key: cord-0730661-bv3uq7bv
authors: Desai, Ankita P; Dirajlal-Fargo, Sahera; Durieux, Jared C; Tribout, Heather; Labbato, Danielle; McComsey, Grace A
title: Vitamin K & D Deficiency Are Independently Associated With Covid-19 Disease Severity
date: 2021-07-29
journal: Open Forum Infect Dis
DOI: 10.1093/ofid/ofab408
sha: 3f951b3b20688907a74f2fe5a8a08def24aff9f3
doc_id: 730661
cord_uid: bv3uq7bv

BACKGROUND: We investigated the status of vitamin K and vitamin D and association to COVID-19 outcomes. METHODS: Levels of inactive vitamin K-dependent dephosphorylated uncarboxylated matrix Gla protein (dp-ucMGP; marker of vitamin K status) and 25-hydroxyvitamin D levels (25(OH)D; vitamin D status) were measured in plasma samples from participants with confirmed acute COVID-19 and were age and sex matched to healthy controls. Unadjusted (UOR) and adjusted odds ratios (AOR) with 95% confidence intervals (CI) were computed using cumulative logistic regression. RESULTS: 150 subjects were included, 100 COVID-19+ and 50 controls. Median agewas 55 (IQR: 48, 63), 50% were females. 34% had mild COVID-19 disease, 51% moderate disease, and 15% severe. Dp-ucMGP levels were higher (i.e. worse K status) in COVID-19+ vs controls (776.5 ng/mL vs 549.8 ng/mL, p <0.0001) with similar 25(OH)D between groups (25.8 vs 21.9 ng/mL, p=0.09). Participants who were vitamin D deficient (<20ng/mL) had the worse vitamin K status (dp-ucMGP >780ng/mL) and experienced the most severe COVID-19 outcomes. In adjusted models, every one-unit increase in the log2 dp-ucMGP nearly doubled the odds of acute critical disease or death [AOR 95%CI: 1.84 (1.01, 3.45)] and every one-unit decrease in the natural log 25(OH)D was associated with more than three times the likelihood of COVID-19 disease severity [AOR 95%CI: 0.29 (0.11, 0.67)]. CONCLUSION: Early in acute COVID-19, both vitamin K and vitamin D deficiency were independently associated with worse COVID-19 disease severity, suggesting a potential synergistic interplay between these two vitamins in COVID-19.

A c c e p t e d M a n u s c r i p t 4

Since the emergence of the novel Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) in late 2019, there has been substantial worldwide effort in understanding the pathogenesis of coronavirus disease 2019 (COVID- 19) , treatment modalities, and prevention. Those infected with this virus may have a wide range of symptoms from an asymptomatic or mild state to severe pneumonia, coagulopathy, and death. [1] The ability to predict severe disease and response to treatment remains elusive. [2] Several risk factors have been identified for disease severity including advanced age, male sex, non-white race, obesity, vitamin and mineral deficiencies, specifically vitamin D, C, and selenium, diabetes and hypertension. Severe outcomes have been associated with multiorgan failure, which may correspond to the underlying inflammatory response post infection.

Host factors triggered by the virus can lead to an exaggerated inflammatory response or "cytokine storm," leading to pulmonary damage through calcification of pulmonary interstitial arteriolar walls, hypercoagulation, and disseminated intravascular coagulation. [3] Vitamin K is the name given to a group of essential fat-soluble vitamins, phylloquinone (vitamin K1) and menaquinones (vitamin K2) that are co-factors for several proteins involved in coagulation homeostasis and calcium homeostasis. Phylloquinone and menaquinones share the same head group (2-methyl-napthoquinone) but have different compositions of the poly-isoprenoid side chain (at the 3-position). In the circulation, there is a differential distribution of vitamin K to lipoproteins, where the majority of short chain vitamin K (phylloquinone) is associated with triacylglycerol-rich lipoproteins, and the longer menaquinones are more associated with low-density lipoproteins (LDL).

