Background: A loss-of-function cardiac ryanodine receptor (RyR2) mutation, I4855M, has recently been linked to a new cardiac disorder termed RyR2 Ca release deficiency syndrome (CRDS) as well as left ventricular noncompaction (LVNC). The mechanism by which RyR2 loss-of-function causes CRDS has been extensively studied, but the mechanism underlying RyR2 loss-of-function-associated LVNC is unknown. Here, we determined the impact of a CRDS-LVNC-associated RyR2-I4855M loss-of-function mutation on cardiac structure and function.
View Article and Find Full Text PDFInositol 1,4,5-trisphosphate receptor type 1 (ITPR1) is an intracellular Ca release channel important for a number of fundamental cellular functions. Consistent with its critical physiological significance, mutations in ITPR1 are associated with disease. Surprisingly, nearly all the disease-associated ITPR1 mutations characterized to date are loss of function.
View Article and Find Full Text PDFInositol 1,4,5-trisphosphate receptor 1 (ITPR1) is an intracellular Ca release channel critical for numerous cellular processes. Despite its ubiquitous physiological significance, ITPR1 mutations have thus far been linked to primarily movement disorders. Surprisingly, most disease-associated ITPR1 mutations generate a loss of function.
View Article and Find Full Text PDFCardiac ryanodine receptor (RyR2) gain-of-function mutations cause catecholaminergic polymorphic ventricular tachycardia, a condition characterized by prominent ventricular ectopy in response to catecholamine stress, which can be reproduced on exercise stress testing (EST). However, reports of sudden cardiac death (SCD) have emerged in EST-negative individuals who have loss-of-function (LOF) RyR2 mutations. The clinical relevance of RyR2 LOF mutations including their pathogenic mechanism, diagnosis, and treatment are all unknowns.
View Article and Find Full Text PDFNeuronal hyperactivity is an early primary dysfunction in Alzheimer's disease (AD) in humans and animal models, but effective neuronal hyperactivity-directed anti-AD therapeutic agents are lacking. Here we define a previously unknown mode of ryanodine receptor 2 (RyR2) control of neuronal hyperactivity and AD progression. We show that a single RyR2 point mutation, E4872Q, which reduces RyR2 open time, prevents hyperexcitability, hyperactivity, memory impairment, neuronal cell death, and dendritic spine loss in a severe early-onset AD mouse model (5xFAD).
View Article and Find Full Text PDFBACKGROUND This study aimed to determine the association between CD4-positive T-helper (Th) cell subsets, T-helper 1 (Th1) and T-helper 2 (Th2) in patients with acute myocardial infarction (AMI) and the severity of coronary artery disease (CAD) determined by coronary artery angiography. MATERIAL AND METHODS Three groups of patients with AMI who underwent coronary angiography and percutaneous coronary intervention (PCI) included patients with stable CAD (n=35), ST-segment elevation myocardial infarction (STEMI) (n=30), and non-STEMI (NSTEMI) (n=35), and controls (n=33). Measurement of high-sensitivity cardiac troponin T (hs-cTnT) was performed.
View Article and Find Full Text PDFReduced protein expression of the cardiac ryanodine receptor type 2 (RyR2) is thought to affect the susceptibility to stress-induced ventricular tachyarrhythmia (VT) and cardiac alternans, but direct evidence for the role of RyR2 protein expression in VT and cardiac alternans is lacking. Here, we used a mouse model () that expresses a reduced level of the RyR2 protein to determine the impact of reduced RyR2 protein expression on the susceptibility to VT, cardiac alternans, cardiac hypertrophy, and sudden death. Electrocardiographic analysis revealed that after the injection of relatively high doses of caffeine and epinephrine (agents commonly used for stress test), wild-type (WT) mice displayed long-lasting VTs, whereas the mutant mice exhibited no VTs at all, indicating that the mutant mice are resistant to stress-induced VTs.
View Article and Find Full Text PDFBeat-to-beat alternations in the amplitude of the cytosolic Ca transient (Ca alternans) are thought to be the primary cause of cardiac alternans that can lead to cardiac arrhythmias and sudden death. Despite its important role in arrhythmogenesis, the mechanism underlying Ca alternans remains poorly understood. Here, we investigated the role of cardiac ryanodine receptor (RyR2), the major Ca release channel responsible for cytosolic Ca transients, in cardiac alternans.
View Article and Find Full Text PDFRecent studies have shown that the phosphorylation and dephosphorylation of ULK1 and ATG13 are related to autophagy activity. Although ATG16L1 is absolutely required for autophagy induction by affecting the formation of autophagosomes, the post-translational modification of ATG16L1 remains elusive. Here, we explored the regulatory mechanism and role of ATG16L1 phosphorylation for autophagy induction in cardiomyocytes.
View Article and Find Full Text PDFAs the mechanisms underlying PKC activation induced arrhythmias are not yet fully verified, we investigated the role of gap junctions in arrhythmias induced by PKC activation.Arterially-perfused rabbit left ventricular preparations were randomly assigned to perfusion with phorbol ester (PMA) or in combination with AAP10. Transmural ECG as well as action potentials from both endocardium and epicardium were simultaneously recorded throughout all experiments.
View Article and Find Full Text PDFDrug-induced torsades de pointes (TdP) is common with class III antiarrhythmic drugs. Increased transmural dispersion of repolarization (TDR) contributes significantly to the development of TdP. Gap junctions play an important role in maintaining TDR in long QT syndrome.
View Article and Find Full Text PDFZhonghua Xin Xue Guan Bing Za Zhi
April 2011
Objective: To investigate the effect and potential mechanism of lysophosphatidic acid (LPA) and antiarrhythmic peptide (AAP10) on rabbit ventricular arrhythmia.
Methods: Twenty-four rabbits were randomly divided into three groups (n = 8 each): control group, LPA group and AAP10 + LPA group. Using arterially perfused rabbit ventricular wedge preparations, transmural ECG and action potentials from both endocardium and epicardium were simultaneously recorded in the whole process of all experiments with two separate floating microeletrodes.
Objective: The aim of this study is to observe the effect of combined amiodarone and antiarrhythmic peptide (AAP10) use on the incidence of induced ventricular arrhythmias in healed myocardial infarction (MI) rabbits.
Methods: Twenty Japanese rabbits underwent thoracotomy without coronary artery ligation (Sham, group A), the middle left circumflex branch were ligated to induce MI in 180 Japanese rabbits. Eight weeks after operation, 124 rabbits survived MI operation and were divided into four groups: control group (group B, n = 31), amiodarone group (group C, n = 31), AAP10 group (group D, n = 31) and amiodarone plus AAP10 group (group E, n = 31).
Arrhythmias is one of the leading causes of death in the world. Current antiarrhythmic drugs are limited by unsatisfactory efficacy and adverse effects such as proarrhythmias. Reentry mechanism plays an important role in persistence of arrhythmias.
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