Low vitamin K status predicts mortality in a cohort of 138 hospitalized patients with COVID-19

AbstractIt has recently been hypothesised that Vitamin K could play a role in COVID-19. We aimed to test the hypothesis that low vitamin K status is a common characteristic of patients hospitalized with COVID-19 compared to population controls; and that low vitamin K status predicts mortality in COVID-19 patients. In a cohort of 138 COVID-19 patients and 140 population controls, we measured plasma dephosphorylated-uncarboxylated Matrix Gla Protein (dp-ucMGP), which reflects the functional Vitamin K status in peripheral tissue. Fourty-three patients died within 90-days from admission. In patients, levels of dp-ucMGP differed significantly between survivors (mean 877; 95% CI: 778; 995) and non-survivors (mean 1445; 95% CI: 1148; 1820). Furthermore, levels of dp-ucMGP (pmol/L) were considerably higher in patients (mean 1022; 95% CI: 912; 1151) compared to controls (mean 509; 95% CI: 485; 540). Cox regression survival analysis showed that increasing levels of dp-ucMGP (reflecting low Vitamin K status) were associated with higher mortality risk (sex- and age-adjusted hazard ratio per doubling of dp-ucMGP was 1.50, 95% CI: 1.03; 2.18). In conclusion, we found that low Vitamin K status predicted mortality in patients with COVID-19 supporting a potential role of Vitamin K in COVID-19.

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The Association of Low Vitamin K Status with Mortality in a Cohort of 138 Hospitalized Patients with COVID-19

Nutrients ◽

10.3390/nu13061985 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1985

Author(s):

Allan Linneberg ◽

Freja Bach Kampmann ◽

Simone Bastrup Israelsen ◽

Liv Rabøl Andersen ◽

Henrik Løvendahl Jørgensen ◽

...

Keyword(s):

Clinical Trials ◽

Survival Analysis ◽

Vitamin K ◽

Potential Role ◽

Randomized Clinical Trials ◽

Cox Regression ◽

Hazard Ratio ◽

Adjusted Hazard Ratio ◽

Matrix Gla Protein ◽

Population Controls

It has recently been hypothesized that vitamin K could play a role in COVID-19. We aimed to test the hypotheses that low vitamin K status is a common characteristic of patients hospitalized with COVID-19 compared to population controls and that low vitamin K status predicts mortality in COVID-19 patients. In a cohort of 138 COVID-19 patients and 138 population controls, we measured plasma dephosphorylated-uncarboxylated Matrix Gla Protein (dp-ucMGP), which reflects the functional vitamin K status in peripheral tissue. Forty-three patients died within 90 days from admission. In patients, levels of dp-ucMGP differed significantly between survivors (mean 877; 95% CI: 778; 995) and non-survivors (mean 1445; 95% CI: 1148; 1820). Furthermore, levels of dp-ucMGP (pmol/L) were considerably higher in patients (mean 1022; 95% CI: 912; 1151) compared to controls (mean 509; 95% CI: 485; 540). Cox regression survival analysis showed that increasing levels of dp-ucMGP (reflecting low vitamin K status) were associated with higher mortality risk (sex- and age-adjusted hazard ratio per doubling of dp-ucMGP was 1.49, 95% CI: 1.03; 2.24). The association attenuated and became statistically insignificant after adjustment for co-morbidities (sex, age, CVD, diabetes, BMI, and eGFR adjusted hazard ratio per doubling of dp-ucMGP was 1.22, 95% CI: 0.82; 1.80). In conclusion, we found that low vitamin K status was associated with mortality in patients with COVID-19 in sex- and age-adjusted analyses, but not in analyses additionally adjusted for co-morbidities. Randomized clinical trials would be needed to clarify a potential role, if any, of vitamin K in the course of COVID-19.

