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Intracellular calcium leak in heart failure and atrial fibrillation: a unifying mechanism and therapeutic target
Dridi, Haikel; Kushnir, Alexander; Zalk, Ran; Yuan, Qi; Melville, Zephan; Marks, Andrew R
Ca2+ is a fundamental second messenger in all cell types and is required for numerous essential cellular functions, including cardiac and skeletal muscle contraction. The intracellular concentration of free Ca2+ ([Ca2+]) is regulated primarily by ion channels, pumps (ATPases), exchangers and Ca2+-binding proteins. Defective regulation of [Ca2+] is found in a diverse spectrum of pathological states that affect all the major organs. In the heart, abnormalities in the regulation of cytosolic and mitochondrial [Ca2+] occur in heart failure (HF) and atrial fibrillation (AF), two common forms of heart disease and leading contributors to morbidity and mortality. In this Review, we focus on the mechanisms that regulate ryanodine receptor 2 (RYR2), the major sarcoplasmic reticulum (SR) Ca2+-release channel in the heart, how RYR2 becomes dysfunctional in HF and AF, and its potential as a therapeutic target. Inherited RYR2 mutations and/or stress-induced phosphorylation and oxidation of the protein destabilize the closed state of the channel, resulting in a pathological diastolic Ca2+ leak from the SR that both triggers arrhythmias and impairs contractility. On the basis of our increased understanding of SR Ca2+ leak as a shared Ca2+-dependent pathological mechanism in HF and AF, a new class of drugs developed in our laboratory, known as rycals, which stabilize RYR2 channels and prevent Ca2+ leak from the SR, are undergoing investigation in clinical trials.
PMID: 32555383
ISSN: 1759-5010
CID: 4552722
Cardiac electrophysiology consultative experience at the epicenter of the COVID-19 pandemic in the United States
Berman, Jeremy P; Abrams, Mark P; Kushnir, Alexander; Rubin, Geoffrey A; Ehlert, Frederick; Biviano, Angelo; Morrow, John P; Dizon, Jose; Wan, Elaine Y; Yarmohammadi, Hirad; Waase, Marc P; Rubin, David A; Garan, Hasan; Saluja, Deepak
BACKGROUND:The COVID-19 pandemic has greatly altered the practice of cardiac electrophysiology around the world for the foreseeable future. Professional organizations have provided guidance for practitioners, but real-world examples of the consults and responsibilities cardiac electrophysiologists face during a surge of COVID-19 patients is lacking. METHODS:In this observational case series we report on 29 consecutive inpatient electrophysiology consultations at a major academic medical center in New York City, the epicenter of the pandemic in the United States, during a 2 week period from March 30-April 12, 2020, when 80% of hospital beds were occupied by COVID-19 patients, and the New York City metropolitan area accounted for 10% of COVID-19 cases worldwide. RESULTS:Reasons for consultation included: Atrial tachyarrhythmia (31%), cardiac implantable electronic device management (28%), bradycardia (14%), QTc prolongation (10%), ventricular arrhythmia (7%), post-transcatheter aortic valve replacement conduction abnormality (3.5%), ventricular pre-excitation (3.5%), and paroxysmal supraventricular tachycardia (3.5%). Twenty-four patients (86%) were positive for COVID-19 by nasopharyngeal swab. All elective procedures were canceled, and only one urgent device implantation was performed. Thirteen patients (45%) required in-person evaluation and the remainder were managed remotely. CONCLUSION/CONCLUSIONS:Our experience shows that the application of a massive alteration in workflow and personnel forced by the pandemic allowed our team to efficiently address the intersection of COVID-19 with a range of electrophysiology issues. This experience will prove useful as guidance for emerging hot spots or areas affected by future waves of the pandemic.
PMCID:7450949
PMID: 32861812
ISSN: 0972-6292
CID: 4587672
High-density substrate and activation mapping of epicardial ventricular tachycardia during left ventricular assist device implant [Case Report]
Kushnir, Alexander; Pallister, Kristin H; Chaudhary, Salma B; Cevasco, Marisa; Naka, Yoshifumi; Saluja, Deepak
PMCID:7573345
PMID: 33101933
ISSN: 2214-0271
CID: 4645672
Restructuring Electrophysiology During the COVID-19 Pandemic: A Practical Guide from a New York City Hospital Network
Rubin, Geoffrey A; Wan, Elaine Y; Saluja, Deepak; Thomas, George; Slotwiner, David J; Goldbarg, Seth; Chaudhary, Salma; Turitto, Gioia; Dizon, Jose; Yarmohammadi, Hirad; Ehlert, Frederick; Rubin, David A; Morrow, John P; Waase, Marc; Berman, Jeremy; Kushnir, Alexander; Abrams, Mark P; Halik, Carolyn; Kumaraiah, Deepa; Schwartz, Allan; Kirtane, Ajay; Kodali, Susheel; Goldenthal, Isaac; Garan, Hasan; Biviano, Angelo
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.
