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Sudden unexpected cardiac death generally occurs in persons with known or previously unrecognized heart disease. However, it has become evident that it occurs often enough in patients without any identifiable structural abnormality to warrant the cardiologist''s attention. Mostly, it concerns young, active, and otherwise healthy individuals. This paper focuses on various categories of patients with life-threatening events considered to have occurred on a solely “electrical” basis. Currently, several entities are recognized with distinct electrophysiological abnormalities, including Wolff-Parkinson-White syndrome, long QT syndrome, the Brugada syndrome, short-coupled torsade de pointes, and catecholamine-induced polymorphic ventricular tachyarrhythmia. The remaining patients without such distinct abnormalities are categorized as having idiopathic ventricular fibrillation. Although mechanical cardiac function may seem normal, such patients might have certain discrete anatomic abnormalities, unidentifiable with current investigational tools. Possibly in the future, with development of newer and more sophisticated tools (magnetic resonance imaging, positron emission tomography, genetic testing), some or all cases of idiopathic ventricular fibrillation must be redefined as having specific genetic and/or anatomic bases. All patients successfully resuscitated from cardiac arrest due to ventricular tachyarrhythmia without clear precipitating factors (acute myocardial infarction, severe electrolyte or metabolic disturbances) are at high risk of recurrences. Long-term prophylactic therapy is indicated. Contrasting with older belief, survivors of idiopathic ventricular fibrillation are now also considered high-risk patients. The implantable cardioverter-defibrillator appears to be the safest and most effective therapy. [Copyright &y& Elsevier]

STUDY QUESTION Are human ovarian aging and the age-related female fertility decline caused by oxidative stress and mitochondrial dysfunction in oocytes? SUMMARY ANSWER We found oxidative damage in oocytes of advanced maternal age, even at the primordial follicle stage, and confirmed mitochondrial dysfunction in such oocytes, which likely resulted in the use of alternative energy sources. WHAT IS KNOWN ALREADY Signs of reactive oxygen species-induced damage and mitochondrial dysfunction have been observed in maturing follicles, and even in early stages of embryogenesis. However, although recent evidence indicates that also primordial follicles have metabolically active mitochondria, it is still often assumed that these follicles avoid oxidative phosphorylation to prevent oxidative damage in dictyate arrested oocytes. Data on the influence of ovarian aging on oocyte metabolism and mitochondrial function are still limited. STUDY DESIGN, SIZE, DURATION A set of 39 formalin-fixed and paraffin-embedded ovarian tissue biopsies were divided into different age groups and used for immunofluorescence analysis of oxidative phosphorylation activity and oxidative damage to proteins, lipids, and DNA. Additionally, 150 immature oocytes (90 germinal vesicle oocytes and 60 metaphase I oocytes) and 15 cumulus cell samples were divided into different age groups and used for targeted metabolomics and lipidomics analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS Ovarian tissues used for immunofluorescence microscopy were collected through PALGA, the nationwide network, and registry of histo- and cytopathology in The Netherlands. Comprehensive metabolomics and lipidomics were performed by liquid–liquid extraction and full-scan mass spectrometry, using oocytes and cumulus cells of women undergoing ICSI treatment based on male or tubal factor infertility, or fertility preservation for non-medical reasons. MAIN RESULTS AND THE ROLE OF CHANCE Immunofluorescence imaging on human ovarian tissue indicated oxidative damage by protein and lipid (per)oxidation already at the primordial follicle stage. Metabolomics and lipidomics analysis of oocytes and cumulus cells in advanced maternal-age groups demonstrated a shift in the glutathione-to-oxiglutathione ratio and depletion of phospholipids. Age-related changes in polar metabolites suggested a decrease in mitochondrial function, as demonstrated by NAD+, purine, and pyrimidine depletion, while glycolysis substrates and glutamine accumulated, with age. Oocytes from women of advanced maternal age appeared to use alternative energy sources like glycolysis and the adenosine salvage pathway, and possibly ATP which showed increased production in cumulus cells. LIMITATIONS, REASONS FOR CAUTION The immature oocytes used in this study were all subjected to ovarian stimulation with high doses of follicle-stimulating hormones, which might have concealed some age-related differences. WIDER IMPLICATIONS OF THE FINDINGS Further studies on how to improve mitochondrial function, or lower oxidative damage, in oocytes from women of advanced maternal age, for instance by supplementation of NAD+ precursors to promote mitochondrial biogenesis, are warranted. In addition, supplementing the embryo medium of advanced maternal-age embryos with such compounds could be a treatment option worth exploring. STUDY FUNDING/COMPETING INTEREST(S) The study was funded by the Amsterdam UMC. The authors declare to have no competing interests. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

