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Hypertension, Thrombosis, Kidney Failure, and Diabetes: Is COVID-19 an Endothelial Disease? A Comprehensive Evaluation of Clinical and Basic Evidence

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The symptoms most commonly reported by patients affected by coronavirus disease (COVID-19) include cough, fever, and shortness of breath. However, other major events usually observed in COVID-19 patients (e.g., high blood pressure, arterial and venous thromboembolism, kidney disease, neurologic disorders, and diabetes mellitus) indicate that the virus is targeting the endothelium, one of the largest organs in the human body. Herein, we report a systematic and comprehensive evaluation of both clinical and preclinical evidence supporting the hypothesis that the endothelium is a key target organ in COVID-19, providing a mechanistic rationale behind its systemic manifestations. Keywords: ACE2, acute kidney injury; blood pressure; catepsin; coronavirus; COVID; cytokine storm; endothelium; heparin; Kawasaki disease.
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J. Clin. Med. 2020, 9, x; doi: FOR PEER REVIEW www.mdpi.com/journal/jcm
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Review
Hypertension, Thrombosis, Kidney Failure, and Diabetes:
Is COVID-19 an Endothelial Disease? A Comprehensive
Evaluation of Clinical and Basic Evidence
Celestino Sardu 1,2,†; Jessica Gambardella 3,4,†; Marco Bruno Morelli 4,5,†; Xujun Wang 4; Raffaele Marfella 1;
Gaetano Santulli 3,4,5*
1 Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80100, Naples,
Italy
2 Department of Medical Sciences, International University of Health and Medical Sciences “Saint Camillus”, 00131,
Rome, Italy
3 Department of Advanced Biomedical Sciences, International Translational Research and Medical Education
Academic Research Unit (ITME),Federico IIUniversity, 80131, Naples, Italy
4 Department of Medicine, Division of Cardiology, Albert Einstein College of Medicine, Wilf Family Cardiovascular
Research Institute, 10461, New York, NY, USA
5 Department of Molecular Pharmacology, Fleischer Institute for Diabetes and Metabolism (FIDAM), Montefiore
University Hospital, 10461, New York, NY, USA
* Author to whom correspondence should be addressed: gaetano.santulli@einsteinmed.org
These authors equally contributed to this work.
Received: 12 April 2020; Accepted: 04 May 2020; Published: 08 May 2020
Abstract The symptoms most commonly reported by patients affected by coronavirus disease (COVID-19)
include cough, fever, and shortness of breath. However, other major events usually observed in COVID-19
patients (e.g., high blood pressure, arterial and venous thromboembolism, kidney disease, neurologic
disorders, and diabetes mellitus) indicate that the virus is targeting the endothelium, one of the largest organs
in the human body. Herein, we report a systematic and comprehensive evaluation of both clinical and
preclinical evidence supporting the hypothesis that the endothelium is a key target organ in COVID-19,
providing a mechanistic rationale behind its systemic manifestations.
Keywords: ACE2, acute kidney injury; blood pressure; cathepsin; coronavirus; COVID; cytokine storm;
endothelium; heparin; Kawasaki disease.
1. Introduction
Coronavirus disease (COVID-19) represents a public health crisis of global proportions [1]. Caused by the
severe acute respiratory syndrome corona virus 2 (SARS-CoV-2), COVID-19 was first announced in December 2019
in Wuhan, the capital of China’s Hubei province [2, 3].
The symptoms most commonly reported include cough, fever, and shortness of breath. The
pathophysiology of the disease explains why respiratory symptoms are so common: indeed, the virus accesses
host cells via the protein angiotensin-converting enzyme 2 (ACE2) [4, 5], which is very abundant in the lungs
[6].
Nevertheless, ACE2 is also expressed by endothelial cells [7, 8], and other major clinical events usually
observed in COVID-19 patients (e.g., high blood pressure [9-13], thrombosis [14-16] kidney disease [17, 18],
pulmonary embolism [19, 20], cerebrovascular and neurologic disorders [21, 22]) indicate that the virus is
targeting the endothelium [23], one of the largest organs in the human body [24-26]. The cases of Kawasaki
disease reported in young COVID-19 patients [27] support our view of a systemic vasculitis caused by SARS-
CoV-2.
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2. Pathogenesis of COVID-19
To access host cells, SARS-CoV-2 uses a surface glycoprotein (peplomer) known as spike; ACE2 has been
shown to be a co-receptor for coronavirus entry [2830]. Therefore, the density of ACE2 in each tissue may
correlate with the severity of the disease in that tissue [3136]. Other receptors on the surface of human cells
have been suggested to mediate the entry of SARS-CoV-2 [5], including transmembrane serine protease 2
(TMPRSS2) [37,38], sialic acid receptors [39,40], and extracellular matrix metalloproteinase inducer (CD147,
also known as basigin) [41]. Additionally, cathepsin B and L have been shown to be critical entry factors in the
pathogenesis of COVID-19 [38,42].
Intriguingly, all of these factors involved in the entry of SARS-CoV-2 in the host cell are known to be
expressed by endothelial cells [43–49] (Figure 1).
ACE2 remains the most studied of these receptors [34,5054]: for instance, its genetic inactivation has
been shown to cause severe lung injury in H5N1-challenged mice [55], whereas administration of recombinant
human ACE2 ameliorates H5N1 virus-induced lung injury in mice [55].
Figure 1. Endothelial dysfunction is a major determinant of COVID-19.
The SARS-CoV-2 coronavirus accesses host cells via the binding of its spike glycoprotein to angiotensin-converting enzyme
2 (ACE2), sialic acid receptor, transmembrane serine protease 2 (TMPRSS2), and extracellular matrix metalloproteinase
inducer (CD147); cathepsin B and L also participate in virus entry. All of these factors are expressed in endothelial cells.
