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      RyR2 and Calcium Release in Heart Failure

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          Abstract

          Heart Failure (HF) is defined as the inability of the heart to efficiently pump out enough blood to maintain the body's needs, first at exercise and then also at rest. Alterations in Ca 2+ handling contributes to the diminished contraction and relaxation of the failing heart. While most Ca 2+ handling protein expression and/or function has been shown to be altered in many models of experimental HF, in this review, we focus in the sarcoplasmic reticulum (SR) Ca 2+ release channel, the type 2 ryanodine receptor (RyR2). Various modifications of this channel inducing alterations in its function have been reported. The first was the fact that RyR2 is less responsive to activation by Ca 2+ entry through the L-Type calcium channel, which is the functional result of an ultrastructural remodeling of the ventricular cardiomyocyte, with fewer and disorganized transverse (T) tubules. HF is associated with an elevated sympathetic tone and in an oxidant environment. In this line, enhanced RyR2 phosphorylation and oxidation have been shown in human and experimental HF. After several controversies, it is now generally accepted that phosphorylation of RyR2 at the Calmodulin Kinase II site (S2814) is involved in both the depressed contractile function and the enhanced arrhythmic susceptibility of the failing heart. Diminished expression of the FK506 binding protein, FKBP12.6, may also contribute. While these alterations have been mostly studied in the left ventricle of HF with reduced ejection fraction, recent studies are looking at HF with preserved ejection fraction. Moreover, alterations in the RyR2 in HF may also contribute to supraventricular defects associated with HF such as sinus node dysfunction and atrial fibrillation.

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          Most cited references163

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          Epidemiology of heart failure with preserved ejection fraction

          Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome associated with poor quality of life, substantial health-care resource utilization, and premature mortality. Dunlay and colleagues summarize the epidemiological data on HFpEF, with a focus on the prevalence and incidence of HFpEF in the community as well as associated conditions and risk factors, morbidity and mortality after diagnosis, and quality of life.
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            Trends in prevalence and outcome of heart failure with preserved ejection fraction.

            The prevalence of heart failure with preserved ejection fraction may be changing as a result of changes in population demographics and in the prevalence and treatment of risk factors for heart failure. Changes in the prevalence of heart failure with preserved ejection fraction may contribute to changes in the natural history of heart failure. We performed a study to define secular trends in the prevalence of heart failure with preserved ejection fraction among patients at a single institution over a 15-year period. We studied all consecutive patients hospitalized with decompensated heart failure at Mayo Clinic Hospitals in Olmsted County, Minnesota, from 1987 through 2001. We classified patients as having either preserved or reduced ejection fraction. The patients were also classified as community patients (Olmsted County residents) or referral patients. Secular trends in the type of heart failure, associated cardiovascular disease, and survival were defined. A total of 6076 patients with heart failure were discharged over the 15-year period; data on ejection fraction were available for 4596 of these patients (76 percent). Of these, 53 percent had a reduced ejection fraction and 47 percent had a preserved ejection fraction. The proportion of patients with the diagnosis of heart failure with preserved ejection fraction increased over time and was significantly higher among community patients than among referral patients (55 percent vs. 45 percent). The prevalence rates of hypertension, atrial fibrillation, and diabetes among patients with heart failure increased significantly over time. Survival was slightly better among patients with preserved ejection fraction (adjusted hazard ratio for death, 0.96; P=0.01). Survival improved over time for those with reduced ejection fraction but not for those with preserved ejection fraction. The prevalence of heart failure with preserved ejection fraction increased over a 15-year period, while the rate of death from this disorder remained unchanged. These trends underscore the importance of this growing public health problem. Copyright 2006 Massachusetts Medical Society.
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              Outcome of heart failure with preserved ejection fraction in a population-based study.

              The importance of heart failure with preserved ejection fraction is increasingly recognized. We conducted a study to evaluate the epidemiologic features and outcomes of patients with heart failure with preserved ejection fraction and to compare the findings with those from patients who had heart failure with reduced ejection fraction. From April 1, 1999, through March 31, 2001, we studied 2802 patients admitted to 103 hospitals in the province of Ontario, Canada, with a discharge diagnosis of heart failure whose ejection fraction had also been assessed. The patients were categorized in three groups: those with an ejection fraction of less than 40 percent (heart failure with reduced ejection fraction), those with an ejection fraction of 40 to 50 percent (heart failure with borderline ejection fraction), and those with an ejection fraction of more than 50 percent (heart failure with preserved ejection fraction). Two groups were studied in detail: those with an ejection fraction of less than 40 percent and those with an ejection fraction of more than 50 percent. The main outcome measures were death within one year and readmission to the hospital for heart failure. Thirty-one percent of the patients had an ejection fraction of more than 50 percent. Patients with heart failure with preserved ejection fraction were more likely to be older and female and to have a history of hypertension and atrial fibrillation. The presenting history and clinical examination findings were similar for the two groups. The unadjusted mortality rates for patients with an ejection fraction of more than 50 percent were not significantly different from those for patients with an ejection fraction of less than 40 percent at 30 days (5 percent vs. 7 percent, P=0.08) and at 1 year (22 percent vs. 26 percent, P=0.07); the adjusted one-year mortality rates were also not significantly different in the two groups (hazard ratio, 1.13; 95 percent confidence interval, 0.94 to 1.36; P=0.18). The rates of readmission for heart failure and of in-hospital complications did not differ between the two groups. Among patients presenting with new-onset heart failure, a substantial proportion had an ejection fraction of more than 50 percent. The survival of patients with heart failure with preserved ejection fraction was similar to that of patients with reduced ejection fraction. Copyright 2006 Massachusetts Medical Society.
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                Author and article information

                Contributors
                Journal
                Front Physiol
                Front Physiol
                Front. Physiol.
                Frontiers in Physiology
                Frontiers Media S.A.
                1664-042X
                08 October 2021
                2021
                : 12
                : 734210
                Affiliations
                Signaling and Cardiovascular Pathophysiology—UMR-S 1180, INSERM, Université Paris-Saclay , Châtenay-Malabry, France
                Author notes

                Edited by: Daniel M. Johnson, The Open University, United Kingdom

                Reviewed by: Bjorn C. Knollmann, Vanderbilt University, United States; Shanna Hamilton, The Ohio State University, United States

                *Correspondence: Ana M. Gómez ana-maria.gomez@ 123456inserm.fr

                This article was submitted to Cardiac Electrophysiology, a section of the journal Frontiers in Physiology

                Article
                10.3389/fphys.2021.734210
                8533677
                34690808
                30891940-8451-4931-bc82-85fd1b411f41
                Copyright © 2021 Benitah, Perrier, Mercadier, Pereira and Gómez.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 30 June 2021
                : 30 August 2021
                Page count
                Figures: 1, Tables: 0, Equations: 0, References: 163, Pages: 13, Words: 12177
                Categories
                Physiology
                Review

                Anatomy & Physiology
                ryanodine receptor,heart failure,calcium,excitation contraction coupling,sinus node,atrial fibrillation

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