All deaths in the population were evaluated, and all cases of SUD identified. Primary causes of death in persons with epilepsy were evaluated independently by three neurologists and one neuropediatrician, using the unified SUDEP criteria.
Results
The three most frequent causes of death in persons with epilepsy were cancer (2.38 per 1000 person‐years), SUDEP (1.65 per 1000 person‐years), and pneumonia (1.09 per 1000 person‐years) compared with cancer (.17 per 1000 person‐years), accident‐related deaths (.14 per 1000 person‐years), and cardiovascular disease (.09 per 1000 person‐years) in persons without epilepsy. Considering definite, definite plus, and probable cases, the SUDEP incidence was .27 per 1000 person‐years (95% confidence interval CI = .11–.64) in children aged 1–17 years and 1.21 per 1000 person‐years (95% CI = .96–1.51) in adults aged 18–49 years. Adjusted for age and sex, persons with epilepsy younger than 50 years had a 10.8‐fold (95% CI = 9.97–11.64, p < .0001) increased all‐cause mortality and a 34.4‐fold (95% CI = 23.57–50.28, p < .0001) increased risk of SUD compared with persons without epilepsy. SUDEP accounted for 23.3% of all SUD.
Significance
This nationwide study of all deaths in persons with epilepsy younger than 50 years found a lower SUDEP risk in children compared with adults, and that epilepsy was a major risk factor for SUD in the background population. This underlines the importance of addressing risk factors for SUDEP to prevent premature death.
Summary
Purpose
Patients with epilepsy are at increased risk of premature death from all causes and likely also from sudden unexplained death (SUD). Many patients with epilepsy have significant ...comorbidity, and it is unclear how much of the increased risk can be explained by epilepsy itself. We aimed to chart the incidence of sudden unexpected death in epilepsy (SUDEP) and estimate the risk of death from all causes and SUD conferred by epilepsy independently.
Methods
We conducted a historical cohort study using data from Danish registries and a complete manual review of all death certificates. The population studied consisted of all Danish residents in the age group 1–35 years, in the period 2000–2006 (inclusive), and the main outcome measures were risk of death and SUD.
Key Findings
We identified 33,022 subjects with epilepsy (median follow‐up 3.7 years) and 3,001,952 subjects without (median follow‐up 7.0 years). Among 685 deaths in the population with epilepsy, we identified 50 cases of definite and probable SUDEP corresponding to an incidence rate of 41.1 (95% confidence interval CI 31.6–54.9) per 100,000 person‐years. Incidence rates increased with age from 17.6 (95% CI 9.5–32.8) in the age group 1–18 years to 73.8 (95% CI 52.5–103.8) for the age group 24–35 years. Having epilepsy increased the crude risk of death with a hazard ratio (HR) of 11.9 (95% CI 11.0–12.9). When adjusting for sex and comorbidities often encountered in patients with epilepsy (neurologic disease including cerebral palsy, psychiatric disease including mental retardation, and congenital disorders), as well as the Charlson comorbidity score, the HR fell to 5.4 (95% CI 4.9–6.0). The crude HR for SUD was 27.5 (95% CI 18.1–41.8) and fell to 16.3 (95% CI 9.8–26.9) when adjusted for the same covariates as above.
Significance
Epilepsy in and of itself carries a significant risk of premature death and SUD. These findings highlight the potential gains of risk factor modification for the prevention of premature death and SUDEP in patients with epilepsy.
Younger adults with epilepsy have an increased mortality. Some deaths are seizure‐related, for example, sudden unexpected death in epilepsy (SUDEP), whereas others, for example, suicide, have ...multiple causes, including adverse effects of the treatment on mood. In this retrospective population‐based study of all Danish persons with epilepsy aged 18 to 49 years during 2007 to 2009 we evaluated the risk of death from seizures and suicide. SUDEP comprised 82.7% of all seizure‐related death. Younger adults with epilepsy had an 8.3‐fold increased risk of death from seizure‐related causes compared with suicide. This underpins the importance of effective seizure control in preventing premature death. ANN NEUROL 2021;90:983–987
Calcium is a crucial second messenger in the cardiovascular system. However, calcium may also be an extracellular first messenger through a G‐protein‐coupled receptor that senses extracellular ...concentration (Ca2+o), the calcium‐sensing receptor (CaR). The most prominent physiological function of the CaR is to maintain the extracellular Ca2+ level in a very tight range by regulating the circulating levels of parathyroid hormone (PTH). This control over PTH and Ca2+ levels is partially lost in patients suffering from primary and secondary hyperparathyroidism. Allosteric modulators of the CaR (calcimimetics) are the first drugs in their class to become available for clinical use and have been shown to successfully treat certain forms of primary and secondary hyperparathyroidism. In addition, several studies suggest beneficial effects of calcimimetics on cardiovascular risk factors associated with hyperparathyroidism. Although a plethora of studies demonstrated the CaR in heart and blood vessels, exact roles of the receptor in the cardiovascular system still remain to be elucidated. However, several studies point toward a possibility that the CaR might be involved in the regulation of vascular tone. This review will summarize the current knowledge on the possible functions of the CaR and calcimimetics on blood pressure regulation.
