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.

doi:10.1038/s41569-020-0394-8

Cited by 124 publications

(110 citation statements)

References 204 publications

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“… 21 ACE 2 counteracts the effect of angiotensin II in states with excessive activation of renin-angiotensin system like heart failure. 1 CHF patients are known to have dysregulation of intracellular calcium handling mechanism 49 and COVID-19 can cause hypoxia induced excessive intracellular calcium leading to cardiac myocyte apoptosis. 50 This can lead to increased mortality observed in patients with CHF.…”

Section: Discussionmentioning

confidence: 99%

Impact of congestive heart failure and role of cardiac biomarkers in COVID-19 patients: A systematic review and meta-analysis

Dalia¹,

Lahan²,

Ranka³

et al. 2021

Indian Heart Journal

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Background Coronavirus disease 2019 (COVID-19) has been reported to cause worse outcomes in patients with underlying cardiovascular disease, especially in patients with acute cardiac injury, which is determined by elevated levels of high-sensitivity troponin. There is a paucity of data on the impact of congestive heart failure (CHF) on outcomes in COVID-19 patients. Methods We conducted a literature search of PubMed/Medline, EMBASE, and Google Scholar databases from 11/1/2019 till 06/07/2020, and identified all relevant studies reporting cardiovascular comorbidities, cardiac biomarkers, disease severity, and survival. Pooled data from the selected studies was used for metanalysis to identify the impact of risk factors and cardiac biomarker elevation on disease severity and/or mortality. Results We collected pooled data on 5,967 COVID-19 patients from 20 individual studies. We found that both non-survivors and those with severe disease had an increased risk of acute cardiac injury and cardiac arrhythmias, our pooled relative risk (RR) was — 8.52 (95% CI 3.63–19.98) (p<0.001); and 3.61 (95% CI 2.03–6.43) (p=0.001), respectively. Mean difference in the levels of Troponin-I, CK-MB, and NT-proBNP was higher in deceased and severely infected patients. The RR of in-hospital mortality was 2.35 (95% CI 1.18–4.70) (p=0.022) and 1.52 (95% CI 1.12–2.05) (p=0.008) among patients who had pre-existing CHF and hypertension, respectively. Conclusion Cardiac involvement in COVID-19 infection appears to significantly adversely impact patient prognosis and survival. Pre-existence of CHF, and high cardiac biomarkers like NT-pro BNP and CK-MB levels in COVID-19 patients correlates with worse outcomes.

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Section: Discussionmentioning

confidence: 99%

Impact of congestive heart failure and role of cardiac biomarkers in COVID-19 patients: A systematic review and meta-analysis

Dalia¹,

Lahan²,

Ranka³

et al. 2021

Indian Heart Journal

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“…Recently it has been shown that the high neutrophil to lymphocyte ratio observed in critically ill patients with COVID-19 is associated with excessive levels of reactive oxygen species (ROS) and that ROS induced tissue damage, contributing to COVID-19 disease severity 26 . The impact of oxidative stress on calcium (Ca 2+ ) homeostasis, a key determinant of cardiac function and rhythm 29 , as well as neuronal activity, remain to be elucidated.…”

Section: Mainmentioning

confidence: 99%

“…Our laboratory has shown that stress-induced ryanodine receptor (RyR)/intracellular calcium release channel post-translational modifications, including oxidation and protein kinase A (PKA) hyper-phosphorylation related to activation of the sympathetic nervous system and the resulting hyper-adrenergic state, deplete the channel stabilizing protein (calstabin) from the channel complex, destabilizing the closed state of the channel causing it to leak in multiple diseases 6–9,29,35,36 . Increased transforming growth factor-β (TGF-β) activity can lead to RyR modification and leaky channels 37 and SR Ca 2+ leak can cause mitochondrial Ca 2+ overload and dysfunction 36 .…”

Section: Mainmentioning

confidence: 99%

Alzheimer’s-like remodeling of neuronal ryanodine receptor in COVID-19

Reiken

Dridi

Sittenfeld

et al. 2021

Preprint

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COVID-19, caused by SARS-CoV-2 involves multiple organs including cardiovascular, pulmonary and central nervous system. Understanding how SARS-CoV-2 infection afflicts diverse organ systems remains challenging. Particularly vexing has been the problem posed by persistent organ dysfunction known as "long COVID", which includes cognitive impairment. Here we provide evidence linking SARS-CoV-2 infection to activation of TGF beta signaling and oxidative overload. One consequence is oxidation of the ryanodine receptor/calcium (Ca2+) release channels (RyR) on the endo/sarcoplasmic (ER/SR) reticuli in heart, lung and brains of patients who succumbed to COVID-19. This depletes the channels of the stabilizing subunit calstabin2 causing them to leak Ca2+ which can promote heart failure, pulmonary insufficiency and cognitive and behavioral defects. Ex-vivo treatment of heart, lung, and brain tissues from COVID-19 patients using a Rycal drug (ARM210) prevented calstabin2 loss and fixed the channel leak. Of particular interest is that neuropathological pathways activated downstream of leaky RyR2 channels in Alzheimer's Disease (AD) patients were activated in COVID-19 patients. Thus, leaky RyR2 Ca2+ channels may play a role in COVID-19 pathophysiology and could be a therapeutic target for amelioration of some comorbidities associated with SARS-CoV-2 infection.

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“…The authors propose a simplified mechanism, in which cAMP-dependent protein kinase (PKA)-mediated phosphorylation of RYR2 at Ser2808 is increased in heart failure and atrial fibrillation, 'hyperphosphorylation' of Ser2808 dissociates the FK506binding protein 12.6 (FKBP12.6) subunit (called 'calstabin 2' almost exclusively by the authors), FKBP12.6-dissociated RYR2 becomes dysfunctional, and RYR2-mediated Ca 2+ leak promotes arrhythmia and impairs contractility 1 . This mechanism has been advanced by the authors not only in heart failure but also in inherited arrhythmias, muscular dystrophy, seizures, cognitive dysfunction and diabetes mellitus (reviewed previously 2 ).…”

mentioning

confidence: 99%