The associations with different lipoproteins allow different distribution in the body, where the long chain menaquinones reach extrahepatic tissues that are possessing LDL receptors. [4] Vitamin K activates both hepatic coagulation factors and extrahepatic endothelial anticoagulant protein S, required for thrombosis prevention. Other important extrahepatic vitamin K dependent proteins are A c c e p t e d M a n u s c r i p t 5 osteocalcin, matrix gla-protein (MGP), Gla-rich protein (GRP), and growth arrest-specific protein 6 (Gas6). Deficiency in vitamin K is linked to vascular calcification and osteoporosis. Vitamin K is also believed to have anti-inflammatory properties, mediated by the reduction of circulating inflammatory mediators. [5] Recent research has reported a poor vitamin K status in hospitalized adults with COVID-19

infection. [6, 7] They also suggested that deficiency in vitamin K may be associated with more severe outcomes, although all patients were hospitalized with more severe disease. The biomarker that has been mostly used for extrahepatic vitamin K status is dp-ucMGP. High levels of dp-ucMGP (poor vitamin K status) has been associated with many additional clinical outcomes, like cardiovascular risk, arterial stiffness, endothelial function, and chronic obstructive pulmonary disease (COPD). [8] [9] [10] [11] [12] In addition, there is currently an ongoing debate about the relevance of vitamin D supplementation in COVID-19. Vitamin D is shown to reduce the incidence of viral respiratory tract infections, in particular within persons that have a low vitamin D status [13] . However, it is not clear if the vitamin D status also plays a role in COVID-19, and whether that role is independent of vitamin K status. In this study, we investigated the status of vitamin K and vitamin D early in the course of COVID-19 and the ability to independently predict COVID outcomes, as well as the potential synergistic interplay between these two vitamins and inflammatory chemical mediators. We hypothesized that COVID-19 participants would show a lower vitamin K status and that a lower status would be associated, independently of vitamin D status and other known risk factors, with poor COVID-19 outcomes.

A c c e p t e d M a n u s c r i p t 6

This was a prospective observational cohort study, participants were enrolled from April 21, 2020 to November 5, 2020 at University Hospitals Cleveland Medical Center, in Cleveland, OH, USA. Patients were confirmed with SARS CoV-2 infection by nasopharyngeal swab real-time polymerase chain reaction (PCR) testing. Participants varied in disease presentation from asymptomatic to life threatening and even death. Additional participants who were asymptomatic had been selected to match by age and sex to the COVID-19 cohort. These healthy controls had been enrolled prior to November 2019 as "healthy controls" for an ongoing HIV study. The COVID-19 participants were enrolled as part of a COVID-19 biorepository, which enrolled any willing patient who presented to University Hospitals Health System, Cleveland, Ohio with documented positive SARS-CoV-2, whether they presented to ambulatory clinic, emergency department, or were hospitalized. In addition, patients self-referred for biorepository enrollment including some who were (and remained) asymptomatic but tested positive by PCR after a known exposure. Blood was collected at multiple timepoints throughout the disease course. We used blood at an early timepoint (within the first seven days after symptoms) for this study. Detailed clinical history was available on these participants, both before the illness and throughout their illness course.

This study was approved by the Institutional Review Board at University Hospitals Case Medical Center, Cleveland, Ohio. All subjects gave written informed consent for collection of blood samples. Patient demographics for age, sex and race were collected. In addition, body mass index (BMI) at the time of initial presentation, as well as comorbidities and laboratory data for creatinine, complete blood count, C-reactive protein (CRP), and liver function were assessed on all subjects.

A c c e p t e d M a n u s c r i p t 7

Participants acute illness severity was assessed according to World Health Organization's ordinal scale for clinical improvement (OSCI) for COVID-19. [14] Acute illness severity ranges from having no clinical signs of infection (low score) to death. The highest score during hospitalization was used for this analysis. These scores were collapsed into three categories according to disease severity and dedicated treatments. The acute mild disease group included those with mild disease, no assistance to moderate disease, no oxygen therapy. The acute moderate disease group included those with moderate disease, requiring oxygen therapy to severe disease, non-invasive oxygen therapy. The acute severe disease group included severe disease, any form of invasive ventilation to death.

Due to inability to directly measure naturally occurring blood vitamin K levels, measuring vitamin K dependent protein in circulation is a valuable method to measure vitamin K deficit.

