SAR-Cov-2 is probably a vasculotropic RNA virus affecting the blood vessels: Endothelial cell infection and endotheliitis in COVID-19
Reporter: Aviva Lev-Ari, PhD, RN – Bold face and colors are my addition
From: “Dr. Larry Bernstein” <larry.bernstein@gmail.com>
Reply-To: “Dr. Larry Bernstein” <larry.bernstein@gmail.com>
Date: Tuesday, June 2, 2020 at 8:50 AM
To: Aviva Lev-Ari <aviva.lev-ari@comcast.net>
Subject: Re: Coronavirus May Be a Vascular Disease, Which Explains Everything | Elemental
“I don’t think the conclusion is fully validated. I would want to see autopsy reports, like that found in China. It can be done safely, and the tools could be discarded.”
Larry
UPDATED on 3/1/2021
COVID Clot Prevention Evidence Beginning to Bud
— Randomized prophylaxis trials have struggled, but some now near initial read-out
Three adaptive platform partner trials — ACTIV-4, REMAP-CAP, and ATTACC — just halted therapeutic anticoagulation for prophylactic use in ICU patients after interim data showed futility in seeking a reduction in need for organ support and possible safety concern.
“It is terrific gain of knowledge to have results from randomized trials, even if they have to be stopped early,” said Stephan Moll, MD, a hematologist-oncologist involved in setting the prophylaxis protocols for the University of North Carolina at Chapel Hill. “This is refreshing news after all the retrospective, limited data of the first 9 months of the COVID-19 pandemic.”
ACTIV-4, REMAP-CAP, and ATTACC data are “urgently” undergoing additional analyses to be made available as soon as possible, according to trial leadership. Non-ICU subgroups, and a range of other treatment arms in those trials, are also ongoing.
UPDATED on 6/29/2020
Another duality and paradox in the Treatment of COVID-19 Patients in ICUs was expressed by Mike Yoffe, MD, PhD, David H. Koch Professor of Biology and Biological Engineering, Massachusetts Institute of Technology. Dr. Yaffe has a joint appointment in Acute Care Surgery, Trauma, and Surgical Critical Care, and in Surgical Oncology @BIDMC
on 6/29 at SOLUTIONS with/in/sight at Koch Institute @MIT
How Are Cancer Researchers Fighting COVID-19? (Part II)” Jun 29, 2020 11:30 AM EST
In COVID-19 patients: two life threatening conditions are seen in ICUs:
- Blood Clotting – Hypercoagulability or Thrombophilia
- Cytokine Storm – immuno-inflammatory response
- The coexistence of 1 and 2 – HINDERS the ability to use effectively tPA as an anti-clotting agent while the cytokine storm is present.
Mike Yoffe’s related domain of expertise:
Signaling pathways and networks that control cytokine responses and inflammation
Misregulation of cytokine feedback loops, along with inappropriate activation of the blood clotting cascade causes dysregulation of cell signaling pathways in innate immune cells (neutrophils and macrophages), resulting in tissue damage and multiple organ failure following trauma or sepsis. Our research is focused on understanding the role of the p38-MK2 pathway in cytokine control and innate immune function, and on cross-talk between cytokines, clotting factors, and neutrophil NADPH oxidase-derived ROS in tissue damage, coagulopathy, and inflammation, using biochemistry, cell biology, and mouse knock-out/knock-in models. We recently discovered a particularly important link between abnormal blood clotting and the complement pathway cytokine C5a which causes excessive production of extracellular ROS and organ damage by neutrophils after traumatic injury.
SOURCE
SAR-Cov-2 is probably a vasculotropic RNA virus affecting the blood vessels: Endothelial cell infection and endotheliitis in COVID-19
Mandeep Mehra, MD, medical director of the Brigham and Women’s Hospital Heart and Vascular Center.
“All these Covid-associated complications were a mystery. We see blood clotting, we see kidney damage, we see inflammation of the heart, we see stroke, we see encephalitis [swelling of the brain],” says William Li, MD, president of the Angiogenesis Foundation. “A whole myriad of seemingly unconnected phenomena that you do not normally see with SARS or H1N1 or, frankly, most infectious diseases.”
“If you start to put all of the data together that’s emerging, it turns out that this virus is probably a vasculotropic virus, meaning that it affects the [blood vessels],”
Mehra explains. “Then it starts to infect endothelial cell after endothelial cell, creates a local immune response, and inflames the endothelium.”