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Role of Matrix Gla Protein in the Complex Network of Coronary Artery Disease: A Comprehensive Review

Life ◽

10.3390/life11080737 ◽

2021 ◽

Vol 11 (8) ◽

pp. 737

Author(s):

Marko Kumric ◽

Josip A. Borovac ◽

Tina Ticinovic Kurir ◽

Dinko Martinovic ◽

Ivan Frka Separovic ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Complex Network ◽

Vascular Calcification ◽

Vitamin K ◽

Clinical Decision Making ◽

Large Body ◽

Matrix Gla Protein ◽

Artery Disease

Coronary artery disease (CAD) is widely recognized as one of the most important clinical entities. In recent years, a large body of accumulated data suggest that coronary artery calcification, a process highly prevalent in patients with CAD, occurs via well-organized biologic processes, rather than passively, as previously regarded. Matrix Gla protein (MGP), a vitamin K-dependent protein, emerged as an important inhibitor of both intimal and medial vascular calcification. The functionality of MGP hinges on two post-translational modifications: phosphorylation and carboxylation. Depending on the above-noted modifications, various species of MGP may exist in circulation, each with their respective level of functionality. Emerging data suggest that dysfunctional species of MGP, markedly, dephosphorylated-uncarboxylated MGP, might find its application as biomarkers of microvascular health, and assist in clinical decision making with regard to initiation of vitamin K supplementation. Hence, in this review we summarized the current knowledge with respect to the role of MGP in the complex network of vascular calcification with concurrent inferences to CAD. In addition, we discussed the effects of warfarin use on MGP functionality, with concomitant implications to coronary plaque stability.

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Serum Procalcitonin Level and Mortality Risk in Critically ill Patients with Ventilator-Associated Pneumonia

Cellular Physiology and Biochemistry ◽

10.1159/000438557 ◽

2015 ◽

Vol 37 (5) ◽

pp. 1967-1972 ◽

Cited By ~ 5

Author(s):

Bo Li ◽

Xin Zhao ◽

Shumei Li

Keyword(s):

Critically Ill ◽

Mortality Risk ◽

Critically Ill Patients ◽

Cox Regression ◽

High Serum ◽

Ventilator Associated Pneumonia ◽

Prognostic Role ◽

Procalcitonin Level ◽

Increased Risk

Background/Aims: The prognostic role of serum procalcitonin level in critically ill patients with ventilator-associated pneumonia was unclear. The aim of our study was to investigate the relationship between serum procalcitonin level and mortality risk in critically ill patients with ventilator-associated pneumonia. Methods: Data of critically ill patients with ventilator-associated pneumonia were retrospectively collected. Demographics, comorbidities, and serum procalcitonin level were extracted from electronic medical records. The primary outcome was mortality within two months after diagnosis. Multivariable Cox regression analyses were performed to assess the prognostic role of serum procalcitonin level in those patients. Results: A total of 115 critically ill patients with ventilator-associated pneumonia were enrolled in our study. Serum procalcitonin level was not associated with age, gender, or other comorbidities. Univariate Cox regression model showed that high serum procalcitonin level was associated increased risk of morality within 2 months after diagnosis (OR = 2.32, 95% CI 1.25-4.31, P = 0.008). Multivariable Cox regression model showed that high serum procalcitonin level was independently associated increased risk of morality within 2 months after diagnosis (OR = 2.38, 95% CI 1.26-4.50, P = 0.008). Conclusion: High serum procalcitonin level is an independent prognostic biomarker of mortality risk in critically ill patients with ventilator-associated pneumonia, and it's a promising biomarker of prognosis in critically ill patients.

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Which treatment options impact outcomes in elderly chronic lymphocytic leukemia patients with high prevalence of comorbidity?

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.7016 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 7016-7016

Author(s):

Sacha Satram-Hoang ◽

Carolina M. Reyes ◽

Khang Hoang ◽

Fayez Momin ◽

Sridhar Guduru ◽

...