PMCID:7188041
PMID: 32324622
ISSN: 1535-2811
CID: 4410212
Performance of electrophysiology procedures at an academic medical center amidst the 2020 coronavirus (COVID-19) pandemic
Rubin, Geoffrey A; Biviano, Angelo; Dizon, Jose; Yarmohammadi, Hirad; Ehlert, Frederick; Saluja, Deepak; Rubin, David A; Morrow, John P; Waase, Marc; Berman, Jeremy; Kushnir, Alexander; Abrams, Mark P; Garan, Hasan; Wan, Elaine Y
A global coronavirus (COVID-19) pandemic occurred at the start of 2020 and is already responsible for more than 74 000 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.
PMID: 32281214
ISSN: 1540-8167
CID: 4410202
Intracellular calcium leak as a therapeutic target for RYR1-related myopathies
Kushnir, Alexander; Todd, Joshua J; Witherspoon, Jessica W; Yuan, Qi; Reiken, Steven; Lin, Harvey; Munce, Ross H; Wajsberg, Benjamin; Melville, Zephan; Clarke, Oliver B; Wedderburn-Pugh, Kaylee; Wronska, Anetta; Razaqyar, Muslima S; Chrismer, Irene C; Shelton, Monique O; Mankodi, Ami; Grunseich, Christopher; Tarnopolsky, Mark A; Tanji, Kurenai; Hirano, Michio; Riazi, Sheila; Kraeva, Natalia; Voermans, Nicol C; Gruber, Angela; Allen, Carolyn; Meilleur, Katherine G; Marks, Andrew R
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 of > 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.
PMID: 32236737
ISSN: 1432-0533
CID: 4410192
Mechanism of adrenergic CaV1.2 stimulation revealed by proximity proteomics
Liu, Guoxia; Papa, Arianne; Katchman, Alexander N; Zakharov, Sergey I; Roybal, Daniel; Hennessey, Jessica A; Kushner, Jared; Yang, Lin; Chen, Bi-Xing; Kushnir, Alexander; Dangas, Katerina; Gygi, Steven P; Pitt, Geoffrey S; Colecraft, Henry M; Ben-Johny, Manu; Kalocsay, Marian; Marx, Steven O
Increased cardiac contractility during the fight-or-flight response is caused by β-adrenergic augmentation of CaV1.2 voltage-gated calcium channels1-4. However, this augmentation persists in transgenic murine hearts expressing mutant CaV1.2 α1C and β subunits that can no longer be phosphorylated by protein kinase A-an essential downstream mediator of β-adrenergic signalling-suggesting that non-channel factors are also required. Here we identify the mechanism by which β-adrenergic agonists stimulate voltage-gated calcium channels. We express α1C or β2B 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 β-adrenergic stimulation. Phosphorylation by protein kinase A of specific serine residues on Rad decreases its affinity for β 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.
PMID: 31969708
ISSN: 1476-4687
CID: 4410182
Cardiac CaV1.2 channels require β subunits for β-adrenergic-mediated modulation but not trafficking
Yang, Lin; Katchman, Alexander; Kushner, Jared; Kushnir, Alexander; Zakharov, Sergey I; Chen, Bi-Xing; Shuja, Zunaira; Subramanyam, Prakash; Liu, Guoxia; Papa, Arianne; Roybal, Daniel; Pitt, Geoffrey S; Colecraft, Henry M; Marx, Steven O
Ca2+ channel β-subunit interactions with pore-forming α-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 α1C subunits lacking capacity to bind CaVβ can traffic to the sarcolemma in adult cardiomyocytes in vivo and sustain normal excitation-contraction coupling. However, these β-less Ca2+ channels cannot be stimulated by β-adrenergic pathway agonists, and thus adrenergic augmentation of contractility is markedly impaired in isolated cardiomyocytes and in hearts. Similarly, viral-mediated expression of a β-subunit-sequestering peptide sharply curtailed β-adrenergic stimulation of WT Ca2+ channels, identifying an approach to specifically modulate β-adrenergic regulation of cardiac contractility. Our data demonstrate that β subunits are required for β-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.
PMID: 30422117
ISSN: 1558-8238
CID: 4410172
Ryanodine receptor dysfunction in human disorders
Kushnir, Alexander; Wajsberg, Benjamin; Marks, Andrew R
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.
PMID: 30040966
ISSN: 1879-2596
CID: 4410162
Ryanodine Receptor Calcium Leak in Circulating B-Lymphocytes as a Biomarker in Heart Failure
Kushnir, Alexander; Santulli, Gaetano; Reiken, Steven R; Coromilas, Ellie; Godfrey, Sarah J; Brunjes, Danielle L; Colombo, Paolo C; Yuzefpolskaya, Melana; Sokol, Seth I; Kitsis, Richard N; Marks, Andrew R
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.
PMCID:6162180
PMID: 29593014
ISSN: 1524-4539
CID: 4410152