Structure-activity optimization of ryanodine receptor modulators for the treatment of catecholaminergic polymorphic ventricular tachycardia.

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia disorder associated with lethal arrhythmias. Most CPVT cases are caused by inherited variants in the gene encoding ryanodine receptor type 2 (RYR2).

Objective: The goal of this study was to investigate the structure-activity relationship of tetracaine derivatives and to test a lead compound in a mouse model of CPVT.

Nonsense Variant PRDM16-Q187X Causes Impaired Myocardial Development and TGF-β Signaling Resulting in Noncompaction Cardiomyopathy in Humans and Mice.

Background: PRDM16 plays a role in myocardial development through TGF-β (transforming growth factor-beta) signaling. Recent evidence suggests that loss of PRDM16 expression is associated with cardiomyopathy development in mice, although its role in human cardiomyopathy development is unclear. This study aims to determine the impact of PRDM16 loss-of-function variants on cardiomyopathy in humans.

Reduction in Junctophilin 2 Expression in Cardiac Nodal Tissue Results in Intracellular Calcium-Driven Increase in Nodal Cell Automaticity.

Background: Spontaneously depolarizing nodal cells comprise the pacemaker of the heart. Intracellular calcium (Ca) plays a critical role in mediating nodal cell automaticity and understanding this so-called Ca clock is critical to understanding nodal arrhythmias. We previously demonstrated a role for Jph2 (junctophilin 2) in regulating Ca-signaling through inhibition of RyR2 (ryanodine receptor 2) Ca leak in cardiac myocytes; however, its role in pacemaker function and nodal arrhythmias remains unknown.

Efficacy of RyR2 inhibitor EL20 in induced pluripotent stem cell-derived cardiomyocytes from a patient with catecholaminergic polymorphic ventricular tachycardia.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited cardiac arrhythmia syndrome that often leads to sudden cardiac death. The most common form of CPVT is caused by autosomal-dominant variants in the cardiac ryanodine receptor type-2 (RYR2) gene. Mutations in RYR2 promote calcium (Ca ) leak from the sarcoplasmic reticulum (SR), triggering lethal arrhythmias.

Reversible cardiac disease features in an inducible CUG repeat RNA-expressing mouse model of myotonic dystrophy.

Myotonic dystrophy type 1 (DM1) is caused by a CTG repeat expansion in the DMPK gene. Expression of pathogenic expanded CUG repeat (CUGexp) RNA causes multisystemic disease by perturbing the functions of RNA-binding proteins, resulting in expression of fetal protein isoforms in adult tissues. Cardiac involvement affects 50% of individuals with DM1 and causes 25% of disease-related deaths.

Targeting pathological leak of ryanodine receptors: preclinical progress and the potential impact on treatments for cardiac arrhythmias and heart failure.

: Type-2 ryanodine receptor (RyR2) located on the sarcoplasmic reticulum initiate systolic Ca transients within cardiomyocytes. Proper functioning of RyR2 is therefore crucial to the timing and force generated by cardiomyocytes within a healthy heart. Improper intracellular Ca handing secondary to RyR2 dysfunction is associated with a variety of cardiac pathologies including catecholaminergic polymorphic ventricular tachycardia (CPVT), atrial fibrillation (AF), and heart failure (HF).

Calmodulin kinase II regulates atrial myocyte late sodium current, calcium handling, and atrial arrhythmia.

Background: Atrial fibrillation (AF) is the most common type of arrhythmia. Abnormal atrial myocyte Ca handling promotes aberrant membrane excitability and remodeling that are important for atrial arrhythmogenesis. The sequence of molecular events leading to loss of normal atrial myocyte Ca homeostasis is not established.

Loss of Protein Phosphatase 1 Regulatory Subunit PPP1R3A Promotes Atrial Fibrillation.

Background: Abnormal calcium (Ca) release from the sarcoplasmic reticulum (SR) contributes to the pathogenesis of atrial fibrillation (AF). Increased phosphorylation of 2 proteins essential for normal SR-Ca cycling, the type-2 ryanodine receptor (RyR2) and phospholamban (PLN), enhances the susceptibility to AF, but the underlying mechanisms remain unclear. Protein phosphatase 1 (PP1) limits steady-state phosphorylation of both RyR2 and PLN.