Keyword(s):

Survival Analysis ◽

Chronic Lymphocytic Leukemia ◽

Risk Reduction ◽

Mortality Risk ◽

Cox Regression ◽

Lymphocytic Leukemia ◽

Medicare Part ◽

Time Period ◽

High Prevalence ◽

Significant Mortality

7016 Background: Therapy selection in chronic lymphocytic leukemia (CLL) patients is based on disease severity as well as patient characteristics such as age and comorbidity. While treatment outcomes are mostly available from clinical trial data in younger patients, less is known about the effect of comorbidities on outcomes in elderly CLL patients in the real-world setting. Methods: The linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database was utilized in this retrospective cohort analysis of 3,366 first primary CLL patients. Patients were diagnosed between 1/1/1998-12/31/2007, were >66 years, continuously enrolled in Medicare Part A and B with no HMO coverage in the year prior to diagnosis and received first-line treatment with any oral or infused therapy. CLB is covered by Medicare Part D and data for its use were only available from 2007-2009 in the dataset. Cox regression with backward elimination and propensity score weighted Cox regression estimated the relative risk of death. Date of last follow-up was 12/31/2009. Results: There were 153 CLB, 606 R-mono, 702 R+IV Chemo, and 1,905 IV Chemo-only patients. CLB and R-mono patients were older at diagnosis with mean age of 77 compared to R+IV Chemo (73 years) and IV Chemo-only (76 years; p<.0001). Patients administered R-mono had a higher comorbidity burden and more advanced disease compared with other treatment groups. In the survival analysis we compared CLB to R-mono during the time period 2007-2009 and R+IV Chemo to IV Chemo-only during the time period 1998-2009. The adjusted multivariate survival analysis revealed a significant mortality risk reduction with R+IV Chemo compared with IV Chemo-only patients (HR, 0.72; 95% CI, 0.62-0.84) while a non-significant mortality risk reduction was noted with R-mono compared to CLB patients (HR, 0.47; 95% CI, 0.21-1.05). Older age and increasing comorbidity score were significantly associated with higher mortality. Conclusions: These findings suggest that chemo-immunotherapy is more effective than chemotherapy in an elderly population with a high prevalence of comorbidity. This extends the conclusions from clinical trials in younger, medically fit patients.

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The Potential Role of Therapeutic Dose of Low Molecular Weight Heparin (LWMH) to Attenuate Hyper-Inflammatory State in Hospitalized COVID-19 Patients

Blood ◽

10.1182/blood-2020-142109 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 11-12

Author(s):

Mohsin Sheraz Mughal ◽

Ikwinder Preet Kaur ◽

Ali R. Jaffery ◽

Chang Wang ◽

Muhammad Asif ◽

...

Keyword(s):

