Title: Reel syndrome, Lead Macrodislodgement.Shubash Adhikari MD FACP2, Frank Annie PhD1, Muhammad Amer MD FACP FACC FHRS21CAMC Health Education and Research Institute3200 MacCorkle Ave. SE, Charleston, WV 25304.2CAMC Cardiology3200 MacCorkle Ave. SE, Charleston, WV, 25304

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The Impact of COVID-19 on Surgery and Procedures: A CommentaryFrank H Annie, PhD1; Jaineet Singh Chhabra3; Aravinda Nanjundappa, MD2;1CAMC Health Education and Research Institute3200 MacCorkle Ave. SE, Charleston, WV 25304.2CAMC Vascular Center of Excellence, Charleston Area Medical Center.3200 MacCorkle Ave SE, Charleston, WV 253043Marshall University, School of Medicine.1600 Medical Center Dr, Huntington, WV 25701

A document by Frank Annie. Click on the document to view its contents.

Frank H Annie, PhD1; Aravinda Nanjundappa, MD2;1CAMC Health Education and Research Institute3200 MacCorkle Ave. SE, Charleston, WV 25304.2CAMC Vascular Center of Excellence, Charleston Area Medical Center.3200 MacCorkle Ave SE, Charleston, WV 25304

Marciano Lee1, Elise Anderson1, Ali Farooq1, Mohammed Yasin1, Yazan Alkawaleet1, Frank Annie2Charleston Area Medical Center, Department of Cardiology, 3200 MacCorkle Ave. SE,Charleston, WV 25304CAMC Health Education and Research Institute, 3200 MacCorkle Ave. SE,Charleston, WV 25304Corresponding:Frank Annie MA; MPA; PhDResearch Scientist (Department of Cardiology)CAMC Health Education and Research Institute3200 MacCorkle Ave. SE,Charleston, WV 25304Cell 304 -395 – 3830Phone 304-388-9921Fax: 304-388-9921Email: [email protected]:COVID-19, GEMFIBROZIL, IMMUNE MODULATING TREATMENTAbstract:The current Covid-19 viral infection has been declared a pandemic causing significant global morbidity and mortality predominantly from the manifestation of severe acute respiratory syndrome (SARS). It has been designated as SARS-CoV 2. Epidemiological studies show predilection in patients with associated chronic medical conditions including those with cardiovascular disease. Exaggerated host immune response known as cytokine storm syndrome (CSS) leading to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is the proposed mechanism for the development of SARS in Covid-19 infection. Gemfibrozil has proven benefits in patients with cardiovascular disease. More importantly, it has established anti-inflammatory, anti-oxidative, and anti-migratory properties. Gemfibrozil has shown survival benefits as immune modulation of ALI/ARDS from viral pathogens. This article reviews the potential of gemfibrozil as adjuntive immue modulating therapy for SARS associated with Covid-19 infected patients who have associated cardiovascular disease.Introduction:The severe acute respiratory syndrome (SARS) seen in Covid-19 infection share similarities with previous coronavirus epidemics, particularly SARS-CoV 1 and the Middle East Respiratory Syndrome (MERS-CoV). (1) It has been designated SARS-CoV 2. Acute lung injury (ALI) with subsequent development of acute respiratory distress syndrome (ARDS) from robust host hyper-immune response is the proposed pathophysiological mechanism. This so called ”cytokine storm” may be independent of viral load and replication. (2) Thus, the rationale for adding immune modulating strategies on top of antiviral/antimicrobial therapies is warranted to prevent this complication and hopefully improve survival. The development of ALI/ARDS amplifies mortality in Covid-19 infection, more so in patients with associated chronic medical conditions including cardiovascular disease. (3)Gemfibrozil, a drug discovered over 40 years ago, have beneficial effects and safety profile in both primary and secondary prevention of cardiovascular disease. (4) In addition to its lipid lowering ability, it has important immune modulating properties that inhibit pro-inflammatory factors involved in cytokine storms.