Benhur Lee, MD, a professor of microbiology at the Icahn School of Medicine at Mount Sinai:
“In SARS1, the protein that’s required to cleave it is likely present only in the lung environment, so that’s where it can replicate. To my knowledge, it doesn’t really go systemic,” Lee says. “[SARS-CoV-2] is cleaved by a protein called furin, and that’s a big danger because furin is present in all our cells, it’s ubiquitous.”
Sanjum Sethi, MD, MPH, an interventional cardiologist at Columbia University Irving Medical Center:
“The endothelial cell layer is in part responsible for [clot] regulation, it inhibits clot formation through a variety of ways, If that’s disrupted, you could see why that may potentially promote clot formation.” Damage to endothelial cells causes inflammation in the blood vessels, and that can cause any plaque that’s accumulated to rupture, causing a heart attack. “Inflammation and endothelial dysfunction promote plaque rupture. Endothelial dysfunction is linked towards worse heart outcomes, in particular myocardial infarction or heart attack.”
Endothelial cell dysfunction: pre-existing conditions like high blood pressure, high cholesterol, diabetes, and heart disease are at a higher risk for severe complications from a virus that’s supposed to just infect the lungs. Why ventilation often isn’t enough to help many Covid-19 patients breathe better. Moving air into the lungs, which ventilators help with, is only one part of the equation. The exchange of oxygen and carbon dioxide in the blood is just as important to provide the rest of the body with oxygen, and that process relies on functioning blood vessels in the lungs.
William Li, MD, president of the Angiogenesis Foundation:
“If you have blood clots within the blood vessels that are required for complete oxygen exchange, even if you’re moving air in and out of the airways, [if] the circulation is blocked, the full benefits of mechanical ventilatory support are somewhat thwarted,” “We were observing virus particles filling up the endothelial cell like filling up a gumball machine. The endothelial cell swells and the cell membrane starts to break down, and now you have a layer of injured endothelium.” “Endothelial cells connect the entire circulation [system], 60,000 miles worth of blood vessels throughout our body,” says Li. “Is this one way that Covid-19 can impact the brain, the heart, the Covid toe? Does SARS-CoV-2 traffic itself through the endothelial cells or get into the bloodstream this way? We don’t know the answer to that.”
If Covid-19 is a vascular disease, the best antiviral therapy might not be antiviral therapy
“I suspect from what we see and what our preliminary data show is that this virus has an additional risk factor for blood clots, but I can’t prove that yet,” Sethi says. An alternative theory is that the blood clotting and symptoms in other organs are caused by inflammation in the body due to an over-reactive immune response — the so-called cytokine storm
SARS-CoV-2 virus can infect the endothelial cells that line the inside of blood vessels. Endothelial cells protect the cardiovascular system, and they release proteins that influence everything from blood clotting to the immune response. In the paper, the scientists showed damage to endothelial cells in the lungs, heart, kidneys, liver, and intestines in people with Covid-19.
Treatment Protocol for COVID-19
The good news is that if Covid-19 is a vascular disease, there are existing drugs that can help protect against endothelial cell damage. In another New England Journal of Medicine paper that looked at nearly 9,000 people with Covid-19, Mehra showed that the use of statins and ACE inhibitors were linked to higher rates of survival. Statins reduce the risk of heart attacks not only by lowering cholesterol or preventing plaque, they also stabilize existing plaque, meaning they’re less likely to rupture if someone is on the drugs.
“It turns out that both statins and ACE inhibitors are extremely protective on vascular dysfunction,” Mehra says. “Most of their benefit in the continuum of cardiovascular illness — be it high blood pressure, be it stroke, be it heart attack, be it arrhythmia, be it heart failure — in any situation the mechanism by which they protect the cardiovascular system starts with their ability to stabilize the endothelial cells.”
- The best therapy might actually be a drug that stabilizes the vascular endothelial.
