Restructuring Electrophysiology During the COVID-19 Pandemic: A Practical Guide from a New York City Hospital Network
The COVID-19 crisis is a global pandemic of a novel infectious disease with far-ranging public health implications. With regard to cardiac electrophysiology (EP) services, we discuss the "real-world" challenges and solutions that have been essential for efficient and successful (i) ramping down of standard clinical practice patterns and (ii) pivoting of workflow processes to meet the demands of this pandemic. The aims of these recommendations are to outline: (1) essential practical steps to approaching procedures, as well as outpatient and inpatient care of EP patients, with relevant examples, (2) successful strategies to minimize exposure risk to patients and clinical staff while also balancing resource utilization, (3) challenges related to redeployment and restructuring of clinical and support staff, and (4) considerations regarding continued collaboration with clinical and administrative colleagues in order to implement these changes. While process changes will vary across practices and hospital systems, we believe that these experiences from four different EP sections in a large New York city hospital network currently based in the global epicenter of the COVID-19 pandemic will prove useful for other EP practices adapting their own practices in preparation for local surges.
Intracellular calcium leak as a therapeutic target for RYR1-related myopathies
RYR1 encodes the type 1 ryanodine receptor, an intracellular calcium release channel (RyR1) on the skeletal muscle sarcoplasmic reticulum (SR). Pathogenic RYR1 variations can destabilize RyR1 leading to calcium leak causing oxidative overload and myopathy. However, the effect of RyR1 leak has not been established in individuals with RYR1-related myopathies (RYR1-RM), a broad spectrum of rare neuromuscular disorders. We sought to determine whether RYR1-RM affected individuals exhibit pathologic, leaky RyR1 and whether variant location in the channel structure can predict pathogenicity. Skeletal muscle biopsies were obtained from 17 individuals with RYR1-RM. Mutant RyR1 from these individuals exhibited pathologic SR calcium leak and increased activity of calcium-activated proteases. The increased calcium leak and protease activity were normalized by ex-vivo treatment with S107, a RyR stabilizing Rycal molecule. Using the cryo-EM structure of RyR1 and a new dataset ofâ€‰>â€‰2200 suspected RYR1-RM affected individuals we developed a method for assigning pathogenicity probabilities to RYR1 variants based on 3D co-localization of known pathogenic variants. This study provides the rationale for a clinical trial testing Rycals in RYR1-RM affected individuals and introduces a predictive tool for investigating the pathogenicity of RYR1 variants of uncertain significance.
Performance of electrophysiology procedures at an academic medical center amidst the 2020 coronavirus (COVID-19) pandemic
A global coronavirus (COVID-19) pandemic occurred at the start of 2020 and is already responsible for more than 74â€‰000 deaths worldwide, just over 100 years after the influenza pandemic of 1918. At the center of the crisis is the highly infectious and deadly SARS-CoV-2, which has altered everything from individual daily lives to the global economy and our collective consciousness. Aside from the pulmonary manifestations of disease, there are likely to be several electrophysiologic (EP) sequelae of COVID-19 infection and its treatment, due to consequences of myocarditis and the use of QT-prolonging drugs. Most crucially, the surge in COVID-19 positive patients that have already overwhelmed the New York City hospital system requires conservation of hospital resources including personal protective equipment (PPE), reassignment of personnel, and reorganization of institutions, including the EP laboratory. In this proposal, we detail the specific protocol changes that our EP department has adopted during the COVID-19 pandemic, including performance of only urgent/emergent procedures, after hours/7-day per week laboratory operation, single attending-only cases to preserve PPE, appropriate use of PPE, telemedicine and video chat follow-up appointments, and daily conferences to collectively manage the clinical and ethical dilemmas to come. We discuss also discuss how we perform EP procedures on presumed COVID positive and COVID tested positive patients to highlight issues that others in the EP community may soon face in their own institution as the virus continues to spread nationally and internationally.