Endothelial dysfunction is a common feature of the clinical manifestations observed in COVID-19 patients. All of the drugs
proposed as a potential therapeutic strategy to treat COVID-19 patients have been shown to improve endothelial function,
including tocilizumab, colchicine, chloroquine/hydroxychloroquine, azithromycin, and famotidine (see text for details and
references).
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ACE2 is currently at the center of a heated debate among physicians [5659], and there are concerns that
medical management of hypertension, including the use of inhibitors of the renin-angiotensin-aldosterone
system (RAAS), may contribute to the adverse health outcomes observed [34,60,61]; TMPRSS2 binds the viral
spike glycoprotein [37]; recent structural assays have suggested that coronaviruses can bind sialic acid
receptors [39]; CD147 has been shown to be essential for the entry of cytomegalovirus into endothelial cells
[46]; both cathepsin B [47] and L [49] are present in endothelial cells (Figure 1).
The endothelium prevents blood clotting by providing an antithrombotic surface, maintained by heparan
sulphate present in the matrix surrounding the cells [62,63], by the expression of tissue factor inhibitor [64],
thrombomodulin [65], and by the production of tissue-type plasminogen activator that promotes fibrinolysis
[66,67].
Endothelial dysfunction refers to a systemic condition in which the endothelium loses its physiological
properties, including the tendency to promote vasodilation, fibrinolysis, and anti-aggregation [6872];
moreover, endothelial dysfunction appears to be a consistent finding in patients with diabetes [69,7378]. Here
we will discuss clinical and preclinical findings supporting our hypothesis [79] that COVID-19 impairs
endothelial function (Figure 1).
3. Hypertension and COVID-19
Several investigators have called attention to the potential over-representation of hypertension among
patients with COVID-19 [13,8082]. Moreover, hypertension appears to track closely with advancing age,
which is emerging as one of the strongest predictors of COVID-19related death [14,83]. Specifically,
observational trials and retrospectives studies conducted near Wuhan area have actually shown that
hypertension is the most common co-morbidity observed in patients affected by COVID-19, ranging from 15%
to over 30% [14,8487].
One of the largest studies has been conducted by Guan et al. between December 11, 2019, and January 29,
2020, providing data on 1099 hospitalized patients and outpatients with laboratory-confirmed COVID-19
infection [84]; in this cohort, 165 (~15%) had high blood pressure [84]. The authors also evaluated the severity
of disease, and the composite outcome of intensive care unit (ICU) admission, mechanical ventilation and
death, concluding that 23.7% of hypertensive patients had disease severity (vs 13.4% of normotensive subjects),
and that 35.8% (vs 13.7%) reached the composite endpoint of ICU admission, mechanical ventilation and death
[84].
The high rate of hypertensive patients with COVID-19 was later confirmed in a prospective analysis on
41 patients admitted to hospital in Wuhan [85] as well as in a large study conducted on 138 hospitalized
patients with confirmed COVID-19 infection [86]. In the latter report, the rate of hypertension was 31.2%, and
58.3% of hypertensive patients with COVID-19 infection were admitted to ICU compared to 21.6% of
individuals with normal blood pressure [86], evidencing the hypertensive state as a common co-morbidity
and cause of ICU admission in COVID-19 patients [86].
Similarly, among 191 COVID-19 patients from Jinyintan Hospital and Wuhan Pulmonary Hospital, 58
(30%) had hypertension, and 26 (48%) did not survive COVID-19, whereas 32 (23%) were survivors [14]. The
30% rate of hypertensive patients was further confirmed in an analysis based on the severity of COVID-19
conducted on 140 patients in Wuhan: 58 patients were classified as severe vs 82 patients classified as not severe:
hypertensive patients represented 37.9% of severe vs 24.4% of not severe COVID-19 patients [87]. In a cohort
of 1590 patients from 575 hospitals, underlying hypertension was independently associated with severe
COVID-19 (hazard ratio 1.58, 95% CI: 1.072.32) [13]. Overall, these findings confirm a dual aspect of
hypertension during COVID-19 pandemic: first, hypertension is the most common co-morbidity observed in
COVID-19 patients; second, hypertension is evidenced in patients with worse prognosis and higher rate of
death.
These studies also raise numerous questions regarding the association between hypertension and
COVID-19. Indeed, hypertension is known to be one of most common diseases and co-morbidities worldwide,
considered a silent killer for the worldwide population [88]. We speculate that the higher rate of hypertension
and the worse prognosis in patients with COVID-19 infection could be seen as the spy of a cause-effect
mechanism, more than as a casual pre-existing association between these two different diseases.
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4. ACE2 and Anti-Hypertensive Drugs: What do we Know?
ACE inhibitors (ACEi) and angiotensin II receptor blockers (ARB) represent very effective strategies for
the treatment of hypertension [88]. These drugs reduce the effects of renin-angiotensin axis by inhibiting ACE
(ACEi) or by blocking the angiotensin receptors (ARB), as shown in Figure 2. A growing question for the
scientific community and physicians is to understand whether ACEi/ARB could affect the prognosis of
hypertensive COVID-19 patients [34,8991].
The exact role of ACEi/ARB in the control of ACE2 molecular pathways is controversial: indeed,
preclinical studies evidenced that the selective blockade of either angiotensin II synthesis or activity in rats
induces increases in ACE2 gene expression and activity [9296]; similarly, treating infarcted rats with ARB
increased plasma concentration of angiotensin 17 and ACE2 [97]. In mice, ARB treatment augmented ACE2
mRNA and protein levels [98,99] and prevented the decrease in ACE2 protein levels induced by Angiotensin
II [100]. Equally important, mineralocorticoid receptor blockers prevented aldosterone-induced reduction in
cardiac ACE2 mRNA expression in rat cardiomyocytes [101] and increased ACE2 expression and activity in
murine hearts and in monocyte-derived macrophages obtained from ten patients with heart failure [102].