Abstract: Background: Early arrhythmia recurrences after pulmonary vein isolation (PVI) for atrial fibrillation (AF) are accepted as part of the blanking period. Their relevance for long-term efficacy is not well-known. We evaluated patients, who came to hospital with a documented recurrence of AF, or had a registered episode of AF on the 24-hour Holter 6weeks after PVI and compared it with long-term outcome. Methods: One hundred consecutive patients with paroxysmal AF were treated with the PVAC. In the 3-month blanking period patients who came to hospital with a documented recurrence of AF on ECG were recorded. 6weeks after procedure a 24-hour Holter was performed. After 3months patients were asked if they felt a relapse. Follow-up was performed at 3, 6, and 12months with ECG, 7-day Holter at 6 and/or 12months, and event recording if needed. Results: Within the blanking period, 25/100 (25%) patients had a documented recurrence of AF while 46/100 (46%) patients felt a relapse. After the blanking period up to 12months, 53/100 (53%) patients were free of AF without anti-arrhythmic drugs. Multivariate regression analyses revealed that absence of AF in the blanking period (OR 0.22 95%CI [0.05–0.98]) and absence of a relapse of symptoms suspect for AF during the blanking period (OR 0.21 95%CI [0.06–0.52]) were independent predictors of successful long-term outcome. Conclusions: Poor long-term outcome is strongly related to patients who experienced palpitations with ECG documented AF, AF on the 24-hour Holter at 6weeks after PVI and a relapse in the blanking period. [Copyright &y& Elsevier]

Background: After pulmonary vein isolation (PVI), patients need to be followed to analyze the effect of the treatment. We evaluated the influence of the duration of Holter monitoring on the detection of arrhythmia recurrences after a single PVI at 12 months. Methods: Consecutive patients with paroxysmal atrial fibrillation (AF) underwent successful PVI with phased radiofrequency and pulmonary vein ablation catheter. Follow-up was performed with electrocardiogram at 3, 6, and 12 months and 7-day Holter at 12 months. Symptomatic patients received additional event recording. The 7-day Holters at 12 months were evaluated for documented left atrial tachyarrhythmia recurrences, and each individual day with AF was categorized. Results: At 12 months after the procedure, 21 of the 96 (22%) patients had AF on their 7-day Holter. In the patients with AF recurrence, there was an increase in sensitivity from 53% of a 1-day Holter up to 88% with 4-day Holter, and 100% of a 7-day Holter. Monitoring with duration of less than 4 days resulted in significantly less detection of patients with AF compared to 7-day Holter. Conclusions: A 4-day Holter at 12 months has an 88% sensitivity for arrhythmia detection, and appears to provide a sufficient monitoring time. Prolonging the monitoring time to 7 days does not significantly increase the yield. PACE 2012; 35:164-169) [ABSTRACT FROM AUTHOR]

We investigated a syndromic disease comprising blindness and neurodegeneration in 11 Saarlooswolfdogs. Clinical signs involved early adult onset retinal degeneration and adult-onset neurological deficits including gait abnormalities, hind limb weakness, tremors, ataxia, cognitive decline and behavioral changes such as aggression towards the owner. Histopathology in one affected dog demonstrated cataract, retinal degeneration, central and peripheral axonal degeneration, and severe astroglial hypertrophy and hyperplasia in the central nervous system. Pedigrees indicated autosomal recessive inheritance. We mapped the suspected genetic defect to a 15 Mb critical interval by combined linkage and autozygosity analysis. Whole genome sequencing revealed a private homozygous missense variant, PCYT2 :c.4A>G, predicted to change the second amino acid of the encoded ethanolamine-phosphate cytidylyltransferase 2, XP_038402224.1:(p.Ile2Val). Genotyping of additional Saarlooswolfdogs confirmed the homozygous genotype in all eleven affected dogs and demonstrated an allele frequency of 9.9% in the population. This experiment also identified three additional homozygous mutant young dogs without overt clinical signs. Subsequent examination of one of these dogs revealed early-stage progressive retinal atrophy (PRA) and expansion of subarachnoid CSF spaces in MRI. Dogs homozygous for the pathogenic variant showed ether lipid accumulation, confirming a functional PCYT2 deficiency. The clinical and metabolic phenotype in affected dogs shows some parallels with human patients, in whom PCYT2 variants lead to a rare form of spastic paraplegia or axonal motor and sensory polyneuropathy. Our results demonstrate that PCYT2 :c.4A>G in dogs cause PCYT2 deficiency. This canine model with histopathologically documented retinal, central, and peripheral neurodegeneration further deepens the knowledge of PCYT2 deficiency. [ABSTRACT FROM AUTHOR]