(5) It is a peroxisome proliferators-activated receptor (PPAR) agonist known to reduce the release of inflammatory cytokines including interleukin-6 (IL-6), tumor necrosing factors (TNF) and interferon-gamma (IFN-g).IL-6 elevation have been reported as an important marker of severity with Covid-19 infection. (3) Together with other markers for inflammation such as CRP, the degree of IL-6 elevation correlates with increased morbidity and mortality.Gemfibrozil has shown survival benefits by attenuating ALI/ARDS development from viral etiologies. (6) Since gemfibrozil is currently indicated for patients with cardiovascular disease, its adjunctive use does not have to be repurposed for SARS associated with Covid-19 infection. Therefore, Gemfibrozil’s potential as an immune modulating strategy to prevent ALI/ARDS cannot be ignored.Immune Modulating Targets for Gemfibrozil in Covid-19 SARS pathogenesis:Gemfibrozil has been shown to attenuate pro-inflammatory effects of disease states through its immune-modulating, anti-inflammatory and anti-migratory properties. (5). It belongs to the fibrate family of drugs used to lower plasma lipds and cholesterol. They are one of several known synthetic lignads acting as agonists to the PPARs. (7) Their action in turn decrease serum levels of TNF, IFN-g and IL-6. (8,9)As an an anti-inflammatory, gemfibrozil reduces superoxide production and expression of nuclear factor kB (NF-kB). (10) Moreover, it inhibits astrocyte production of TNF, IL-1b, IL-6 and nitric oxide (NO) production. (11) Gemfibrozil also promotes the production of anti-inflammatory cytokine IL-4. (12) It reduces the production of C-reactive protein (CRP), TNF-a and IL-6 in peripheral blood mononuclear cells. It inhibits the production of cyclooxygenase-2 (COX-2) and prostaglandins. (13)As an immune-modulating agent, gemfibrozil attenuates pro-inflammatory transcription factor activation. This includes IFN-g regulatory factor 1 (IRF-1)bidning to gamma activation site (GAS), nuclear factor-kB (NF-kB), activator protein 1 (AP-1), and CCAT/enhancer binding protein beta (C/EBPb). (5) It also promotes switching of T helper (Th) cells from the pro-inflammatory Th1 to anti-inflammatory Th2. Production of Th2-specific cytokines is amplified including IL-4, IL-5 and IL-10. (14)As an anti-oxidant, gemfibrozil not only prevents low density lipoprotein (LDL) peroxidation but also acts on other signals of inflammation. Reactive oxygen species (ROS) have emerged as important signaling molecules during inflammatory conditions. Excessive ROS generation results in damage to most cellular components of the living organism. Gemfibrozil is known to inhibit ROS-mediated inflammation. (15) It has free radical scavenging ability as well. Its para-hydroxyl metabolite has been shown to reduce the burden of ROS. (16)As an anti-migratory agent, gemfibrozil affects the expression of cell-surface adhesion molecules icluding intracellular adhesion molecule 1 (ICAM-1), VCAM-1 and selectins inhibiting trans endothelial migration of mononuclear cells and macrophages. (17) It also down-regulates the expression of chemokines including monocyte chemotactic protein 1 (MCP-1), macrophage inflammatory protein 1 (MIP-1), monokines induced by IFN-g (MIG) and IL-8. The expression of IL-8 induces inflammation, monocyte/macrophage recruitment, angiogenesis and vascular smooth muscle migration. Thus, gemfibrozil can function as an anti-migratory factor by down-regulating the expression of different soluble chemokines and inhibit the expression of different cell surface proteins and selectins.Discussion:Over the years, viral pathogens including Influenzas and Coronaviruses cause ALI/ARDS from excessive release of pro-inflammatory cytokines and chemokines described in cytokine storm syndromes. They induce much higher transcription and up regulation of TNF genes including TNF related aptoptosis-inducing lignad and TNF-mRNA in human monocyte-derived macrophages. (18) This macrophage activation syndrome (MAS) seen with the current SARS-CoV 2 may be a dysregulated host response to Covid-19 viral induced immunosuppression and lymphopenia leading to unintended ALI/ARDS consequences at the site of infection. (19) The development of ALI/ARDS and the need for ventilator support portends to increased mortality rates. Markers of inflammation including CRP and IL-6 have been used as surrogates for MAS, and their degree of elevation have correlated