Mechanism of adrenergic CaV1.2 stimulation revealed by proximity proteomics
Increased cardiac contractility during the fight-or-flight response is caused by Î²-adrenergic augmentation of CaV1.2 voltage-gated calcium channels1-4. However, this augmentation persists in transgenic murine hearts expressing mutant CaV1.2 Î±1C and Î² subunits that can no longer be phosphorylated by protein kinase A-an essential downstream mediator of Î²-adrenergic signalling-suggesting that non-channel factors are also required. Here we identify the mechanism by which Î²-adrenergic agonists stimulate voltage-gated calcium channels. We express Î±1C or Î²2B subunits conjugated to ascorbate peroxidase5 in mouse hearts, and use multiplexed quantitative proteomics6,7 to track hundreds of proteins in the proximity of CaV1.2. We observe that the calcium-channel inhibitor Rad8,9, a monomeric G protein, is enriched in the CaV1.2 microenvironment but is depleted during Î²-adrenergic stimulation. Phosphorylation by protein kinase A of specific serine residues on Rad decreases its affinity for Î² subunits and relieves constitutive inhibition of CaV1.2, observed as an increase in channel open probability. Expression of Rad or its homologue Rem in HEK293T cells also imparts stimulation of CaV1.3 and CaV2.2 by protein kinase A, revealing an evolutionarily conserved mechanism that confers adrenergic modulation upon voltage-gated calcium channels.
Cardiac CaV1.2 channels require Î² subunits for Î²-adrenergic-mediated modulation but not trafficking
Ca2+ channel Î²-subunit interactions with pore-forming Î±-subunits are long-thought to be obligatory for channel trafficking to the cell surface and for tuning of basal biophysical properties in many tissues. Unexpectedly, we demonstrate that transgenic expression of mutant Î±1C subunits lacking capacity to bind CaVÎ² can traffic to the sarcolemma in adult cardiomyocytes in vivo and sustain normal excitation-contraction coupling. However, these Î²-less Ca2+ channels cannot be stimulated by Î²-adrenergic pathway agonists, and thus adrenergic augmentation of contractility is markedly impaired in isolated cardiomyocytes and in hearts. Similarly, viral-mediated expression of a Î²-subunit-sequestering peptide sharply curtailed Î²-adrenergic stimulation of WT Ca2+ channels, identifying an approach to specifically modulate Î²-adrenergic regulation of cardiac contractility. Our data demonstrate that Î² subunits are required for Î²-adrenergic regulation of CaV1.2 channels and positive inotropy in the heart, but are dispensable for CaV1.2 trafficking to the adult cardiomyocyte cell surface, and for basal function and excitation-contraction coupling.
Ryanodine receptor dysfunction in human disorders
Regulation of intracellular calcium (Ca2+) is critical in all cell types. The ryanodine receptor (RyR), an intracellular Ca2+ release channel located on the sarco/endoplasmic reticulum (SR/ER), releases Ca2+ from intracellular stores to activate critical functions including muscle contraction and neurotransmitter release. Dysfunctional RyR-mediated Ca2+ handling has been implicated in the pathogenesis of inherited and non-inherited conditions including heart failure, cardiac arrhythmias, skeletal myopathies, diabetes, and neurodegenerative diseases. Here we have reviewed the evidence linking human disorders to RyR dysfunction and describe novel approaches to RyR-targeted therapeutics.
Ryanodine Receptor Calcium Leak in Circulating B-Lymphocytes as a Biomarker in Heart Failure
BACKGROUND:handling because of leaky RyR channels in CHF. METHODS:stores within the endoplasmic reticulum. RESULTS:leak was significantly reduced in mice treated with the Rycal S107. Patients with CHF treated with left-ventricular assist devices exhibited a heterogeneous response. CONCLUSIONS:handling and systemic sympathetic burden, presenting a novel biomarker for monitoring response to pharmacological and mechanical CHF therapy.
Voltage-Gated Calcium Channels
[S.l] : Elsevier, 2017
Giant Cell Arteritis as a Cause of Myocarditis and Atrial Fibrillation [Case Report]
Ryanodine receptor patents
Research over the past two decades has implicated dysfunction of the ryanodine receptor (RyR), a Ca(2+) release channel on the sarcoplasmic reticulum (SR) required for excitation-contraction (EC) coupling, in the pathogenesis of cardiac and skeletal myopathies. These discoveries have led to the development of novel drugs, screening tools, and research methods. The patents associated with these advances tell the story of the initial discovery of RyRs as a target for plant alkaloids, to their central role in cardiac and skeletal muscle excitation-contraction coupling, and ongoing clinical trials with a novel class of drugs called RycalsTM that inhibit pathological intracellular Ca(2+) leak. Additionally, these patents highlight questions, controversies, and future directions of the RyR field.