Nevertheless, there is no clinical evidence that ACEi could directly affect molecular pathways linked to
ACE2 activity. For instance, urinary ACE2 levels were reported to be higher in patients treated with
olmesartan vs untreated controls, but this finding was not observed in patients treated with other ARB or
enalapril [103]; instead, another study reported no difference in ACE2 activity in patients who were taking
ACEi or ARB vs untreated patients [89]. Of note, ACE2, which functions as a carboxypeptidase [104] is not
inhibited by clinically prescribed ACEi.
In particular, ACE2 acts to counterbalance the effect of ACE [105]; indeed, whereas ACE generates
angiotensin II from angiotensin I, ACE2 converts angiotensin II into an active heptapeptide (angiotensin 1-7),
which binds the Mas receptor (MasR), triggering vasodilative, anti-oxidant, and anti-inflammatory properties
[106109] (Figure 2).
Figure 2. Angiotensin-converting enzyme inhibitors (ACEi) and blockers of the angiotensin receptor 1 (ARB).
Angiotensin II and Angiotensin 17 binds heptahelical receptors; namely, angiotensin II can activate AT1R (type 1
angiotensin II receptor) and AT2R (type 2 angiotensin II receptor), whereas angiotensin 17 binds the Mas Receptor
(MasR). The actions mediated by these receptors are depicted in the figure.
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Some media sources have recently called for the discontinuation of ACEi and ARB, both prophylactically
and in the context of suspected COVID-19 [110]. However, several associations have recommended not to
suspend these therapies [61,111114], and these recommendations have been confirmed by three recent
studies: the first one performed on 362 hypertensive patients showed that ACEIs/ARBs are not associated with
the severity or mortality of COVID-19 [91]; the second one verified the effects of ACEI/ARB on 1128
hypertensive COVID-19 patients, showing that the use of ACEI/ARB was associated with lower risk of all-
cause mortality compared with ACEI/ARB non-users [115]; the third one demonstrated that without
increasing the risk for SARS-CoV-2 infection, ACEI/ARB outcompeted other antihypertensive drugs in
reducing inflammatory markers like C-reactive protein and procalcitonin levels in COVID-19 patients with
preexisting hypertension [116]. Consistent with these findings, three observational studies performed in
different populations and with different designs [117119] (published in the same issue of the New England
Journal of Medicine), arrived at the consistent message that the continued use of ACEI/ARB is unlikely to be
harmful in COVID-19 patients. Notably, in one of these studies [117], the use of either ACEI or statins two
classes of drugs that are known to ameliorate endothelial function [120123] – was found to be associated with
a lower risk of in-hospital death than non-use.
The binding of the SARS-CoV-2 spike protein to ACE2 has been suggested to cause the down-regulation
of ACE2 from the cell membrane [124]. Consequently, ACE2 down-regulation could lead to a loss of protective
effects exerted by ACEi/ARB in humans [125]. Such down-regulation of ACE2 is an attractive research field
[95,126128]. Indeed, it could be a valid therapeutic target to ameliorate response and clinical prognosis in
hypertensive patients affected by COVID-19. Moreover, some investigators proposed the restoration of ACE2
by administration of recombinant ACE2 to reverse the lung-injury process during viral infections [4]. Actually,
these effects are being investigated in ongoing clinical trials (ClinicalTrials.gov NCT04287686), alongside the
use of losartan as first therapy for COVID-19 in hospitalized (NCT04312009) or not hospitalized patients
(NCT04311177). A major role in the pathogenesis of (as well as in the clinical response to) COVID-19 could
also be played by ACE2 polymorphisms, which are relatively under-investigated if compared to ACE
[129,130].
Finally, we have to consider the higher rate of cardiac injury and adverse outcomes in hypertensive
patients during the COVID-19 pandemic [131-133]. Therefore, ACEi/ARB chronic therapy should not be
discontinued in hypertensive patients with COVID-19. Indeed, the loss of their pneumo- and cardio- protective
effects could be detrimental [88]. In addition, in the absence of adequate follow-up visits, switching from
ACEi/ARB to another anti-hypertensive therapy could cause a suboptimal control of blood pressure.
Thus, as suggested by several medical associations [110], in the absence of definitive clinical studies and
without clear evidence, hypertensive patients should avoid discontinuation and/or therapeutic switching
during COVID-19 infection.
Another noteworthy feature of COVID-19 for cardiologists is the significant decrease in the rates of
hospital admissions for acute coronary syndromes which has been reported both in Italy [134] and US [135]
during the COVID-19 outbreak, and despite being initially attributed to reduced air pollution, better
adherence to treatment, or absence of occupational stress during lockdown, this phenomenon seems to be
most likely due to the fear of going to the hospital and/or seeking medical attention during a pandemic.
Unfortunately, the current decline in hospitalization for acute coronary syndromes will trigger an increase in
cases of heart failure in the near future.
5. Kidney Disease in COVID-19
Acute kidney injury (AKI) has been reported in > 20% of critically ill or deceased COVID-19 patients, a
percentage that is consistent in studies from China [136], Italy [137] and United States [10]. It is important to
note that AKI, proteinuria, and hematuria have been independently associated with a higher risk of death in
COVID-19 patients [138]. Furthermore, in a meta-analysis including 1389 COVID-19 patients [139], the
prevalence of underlying chronic kidney disease was significantly more frequent among those with a severe
COVID-19 disease (3.3% vs 0.4%; odds ratio 3.03, 95% CI: 1.098.47).