Pulmonary Embolism ◽

Disease Severity ◽

Inflammatory Markers ◽

Potential Role ◽

Hospitalized Patients ◽

Inflammatory State ◽

Anti Inflammatory ◽

D Dimer ◽

Inflammatory Effect

Introduction:The underlying pathophysiology of severe COVID-19 involves cytokine storm syndrome that is associated with an elevation of immunoinflammatory cytokines [1]. This hyper-inflammatory state has been implicated with coagulopathy among severely sick patients with COVID-19. Inflammation and coagulopathy are interlinked processes [2]. Coagulopathy has been associated with high mortality in COVID-19 patients [3]. LMWH is traditionally used for its anticoagulant and antithrombotic properties, however, its anti-inflammatory effect has not been fully elucidated. A study done by Shastri et al. suggested that LMWH can inhibit the release of different cytokines (IL-4, IL-5, IL-13, and TNF-α) [4]. Recent retrospective studies on COVID-19 illustrated that the LMWH (40-60 mg, subcutaneously every day) was associated with better prognosis as measured by (28 days of survival) in severely sick patients meeting sepsis-induced coagulopathy (SIC≥4) criteria compared to nonusers [5]. The potential role of escalated/therapeutic LMWH (1mg/kg/subcutaneously every 12 hours) remains unclear. This study involves a retrospective analysis of the potential role of an escalated dose of LMWH to alter the hyper-inflammatory state in hospitalized patients with COVID-19 and compared outcomes to those patients who received a low dose (40-60 mg, subcutaneously every day) of LMWH. Methods:Adult patients with confirmed SARS-CoV-2 infection by nasopharyngeal (NP) polymerase chain reaction (PCR) who were hospitalized from March 1st to April 20, 2020, were included. They were divided into two cohorts based on the dose of LMWH; cohort 1 (40-60 mg, subcutaneously every day) and cohort 2 (1mg/kg/subcutaneously every 12 hours). Categorical variables were compared by conducting a chi-square test or Fisher's exact test while continuous ones were compared by conducting a median two-sample test. Results:The median values of PT, PTT, INR, CRPmax, LDHmax, ferritinmax, D-dimermax, are mentioned in table 1. Incidence of thrombotic events (deep venous thrombosis, ischemic stroke, pulmonary embolism) was higher in cohort 1 (n=3, 4.8%) compared to cohort 2 (n=1, 2.6%). Cohort 2 had a higher number of patients who received ICU level of care (n=24) compared to the 6 patients in cohort 1. Out of 24 patients in cohort 2, 18 patients received invasive mechanical ventilation. The median value of length of stay in the hospital (10.0 days) and all-cause mortality (31.6 %) were higher in cohort 2 as compared to cohort 1 (p<0.05). Discussion:Infections have the ability to trigger systemic inflammation [6]. The interplay between the host system and its response to foreign pathogens can lead to the activation of coagulation pathways. SARS-CoV-2 entry via ACE-2 receptors on endothelial cells is likely associated with endothelial dysfunction. This endotheliopathy plays a significant role in COVID-19 related microcirculatory changes [7]. Severe COVID-19, a hyperinflammatory state, is marked by elevated inflammatory markers including D-dimer, ferritin, IL-6, LDH, and CRP levels. Elevated D-dimer levels have been correlated with disease severity and poor outcomes in hospitalized patients with COVID-19 [8]. The incidence of VTE and pulmonary embolism among COVID-19 ICU patients was higher in a study from France [9]. The patient population who received the escalated dose of LMWH in our study either had SIC score ≥ 4 or D-dimer ≥ 2.2 (FEU). This data indicated that the median value of peak inflammatory markers in cohort 1 was lower (p<0.05) when compared to cohort 2. Patients in cohort 2 were sicker than cohort 1, as evidenced by a statistically significant longer length of hospital stay and a higher rate of ICU admission. However, the potential dose-dependent anti-inflammatory effect of LMWH was not observed. Additional studies evaluating comorbidities and disease severity in both cohorts may yield different results. Conclusion:Aside from the known anticoagulant benefit of LMWH, there was no additional anti-inflammatory role with higher doses (1mg/kg/subcutaneously every 12 hours) of LMWH. Disclosures No relevant conflicts of interest to declare.

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The Impact of Obesity and Adiposity on Mortality Risk in Older Adults: A Ten-year Survival Analysis

10.21203/rs.3.rs-777627/v1 ◽

2021 ◽

Author(s):

Letícia Almeida Nogueira Moura ◽

Valéria Pagotto ◽

Cristina Camargo Pereira ◽

Rômulo Roosevelt da Silva Filho ◽

César de Oliveira ◽

...

Keyword(s):

Older Adults ◽

Survival Analysis ◽

Mortality Risk ◽

Cancer Mortality ◽

Cox Regression ◽

Clinical History ◽

The Body ◽

Increased Risk ◽

Multifrequency Bioimpedance ◽

The Impact

Abstract There are not much information about the impact of obesity on all-cause, cardiovascular and cancer mortality in older adults. We have investigated the impact of obesity and adiposity on all-cause, cardiovascular and cancer mortality, in older adults after a 10-year follow-up. Prospective cohort study has been carried out with individuals ≥ 60 years. Sociodemographic characteristics, lifestyle, clinical history, laboratory tests and anthropometric data were collected. Adiposity was defined as tertiles of the percentage of body fat assessed by multifrequency bioimpedance. For obesity, three classifications were considered using the body mass index (BMI) as follows: ≥ 25.0 kg/m² in men and ≥ 26.6 kg/m² in women, ≥ 27.0 kg/m² and ≥ 30.0 kg/m². The BMI ≥ 30.0 kg/m² was associated a reduction in the all-cause mortality risk in non-ajusted Cox regression (HR: 0.65; 95% CI: 0.43 - 0.97) and in the Kaplan-Meier curves (p = 0.032). However, in multivariate Cox regression none of the diagnostic criteria for obesity and adiposity were significantly associated with all-cause, cardiovascular or cancer mortality. This 10-year survival analysis has showed that obesity and adiposity were not associated with an increased risk of all-cause, cardiovascular or cancer mortality in the older adults.

