COVID-19: Is it time to revisit the research on calcium channel drug targets?

Balasubramanyam, Muthuswamy

doi:10.33590/emjdiabet/200608

Cited by 4 publications

(5 citation statements)

References 20 publications

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“…Moreover, there are emerging reports that other drug classes such as anticoagulants, calcium channel blockers and statins could be beneficial. [9][10][11] Additionally, many cardiovascular disease patients are on combination therapies and a broader review may facilitate understanding of the interplay between the different classes of cardiovascular drugs.…”

Section: Introductionmentioning

confidence: 99%

Cardiovascular drugs and COVID‐19 clinical outcomes: A living systematic review and meta‐analysis

Asiimwe

Pushpakom

Turner

et al. 2021

Brit J Clinical Pharma

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Aims To continually evaluate the association between cardiovascular drug exposure and COVID‐19 clinical outcomes (susceptibility to infection, disease severity, hospitalization, hospitalization length, and all‐cause mortality) in patients at risk of/with confirmed COVID‐19. Methods Eligible publications were identified from >500 databases on 1‐Nov‐2020. One reviewer extracted data with 20% of the records independently extracted/evaluated by a second reviewer. Results Of 52,735 screened records, 429 and 390 studies were included in the qualitative and quantitative syntheses, respectively. The most‐reported drugs were angiotensin‐converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) with ACEI/ARB exposure having borderline association with confirmed COVID‐19 infection (OR 1.14, 95% CI 1.00–1.31). Among COVID‐19 patients, unadjusted estimates showed that ACEI/ARB exposure was associated with hospitalization (OR 1.76, 1.34–2.32), disease severity (OR 1.40, 1.26–1.55) and all‐cause mortality (OR 1.22, 1.12–1.33) but not hospitalization length (mean difference ‐0.27, ‐1.36; 0.82 days). After adjustment, ACEI/ARB exposure was not associated with confirmed COVID‐19 infection (OR 0.92, 0.71–1.19), hospitalization (OR 0.93, 0.70–1.24), disease severity (OR 1.05, 0.81–1.38), or all‐cause mortality (OR 0.84, 0.70–1.00). Similarly, subgroup analyses involving only hypertensive patients revealed that ACEI/ARB exposure was not associated with confirmed COVID‐19 infection (OR 0.93, 0.79–1.09), hospitalization (OR 0.84, 0.58–1.22), hospitalization length (mean difference ‐0.14, ‐1.65; 1.36 days), disease severity (OR 0.92, 0.76–1.11) while it decreased the odds of dying (OR 0.76, 0.65–0.88). A similar trend was observed for other cardiovascular drugs. However, the validity of these findings is limited by a high level of heterogeneity and serious risk of bias. Conclusion Cardiovascular drugs are not associated with poor COVID‐19 outcomes in adjusted analyses. Patients should continue taking these drugs as prescribed.

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Section: Introductionmentioning

confidence: 99%

Cardiovascular drugs and COVID‐19 clinical outcomes: A living systematic review and meta‐analysis

Asiimwe

Pushpakom

Turner

et al. 2021

Brit J Clinical Pharma

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“…The potential mechanisms in which cardiovascular drugs can influence COVID-19 outcomes have been previously discussed. 6-9 22- 25…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, there are emerging reports that other drug classes such as anticoagulants, calcium channel blockers and statins could be beneficial. [22][23][24][25] Additionally, many cardiovascular disease patients are on combination therapies and a broader review may facilitate understanding of the interplay between the different classes of cardiovascular drugs. Lastly, evidence in this field is rapidly evolving which means that recently published reviews soon become outdated.…”

Section: Introductionmentioning

confidence: 99%

Cardiovascular drugs and COVID-19 clinical outcomes: a living systematic review and meta-analysis