well with disease severity. (3)Experiments with SARS-CoV indicate that MAS induced cytokine storms result more from amplification of gene related inflammatory signals regardless of viral load. In one model, immune modulation of receptor sites or alteration of recruitment signals resulted in dramatic improvement in host survival with viral load remaining constant. (20) This suggests that immune modulating therapy may have as important a role in addition to antiviral therapy in altering the course of Covid-19 infection. Reports of clinical improvement have been reported with the adjuvant use of IL-6 antagonists including tocilizumab. However, cost and repurposing use of these medications may be limiting factors.Gemfibrozil has been in clinical use for patients with cardiovascular disease and has achieved generic status. In addition, it has vital immune modulating properties against cytokine storms that mitigate the development of ALI/ARDS from both viral and nonviral pathogens. (21). It not only reduces the levels of IL-6, TNF and IFN-g. But it has also been shown to attneuate gene recruiting signals of inflammation utlizing human equivalent dosing. In one animal study, the adjuvant use of gemfibrozil resulted in enhanced host survival that developed ALI/ARDS from viral pathogens. (6) Enhanced survival is seen even after exposure to the virus. This implies that gemfibrozil has the potential to be a treatment rather than a preventive therapy in human disease.Therefore, the potential of gemfibrozil as adjunct immune modulating therapy in conjunction with antiviral treatment for SARS associated with Covid-19 infection in patients with associated cardiovascular disease is emphasized.References:1. Petrosillo N, Vicenconte G, et al. Covid-19, SARS and MERS: are they closely related? JCMI. 20202. Smits S, Lang A, et al. Exacerbated inane host response to SARS-CoV in aged non-human primates. PLos Patholog. 20103. Zhou F, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with Covid-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020. 3954. Rubins HB, Robins SJ, et al. Gemfibrozil for the secondary prevention of coronary aretery disease inmen with low levels of high-density lipoprotein cholesterol. Veterans Affairs high-density lipoprotein cholesterol intervention trial group. N Engl J Med. 1999. 341: 410-4185. Roy A, Pahan K, et al. Gemfibrozil, stretching the arms beyond lipid lowering. Immunopharmacol Immunotoxicol. 2009. 31: 339-3516. Budd A, Alleva L, et al. Increased survival after gemfibrozil treatment of severe mouse influenza. Antimicrobial Agents and Chemotherapy. 2007. 2965-29687. Berger J, Moler DE. The mechanisms of action of PPARs. Annu Rev Med. 53: 409-4358. Madej A, Okopien B, et al. Effects of fenofibrate on plasma cytokine concentrations in patients with atherosclerosis and hyperlipoproteinemia IIb. Int J Clin Pharmacol. 36: 345-3499. Staels B, Koenig W, et al. Activation of human oartic smooth muscle cells is inhibited by PPARa. Nature. 303: 790-79310. Calkin AC, Cooper KA, et al. Gemfibrozil decreases atherosclerosis in experimental diabetes in association with a reduction in oxidative stress and inflammation. Diabetologia. 49: 766-77411. Xu J, Chavis JA, et al. Gemfibrozil reduces release of tumor necrosis factor-alpha in peripheral blood mononuclear cells from healthy subjects and patients with coronary heart disease. Clin Chem Acta. 332: 61-6712. Lovette-Racke AE, Hussain RZ, et al. Peroxisome proliferator-activated receptor-alpha agonists as therapy for autoimmune diesease. J Immunol. 172: 5790-579813. neve BP, Frutchart JC, et al. Role of PPAR in atherosclerosis. Biochem Pharmacol. 2000. 60: 1245-125014. Heyworth PG, Bohl BP, et al. Rac translocates independently of the neutrophil NADPH oxidase components p47phox and p67phox. Evidence for its ineteraction with flavocytochrome b558. J Biol Chem. 1994. 269: 30749-3075215. Aviram M, Rosenblat M, et al. Atorvastatin and gemfibrozil metabolites, but not the parent drugs, are potent antioxidants against lipoprotein oxidation. Ahterosclerosis. 1998. 