According to immunohistochemistry assays [140], ACE2 seems not to be expressed in renal endothelial
cells; however, a study based on single-cell analysis has confirmed the expression of ACE2 and TMPRSS2 in
human renal endothelial cells [141], and most recently the presence of viral particles was confirmed by electron
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microscopy in endothelial cells of the glomerular capillary loops of a COVID-19 patient [142]. Besides,
endothelial damage was a common finding in renal histopathological analyses of 26 COVID-19 patients, in the
absence of interstitial inflammatory infiltrates [143].
6. Diabetes and COVID-19
Diabetes mellitus is a frequent co-morbidity and a cause of worse prognosis in COVID-19 patients
[12,144148]. Indeed, evaluating pneumonia cases of unknown causes reported in Wuhan and in patients with
history of exposure to Huanan seafood market before Jan 1, 2020, 20% had diabetes [85]. Similarly, among
1099 COVID-19 patients analyzed by Guan and colleagues, 7.4% had diabetes: this percentage goes up to 16.2%
among patients with severe disease (vs 5.7% in patients with non-severe disease) [84]; furthermore, 35.8% of
patients experiencing the composite endpoint of ICU admission, mechanical ventilation and death, had
diabetes (vs 13.7% of patients that did not experience such endpoint) [84]. Data from Italy show that more than
two-thirds of COVID-19 patients that did not survive had diabetes [149]. In summary, diabetes is a frequent
co-morbidity, a risk factor, and an independent prognostic factor in COVID-19 patients. A strong evidence of
the negative effects of diabetes in COVID-19 patients is also corroborated by two meta-analyses [150,151].
The worse prognosis in patients with diabetes and COVID-19 could be attributed to the fact that the
pneumonia evolves towards clinical stages more refractory to medical therapies, oxygen administration and
mechanical ventilation, with necessity of ICU care. These data have been investigated in a previous study
conducted in patients with SARS [152], in which the relationship between a known history of diabetes and
fasting plasma glucose (FPG) levels with death and morbidity rate was assessed, showing that the percentage
of patients with diabetes was significantly higher in deceased vs survivors (21.5% vs 3.9%, p < 0.01) [152].
Moreover, diabetic subjects with hypoxemia (SaO2 < 93%) had higher FPG levels and FPG was independently
associated with an increased hazard ratio of mortality (1.1, 95% CI: 1.01.1) and hypoxia (1.1, 95% CI: 1.01.1)
after controlling for age and gender [152]; the authors concluded that both diabetes (3.0, 95% CI: 1.46.3) and
FPG > or = 7.0 mmol/l (3.3, 95% CI: 1.47.7) were independent predictors of death [152].
In COVID-19 patients, the incidence of diabetes is two times higher in ICU/severe vs non-ICU/severe
cases [151]. Indeed, the diagnosis of diabetes in a cohort of patients with COVID-19 infection evidenced a sub-
group of patients with a 2.26-fold higher risk of experiencing adverse disease outcome analyses [150].
Additionally, patients with obesity and/or glucose intolerance seem to be particularly vulnerable to COVID-
19 [10,148,153,154]. Unfortunately, no data are hitherto available on anti-diabetic medications and glucose
homeostasis in COVID-19 patients. This aspect is really limiting, because diabetes and altered glucose
homeostasis during a condition of severe pneumonia with SARS are reported as main factors of worse
prognosis and death [152]. COVID-19 could also induce new onset diabetes, by augmenting insulin resistance
and/or by a direct action [155] on the islets of Langerhans; supporting this view, previous studies have shown
that ACE2 can be a therapeutic target to ameliorate microcirculation in the islets [156], and ACE2 is known to
be expressed by pancreatic beta cells [157162].
Moreover, frequent cases of ketoacidosis in COVID-19 patients have been reported [163]. Therefore, the
investigation of anti-diabetic medications and glucose homeostasis could be harnessed to evaluate patients
with higher risk of experiencing worse prognosis and death by COVID-19. We speculate that the amelioration
of glucose homeostasis in diabetic COVID-19 patients by specific hypoglycemic drugs could result in the
amelioration of clinical outcomes with death reduction. However, these data are not reported in trials on
COVID-19, and they need to be investigated in further studies [164].
7. Thromboembolism and COVID-19
Patients with COVID19 often show clotting disorders, with organ dysfunction and coagulopathy,
resulting in higher mortality [15,165,166]. Critical data came from the analysis of coagulation tests including
prothrombin time (PT), activated partial thromboplastin time (APTT), antithrombin activity (AT), fibrinogen,
fibrin degradation product (FDP), and D-dimer, in samples collected on admission and during the hospital
stay of COVID-19 patients [167]. Non-survivors had significantly higher D-dimer and FDP levels, and longer
PT vs survivors on admission [167]. Moreover, significant reduction and lowering of fibrinogen and AT levels
were observed in non-survivors during late stages of hospitalization, which is compatible with a clinical
diagnosis of disseminated intravascular coagulation (DIC) [167,168]. Specifically, among 191 COVID-19
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patients seen at two hospitals in Wuhan, D-dimer levels over 1 µg/L at admission predicted an 18-fold increase
in odds of dying before discharge [14]. Of note, when DIC is caused by a systemic infection, it features an acute
systemic over-inflammatory response, strictly linked to endothelial dysfunction [169].
