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Circulation. 2018 Sep 11;138(11):1144-1154. doi: 10.1161/CIRCULATIONAHA.117.032703.

Ryanodine Receptor Calcium Leak in Circulating B-Lymphocytes as a Biomarker in Heart Failure.

Author information

1
Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Columbia University College of Physicians and Surgeons, New York (A.K., G.S., S.R.R., A.R.M.).
2
Department of Medicine, Division of Cardiology, Columbia University Medical Center, New York (A.K., E.C., S.J.G., D.L.B., P.C.C., M.Y., A.R.M.).
3
Department of Medicine, Division of Cardiology, Jacobi Medical Center, Bronx, NY (S.I.S.).
4
Departments of Medicine and Cell Biology, Wilf Family Cardiovascular Research Institute, Albert Einstein Cancer Center, Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY (R.N.K.).

Abstract

BACKGROUND:

Advances in congestive heart failure (CHF) management depend on biomarkers for monitoring disease progression and therapeutic response. During systole, intracellular Ca2+ is released from the sarcoplasmic reticulum into the cytoplasm through type-2 ryanodine receptor/Ca2+ release channels. In CHF, chronically elevated circulating catecholamine levels cause pathological remodeling of type-2 ryanodine receptor/Ca2+ release channels resulting in diastolic sarcoplasmic reticulum Ca2+ leak and decreased myocardial contractility. Similarly, skeletal muscle contraction requires sarcoplasmic reticulum Ca2+ release through type-1 ryanodine receptors (RyR1), and chronically elevated catecholamine levels in CHF cause RyR1-mediated sarcoplasmic reticulum Ca2+ leak, contributing to myopathy and weakness. Circulating B-lymphocytes express RyR1 and catecholamine-responsive signaling cascades, making them a potential surrogate for defects in intracellular Ca2+ handling because of leaky RyR channels in CHF.

METHODS:

Whole blood was collected from patients with CHF, CHF following left-ventricular assist device implant, and controls. Blood was also collected from mice with ischemic CHF, ischemic CHF+S107 (a drug that specifically reduces RyR channel Ca2+ leak), and wild-type controls. Channel macromolecular complex was assessed by immunostaining RyR1 immunoprecipitated from lymphocyte-enriched preparations. RyR1 Ca2+ leak was assessed using flow cytometry to measure Ca2+ fluorescence in B-lymphocytes in the absence and presence of RyR1 agonists that empty RyR1 Ca2+ stores within the endoplasmic reticulum.

RESULTS:

Circulating B-lymphocytes from humans and mice with CHF exhibited remodeled RyR1 and decreased endoplasmic reticulum Ca2+ stores, consistent with chronic intracellular Ca2+ leak. This Ca2+ leak correlated with circulating catecholamine levels. The intracellular Ca2+ 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:

In CHF, B-lymphocytes exhibit remodeled leaky RyR1 channels and decreased endoplasmic reticulum Ca2+ stores consistent with chronic intracellular Ca2+ leak. RyR1-mediated Ca2+ leak in B-lymphocytes assessed using flow cytometry provides a surrogate measure of intracellular Ca2+ handling and systemic sympathetic burden, presenting a novel biomarker for monitoring response to pharmacological and mechanical CHF therapy.

KEYWORDS:

biomarker; calcium; heart failure; ion channels

PMID:
29593014
PMCID:
PMC6162180
DOI:
10.1161/CIRCULATIONAHA.117.032703
[Indexed for MEDLINE]
Free PMC Article

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