LINKED ARTICLES This article is part of a themed issue on Vascular Endothelium in Health and Disease. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue‐3
The aim of this study was to evaluate the pharmacokinetic variability of beta‐adrenergic blocking agents used in cardiology by reviewing single‐dose and steady‐state pharmacokinetic studies from the ...literature. PubMed was searched for pharmacokinetic studies of beta‐adrenergic blocking agents, both single‐dose and steady‐state studies. The studies included reported maximum plasma concentration (Cmax) and/or area under the concentration curve (AUC). The coefficient of variation (CV%) was calculated for all studies, and a CV% <40% was considered low or moderate variability, and a CV% >40% was considered high variability. The Cmax and AUC were reported a total of 672 times in 192 papers. Based on AUC, metoprolol, propranolol, carvedilol, and nebivolol showed high pharmacokinetic variability (highest first), whereas bisoprolol, atenolol, sotalol, labetalol, nadolol, and pindolol showed low to moderate variability (lowest first). We have shown a high interindividual pharmacokinetic variability that varies markedly in different beta‐adrenergic blocking agents; the extreme being steady state ratios as high as 30 in metoprolol. A more personalized approach to the medical treatment of patients may be obtained by combining known pharmacokinetic information about variability, pharmaco‐genetics and ‐dynamics, and patient characteristics, to avoid adverse events or lack of treatment effect.
Aims
The current knowledge of idiopathic ventricular fibrillation (IVF) is limited. We aimed to investigate the nature of IVF, including clinical assessment and later diagnosis, and risk factors of ...implantable cardioverter defibrillator (ICD) therapy in the follow‐up period.
Methods
Between 2007 and 2019 we systematically identified all patients from Rigshospitalet, Denmark, with a resuscitated sudden cardiac arrest (SCA) with no identifiable cause. All patients were followed routinely in the ICD outpatient clinic and the majority also in an inherited heart disease outpatient clinic. Outcomes were analysed with Cox regressions models and cumulative incidence curves.
Results
We identified 84 patients with an initial diagnosis of IVF; of these, three (3.6%) patients were later diagnosed with a cardiac disease. The remaining IVF patients (n = 81, median age 45 years; men 71.6%) were followed a median follow‐up of 5.2 years (interquartile range, 2.0–7.6). A total of 24 (29.6%) patients had appropriate ICD therapy and 12 (14.8%) patients had inappropriate ICD therapy. No predominant type of ventricular arrhythmia at first appropriate ICD therapy was observed. Early repolarization at baseline was not associated with an increased risk of appropriate ICD therapy (P = .842). Repeated cardiac arrest at index SCA increased the risk of appropriate ICD therapy (hazard ratio, 2.63 95% CI, 1.08–6.40; P = .033).
Conclusion
Most patients remained idiopathic throughout the follow‐up period and the overall long‐term prognosis of IVF was good. Repeated cardiac arrest at index SCA was a risk factor of appropriate ICD therapy and early repolarization was not associated with an increased risk of appropriate ICD therapy.
Background
Obstructive sleep apnea (OSA) creates a complex substrate for atrial fibrillation (AF), which is refractory to many clinically available pharmacological interventions. We investigated ...atrial antiarrhythmogenic properties and ventricular electrophysiological safety of small‐conductance Ca2+‐activated K+ (SK)‐channel inhibition in a porcine model for obstructive respiratory events.
Methods
In spontaneously breathing pigs, obstructive respiratory events were simulated by intermittent negative upper airway pressure (INAP) applied via a pressure device connected to the intubation tube. INAP was applied for 75 s, every 10 min, three times before and three times during infusion of the SK‐channel inhibitor AP14145. Atrial effective refractory periods (AERP) were acquired before (pre‐INAP), during (INAP) and after (post‐) INAP. AF‐inducibility was determined by a S1S2 atrial pacing protocol. Ventricular arrhythmicity was evaluated by heart rate adjusted QT‐interval duration (QT‐paced) and electromechanical window (EMW) shortening.