Most recently a case of a COVID-19 patient with an increase of Factor VIII clotting activity and a massive
elevation of von Willebrand Factor (vWF) has been reported [170], further supporting our theory: indeed, vWF
can be seen as a marker of endothelial damage, since it is normally stored in Weibel-Palade bodies within
endothelial cells [171]. Equally important, angiotensin II level in the plasma of COVID-19 patients was
markedly elevated and linearly associated to viral load and lung injury [172]; notably, angiotensin II is known
to increase microvascular permeability [173,174], to induce the transcription of tissue factor in endothelial cells
[175177], and to activate platelets [178180]. Additionally, angiotensin II can trigger the release of several
components of the complement system from endothelial cells [181187], further corroborating the key role of
endothelium in the pathogenesis of venous and arterial thrombosis in COVID-19 patients [188, 189].
A dysregulated immune response, as observed in COVID-19, especially in the late stages of the disease,
plays a decisive role in endothelial dysfunction and thrombosis [190,191], and microvascular permeability is
crucial in viral infections [192]. Indeed, pulmonary endothelium represent a fundamental barrier between the
blood and interstitium and have vital regulatory functions; specifically, endothelial cells represent one-third
of the cell population of the lung [193], and pulmonary endothelial damage is considered the hallmark of acute
respiratory distress syndrome (ARDS) [194]. Animal models of coronavirus-induced severe ARDS have shown
that reduced ACE2 activity and loss of ACE2 in the lungs is mirrored by enhanced vascular permeability, and
exacerbated pulmonary edema [108]. The functional role of endothelium in pulmonary disease is also
suggested by previous reports [195,196]; for instance, the H3N2 influenza virus has been shown to infect
endothelial cells in vitro and to trigger endothelial cell apoptosis, which is known to enhance platelet adhesion
[197]: endothelial cell death would cause exposure of the extracellular matrix to circulating blood, favoring
platelet binding; similarly, the endothelium has been shown to contribute to the development of severe disease
during H5N1 influenza infection [198].
Deep vein thrombosis and/or pulmonary embolism have been previously described in patients with
SARS [199202] and cases of thrombosis complicating influenza-associated pneumonia have also been
reported [203205]. Excessive activation of the immune system in response to pathogens can lead to
pathological inflammatory consequences. In the case of highly virulent 1918 and avian H5N1 influenza virus
infections, the recruitment of inflammatory leukocytes followed by excessive cytokine responses is considered
to be the key contributor to morbidity and mortality of the infection [206,207]. Cytokine storm syndromes
(CSS) are a group of disorders representing a variety of inflammatory etiologies with the final result of
overwhelming systemic inflammation, hemodynamic instability, multiple organ dysfunction, and potentially
death [208,209]. Specifically, macrophage activation syndrome [210] and hemophagocytic lymphohistiocytosis
(HLH) [211] represent two clinically similar CSS with an unknown degree of etiopathogenic overlap [208]. The
interaction between endothelial and immune cells could play a crucial role in COVID-19, especially in severe
cases and in the late stages of the disease [212]. For instance, the cytokine storm might lead to an abrupt
deterioration of the inflammatory response and hyper-coagulation; the increased vulnerability of patients with
cardiovascular diseases and/or diabetes might therefore simply reflect the impact of the underlying chronic
inflammation and its response during SARS-CoV-2 infection. If this is the case, endothelial alterations could
just be seen as an epiphenomenon.
However, according to numerous investigators, the inflammatory response observed in COVID-19
patients can be considered mild if compared to the one observed in typical ARDS and in cytokine-release
syndrome [212215]: indeed, in ARDS patients, levels of interleukin-1b and interleukin-6 have been shown to
be 10 to 60 fold higher than in COVID-19 [216,217]. Therefore, other mechanisms have to be involved in order
to explain the systemic manifestations reported in COVID-19 patients, and endothelial cells, known
orchestrators of cytokine amplification during viral infections [218], seem to be one of the best candidates in
this sense. Further supporting our view, catecholamines are considered an essential component of the cytokine
release syndrome [215] and we have demonstrated that endothelial cells are able to synthetize and release
catecholamines [219].
Acute pulmonary embolism, reported in COVID-19 patients [20,220222], has been shown to be a cause
of clinical deterioration in viral pneumonias [205,223]. Endothelial dysfunction is known to be a key
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determinant in hypertension, thrombosis, and DIC [72,224227]. Henceforth, it is important to select COVID-
19 patients at higher risk of pulmonary embolism, and practice computed tomography pulmonary
angiography for the diagnosis of pulmonary thromboembolism especially in case of significant increase of D-
dimer values. Anticoagulation could be a necessary therapy to control and reduce pro-thrombotic events, as
well as to prevent pulmonary embolism [228].
7. Anticoagulation as a Key Therapy for COVID-19.
The clinical course of COVID-19 consists of two main phases: viral infection and immune/inflammatory
response (Figure 3), which require distinct therapeutic approaches. Strikingly, several drugs suggested as a
potential therapeutic strategy for COVID-19 [229231] have been shown to ameliorate endothelial function,
including interleukin 6 (IL-6) receptor antagonists (e.g., tocilizumab [232]), colchicine [233], azithromycin [234],
and famotidine [235].
Even the antimalaric agents chloroquine and hydroxychloroquine, initially proposed as a therapy for
COVID-19 based on anecdotal data [229,236], have been shown to improve endothelial function [237,238]. If
our theory is correct [239], other drugs that might be effective in treating COVID-19 patients through their
beneficial effects on endothelial cells include a1 adrenergic receptor blockers (e.g., doxazosin) [240],
modulators of Sigma receptors [241243], metformin [244], indomethacin [245], and endothelin receptor
antagonists (e.g., bosentan) [246]. However, data from randomized trials confirming the actual efficacy of these
drugs are not (yet) available.