138: 271-28016. Dasgupta S, Roy A, et al. Gemfibrozil ameliorates relapsing-remitting experimental autoimmune encephalomyelitis of peroxisome proliferator-acivated receptor-alpha. Molecular Pharmacol. 2007. 72: 934-94617. Zhou JF, Law HK, et al. Functional tumor necrosis factor-related apoptosis-inducing ligand production by avian flu influenza virus-infected macrophages. J Infect Dis. 193: 945-95318. Xu J, Shi I, et al. Pathological findings of Covid-19 associated with acute respiratory distress syndrome. Lancet. 2020. Epub ahead of print19. McGonagle D, Sharif K, et al. The role of cytokines including interleukin-6 in Covid-19 induced pneumonia and macrophage activation syndrome-like disease. J AutRev. 2020. 10253720. Channappanavar AR, Fehr R, et al. Dysregulated type 1 interferon and inflammatory monocytes-macrophage responses cause lethal pneumonia in SARS-CoV infected mice. Cell Host Microbe. 2016.19: 181-19321. Kim YS, Kim JK, et al. The peroxisome proliferator-activated receptor-alpha agonist gemfibrozil promotes defense against mycobacterium abcessus infections. Cells. 2020. 9: 648

Effect of VA - ECMO Vs Impella on Survival from Jan 1st 2017 – Aug 3rd 2020Frank H Annie, PhD1; Kayce Boggess1; Aravinda Nanjundappa, MD2;1. CAMC Health Education and Research Institute3200 MacCorkle Ave. SE, Charleston, WV 25304.2. CAMC Vascular Center of Excellence, Charleston Area Medical Center.3200 MacCorkle Ave SE, Charleston, WV 25304Study Locations:Charleston Area Medical Center, 3100 McCorkle Ave SE, Charleston, WV, 25302 and Charleston Area Medical Center Research Institute and Center for Clinical Sciences Research, 3200 McCorkle Ave SE, Charleston, WV, 25302Correspondence:Frank Annie M.A; MPA, PhDResearch ScientistCAMC Health Education and Research Institute3200 MacCorkle Ave. SE,Charleston, WV 25304Phone 304-388-9921Fax: 304-388-9921Email: [email protected] word count: 451Author Disclosure Block: NoneKey words: ECMO, Impella, MIRunning Title: Effect of VA - ECMO Vs Impella on SurvivalTotal Number of Tables and Figures: Figures 1Extracorporeal membrane oxygenation (ECMO) is used as a heart-lung bypass to oxygenate and pump blood outside the body. VA – ECMO supports both heart and lungs. Impella catheter is a pump that is used to increase blood flow from the inlet area which pulls from the left ventricle through the aorta of the heart. As both of these devices are support devices their effectiveness in terms of mortality as a result of individuals having a myocardial infarction then that required the implantation of either an ECMO and or Impella or their long term survival outcome(1-2).In order to understand long term survival of ECMO vs Impella we queried the TriNetx database (Research Network) which is a network of 38 health care organizations with cases from Jan 1st 2017 – August 3, 2020. We identified VA-ECMO (N=579) and Impella (N=1,377). We followed the cases until follow-up was lost. In order to compare the differences we conducted a Prosperity Score Match with a 1:1 (N= 482/482) match with the covariates (Age, Male, Female, Hypertension, CAD, CHF, Diabetes, CKD, Smoking History, COPD, Stroke History, Liver Disease History, Cardiogenic Shock, Medications, ACE, ARB Warfarin). After the match was complete a measure of association and a Kaplan Meir survival curve was conducted as long with a long-rank test.The unmatched age at event of MI that required the use of VA – ECMO was (56.1± 13.5), Impella (67.1±11.9) (P = <0.01), CAD (70.2% vs 81.3%) (P= <0.01) COPD (13.6% vs 20.4%) (P = 0.04), ACE (26.5% vs 41.4%) (P= < 0.01) Cardiogenic Shock (82.9% vs 54.8%) (P=<0.001). The matched cohort had a difference of mortality of (45.8% vs 25.1%) (P = <0.01). The Kaplan Meir Survival Curve showed that VA-ECMO had a much lower chance of survival compared to Impella with a log-rank test of (P=<0.01) as seen in and a lower survival probability of (0.49/0.72).We found that it appears that VA-ECMO cases even after the PSM was conducted had worse outcome as compared to Impella cases in terms of mortality. Even controlling for literature driven covariates it appears that VA-ECMO as a result of MI have worse outcomes compared to Impella.Figure Legend - ECMO V IMPELLA (Morality)