Circulating dp-ucMGP level was used indirectly quantify extrahepatic vitamin K status. [9] High dp-ucMGP levels is considered the best marker of low vitamin K status. Plasma samples that were never previously thawed were processed at the Maine Medical Center Research Institute. For the analysis, vitamin K (dp-ucMGP) was categorized by distribution tertiles defined as low vitamin K (dp-ucMGP > 897 ng/mL), mid vitamin K (dp-ucMGP between 520 and 897 ng/mL), and high vitamin K (dp-ucMGP < 520 ng/mL).

Vitamin D status was assessed through measurement of 25-hydroxyvitamin D levels. [15] Plasma samples never previously thawed were processed at the Maine Medical Center Research Institute.

For the analysis, vitamin D (25-hydroxyvitamin D) was categorized by distribution tertiles and A c c e p t e d M a n u s c r i p t 8 defined as optimal vitamin D status (>30 ng/mL), insufficient (20-30ng/mL), and deficient (<20 ng/mL).

Characteristics of study participants were described using median and interquartile range for continuous variables and frequency and percentage for categorical variables. Differences between COVID-19 positive and healthy controls were computed using either non-parametric Wilcoxon Rank-Sum (Mann-Whitney U) for continuous variables or X 2 for categorical variables. Log transformations were used to stabilize the error variance. Independent associations between demographics, comorbidities, lab values, and inflammation markers with dp-ucMGP and 25(OH)D were computed using generalized linear models by method of least squares. To assess if suboptimal vitamin K and vitamin D levels are associated with worse COVID-19 outcomes, estimated unadjusted (UOR) and adjusted odds ratios (AOR) with 95% profile likelihood confidence intervals (CI) were computed using cumulative logistic regression and adjusted for age, sex, race, comorbidities and marker of systemic inflammation. Variance inflation factor and tolerance (or 1-R 2 ) was used to assess linear dependencies among explanatory variables and the likelihood ratio chi-square statistic was used to test the proportional odds assumption. P-values less than alpha <.05 were considered statistically significant. All analyses were conducted using SAS 9.4 (SAS Inc., Cary, N.C., USA).

Baseline characteristics 150 participants were included in the final analysis, 100 with SARS-CoV2 and 50 age and sex matched healthy controls. Demographic data is summarized in Table 1 A c c e p t e d M a n u s c r i p t 9 58.6, p<0.0001), and aspartate aminotransferase (AST) values (29.5 U/L vs. 17, p<0.0001) were higher in the COVID-19 positive cohort. However, there were no differences in total white blood cell count (8,000 vs. 5,800, p=0.14), lymphocyte percentage (30.8 vs. 29.5, p=0.6), and alanine aminotransferase (19 U/L vs. 20.5, p=0.73).

Among the COVID-19 positive cohort, 52% (52/100) had at least one comorbidity with hypertension being the most prevalent, 48% (48/100). The most common presenting symptoms at admission included nausea/vomiting (41%), followed by cough (33%) and fatigue (32%). 34 had mild disease (4 asymptomatic and 30 symptomatic, not requiring hospitalization or oxygen), 51 had moderate disease (all hospitalized, requiring oxygen by nasal cannula, face mask or other non-invasive oxygen therapy), and 15 were classified as severe (8 requiring mechanical ventilation and 7 deaths). There was no gender or racial differences in disease severity (p=0.75). In terms of treatments received, only two participants received remdesivir, one in the moderate disease category and one severe.

Tocilizumab was given to only one participant who died. Steroid therapy was given to three participants (dexamethasone to two and prednisone to one), all in the moderate category.