In Vivo Ryr2 Editing Corrects Catecholaminergic Polymorphic Ventricular Tachycardia.

Rationale: Autosomal-dominant mutations in ryanodine receptor type 2 ( RYR2) are responsible for ≈60% of all catecholaminergic polymorphic ventricular tachycardia. Dysfunctional RyR2 subunits trigger inappropriate calcium leak from the tetrameric channel resulting in potentially lethal ventricular tachycardia. In vivo CRISPR/Cas9-mediated gene editing is a promising strategy that could be used to eliminate the disease-causing Ryr2 allele and hence rescue catecholaminergic polymorphic ventricular tachycardia.

EL20, a potent antiarrhythmic compound, selectively inhibits calmodulin-deficient ryanodine receptor type 2.

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an arrhythmogenic disorder caused by mutations in the cardiac ryanodine receptor RyR2 that increase diastolic calcium cation (Ca) leak from the sarcoplasmic reticulum (SR). Calmodulin (CaM) dissociation from RyR2 has been associated with diastolic Ca leak in heart failure.

Objective: Determine whether the tetracaine-derivative compound EL20 inhibits abnormal Ca release from RyR2 in a CPVT model and investigate the underlying mechanism of inhibition.

Time resolved calorimetry of photo-induced folding in horse heart cytochrome c at high pH.

Here the molar volume and enthalpy changes associated with the early events in the folding of ferrocytochrome c (Cc) at high pH have been examined using time resolved photoacoustic calorimetry (PAC). The data reveal an overall volume change of 1.3 ± 0.

Treatment of catecholaminergic polymorphic ventricular tachycardia in mice using novel RyR2-modifying drugs.

Rationale: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal arrhythmic disorder caused by mutations in the type-2 ryanodine receptor (RyR2). Mutant RyR2 cause abnormal Ca leak from the sarcoplasmic reticulum (SR), which is associated with the development of arrhythmias.

Objective: To determine whether derivatives of tetracaine, a local anesthetic drug with known RyR2 inhibiting action, could prevent CPVT induction by suppression of RyR2-mediated SR Ca leak.

Photoacoustic calorimetry studies of CO photo-dissociation from chloramine-T modified horse heart cytochrome-c.

Treatment of horse heart Cytochrome-c (Cc) with N-chloro-4-toluosulfonamide (Chloramine-t, CT) results in the oxidation of methionine (Met) residues to the corresponding sulfoxide including the distal heme ligand, Met80. The resulting Fe-sulfoxide coordination is sufficiently labile in the ferrous form to be displaced by gaseous ligands, including CO. Photolysis of the CO-CT-Cc complex provides an opportunity to examine ligand binding dynamics that are associated with a relatively rigid distal heme pocket.

Removal of selected NSAIDs (nonsteroidal anti-inflammatory drugs) in aqueous samples by Octolig®.

The possibility of removing representative nonsteroidal anti-inflammatory drugs (NSAIDs) from water was tested using Octolig®, a commercially available material with polyethylenediimine moieties covalently attached to high-surface area silica gel. The effectiveness of removal should depend on selected NSAIDs having appropriate anionic functional groups. NSAIDs selected had aromatic carboxylic groups: diclofenac, fenoprofen, indomethacin, ketoprofen, mefenamic acid, naproxen, and sulindac.

Removal of pain-relieving drugs from aqueous solutions using Octolig and selected metalloligs.

The possibility of removing certain pharmaceuticals (acetaminophen and naproxen) from water was tested using Octolig, a commercially available material with polyethylenediimine moieties covalently attached to high-surface area silica gel. In addition, the efficacy of two transition metals (cupric and ferric) derivatives of Octolig was tested. Previously amoxicillin had been successfully subjected to column chromatography for removal by means of ion encapsulation, the effectiveness of which would depend upon having appropriate anionic functional groups.