Platelets and Cardiac Arrhythmia

Sudden cardiac death (SCD) remains one of the most prevalent modes of death in industrialized countries, and myocardial ischemia due to thrombotic coronary occlusion is its primary cause. The role of platelets in the occurrence of SCD extends beyond coronary flow impairment by clot formation. Here we review the substances released by platelets during clot formation and their arrhythmic properties. Platelet products are released from three types of platelet granules: dense core granules, alpha-granules, and platelet lysosomes. The physiologic properties of dense granule products are of special interest as a potential source of arrhythmic substances. They are released readily upon activation and contain high concentrations of serotonin, histamine, purines, pyrimidines, and ions such as calcium and magnesium. Potential arrhythmic mechanisms of these substances, e.g., serotonin and high energy phosphates, include induction of coronary constriction, calcium overloading, and induction of delayed after-depolarizations. Alpha-granules produce thromboxanes and other arachidonic-acid products with many potential arrhythmic effects mediated by interference with cardiac sodium, calcium, and potassium channels. Alpha-granules also contain hundreds of proteins that could potentially serve as ligands to receptors on cardiomyocytes. Lysosomal products probably do not have an important arrhythmic effect. Platelet products and ischemia can induce coronary permeability, thereby enhancing interaction with surrounding cardiomyocytes. Antiplatelet therapy is known to improve survival after myocardial infarction. Although an important part of this effect results from prevention of coronary clot formation, there is evidence to suggest that antiplatelet therapy also induces anti-arrhythmic effects during ischemia by preventing the release of platelet activation products

Arrhythmia mechanism dependent pulmonary vein ablation in paroxysmal atrial fibrillation

Atrial fibrillation (AF) often requires invasive treatment by ablation to decrease symptom burden. The pulmonary veins (PV) are thought to trigger paroxysms of AF, and ablative PV isolation (PVI) is a cornerstone in AF treatment. However, incomplete PVI, where electrical conduction between the PV and left atrium (LA) is maintained, is curative of AF in a subset of patients. This implies that an antiarrhythmic effect other than electrical isolation between the PV and LA plays a role in AF prevention in these patients. We reason that the PV myocardium constitutes an arrhythmogenic substrate conducive to reentry in the patients with curative incomplete PVI. This PV substrate is amenable to ablation, even when conduction between the LA and PV persists. We propose that PV ablation strategies are differentiated to fit the arrhythmogenic mechanisms in the individual patient. PV substrate modification in patients with PV reentry may constitute a new therapeutic approach that is potentially simpler and more effective, in this subgroup of patients

Careful Curation of Care Content:A Case Study of a Technology-Supported Atrial Fibrillation Outpatient Clinic

Medical care received outside the doctor’s office and the hospital is gaining traction. Lifestyle programs for transmural and remote care are increasingly facilitated by hospitals as part of rehabilitation, by general practitioners as preventative measures, and by various private (health) organizations through consumer apps. What is often overlooked is the time and energy spent on creating the content (i.e., health information and education) in these programs so that it is effective, appealing, relatable, and personalized. In this article, we discuss the elaborate content creation process of lifestyle content for an outpatient clinic for atrial fibrillation patients. We describe the close collaboration between clinicians, design researchers, data designers, and a copywriter, and reflect on how to streamline and formalize the clinical content creation process. Additionally, we highlight opportunities for further content personalization by making it dynamic, more versatile in terms of delivery and expanding the system further into the home context

Processing time not modality dominates shift costs in the modality-shifting effect

Shifting attention between visual and auditory targets is associated with reaction time costs, known as the modality-shifting effect. The type of modality shifted from e.g., auditory or visual is suggested to have an effect on the degree of cost. Studies report greater costs shifting from visual stimuli, yet notably used visual stimuli that are also identified slower than the auditory. It is not clear whether the cost is specific to modality effects, or with identification speed independent of modality. Here, in order to interpret whether the effects are due to modality or identification time, switch costs are instead compared with auditory stimuli that are identified slower than the visual (inverse of tested previously). A second condition used the same auditory stimuli at a low intensity, allowing comparison of semantically identical stimuli that are even slower to process. The current findings contradicted suggestions of a general difficulty in shifting from visual stimuli (as previously reported), and instead suggest that cost is reduced when targets are preceded by a more rapidly processed stimulus. ‘Modality-Shifting’ as it is often termed induces shifting costs, but the costs are not because of a change of modality per se, but because of a change in identification speed, where the degree of cost is dependent on the processing time of the surrounding stimuli

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons. A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons. A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology

Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

A. Palotie on työryhmän Schizophrenia Working Grp Psychiat jäsen.We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P = 1 x 10(-4)) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P = 8.4 x 10(-7)). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.Peer reviewe

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons