Browsing by Subject "Cardiac arrhythmia"

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    Cardiac sodium channel palmitoylation regulates channel function and cardiac excitability with implications for arrhythmia generation
    (2016-12-09) Pei, Zifan; Cummins, Theodore R.; Oxford, Gerry S.; Hudmon, Andy; Rubart-von der Lohe, Michael; Sheets, Patrick L.
    The  cardiac  voltage-­gated  sodium  channels  (Nav1.5)  play  a  specific  and   critical  role  in  regulating  cardiac  electrical  activity  by  initiating  and  propagating   action  potentials  in  the  heart.  The  association  between  Nav1.5  dysfunctions  and   generation  of  various  types  of  cardiac  arrhythmia  disease,  including  long-­QT3   and  Brugada  syndrome,  is  well  established.  Many  types  of  post-­translational   modifications  have  been  shown  to  regulate  Nav1.5  biophysical  properties,   including  phosphorylation,  glycosylation  and  ubiquitination.  However,  our   understanding  about  how  post-­translational  lipid  modification  affects  sodium   channel  function  and  cellular  excitability,  is  still  lacking.  The  goal  of  this   dissertation  is  to  characterize  Nav1.5  palmitoylation,  one  of  the  most  common   post-­translational  lipid  modification  and  its  role  in  regulating  Nav1.5  function  and   cardiac  excitability.     In  our  studies,  three  lines  of  biochemistry  evidence  were  shown  to  confirm   Nav1.5  palmitoylation  in  both  native  expression  background  and  heterologous   expression  system.  Moreover,  palmitoylation  of  Nav1.5  can  be  bidirectionally   regulated  using  2-­Br-­palmitate  and  palmitic  acid.  Our  results  also  demonstrated   that  enhanced  palmitoylation  in  both  cardiomyocytes  and  HEK293  cells   increases  sodium  channel  availability  and  late  sodium  current  activity,  leading  to   enhanced  cardiac  excitability  and  prolonged  action  potential  duration.  In  contrast,   blocking  palmitoylation  by  2-­Br-­palmitiate  increases  closed-­state  channel inactivation  and  reduces  myocyte  excitability.  Our  computer  simulation  results   confirmed  that  the  observed  modification  in  Nav1.5  gating  properties  by  protein   palmitoylation  are  adequate  for  the  alterations  in  cardiac  excitability.  Mutations  of   potential  palmitoylation  sites  predicted  by  CSS-­Palm  bioinformatics  tool  were   introduced  into  wild-­type  Nav1.5  constructs  using  site-­directed  mutagenesis.   Further  studies  revealed  four  cysteines  (C981,  C1176,  C1178,  C1179)  as   possible  Nav1.5  palmitoylation  sites.  In  particular,  a  mutation  of  one  of  these   sites(C981)  is  associated  with  cardiac  arrhythmia  disease.  Cysteine  to   phenylalanine  mutation  at  this  site  largely  enhances  of  channel  closed-­state   inactivation  and  ablates  sensitivity  to  depalmitoylation.  Therefore,  C981  might  be   the  most  important  site  that  regulates  Nav1.5  palmitoylation.  In  summary,  this   dissertation  research  identified  novel  post-­translational  modification  on  Nav1.5   and  revealed  important  details  behind  this  process.  Our  data  provides  new   insights  on  how  post-­translational  lipid  modification  alters  cardiomyocyte   excitability  and  its  potential  role  in  arrhythmogenesis.
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    Complex Arrhythmia Syndrome in a Knock-In Mouse Model Carrier of the N98S Calm1 Mutation
    (American Heart Association, 2020) Tsai, Wen-Chin; Guo, Shuai; Olaopa, Michael A.; Field, Loren J.; Yang, Jin; Shen, Changyu; Chang, Ching-Pin; Chen, Peng-Sheng; Rubart, Michael; Medicine, School of Medicine
    Background: Calmodulin mutations are associated with arrhythmia syndromes in humans. Exome sequencing previously identified a de novo mutation in CALM1 resulting in a p.N98S substitution in a patient with sinus bradycardia and stress-induced bidirectional ventricular ectopy. The objectives of the present study were to determine if mice carrying the N98S mutation knocked into Calm1 replicate the human arrhythmia phenotype and to examine arrhythmia mechanisms. Methods: Mouse lines heterozygous for the Calm1N98S allele (Calm1N98S/+) were generated using CRISPR/Cas9 technology. Adult mutant mice and their wildtype littermates (Calm1+/+) underwent electrocardiographic monitoring. Ventricular de- and repolarization was assessed in isolated hearts using optical voltage mapping. Action potentials and whole-cell currents and [Ca2+]i, as well, were measured in single ventricular myocytes using the patch-clamp technique and fluorescence microscopy, respectively. The microelectrode technique was used for in situ membrane voltage monitoring of ventricular conduction fibers. Results: Two biologically independent knock-in mouse lines heterozygous for the Calm1N98S allele were generated. Calm1N98S/+ mice of either sex and line exhibited sinus bradycardia, QTc interval prolongation, and catecholaminergic bidirectional ventricular tachycardia. Male mutant mice also showed QRS widening. Pharmacological blockade and activation of β-adrenergic receptors rescued and exacerbated, respectively, the long-QT phenotype of Calm1N98S/+ mice. Optical and electric assessment of membrane potential in isolated hearts and single left ventricular myocytes, respectively, revealed β-adrenergically induced delay of repolarization. β-Adrenergic stimulation increased peak density, slowed inactivation, and left-shifted the activation curve of ICa.L significantly more in Calm1N98S/+ versus Calm1+/+ ventricular myocytes, increasing late ICa.L in the former. Rapidly paced Calm1N98S/+ ventricular myocytes showed increased propensity to delayed afterdepolarization-induced triggered activity, whereas in situ His-Purkinje fibers exhibited increased susceptibility for pause-dependent early afterdepolarizations. Epicardial mapping of Calm1N98S/+ hearts showed that both reentry and focal mechanisms contribute to arrhythmogenesis. Conclusions: Heterozygosity for the Calm1N98S mutation is causative of an arrhythmia syndrome characterized by sinus bradycardia, QRS widening, adrenergically mediated QTc interval prolongation, and bidirectional ventricular tachycardia. β-Adrenergically induced ICa.L dysregulation contributes to the long-QT phenotype. Pause-dependent early afterdepolarizations and tachycardia-induced delayed afterdepolarizations originating in the His-Purkinje network and ventricular myocytes, respectively, constitute potential sources of arrhythmia in Calm1N98S/+ hearts.