As discussed before, COVID-19 infection could cause endothelial dysfunction and a hyper-coagulation
state. This condition is aggravated by hypoxia, which augments thrombosis by both increasing blood viscosity
and hypoxia-inducible transcription factor-dependent signaling pathway [247]. Consequently, these
phenomena could result in pulmonary embolism with occlusion and micro-thrombosis in pulmonary small
vessels, as observed in critical COVID-19 patients [248]. Apart from cases of pulmonary embolism, COVID-19
can cause a sepsis-associated DIC, which is defined as “sepsis-induced coagulopathy” (SIC) [169]. Thus, there
is an increasing interest in anticoagulant therapy to treat COVID-19 [249].
Figure 3. Clinical course of COVID-19 patients. Two main overlapping phases constitute the key pathogenic
events in COVID-19: the acute phase represented by viral infection, followed by the immune/inflammatory
response. Common clinical and laboratory findings are reported within the arrows at the bottom of the figure.
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In a retrospective analysis conducted at Tongji Hospital of Huazhong University of Science and
Technology in Wuhan, the authors examined 449 patients affected by severe COVID-19 [228]. The diagnosis
of severe COVID-19 disease was made by evidence of respiratory rate30 breaths/min, arterial oxygen
saturation ≤ 93% at rest and PaO2/FiO2300 mmHg [228]. In these patients, they reviewed and compared the
parameters of coagulation tests and clinical characteristics between survivors and non-survivors to evaluate
the effects of heparin therapy [228]: 94 patients received low molecular weight heparin (LMWH, 4060 mg
enoxaparin/day) and 5 received unfractionated heparin (UFH, 1000015000 U/day), without other anti-
coagulants [228]. Heparin therapy significantly reduced mortality in patients with SIC score ≥4 (40.0% vs
64.2%, p < 0.05), but not in those with SIC score < 4 (29.0% vs 22.6%, p > 0.05) [228]. D-dimer, PT, and age were
positively, while platelet count was negatively, correlated with 28-day mortality [228]. In addition, stratifying
by D-dimer values the study population, the authors reported in heparin non-users a rise of mortality linked
to the rising D-dimer, and 20% reduction of mortality for patients under heparin with D-dimer exceeding 3.0
µg/mL [228]. Therefore, heparin treatment appears to be associated with better prognosis in severe COVID-19
patients with coagulopathy. The beneficial effects of heparin-based therapies are also supported by the
structural analogies between heparin and heparan-sulphate, which according to some investigators may
confer heparin with antiviral properties [250254]. In absence of contraindications, we suggest the use of
enoxaparin 40 mg/day in all COVID-19 patients, to be raised up to 1 mg/kg every 12 h in case of D-dimer > 3.0
µg/mL; apixaban (5 mg every 12 h) could represent a useful alternative.
Of course, the full clinical evaluation of patients with COVID-19 infection cannot leave aside the analysis
of laboratory and imaging data. We believe that PT/PTT, fibrinogen, and D-Dimer should be monitored daily
and anticoagulation therapy should be recommended for COVID-19 patients when the D-Dimer value is four
times higher than the normal upper limit, except for patients with anticoagulant contraindications. The
confirmed diagnosis of severe COVID-19 disease in patients with hypercoagulation and organ failure could
evidence an early stage of sepsis-induced DIC. On the other hand, anticoagulant may not benefit unselected
patients. Consequently, further prospective studies are needed to confirm these findings in COVID-19
patients, also testing other anti-aggregants and anti-coagulants (at different doses).
Author Contributions: Conceptualization, G.S.; data curation, C.S., J.G., M.B.M., X.W., R.M. and G.S. and SR; writing
original draft preparation, C.S., J.G. and G.S.; writingreview and editing, J.G., M.B.M. and G.S.; visualization, M.B.M
and G.S.; supervision, G.S.; funding acquisition, G.S. and J.G. All authors have read and agreed to the published version
of the manuscript. A preprint version of the manuscript was sent to preprints.org by on 9 April 2020: Preprints 2020,
2020040204 (doi: 10.20944/preprints202004.0204.v1).
Funding: The Santulli’s lab is supported in part by the NIH (R01-DK123259, R01-HL146691, R01-DK033823, and R00-
DK107895 to G.S.) and by the American Heart Association (AHA-20POST35211151 to J.G.).
Conflicts of Interest: The authors declare no conflict of interest. The funders had no role in the design of the study; in the
collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the paper.
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© 2020 by the authors. Submitted for possible open access publication under the terms
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... As expected, COVID-19, the kidneys and the CV system are linked in a bidirectional way. On one hand, both CVD and renal disease represent a risk amplifier for morbi-mortality in the COVID-19 setting [12,13]; on the other hand COVID-19 can exacerbate associated CVD and determine de novo cardiac complications (acute myocardial injury, stress cardiomyopathy, myocarditis, pericarditis, arrhythmias, heart failure and cardiogenic shock) [3,12]. Furthermore, myocardial injury is also an important prognostic factor for the disease severity [14], as well as in-hospital and long-term mortality [14,15]. ...
... The underlying mechanisms of these manifestations and long-term complications are not completely understood, but emerging data emphasize the endothelium, as a central pillar in the long COVID conundrum, with implications in inflammation, the pro-thrombotic phenotype and disseminated intravascular coagulation [26]. Endothelial dysfunction (ED) refers to a systemic condition in which the endothelium loses its physiological properties, including the tendency to promote vasodilation, fibrinolysis, and anti-aggregation [13]. ...
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... As our meta-analysis focused specifically on the prevaccination phase of the pandemic, we are unable to comment on the association between DM, HTN, IHD and myocardial injury with biomarkers of disease severity including coagulation indicators such as fibrinogen degradation products, prothrombin time, D-dimer and platelets, as these were infrequently reported in earlier studies included. Indeed, the pro-coagulation state in COVID-19 disease is now well-recognized and biomarkers such as D-dimer are used to guide routine use of anticoagulants in COVID-19 patients (35). Whilst findings from the REMAP-CAP trial have not shown a protective effect of antiplatelets in patients with critically-ill patients with COVID-19, it would be interesting to further stratify whether empirical antiplatelet and anticoagulant therapy in patients with different risk profiles (e.g., DM vs. non-DM) will improve overall outcomes (36). ...