Author BlockFrank H Annie, PhD1, Mark C Bates, MD2, Aravinda Nanjundappa,MD2, Ali Farooq, MD2, Elise Anderson, MD2, Megan Wood, DNP21CAMC Health Education and Research Institute3200 MacCorkle Ave. SE, Charleston, WV 25304.2CAMC Vascular Center of Excellence, Charleston Area Medical Center.3200 MacCorkle Ave SE, Charleston, WV 25304

THE DISTRIBUTION OF CHF WITHIN SOUTHERN WEST VIRGINIAFrank H Annie, PhD1; Muhammad Yasin, MD2, Aravinda Nanjundappa, MD2;1. CAMC Health Education and Research Institute3200 MacCorkle Ave. SE, Charleston, WV 25304.2. CAMC Vascular Center of Excellence, Charleston Area Medical Center.3200 MacCorkle Ave SE, Charleston, WV 25304Study Locations:Charleston Area Medical Center, 3100 McCorkle Ave SE, Charleston, WV, 25302 and Charleston Area Medical Center Research Institute and Center for Clinical Sciences Research, 3200 McCorkle Ave SE, Charleston, WV, 25302Correspondence:Frank Annie M.A; MPA, PhDResearch ScientistCAMC Health Education and Research Institute3200 MacCorkle Ave. SE,Charleston, WV 25304Phone 304-388-9921Fax: 304-388-9921Email: [email protected] word count: 593Author Disclosure Block: NoneKey words: Access, CHFRunning Title: The Distribution of CHFTotal Number of Tables and Figures: Figures 1Per the United States (U.S) Census Bureau, rural areas are geographic designations excluding all population, housing, and territory included within an urbanized area or cluster (1). Approximately 20% of the U.S. population lives in these rural designations. The literature reports that rural populations face more barriers associated with access and quality of care compared with urban groups. Cultural attitudes, access difficulty, and absence of services are a few of several contributing factors (2).However, there is little evidence that specifically addresses the needs of rural patients suffering from congestive heart failure (CHF). A number of factors can cause CHF, including coronary artery disease, valvular disease, and systemic hypertension. Poor health literacy, roughly defined as the degree of difficulty an individual has while attempting to obtain, process, and understand basic health information and services, is associated with earlier heart failure hospitalization and all-cause mortality in rural patients with CHF in the U.S. (3). Elderly U.S. veterans who reside in rural designations are more vulnerable to delayed CHF treatment due to lack of transportation (4).Whether patients with CHF who reside in rural designations struggle to comprehend information due to culturally-based reservations or lack resources available to their urban counterparts, it is important to identify those who require improved access so that their perspective and needs can be better assessed. Appalachia is a distinct, non-homogenous region within the U.S. that is comprised of 13 states, in which 42% reside in rural areas or clusters (5). We conducted a retrospective analysis of CHF cases from 2005-2016 obtained from our Charleston Area Medical Center (CAMC) data warehouse in Charleston, West Virginia. Using a Hot Spot Analysis, we aimed to identify patients with CHF from rural territories and housing who have limited access. After the data were analyzed (n=22,404), patients were identified and examined using Arch 10.8 and geocoded. To investigate any potential spatial relationships, and a Hot Spot Analysis was performed. We controlled for population in order to understand the areas in which CHF had statistical significant hot and cold zones.The results suggest within (Figure 1) that areas in which CHF cases are further from major hospitals in Southern West Virginia appear to have increased cold spots within these zones. These zones are illustrated in bright blue and have a (P = 0.001). These results suggest access and health care resources are still a significant issue within Southern West Virginia, as illustrated in (Figure 1). These at-risk zones are outside the baseline 5 miles radius of the majority of substantial statistical zones. These results also suggest that further access in the form of CHF clinics and other households of access is essential.Figure LegendFigure 1 – Hot Spot Analysis of Congestive heart failure (CHF) (n=22,404)