The overall median dp-ucMGP was 638.10 ng/mL (IQR: 519.79, 897.12) and was higher (i.e. worse vitamin K status) in the COVID-19 positive cohort compared to controls (776.5 ng/mL vs 549.8 ng/mL, p <.0001). Chronic kidney disease (p<.0001), cardiovascular disease (p=0.001), hypertension (p=0.02), cancer/immunosuppression (p=0.0002), creatinine (p<.0001), lymphocyte percentage (p=0.02), and CRP (p=<.0001) were independently associated with dp-ucMGP ( Table 2 ). As shown in Table 3 and Figure 1 , in the adjusted model, every one-unit increase in the log2 dp-ucMGP nearly 

The overall median vitamin D was 24.40 ng/mL (IQR: 15.43, 31.58). Although vitamin D levels were higher in the COVID-19 positive cohort, there was not enough evidence to suggest these values were different when compared to the control group (25.8 vs. 21.9, p=0.09). Age (p<.0001), sex (p=0.02), and race (p=0.01) were independently associated with 25(OH)D ( Table 2 ). In adjusted models, as shown in Table 3 and Figure 1 , every one-unit decrease in the natural log 25(OH)D was associated with more than three times the likelihood of COVID-19 disease severity [AOR 95%CI: 0.29 (0.11, 0.67)].

Although there was not enough evidence to suggest that 25(OH)D was independently associated with dp-ucMGP (p=0.26), participants with sufficient vitamin D (>30 ng/mL) as well as those who were vitamin D deficient (<20ng/mL) had the worse vitamin K status (dp-ucMGP >780ng/mL) and experienced the most severe COVID-19 disease outcomes ( Figure 2 ). CRP (mg/dL) was independently associated with dp-ucMGP (p=<.0001) and acute severe COVID outcome (p<.0001) and was not associated with 25(OH)D (p=0.66). As shown in Table 3 and There is some evidence to suggest that CRP may confound the relationship of dp-ucMGP on COVID-

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In separate models, we also adjusted for lymphocyte and creatinine, which did not remain associated with acute critical disease (p≥0.36 for both), and neither lymphocytes nor creatinine changed the effect of log2 dp-ucMGP on COVID-19 disease severity (AOR 95% CI 2.66 (1.49, 5.12) and AOR 95% CI 2.51 (1.32, 5.09) for models adjusting for log lymphocytes and log creatinine respectively).

This is the first study to measure both vitamin D and vitamin K status in COVID-19. Our study suggests an independent role of both poor vitamin K and D status in COVID-19 disease severity. Even more, vitamin K was associated with factors that have been described to be associated with COVID-19 outcomes, including demographics, BMI, inflammation marker CRP, and comorbidities. However, after accounting for vitamin K status, the association between these known risk factors and COVID-19 outcome was no longer present, suggesting that the role of demographics and comorbidities may be mediated by their association with vitamin K (and possibly also vitamin D status).

There are 20 described vitamin K dependent proteins (VKDP) in the human body, where vitamin K serves as a co-factor to activate these proteins through a carboxylation process. [16] We measured the inactive form of MGP, the dephosphorylated uncarboxylated MGP (dp-ucMGP) as it is the biomarker that has been mostly used for extrahepatic vitamin K status. High levels of dp-ucMGP has been associated with many clinical outcomes, like cardiovascular risk, arterial stiffness, endothelial function, and chronic obstructive pulmonary disease (COPD). [8] [9] [10] [11] [12] In an active, carboxylated state, MGP is a strong binder of calcium. A low vitamin K status leads to higher levels of the inactive form, dp-ucMGP, which do not bind calcium. The role of vitamin K in COPD was discussed by Piscaer and colleagues in 2019, where they proposed that a decreased activation of MGP lead to calcification of A c c e p t e d M a n u s c r i p t 12 elastin, something that further led to increased elastase activity, accelerated elastolysis, and elevated plasma desmosine levels. [10] The importance of vitamin K in lung health was also recently presented by another research group. By using NHANES 2007-2016 data (n=17,681), Shen et al., showed that consumption of recommended amounts of vitamin K was associated with a 39% decrease in odds of emphysema, and they concluded that vitamin K is important for lung health. [17] Recently, two independent European research groups have reported vitamin K status as a potentially modifiable risk factor for COVID-19. [6, 7] Dofferhoff and colleagues used two assays to measure vitamin K status on COVID-19 patients: [7] dp-ucMGP to measure extra-hepatic vitamin K and Protein Induced by Vitamin K Absence (PIVKA)-II to detect hepatic vitamin K status. The vitamin K status in 135 hospitalized COVID-19 patients were compared to controls. Similar to our findings, the extrahepatic vitamin K status was lower in the COVID-19 patients compared to the controls, and it was even lower in the poor outcome patients (invasive ventilation and/or death). In another study, in 62 COVID-19 patients, 72% of the males and 36% of the females were vitamin K deficient. Our study extend these findings to a US cohort, and also to a cohort with largely varying clinical presentation (varying from asymptomatic status to death), in which we report a significant association between vitamin K status and COVID-19 disease severity.