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Expression Status and Prognostic Value of m6A RNA Methylation Regulators in Lung Adenocarcinoma

10.21203/rs.3.rs-120253/v1 ◽

2020 ◽

Author(s):

Rui Wang ◽

Zian Feng ◽

Jie Hu ◽

Xiaodong He ◽

Zuojun Shen

Keyword(s):

Regression Analysis ◽

Survival Analysis ◽

Roc Curve ◽

Cox Regression ◽

Risk Group ◽

Cox Regression Analysis ◽

Rna Methylation ◽

Kaplan Meier ◽

Prediction Efficiency

Abstract Background: N6-methyladenosine (m6A) RNA modification is the most abundant modification method in mRNA, and it plays an important role in the occurrence and development of many cancers. However, data on the role of m6A RNA methylation regulators in lung adenocarcinoma (LUAD) are still lacking. This paper mainly discusses the role of m6A RNA methylation regulators in LUAD, to identify novel prognostic biomarkers.Methods: The gene expression data of 19 m6A methylation regulator in LUAD patients and its relevant clinical parameters were extracted from The Cancer Genome Atlas (TCGA) database. The least absolute shrinkage and selection operator (LASSO) Cox regression algorithm were performed to construct a risk signature and evaluated its prognostic prediction efficiency by using the receiver operating characteristic (ROC) curve. The risk score of each patient was calculated according to the risk signature, and LUAD patients were divided into high-risk group and low-risk group. Kaplan-Meier survival analysis and Cox regression analysis were used to identify the independent prognostic significance of risk signature. Finally, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) were used to explore the differential signaling pathways and cellular processes between the two groups.Results: The expression of 15 m6A RNA methylation regulators in LUAD tissues was significantly different than that in normal tissues. YTHDF3, YTHDF2, KIAA1429, HNRNPA2B1, RBM15, METTL3, HNRNPC, YTHDF1, IGF2BP2, IGF2BP3, IGF2BP1 were significantly up-regulated in LUAD, and the expressions of FTO, ZC3H13, WTAP, and METL14 were significantly down-regulated. We selected IGF2BP1, HNRNPC, and HNRNPA2B1 to construct the risk signature. ROC curve indicated the area under the curve (AUC) was 0.659, which means the risk signature had a good prediction efficiency. The results of Kaplan-Meier survival analysis and Cox regression analysis showed that the risk score can be used as an independent prognostic factor for LUAD.Conclusions: The m6A RNA methylation regulators IGF2BP1, HNRNPC, and HNRNPA2B1 have a significant correlation with the clinicopathological characteristics of LUAD, which may be a promising prognostic feature and clinical treatment target.

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The Potential Role of Flavonoids in Ameliorating Diabetic Cardiomyopathy via Alleviation of Cardiac Oxidative Stress, Inflammation and Apoptosis

International Journal of Molecular Sciences ◽

10.3390/ijms22105094 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5094

Author(s):

Fatin Farhana Jubaidi ◽

Satirah Zainalabidin ◽

Izatus Shima Taib ◽

Zariyantey Abd Hamid ◽

Siti Balkis Budin

Keyword(s):

Oxidative Stress ◽

Risk Factors ◽

Diabetic Cardiomyopathy ◽

Mortality Risk ◽

Potential Role ◽

Therapeutic Potential ◽

Biological Activities ◽

Diabetic Patients ◽

Remedial Actions

Diabetic cardiomyopathy is one of the major mortality risk factors among diabetic patients worldwide. It has been established that most of the cardiac structural and functional alterations in the diabetic cardiomyopathy condition resulted from the hyperglycemia-induced persistent oxidative stress in the heart, resulting in the maladaptive responses of inflammation and apoptosis. Flavonoids, the most abundant phytochemical in plants, have been reported to exhibit diverse therapeutic potential in medicine and other biological activities. Flavonoids have been widely studied for their effects in protecting the heart against diabetes-induced cardiomyopathy. The potential of flavonoids in alleviating diabetic cardiomyopathy is mainly related with their remedial actions as anti-hyperglycemic, antioxidant, anti-inflammatory, and anti-apoptotic agents. In this review, we summarize the latest findings of flavonoid treatments on diabetic cardiomyopathy as well as elucidating the mechanisms involved.