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... Coronavirus has become a pandemic disease in the world. The COVID-19 virus has much adverse impact on human bodies resulting in pneumonia, kidney dysfunction, hypertension, thrombosis, cardiovascular diseases, and diabetes [2], [20], [21]. ...
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ABSTRACT— COVID-19 diseases due to the SARS-Cov-2 virus have become a global infectious disease. It is, therefore, crucial to investigate biomarkers that are involved in the pathogenicity and severity of the disease. This study aimed to investigate some immune-inflammatory and pathological biomarkers s during COVID-19 diseases. After providing written consent, 5 ml blood samples were drawn from 121 COVID-19 patients confirmed by Real Time Polymerase Chain Reaction (RT-PCR), including 77 Male and 44 Female COVID-19 cases with 52.64 years of mean age. Clinical analysis was performed including White blood cells (WBC), Lymphocytes (Lymph), D-dimer, Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), Ferritin, creatinine, urea and blood glucose were analysed after adjusting for sex, presence of comorbidity, weight and smoking status. Elevation of some clinical parameters was elevated in severe COVI D-19 patients compared to mild patients, also female COVID-19 patients had higher WBC and ferritin level compared to male patients. It can be concluded that some clinical biomarkers in COVID-19 patients, such as WBC, lymph percent, D-Dimer, Ferritin, ESR, CRP urea, and creatinine, are distinct predictive indicators for severe male COVID-19 patients, which are more frequent than opposite-sex gender. KEYWORDS: COVID-19 disease, immuno-inflammatory markers, pathogenicity, severe and non-sever patients
... Virus phagocytosed by macrophages and those that are free could target the different sites where ACE2 is expressed [83]. This would explain how SARS-CoV-2 virus can cause multiple clinical manifestations such as respiratory, gastrointestinal, cardiovascular and renal problems observed in critically ill patients [84,85]. The difference of ACE2 expression levels in some organs is variable with respect to the vulnerability of SAR-CoV 2 infection. ...
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SARS-CoV-2 virus has become a global health problem that has caused millions of deaths worldwide. The infection can present with multiple clinical features ranging from asymptomatic or mildly symptomatic patients to patients with severe or critical illness that can even lead to death. Although the immune system plays an important role in pathogen control, SARS-CoV-2 can drive dysregulation of this response and trigger severe immunopathology. Exploring the mechanisms of the immune response involved in host defense against SARS-CoV-2 allows us to understand its immunopathogenesis and possibly detect features that can be used as potential therapies to eliminate the virus. The main objective of this review on SARS-CoV-2 is to highlight the interaction between the virus and the immune response. We explore the function and action of the immune system, the expression of molecules at the site of infection that cause hyperinflammation and hypercoagulation disorders, the factors leading to the development of pneumonia and subsequent severe acute respiratory distress syndrome which is the leading cause of death in patients with COVID-19.
... Hypertension is considered a major risk factor for poor prognosis and death. The exact incidence of new diagnosed hypertension after COVID-19 is unknown, due to lack of data (28). ...
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Since WHO declared COVID-19 a pandemic, globally more than 212 milion people were infected and approximately 4.4 milion died (25 August 2021). As the pandemic evolved, it became clear that there are many more things to research and discover about the SARS-CoV-2 infection. Besides the fact that SARS-CoV-2 primarily affects the respiratory system, more and more articles indicate a systemic involvement which could be responsible for long term consequences. The aim of this review was to evaluate the long- term signs and symptoms of COVID-19 infection. We looked for information regarding the prevalence and persistence of symptoms associated with COVID-19 infection and the persistence of organ dysfunction beyond the acute phase. We also searched data regarding the impact of the infection on the quality of life, physical, mental and psychosocial function. Recent studies have shown that some symptoms can persist a long time after the acute episode of COVID-19. Furthermore, organ sequalae can be present after the acute episode. The most common symptoms of “long COVID” are: fatigue and shortness of breath, lack of taste/smell, cough, myalgia and arthralgia, headache. Also, cardiac abnormalities, cognitive impairment, insomnia, anxiety and concentration issues can be present.
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BACKGROUND: Coronavirus disease 2019 (COVID-19) causes a hypercoagulable state with a high incidence of thrombotic complications. Patients with a history of myocardial revascularization have more severe complications due to COVID-19. Coronary stent thrombosis has become significantly more common during the COVID-19 pandemic. AIM: The aim of our study is to analyze scientific information on the risks of stent thrombosis in patients who underwent COVID-19. METHODS: A search was made for scientific publications in evidence-based medicine databases and web resources: PubMed, MEDLINE, UpToDate, TripDatabase, ResearchGate, and Google Scholar. Inclusion criteria were: (1) Observational studies or case series involving patients with a confirmed diagnosis of COVID-19 and myocardial infarction requiring myocardial revascularization; (2) the division of the population into survivors and non-survivors; and (3) data on the presence of the previous myocardial revascularization. Exclusion criteria: Case description and editorials/bulletins. In all articles selected for further analysis, 49 sources were considered that met the inclusion criteria and excluded duplication or repetition of information. RESULTS: Coronavirus infection has contributed to the change in the course of myocardial infarction in patients undergoing myocardial revascularization. The incidence of stent thrombosis has a positive correlation with the severity of the coronavirus infection. The previous myocardial revascularization procedures significantly increase the risk of mortality in patients with coronavirus infection. This is especially actual for elderly patients. CONCLUSION: One of the most vulnerable groups is elderly patients who have undergone myocardial revascularization after myocardial infarction in the past and have concomitant diseases. An analysis of scientific publications has shown that further larger-scale clinical studies are needed to confirm the hypothesis about the negative impact of coronavirus infection on stent thrombosis in patients who have undergone COVID-19.