A state of heightened inflammation, usually measured by soluble cytokines, seems to play an important role in the pathophysiology of COVID-19. Some cytokines are potentially beneficial (type-I interferon, interleukin (IL)-7), and others harmful (TNF-α, IL-1β, IL-6). [18] Anastasi and colleagues have showed a positive correlation between low hepatic vitamin K status and elevated interleukin 6 (IL-6). The anti-inflammatory action of vitamin K is shown in several studies outside of COVID-19. By using human monocyte-derived macrophages, Pan and colleagues showed inhibition of cytokine release (TNF-α, IL-1α, IL-1β) when the cells were pretreated by vitamin K2 (menaquinone-7), and the scientists were able to show a dose response relationship. [19] Similar inhibitory effects are also seen A c c e p t e d M a n u s c r i p t 13 on IL-6, by other research groups. [20, 21] The release of pro-inflammatory cytokines is mainly regulated through the NF-kB signaling pathway, and vitamin K is shown to inhibit the release of IkB from NF-kB to allow its entry into the nucleus. [22] [23] [24] We were able to show that CRP was associated with more severe COVID-19 outcome and with lower vitamin K status. In addition, when adjusting for CRP, we saw an attenuation in the relationship between vitamin K and COVID-19 outcomes.

These observations suggest the association between vitamin K, but not vitamin D, and COVID-19 severity outcome is likely partially due to vitamin K's anti-inflammatory effect. In addition, vitamin K A c c e p t e d M a n u s c r i p t 14 Vitamin D is mainly synthesized in the skin after exposure to UVB, with a part being derived from dietary sources. [28] Endogenous vitamin D status highly depends on several factors including nutritional habits, latitude, season, skin pigmentation and lifestyle. [15] It has important pleiotropic immunomodulatory effects. In a meta-analysis of 25 randomized controlled trials, vitamin D supplementation reduced the risk of developing acute respiratory tract infections, with a higher protective effect in those with low levels of vitamin D at baseline (25-hydroxyvitamin D levels < 25 nmol/L). [13] We have previously investigated the role of vitamin D supplementation in other diseases associated with ongoing inflammation, specifically we focused on markers of T-cell activation/exhaustion and monocyte activation in HIV-infected youth whose HIV was controlled on antiretrovirals. [29] In a randomized, active-control, double-blind trial investigating 3 different vitamin D doses in HIV-infected youth on ART with serum 25-hydroxyvitamin D concentrations ≤30 ng/mL, we found that all measured markers decreased including CD4+ and CD8+ T cell activation, CD4+ exhaustion, and inflammatory mediators.

Our findings suggest a potential relationship between vitamin D and K at the time of acute COVID-19 and association with worse disease severity. Interestingly, both vitamin D and K may display complementary effects on the cytokine storm, thrombosis, and lung damage during COVID-19.

Specifically, they display similar inhibitory effects on inhibition of NF-kB and cytokine release, and vitamin D and K appear to work synergistically to help protect against calcification and damage in the lungs. While vitamin D promotes MGP synthesis, vitamin K is crucial for activation of MGP. Active MGP helps remove calcium from soft tissues. Without this action, accumulation of calcium on elastic fibers leads to degradation. Low active MGP results in a higher risk for elastic fiber damage in the lungs. As such concomitantly measuring the status of both vitamins in COVID-19, and relating it to pro-and anti-inflammatory markers is of major importance in COVID-19. In addition, optimizing vitamin K and D prior to acute COVID-19 infection may help to regulate overwhelming calcification, A c c e p t e d M a n u s c r i p t 15 inflammation, and coagulopathy, which may subsequently lead to improved clinical outcomes. Since the long-chain menaquinones of vitamin K2 has an extrahepatic distribution, they possess the capacity to optimize the vitamin K status in tissues that are deficient, however, large preventative clinical trials are needed.