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Non-vitamin K Antagonist Oral Anticoagulants and Drug-Food Interactions: Implications for Clinical Practice and Potential Role of Probiotics and Prebiotics

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.787235 ◽

2022 ◽

Vol 8 ◽

Author(s):

Ana Sánchez-Fuentes ◽

José Miguel Rivera-Caravaca ◽

Raquel López-Gálvez ◽

Francisco Marín ◽

Vanessa Roldán

Keyword(s):

Clinical Practice ◽

Vitamin K ◽

Potential Role ◽

Therapeutic Option ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Vitamin K Antagonist ◽

Pharmacodynamic Profile ◽

Potential Interactions

Non-vitamin K antagonist oral anticoagulants (NOACs) are a therapeutic option to prevent stroke in patients with atrial fibrillation (AF). In fact, NOACs have become the recommended choice by international clinical practice guidelines over vitamin K antagonists (VKA), because of their efficacy and safety profile, especially in newly initiated patients. The more predictable pharmacokinetic and pharmacodynamic profile of this family of drugs allows preventing anticoagulation drug monitoring. Furthermore, NOACs have significantly fewer drug and food interactions in comparison with VKAs. Despite this, there are no studies that compare the effects on the quality of anticoagulation of NOACs with the intake of potential interactions drugs of P-glycoprotein and cytochrome P450 (CYP). This review brings an overview of NOACs pharmacokinetics profile and their potential drug-food interactions. We also briefly discuss the potential role of prebiotics and probiotics in patients under therapy with NOACs.

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The Association of Vitamin D and Vitamin K Status with Subclinical Measures of Cardiovascular Health and All-Cause Mortality in Older Adults: The Hoorn Study

Journal of Nutrition ◽

10.1093/jn/nxaa293 ◽

2020 ◽

Vol 150 (12) ◽

pp. 3171-3179

Author(s):

Elisa Dal Canto ◽

Joline W J Beulens ◽

Petra Elders ◽

Femke Rutters ◽

Coen D A Stehouwer ◽

...

Keyword(s):

Vitamin D ◽

Vitamin K ◽

Cardiovascular Health ◽

Cox Regression ◽

Left Ventricular ◽

Matrix Gla Protein ◽

Cvd Risk ◽

Increased Risk ◽

Normal Vitamin ◽

All Cause Mortality

ABSTRACT Background A low vitamin D and K status has been associated with increased cardiovascular disease (CVD) risk but the evidence of their combined effect on cardiovascular health is limited. Objectives Our study aimed to investigate the prospective association of vitamin D and K status with subclinical measures of cardiovascular health and all-cause mortality among a population of Dutch Caucasians. Methods We performed an observational prospective study on 601 participants of the Hoorn Study (mean ± SD age: 70 ± 6 y, 50.4% women, BMI: 27.2 ± 4.0 kg/m2), of whom 321 underwent an echocardiogram in 2000–2001 and 2007–2009. Vitamin D and K status was assessed at baseline by serum 25-hydroxyvitamin D [25(OH)D] and plasma desphospho-uncarboxylated matrix-gla protein (dp-ucMGP)—high concentrations indicate low vitamin K status. Vital status was assessed from baseline until 2018. We studied the association of categories of 25(OH)D (stratified by the clinical cutoff of 50 mmol/L) and dp-ucMGP (stratified by the median value of 568 pmol/L) with echocardiographic measures using linear regression and with all-cause mortality using Cox regression, adjusted for confounders. Results Compared with markers of normal vitamin D and K status, markers of low vitamin D and K status were prospectively associated with increased left ventricular mass index (5.9 g/m2.7; 95% CI: 1.8, 10.0 g/m2.7). Participants with low vitamin D and K status were also at increased risk of all-cause mortality with an HR of 1.64 (95% CI: 1.12, 2.39) compared with normal vitamin D and K status. Conclusions A combination of low vitamin D and K status is associated with adverse cardiac remodeling and increased risk of all-cause mortality in men and women. Future studies should investigate whether vitamin D and K supplementation could help to improve cardiovascular health and to decrease CVD risk.

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