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    Diabetic Ketoacidosis With Refractory Hypokalemia Leading to Cardiac Arrest
    (Cureus, 2022-03-24) Grout, Sarah; Maue, Danielle; Berrens, Zachary; Swinger, Nathan; Malin, Stefan; Pediatrics, School of Medicine
    Diabetic ketoacidosis (DKA) is known to cause total body potassium depletion, but during initial presentation, very few patients are hypokalemic, and even fewer patients experience clinical effects. As the correction of acidosis and insulin drive potassium intracellularly, measured serum potassium levels decrease and require repletion. This phenomenon is well described, and severe hypokalemia necessitates delaying insulin therapy. Less well described is the kaliuretic nature of treatments of cerebral edema. We present a case of an adolescent male with new-onset type 2 diabetes who presented in DKA with signs of cerebral edema, hyperosmolarity, and hypokalemia. As insulin and cerebral edema therapy were initiated, his hypokalemia worsened despite significant IV repletion, eventually leading to ventricular tachycardia and cardiac arrest. Over the following 36 hours, the patient received >590 milliequivalents (mEq) of potassium. He was discharged home 12 days after admission without sequelae of his cardiac arrest.
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    Noncoding RNAs as Key Regulators for Cardiac Development and Cardiovascular Diseases
    (MDPI, 2023-04-12) Kawaguchi, Satoshi; Moukette, Bruno; Hayasaka, Taiki; Haskell, Angela K.; Mah, Jessica; Sepúlveda, Marisa N.; Tang, Yaoliang; Kim, Il-man; Anatomy, Cell Biology and Physiology, School of Medicine
    Noncoding RNAs (ncRNAs) play fundamental roles in cardiac development and cardiovascular diseases (CVDs), which are a major cause of morbidity and mortality. With advances in RNA sequencing technology, the focus of recent research has transitioned from studies of specific candidates to whole transcriptome analyses. Thanks to these types of studies, new ncRNAs have been identified for their implication in cardiac development and CVDs. In this review, we briefly describe the classification of ncRNAs into microRNAs, long ncRNAs, and circular RNAs. We then discuss their critical roles in cardiac development and CVDs by citing the most up-to-date research articles. More specifically, we summarize the roles of ncRNAs in the formation of the heart tube and cardiac morphogenesis, cardiac mesoderm specification, and embryonic cardiomyocytes and cardiac progenitor cells. We also highlight ncRNAs that have recently emerged as key regulators in CVDs by focusing on six of them. We believe that this review concisely addresses perhaps not all but certainly the major aspects of current progress in ncRNA research in cardiac development and CVDs. Thus, this review would be beneficial for readers to obtain a recent picture of key ncRNAs and their mechanisms of action in cardiac development and CVDs.
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    Will Automated Compressing Devices Save More Lives in Recalcitrant Ventricular Fibrillation Cardiac Arrest?
    (Cureus, 2022-02-20) Chang, Eduardo E.; Segura, Esther; Vellanki, Sruthi; Kumar, Anup Kumar Trikannad Ashwini; Medicine, School of Medicine
    We present a 55-year-old male that developed ventricular fibrillation cardiac arrest in the setting of ST-elevation acute myocardial infarction with recalcitrant and persistent ventricular fibrillation arrest that was successfully resuscitated with a good neurological outcome. The persistent chest compressions were performed in our intensive care unit with an automated chest compression system. The patient required defibrillations and nonstop chest compressions which were the key factors for his survival. This is an example we should consider in all our intensive care units. It's time for a paradigm shift in replacing the compressor of a code team with an automated system. The out-of-hospital evidence in acute care is compelling to bring this technology that has been proven crucial in transports from hospital areas, ambulances, helicopters, and ships to the inpatient ICU bedside. In ventricular tachycardia and ventricular fibrillation (Vt/Vf), the electrical storm created is the perfect example of the need to have the best compressions to provide the best care possible with the best survival and neurological outcomes.