Several factors are frequently cited as risk factors for severe COVID-19 outcomes including race, BMI, and comorbidities. Persons with black race have higher mortality in the US, with an infection rate more than three-fold higher in predominantly black counties compared to predominantly white counties. [30] Hypertension has been identified as the most common comorbidity in COVID-19 and obesity is a risk factor for COVID-19 disease severity. In our study, being non-white, and having a higher BMI were independently associated with worse vitamin D and K levels, however, neither race or BMI were associated with COVID-19 outcome after adjusting for vitamin D and K status.

Similarly, hypertension was independently associated with worse vitamin K status but not with COVID-19 severity when adjusting for vitamin D and K levels. Most African Americans lack normal serum levels of vitamin D, in addition greater adiposity is associated with lower vitamin D levels suggesting a role for vitamin D in abdominal fat storage and function. Race, BMI, and co-morbidities, specifically hypertension, may be inter-related and racial differences in COVID-19 disease severity may be due to additional socioeconomic and health care disparities, however, our findings suggest that vitamin D and K may play a role in modulating the associations between these factors and COVID-19 disease severity.

Our study has several strengths including the detailed analysis of the COVID-19 outcomes, the large varying presentation of COVID-19 illness, the concomitant measurements of vitamin D and K, and the enrollment of participants in the narrow time frame starting at the beginning of the COVID-19

A c c e p t e d M a n u s c r i p t 16 pandemic in Ohio, USA. In the clinical records and outcomes of COVID-19 illness were recorded for at least 28 days after the illness. All participants were enrolled in the same location in the northern hemisphere. Our limitations include the blood testing was cross-sectional, and therefore we cannot exclude the possibility of residual confounding and show causation, as well as the lack of dietary information which may affect vitamin D and K.

Early in acute COVID-19, both vitamin K and D deficiency were independently associated with worse COVID-19 disease severity, even after adjusting for demographics and comorbidities. This suggests a potential synergistic interplay between these two vitamins in COVID-19 as important modifiable risk factors. Further studies are needed to determine whether optimizing vitamin D and K status will improve clinical outcomes in those with COVID-19. GM and JD verified the datasets and have access to the raw data.

This study was approved by the Institutional Review Board at University Hospitals Case Medical Center, Cleveland, Ohio. All subjects gave written informed consent for collection of blood samples.

GM have served as scientific consultant for Gilead, GSK/ViiV, Merck, Theratechnologies, Jannsen, and has received funding support from Gilead, ViiV, Tetraphase, Roche, Genentech, Vanda, Astellas, Merck. All other authors had no conflict of interest.

All of the individual participant data collected during the trial, after de-identification, will be shared upon request. Table 3 . Unadjusted (UOR) and Adjusted Odds Ratio (AOR) and 95% Confidence Intervals (CI) A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t 28 Figure 2 

Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19): A Review

Risk Factors for Severe Disease and Efficacy of Treatment in Patients Infected With COVID-19: A Systematic Review

COVID-19: The Inflammation Link and the Role of Nutrition in Potential Mitigation

Differential lipoprotein transport pathways of K-vitamins in healthy subjects

Protein S: A multifunctional anticoagulant vitamin K-dependent protein at the crossroads of coagulation, inflammation, angiogenesis, and cancer

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Combined low vitamin D and K status amplifies mortality risk: a prospective study

Circulating phylloquinone, inactive Matrix Gla protein and coronary heart disease risk: A two-sample Mendelian Randomization study

Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data

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Vitamin K as a Diet Supplement with Impact in Human Health: Current Evidence in Age-Related Diseases

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Should we stimulate or suppress immune responses in COVID-19? Cytokine and anti-cytokine interventions

Inhibition of TNF-alpha, IL-1alpha, and IL-1beta by Pretreatment of Human Monocyte-Derived Macrophages with Menaquinone-7 and Cell Activation with TLR Agonists In Vitro

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Vitamin K suppresses the

Pulmonary Diseases, Diabetes, Cardiovascular Diseases, Chronic Kidney Disease, and Cancer or Immunosuppression ***Includes Chronic Pulmonary Disease, Asthma, and Pulmonary Circulation Disorder ****Includes Coronary artery disease

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