Results
During vehicle infusion, INAP transiently shortened AERP (pre‐INAP: 135 ± 10 ms vs. post‐INAP 101 ± 11 ms; p = .008) and increased AF‐inducibility. QT‐paced prolonged during INAP (pre‐INAP 270 ± 7 ms vs. INAP 275 ± 7 ms; p = .04) and EMW shortened progressively throughout INAP and post‐INAP (pre‐INAP 80 ± 4 ms; INAP 59 ± 6 ms, post‐INAP 46 ± 10 ms). AP14145 prolonged baseline AERP, partially prevented INAP‐induced AERP‐shortening and reduced AF‐susceptibility. AP14145 did not alter QT‐paced at baseline (pre‐AP14145 270 ± 7 ms vs. AP14145 268 ± 6 ms, p = .83) or QT‐paced and EMW‐shortening during INAP.
Conclusion
In a pig model for obstructive respiratory events, the SK‐channel‐inhibitor AP14145 prevented INAP‐associated AERP‐shortening and AF‐susceptibility without impairing ventricular electrophysiology. Whether SK‐channels represent a target for OSA‐related AF in humans warrants further study.
Obstructive respiratory events, shortening of atrial refractoriness and efficacy of AAD: Obstructive respiratory events may be associated with venous preload, arousal, thoracic pressure swings and asphyxic blood gas changes (hypoxia and hypercapnia). These pathophysiological elements may contribute to shortened atrial refractoriness in the setting of OSA. While established AADs could not blunt apnea‐related shortening in atrial refractoriness, AP14145, as a novel SK‐channel inhibitor could. Nevertheless, SK‐channel involvement in OSA‐related AF remains putative and further investigations are warranted. AAD, atrial antiarrhythmic drugs, OSA, obstructive sleep apnea.
Background
Cardiac arrhythmias in horses are diagnosed by auscultation or electrocardiogram (ECG), which results in a low sensitivity for detecting arrhythmias that occur sporadically. Implantable ...loop recorders (ILRs) are small ECG devices placed subcutaneously, to automatically detect arrhythmias in human patients.
Objectives
To test ILRs ability to detect atrial fibrillation (AF) in horses. Furthermore, we hypothesised that anatomical location of the implant site might influence signal quality. Signal quality was evaluated both during exercise and over time.
Study design
Experimental study.
Methods
In five Standardbred mares, eleven ILRs were implanted subcutaneously in up to three different positions (Front: pectoral region, Left‐6: sixth left intercostal space and Ventral: xiphoid region) and AF induced. The R‐ and T‐wave amplitudes were measured in all positions over time during AF. AF burden automatically registered by the ILRs over a 2‐month period was compared with selected Holter ECG recordings.
Results
All three positions had stable R‐ and T‐wave amplitudes during the study period and were of sufficient quality to allow AF detection at rest. The position Left‐6 showed significantly higher R‐ and T‐wave amplitudes compared with the other positions. During submaximal exercise only the Left‐6 position was able to record ECG signals of diagnostic quality. No position yielded diagnostic signals at maximum exercise due to artefacts.
Main limitations
Few horses and ILRs included and no spontaneous AF episodes were studied.
Conclusions
This preliminary study indicates that ILRs can be used for AF detection in horses, but the anatomical location is important for optimal ECG quality. Despite insufficient quality during exercise, ILRs were suitable for AF detection at rest. Therefore, the ILR may be a valuable diagnostic tool for detecting paroxysmal AF in horses.
Background
International guidelines recommend work‐up of relatives to autopsy negative sudden cardiac death victims, denoted as sudden unexplained death (SUD) and nonautopsied possible sudden cardiac ...death (pSCD) victims. This study assesses and compare baseline characteristics and clinical outcome at initial evaluation and during follow‐up of relatives to SUD and pSCD victims.
Methods
We retrospectively included data from systematic screening and routine follow‐up of first‐degree relatives to SUD and pSCD victims referred to our Unit for Inherited Cardiac Diseases, Copenhagen, 2005–2018. Victims with an antemortem known inherited cardiac disease were excluded.
Results
We included 371 first‐degree relatives from 187 families (120 SUD, 67 pSCD): 276 SUD relatives (age 33 ± 18 years, 54% men) and 95 pSCD relatives (age 40 ± 15 years, 51% men). The diagnostic yields of inherited cardiac diseases in SUD and pSCD families were 16% and 13%, respectively (p = .8). The diagnoses in SUD families were mainly channelopathies (68%), whereas pSCD families were equally diagnosed with cardiomyopathies, channelopathies, and premature ischemic heart disease. Ninety‐three percent of diagnosed families were diagnosed at initial evaluation and 7% during follow‐up (5.4 ± 3.3 years). During follow‐up 34% of relatives with a diagnosed inherited cardiac disease had an arrhythmic event, compared to 5% of relatives without established diagnosis (p < .0001).
Conclusions
Channelopathies dominated in SUD families whereas a broader spectrum of inherited diseases was diagnosed in pSCD families. Most affected relatives were diagnosed at initial evaluation. The event rate was low in relatives without an established diagnosis. Long‐term clinical follow‐up may not be warranted in all relatives with normal baseline‐findings.
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