Asiimwe

Pushpakom

Turner

et al. 2020

Preprint

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OBJECTIVE To continually evaluate the rapidly evolving evidence base on the role of cardiovascular drugs in COVID-19 clinical outcomes (susceptibility to infection, hospitalization, hospitalization length, disease severity, and all-cause mortality). DESIGN Living systematic review and meta-analysis. DATA SOURCES Eligible publications identified from >500 databases indexed through 31st July 2020 and additional studies from reference lists, with planned continual surveillance for at least two years. STUDY SELECTION Observational and interventional studies that report on the association between cardiovascular drugs and COVID-19 clinical outcomes. DATA EXTRACTION Single-reviewer extraction and quality evaluation (using ROBINS-I), with half the records independently extracted and evaluated by a second reviewer. RESULTS Of 23,427 titles screened, 175 studies were included in the quantitative synthesis. The most reported drug classes were angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) with ACEI/ARB exposure being associated with higher odds of testing positive for COVID-19 (pooled unadjusted OR 1.15, 95% CI 1.02 to 1.30). Among patients with COVID-19, unadjusted estimates showed that ACEI/ARB exposure was associated with being hospitalized (OR 2.25, 1.70 to 2.98) and having severe disease (OR 1.50, 1.27 to 1.77) but not with the length of hospitalization (mean difference -0.45, -1.33 to 0.43 days) or all-cause mortality (OR 1.25, CI 0.98 to 1.58). However, after adjustment, ACEI/ARB exposure was not associated with testing positive for COVID-19 (pooled adjusted OR 1.01, 0.93 to 1.10), being hospitalized (OR 1.16, 0.80 to 1.68), having severe disease (1.04, 0.76 to 1.42), or all-cause mortality (0.86, 0.64 to 1.15). Similarly, subgroup analyses involving only hypertensive patients revealed that ACEI/ARB exposure was not associated with being hospitalized (OR 0.84, 0.58 to 1.22), disease severity (OR 0.88, 0.68 to 1.14) or all-cause mortality (OR 0.77, 0.54 to 1.12) while it decreased the length of hospitalization (mean difference -0.71, -1.11 to -0.30 days). After adjusting for relevant covariates, other cardiovascular drug classes were mostly not found to be associated with poor COVID-19 clinical outcomes. However, the validity of these findings is limited by a high level of heterogeneity in terms of effect sizes and a serious risk of bias, mainly due to confounding in the included studies. CONCLUSION Our comprehensive review shows that ACEI/ARB exposure is associated with COVID-19 outcomes such as susceptibility to infection, severity, and hospitalization in unadjusted analyses. However, after adjusting for potential confounding factors, this association is not evident. Patients on cardiovascular drugs should continue taking their medications as currently recommended. Higher quality evidence in the form of randomized controlled trials will be needed to determine any adverse or beneficial effects of cardiovascular drugs. PRIMARY FUNDING SOURCE None SYSTEMATIC REVIEW REGISTRATION PROSPERO (CRD42020191283)

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“…35 In view of the clinical relevance of excessive intracellular calcium, the use of calcium channel blockers has been repeatedly suggested in the patients affected by COVID-19. [36][37][38][39][40][41] In confirmation of the possible value of these drugs, a recently published retrospective cohort study among 4569 hospitalized hypertensive patients with COVID-19 showed a dramatic reduction of mortality in patients treated with calcium channel blockers (risk ratio [RR]: 0.32, 95% confidence interval [CI]: 0.13-0.76, P = 0.0058). 42 Decreased calcium levels in blood, in absence of a documented hypercalciuria, indicate a detrimental increased concentration of this cation inside the cells.…”

Section: Introductionmentioning

confidence: 99%

COVID-19, Cation Dysmetabolism, Sialic Acid, CD147, ACE2, Viroporins, Hepcidin and Ferroptosis: A Possible Unifying Hypothesis

Cavezzi

Menicagli

Troiani³

et al. 2022

F1000Res

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Background: iron and calcium dysmetabolism, with hyperferritinemia, hypoferremia, hypocalcemia and anemia have been documented in the majority of COVID-19 patients at later/worse stages. Furthermore, complementary to ACE2, both sialic acid (SA) molecules and CD147 proved relevant host receptors for SARS-CoV-2 entry, which explains the viral attack to multiple types of cells, including erythrocytes, endothelium and neural tissue. Several authors advocated that cell ferroptosis may be the core and final cell degenerative mechanism. Methods: a literature research was performed in several scientific search engines, such as PubMed Central, Cochrane Library, Chemical Abstract Service. More than 500 articles were retrieved until mid-December 2021, to highlight the available evidence about the investigated issues. Results: based on COVID-19 literature data, we have highlighted a few pathophysiological mechanisms, associated with virus-based cation dysmetabolism, multi-organ attack, mitochondria degeneration and ferroptosis. Our suggested elucidated pathological sequence is: a) spike protein subunit S1 docking with sialylated membrane glycoproteins/receptors (ACE2, CD147), and S2 subunit fusion with the lipid layer; b) cell membrane morpho-functional changes due to the consequent electro-chemical variations and viroporin action, which induce an altered ion channel function and intracellular cation accumulation; c) additional intracellular iron concentration due to a deregulated hepcidin-ferroportin axis, with higher hepcidin levels. Viral invasion may also affect erythrocytes/erythroid precursors, endothelial cells and macrophages, through SA and CD147 receptors, with relative hemoglobin and iron/calcium dysmetabolism. AB0 blood group, hemochromatosis, or environmental elements may represent possible factors which affect individual susceptibility to COVID-19. Conclusions: our literature analysis confirms the combined role of SA molecules, ACE2, CD147, viroporins and hepcidin in determining the cation dysmetabolism and final ferroptosis in the cells infected by SARS-CoV-2. The altered ion channels and electrochemical gradients of the cell membrane have a pivotal role in the virus entry and cell dysmetabolism, with subsequent multi-organ immune-inflammatory degeneration and erythrocyte/hemoglobin alterations.

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COVID-19: Is it time to revisit the research on calcium channel drug targets?

Cited by 4 publications

References 20 publications

Cardiovascular drugs and COVID‐19 clinical outcomes: A living systematic review and meta‐analysis

Cardiovascular drugs and COVID‐19 clinical outcomes: A living systematic review and meta‐analysis

Cardiovascular drugs and COVID-19 clinical outcomes: a living systematic review and meta-analysis

COVID-19, Cation Dysmetabolism, Sialic Acid, CD147, ACE2, Viroporins, Hepcidin and Ferroptosis: A Possible Unifying Hypothesis

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