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                <text>Diseases of the circulatory (Cardiovascular) system&#13;
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                <text>&lt;span&gt;Copyright&lt;/span&gt;&lt;span&gt; © 2022 Mahmood, Ahmed and Zhang. This is an open-access article distributed under the terms of the &lt;/span&gt;&lt;a href="http://creativecommons.org/licenses/by/4.0/" target="_blank" rel="noreferrer noopener"&gt;Creative Commons Attribution License (CC BY)&lt;/a&gt;&lt;span&gt;. 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.&lt;/span&gt;</text>
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                <text>Cardiac sympathetic activation, mediated by β-adrenergic receptors (β-ARs), normally increases cardiac contraction and relaxation. Accomplishing this task requires a physiological, concerted Ca2+ signaling, being able to increase Ca2+ release from sarcoplasmic reticulum (SR) in systole and speed up Ca2+ re-uptake in diastole. In heart failure (HF) myocardial β-ARs undergo desensitization/down-regulation due to sustained sympathetic adrenergic activation. β-AR desensitization/down-regulation diminishes adrenergic signaling and cardiac contractile reserve, and is conventionally considered to be detrimental in HF progression. Abnormal Ca2+ handling, manifested as cardiac ryanodine receptor (RyR2) dysfunction and diastolic Ca2+ leak (due to sustained adrenergic activation) also occur in HF. RyR2 dysfunction and Ca2+ leak deplete SR Ca2+ store, diminish Ca2+ release in systole and elevate Ca2+ levels in diastole, impairing both systolic and diastolic ventricular function. Moreover, elevated Ca2+ levels in diastole promote triggered activity and arrhythmogenesis. In the presence of RyR2 dysfunction and Ca2+ leak, further activation of the β-AR signaling in HF would worsen the existing abnormal Ca2+ handling, exacerbating not only cardiac dysfunction, but also ventricular arrhythmogenesis and sudden cardiac death. Thus, we conclude that β-AR desensitization/down-regulation may be a self-preserving, adaptive process (acting like an intrinsic β-AR blocker) protecting the failing heart from developing lethal ventricular arrhythmias under conditions of elevated sympathetic drive and catecholamine levels in HF, rather than a conventionally considered detrimental process. This also implies that medications simply enhancing β-AR signaling (like β-AR agonists) may not be so beneficial unless they can also correct dysfunctional Ca2+ handling in HF.</text>
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