Deficiency of succinate semialdehyde dehydrogenase (SSADH; aldehyde dehydrogenase 5a1 (ALDH5A1), OMIM 271980, 610045), the second enzyme of GABA degradation, represents a rare autosomal-recessively inherited disorder which manifests metabolically as gamma-hydroxybutyric aciduria. The neurological phenotype includes intellectual disability, autism spectrum, epilepsy and sleep and behavior disturbances. Approximately 70 variants have been reported in the ALDH5A1 gene, half of them being missense variants. In this study, 34 missense variants, of which 22 novel, were evaluated by in silico analyses using PolyPhen2 and SIFT prediction tools. Subsequently, the effect of these variants on SSADH activity was studied by transient overexpression in HEK293 cells. These studies showed severe enzymatic activity impairment for 27 out of 34 alleles, normal activity for one allele and a broad range of residual activities (25 to 74%) for six alleles. To better evaluate the alleles that showed residual activity above 25%, we generated an SSADH-deficient HEK293-Flp-In cell line using CRISPR-Cas9, in which these alleles were stably expressed. This model proved essential in the classification as deficient for one out of the seven studied alleles. For 8 out of 34 addressed alleles, there were discrepant results among the used prediction tools, and/or in correlating the results of the prediction tools with the functional data. In case of diagnostic urgency of missense alleles, we propose the use of the transient transfection model for confirmation of their effect on the SSADH catalytic function, since this model resulted in fast and robust functional characterization for the majority of the tested variants. In selected cases, stable transfections can be considered and may prove valuable. [ABSTRACT FROM AUTHOR]

Alkylglycerol monooxygenase (AGMO) and plasmanylethanolamine desaturase (PEDS1) are enzymes involved in ether lipid metabolism. While AGMO degrades plasmanyl lipids by oxidative cleavage of the ether bond, PEDS1 exclusively synthesizes a specific subclass of ether lipids, the plasmalogens, by introducing a vinyl ether double bond into plasmanylethanolamine phospholipids. Ether lipids are characterized by an ether linkage at the sn -1 position of the glycerol backbone and they are found in membranes of different cell types. Decreased plasmalogen levels have been associated with neurological diseases like Alzheimer's disease. Agmo- deficient mice do not present an obvious phenotype under unchallenged conditions. In contrast, Peds1 knockout mice display a growth phenotype. To investigate the molecular consequences of Agmo and Peds1 deficiency on the mouse lipidome, five tissues from each mouse model were isolated and subjected to high resolution mass spectrometry allowing the characterization of up to 2013 lipid species from 42 lipid subclasses. Agmo knockout mice moderately accumulated plasmanyl and plasmenyl lipid species. Peds1 -deficient mice manifested striking changes characterized by a strong reduction of plasmenyl lipids and a concomitant massive accumulation of plasmanyl lipids resulting in increased total ether lipid levels in the analyzed tissues except for the class of phosphatidylethanolamines where total levels remained remarkably constant also in Peds1 knockout mice. The rate-limiting enzyme in ether lipid metabolism, FAR1, was not upregulated in Peds1 -deficient mice, indicating that the selective loss of plasmalogens is not sufficient to activate the feedback mechanism observed in total ether lipid deficiency. [Display omitted] • High-resolution lipidomics of mouse models with defects in ether lipid metabolism • Profound changes found for Peds1 -deficient mice presenting with a distinct phenotype. • Minor changes found for Agmo -deficient mice with so far undetected phenotype. • Peds1 knockout had overall higher total ether lipids but PE[O + P] remained constant. • FAR1 feedback regulation is exerted by both, plasmanyl- and plasmenylethanolamines. [ABSTRACT FROM AUTHOR]

Objective The purpose of the present study was to determine the incidence of ventricular arrhythmias before and after alcohol septal ablation (ASA). Background In patients with hypertrophic obstructive cardiomyopathy (HOCM), gradient reduction by ASA is an alternative for surgical myectomy. However, concerns exist about whether the induction of a myocardial scar during ASA may create substrate for ventricular arrhythmias. Methods The study group consisted of 44 patients in whom ASA was performed for symptomatic, drug- refractory hypertrophic cardiomyopathy. Continuous rhythm monitoring was obtained by implantable loop recorder (n=30) or pacemaker (n=14). Occurrence of ventricular and supraventricular arrhythmias before and after ASA was noted, retrospectively. Results The ASA procedure was considered successful (resting gradient <30 mm Hg, and provoked gradient <50 mm Hg at 4 months in combination with NYHA Class functional status ≤2) in 30 (68%) patients. Rhythm monitoring before ASA was available in 28 patients. The median duration of rhythm monitoring after ASA was 3.0 years (IQR 1.3-4.3). Sustained VT/VF within 30 days after ASA occurred in three patients (7%), including 2 cases of procedural VF, while no VT/ VF was observed before ASA (p=0.10). No sustained VT/VF was observed >30 days after ASA. No cardiac deaths occurred during follow-up. Conclusions In a low-risk cohort of patients who underwent ASA, in which continuous rhythm monitoring was performed, sustained VT or VF within 30 days occurred in 3 patients (7%) while no VT/VF was observed before ASA. During long-term follow-up, no sustained VT or VF was observed >30 days after ASA. [ABSTRACT FROM AUTHOR]