Endothelial cell infection and endotheliitis in COVID-19
Cardiovascular complications are rapidly emerging as a key threat in coronavirus disease 2019 (COVID-19) in addition to respiratory disease. The mechanisms underlying the disproportionate effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on patients with cardiovascular comorbidities, however, remain incompletely understood.1,2
SARS-CoV-2 infects the host using the angiotensin converting enzyme 2 (ACE2) receptor, which is expressed in several organs, including the lung, heart, kidney, and intestine. ACE2 receptors are also expressed by endothelial cells.3Whether vascular derangements in COVID-19 are due to endothelial cell involvement by the virus is currently unknown. Intriguingly, SARS-CoV-2 can directly infect engineered human blood vessel organoids in vitro.4
Here we demonstrate endothelial cell involvement across vascular beds of different organs in a series of patients with COVID-19 (further case details are provided in the appendix).Patient 1 was a male renal transplant recipient, aged 71 years, with coronary artery disease and arterial hypertension. The patient’s condition deteriorated following COVID-19 diagnosis, and he required mechanical ventilation. Multisystem organ failure occurred, and the patient died on day 8.Post-mortem analysis of the transplanted kidney by electron microscopy revealed viral inclusion structures in endothelial cells (figure A, B). In histological analyses, we found an accumulation of inflammatory cells associated with endothelium, as well as apoptotic bodies, in the heart, the small bowel (figure C) and lung (figure D). An accumulation of mononuclear cells was found in the lung, and most small lung vessels appeared congested.
See Figures in https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30937-5/fulltext
Findings We found evidence of direct viral infection of the endothelial cell and diffuse endothelial inflammation. Although the virus uses ACE2 receptor expressed by pneumocytes in the epithelial alveolar lining to infect the host, thereby causing lung injury, the ACE2 receptor is also widely expressed on endothelial cells, which traverse multiple organs.3Recruitment of immune cells, either by direct viral infection of the endothelium or immune-mediated, can result in widespread endothelial dysfunction associated with apoptosis (figure D).The vascular endothelium is an active paracrine, endocrine, and autocrine organ that is indispensable for the regulation of vascular tone and the maintenance of vascular homoeostasis.5Endothelial dysfunction is a principal determinant of microvascular dysfunction by shifting the vascular equilibrium towards more vasoconstriction with subsequent organ ischaemia, inflammation with associated tissue oedema, and a pro-coagulant state.6Our findings show the presence of viral elements within endothelial cells and an accumulation of inflammatory cells, with evidence of endothelial and inflammatory cell death. These findings suggest that SARS-CoV-2 infection facilitates the induction of endotheliitis in several organs as a direct consequence of viral involvement (as noted with presence of viral bodies) and of the host inflammatory response. In addition, induction of apoptosis and pyroptosis might have an important role in endothelial cell injury in patients with COVID-19.COVID-19-endotheliitis could explain the systemic impaired microcirculatory function in different vascular beds and their clinical sequelae in patients with COVID-19. This hypothesis provides a rationale for therapies to stabilise the endothelium while tackling viral replication, particularly with anti-inflammatory anti-cytokine drugs, ACE inhibitors, and statins.7, 8, 9, 10, 11This strategy could be particularly relevant for vulnerable patients with pre-existing endothelial dysfunction, which is associated with male sex, smoking, hypertension, diabetes, obesity, and established cardiovascular disease, all of which are associated with adverse outcomes in COVID-19.References
Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.Lancet.2020; 395: 1054-1062
Offline: COVID-19—bewilderment and candour.Lancet.2020; 3951178
Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2.Circulation.2005; 111: 2605-2610
Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2.Cell.2020; (published online in press.)
https://www.cell.com/pb-assets/products/coronavirus/CELL_CELL-D-20-00739.pdf
Date accessed: April 17, 2020 The assessment of endothelial function: from research into clinical practice.Circulation.2012; 126: 753-767
Endothelial dysfunction – a marker of atherosclerotic risk.Arterioscl Throm Vas.2003; 23: 168-175
The effect of cholesterol-lowering and antioxidant therapy on endothelium-dependent coronary vasomotion.N Engl J Med.1995; 332: 488-493
Effects of angiotensin converting enzyme inhibition on endothelium-dependent vasodilatation in essential hypertensive patients.J Hypertens.1998; 16: 447-456
Angiotensin-converting enzyme inhibition improves vascular function in rheumatoid arthritis.Circulation.2008; 117: 2262-2269
Anti-tumor necrosis factor-alpha treatment improves endothelial function in patients with rheumatoid arthritis.Circulation.2002; 106: 2184-2187
Trials of anti-tumour necrosis factor therapy for COVID-19 are urgently needed.Lancet.2020; (published online April 9.)
SOURCE
Cardiovascular Disease, Drug Therapy, and Mortality in Covid-19
List of authors.