Aims: Left atrial (LA) stretch-associated electrophysiological changes in patients with mitral stenosis (MS) predispose to atrial fibrillation. We hypothesized that the normalization of the pressure gradient by percutaneous transvenous mitral balloon valvotomy (PTMV) affects LA but not right atrial (RA) conduction, depending on the site of stimulation. Because direction-dependent (asymmetric) changes of conduction may contribute to arrhythmogenesis, we assessed conduction symmetry in MS patients and tested whether it is restored by PTMV. [ABSTRACT FROM PUBLISHER]

Retinal degeneration is a common feature in peroxisomal disorders leading to blindness. Peroxisomes are present in the different cell types of the retina; however, their precise contribution to retinal integrity is still unclear. We previously showed that mice lacking the central peroxisomal β-oxidation enzyme, multifunctional protein 2 (MFP2), develop an early onset retinal decay including photoreceptor cell death. To decipher the function of peroxisomal β-oxidation in photoreceptors, we generated cell type selective Mfp2 knockout mice, using the Crx promotor targeting photoreceptors and bipolar cells. Surprisingly, Crx-Mfp2−/− mice maintained photoreceptor length and number until the age of 1 year. A negative electroretinogram was indicative of preserved photoreceptor phototransduction, but impaired downstream bipolar cell signaling from the age of 6 months. The photoreceptor ribbon synapse was affected, containing free-floating ribbons and vesicles with altered size and density. The bipolar cell interneurons sprouted into the ONL and died. Whereas docosahexaenoic acid levels were normal in the neural retina, levels of lipids containing very long chain polyunsaturated fatty acids were highly increased. Crx-Pex5−/− mice, in which all peroxisomal functions are inactivated in photoreceptors and bipolar cells, developed the same phenotype as Crx-Mfp2−/− mice. In conclusion, the early photoreceptor death in global Mfp2−/− mice is not driven cell autonomously. However, peroxisomal β-oxidation is essential for the integrity of photoreceptor ribbon synapses and of bipolar cells. [ABSTRACT FROM AUTHOR]

Context: Very-long-chain n-3 polyunsaturated fatty acids (omega-3 PUFAs) from fish are thought to reduce risk of sudden death, possibly by reducing susceptibility to cardiac arrhythmia.Objective: To study the effect of supplemental fish oil vs placebo on ventricular tachyarrhythmia or death.Design, Setting, and Patients: The Study on Omega-3 Fatty acids and ventricular Arrhythmia (SOFA) was a randomized, parallel, placebo-controlled, double-blind trial conducted at 26 cardiology clinics across Europe. A total of 546 patients with implantable cardioverter-defibrillators (ICDs) and prior documented malignant ventricular tachycardia (VT) or ventricular fibrillation (VF) were enrolled between October 2001 and August 2004. Patients were randomly assigned to receive 2 g/d of fish oil (n = 273) or placebo (n = 273) for a median period of 356 days (range, 14-379 days).Main Outcome Measure: Appropriate ICD intervention for VT or VF, or all-cause death.Results: The primary end point occurred in 81 (30%) patients taking fish oil vs 90 (33%) patients taking placebo (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.64-1.16; P = .33). In prespecified subgroup analyses, the HR was 0.91 (95% CI, 0.66-1.26) for fish oil vs placebo in the 411 patients who had experienced VT in the year before the study, and 0.76 (95% CI, 0.52-1.11) for 332 patients with prior myocardial infarctions.Conclusion: Our findings do not indicate evidence of a strong protective effect of intake of omega-3 PUFAs from fish oil against ventricular arrhythmia in patients with ICDs.Trial Registration: clinicaltrials.gov Identifier: NCT00110838. [ABSTRACT FROM AUTHOR]

This article presents a study examining the effects of fish oil on ventricular tachyarrhythmia and subsequent death in patients with implantable cardioverter defibrillators. The study involved two groups of patients with implantable cardioverter-defibrillators across 26 cardiology clinics, examined with a placebo-controlled trial of fish oil for approximately one year. The study discovered that evidence of a significant protective effect against ventricular arrhythmia with intake of omega-3 fatty acids from fish oil was not found in patients with implantable cardioverter-defibrillators.