Abstract
BACKGROUND
Coronavirus disease 2019 (Covid-19) may disproportionately affect people with cardiovascular disease. Concern has been aroused regarding a potential harmful effect of angiotensin-converting–enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) in this clinical context.
METHODS
Using an observational database from 169 hospitals in Asia, Europe, and North America, we evaluated the relationship of cardiovascular disease and drug therapy with in-hospital death among hospitalized patients with Covid-19 who were admitted between December 20, 2019, and March 15, 2020, and were recorded in the Surgical Outcomes Collaborative registry as having either died in the hospital or survived to discharge as of March 28, 2020.
CONCLUSIONS
Our study confirmed previous observations suggesting that underlying cardiovascular disease is associated with an increased risk of in-hospital death among patients hospitalized with Covid-19. Our results did not confirm previous concerns regarding a potential harmful association of ACE inhibitors or ARBs with in-hospital death in this clinical context. (Funded by the William Harvey Distinguished Chair in Advanced Cardiovascular Medicine at Brigham and Women’s Hospital.)
Discussion
Our investigation confirms previous reports of the independent relationship of older age, underlying cardiovascular disease (coronary artery disease, heart failure, and cardiac arrhythmias), current smoking, and COPD with death in Covid-19. Our results also suggest that women are proportionately more likely than men to survive the infection. Neither harmful nor beneficial associations were noted for antiplatelet therapy, beta-blockers, or hypoglycemic therapy. It is important to note that we were not able to confirm previous concerns regarding a potential harmful association of either ACE inhibitors or ARBs with in-hospital mortality in this clinical context.
In viral infections such as influenza, older age is associated with an increased risk of cardiovascular events and death.5 In the 2003 epidemic of severe acute respiratory syndrome (SARS, caused by SARS-CoV-1 infection), sex differences in the risk of death similar to those we observed were noted.17 Women have stronger innate and adaptive immunity and greater resistance to viral infections than men.18 In animal models of SARS-CoV-1 infection, higher susceptibility of male mice to SARS-CoV-1 and greater accumulation of macrophages and neutrophils in the lungs have been described.19 Ovariectomy or the use of estrogen-receptor antagonists increased mortality from SARS-CoV-1 infection in female animals. Furthermore, the difference in risk between the sexes increased with advancing age.19 These findings may support the observation in our investigation that suggested an association between survival and female sex, independent of older age.
Infection with SARS-CoV-2 is a mild disease in most people, but in some the disease progresses to a severe respiratory illness characterized by a hyperinflammatory syndrome, multiorgan dysfunction, and death.20 In the lung, the viral spike glycoprotein of SARS-CoV-2 interacts with cell-surface ACE2, and the virus is internalized by endocytosis. The endocytic event up-regulates the activity of ADAM metallopeptidase domain 17 (ADAM17), which cleaves ACE2 from the cell membrane, resulting in a loss of ACE2-mediated protection against the effects of activation of the tissue renin–angiotensin–aldosterone system while mediating the release of proinflammatory cytokines into the circulation.21 The stress of critical illness and inflammation may unite in destabilizing preexisting cardiovascular illness. Vascular endothelial cell dysfunction, inflammation-associated myocardial depression, stress cardiomyopathy, direct viral infection of the heart and its vessels, or the host response may cause or worsen heart failure, demand-related ischemia, and arrhythmias.22 These factors may underlie the observed associations between cardiovascular disease and death in Covid-19.
In our analyses, use of either ACE inhibitors or statins was associated with better survival among patients with Covid-19. However, these associations should be considered with extreme caution. Because our study was not a randomized, controlled trial, we cannot exclude the possibility of confounding. In addition, we examined relationships between many variables and in-hospital death, and no primary hypothesis was prespecified; these factors increased the probability of chance associations being found. Therefore, a cause-and-effect relationship between drug therapy and survival should not be inferred. These data also offer no information concerning the potential effect of initiation of ACE inhibitor or statin therapy in patients with Covid-19 who do not have an appropriate indication for these medications. Randomized clinical trials evaluating the role of ACE inhibitors and statins will be necessary before any conclusion can be reached regarding a potential benefit of these agents in patients with Covid-19.
In this multinational observational study involving patients hospitalized with Covid-19, we confirmed previous observations suggesting that underlying cardiovascular disease is independently associated with an increased risk of in-hospital death. We were not able to confirm previous concerns regarding a potential harmful association of ACE inhibitors or ARBs with in-hospital mortality in this clinical context.
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