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Проблема COVID-19 на сьогодні є найбільш невирішеною. Хвороба маніфестує симптомами ураження легеневої системи з подальшим ушкодженням інших систем і органів. Враховуючи, що серцево-судинні захворювання залишаються головною причиною смертності у всьому світі, вкрай необхідним є вивчення особливостей перебігу COVID-19 на тлі існуючої серцево-судинної патології. В статті проаналізовані існуючі дані мета-аналізів щодо особливостей перебігу COVID-19 на фоні існуючої серцево-судинної патології.
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After analyzing the immune characteristics of patients with severe coronavirus disease 2019 (COVID-19), we have identified that pathogenic T cells and inflammatory monocytes with large amount of interleukin 6 secreting may incite the inflammatory storm, which may potentially be curbed through monoclonal antibody that targets the IL-6 pathways. Here, we aimed to assess the efficacy of tocilizumab in severe patients with COVID-19 and seek a therapeutic strategy. The patients diagnosed as severe or critical COVID-19 in The First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital) and Anhui Fuyang Second People’s Hospital were given tocilizumab in addition to routine therapy between 5 and 14 February 2020. The changes of clinical manifestations, computerized tomography (CT) scan image, and laboratory examinations were retrospectively analyzed. Fever returned to normal on the first day, and other symptoms improved remarkably within a few days. Within 5 d after tocilizumab, 15 of the 20 patients (75.0%) had lowered their oxygen intake, and 1 patient needed no oxygen therapy. CT scans manifested that the lung lesion opacity absorbed in 19 patients (90.5%). The percentage of lymphocytes in peripheral blood, which decreased in 85.0% of patients (17/20) before treatment (mean, 15.52 ± 8.89%), returned to normal in 52.6% of patients (10/19) on the fifth day after treatment. Abnormally elevated C-reactive protein decreased significantly in 84.2% of patients (16/19). No obvious adverse reactions were observed. All patients have been discharged on average 15.1 d after giving tocilizumab. Preliminary data show that tocilizumab, which improved the clinical outcome immediately in severe and critical COVID-19 patients, is an effective treatment to reduce mortality.
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The coronavirus disease 2019 (COVID-19) pandemic, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has affected millions of people worldwide, igniting an unprecedented effort from the scientific community to understand the biological underpinning of COVID19 pathophysiology. In this review, we summarize the current state of knowledge of innate and adaptive immune responses elicited by SARS-CoV-2 infection and the immunological pathways that likely contribute to disease severity and death. We also discuss the rationale and clinical outcome of current therapeutic strategies as well as prospective clinical trials to prevent or treat SARS-CoV-2 infection.
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Background A potential association between the use of angiotensin-receptor blockers (ARBs) and angiotensin-converting–enzyme (ACE) inhibitors and the risk of coronavirus disease 2019 (Covid-19) has not been well studied. Methods We carried out a population-based case–control study in the Lombardy region of Italy. A total of 6272 case patients in whom infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was confirmed between February 21 and March 11, 2020, were matched to 30,759 beneficiaries of the Regional Health Service (controls) according to sex, age, and municipality of residence. Information about the use of selected drugs and patients’ clinical profiles was obtained from regional databases of health care use. Odds ratios and 95% confidence intervals for associations between drugs and infection, with adjustment for confounders, were estimated by means of logistic regression. Results Among both case patients and controls, the mean (±SD) age was 68±13 years, and 37% were women. The use of ACE inhibitors and ARBs was more common among case patients than among controls, as was the use of other antihypertensive and non-antihypertensive drugs, and case patients had a worse clinical profile. Use of ARBs or ACE inhibitors did not show any association with Covid-19 among case patients overall (adjusted odds ratio, 0.95 [95% confidence interval {CI}, 0.86 to 1.05] for ARBs and 0.96 [95% CI, 0.87 to 1.07] for ACE inhibitors) or among patients who had a severe or fatal course of the disease (adjusted odds ratio, 0.83 [95% CI, 0.63 to 1.10] for ARBs and 0.91 [95% CI, 0.69 to 1.21] for ACE inhibitors), and no association between these variables was found according to sex. Conclusions In this large, population-based study, the use of ACE inhibitors and ARBs was more frequent among patients with Covid-19 than among controls because of their higher prevalence of cardiovascular disease. However, there was no evidence that ACE inhibitors or ARBs affected the risk of COVID-19.
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Background There is concern about the potential of an increased risk related to medications that act on the renin–angiotensin–aldosterone system in patients exposed to coronavirus disease 2019 (Covid-19), because the viral receptor is angiotensin-converting enzyme 2 (ACE2). Methods We assessed the relation between previous treatment with ACE inhibitors, angiotensin-receptor blockers, beta-blockers, calcium-channel blockers, or thiazide diuretics and the likelihood of a positive or negative result on Covid-19 testing as well as the likelihood of severe illness (defined as intensive care, mechanical ventilation, or death) among patients who tested positive. Using Bayesian methods, we compared outcomes in patients who had been treated with these medications and in untreated patients, overall and in those with hypertension, after propensity-score matching for receipt of each medication class. A difference of at least 10 percentage points was prespecified as a substantial difference. Results Among 12,594 patients who were tested for Covid-19, a total of 5894 (46.8%) were positive; 1002 of these patients (17.0%) had severe illness. A history of hypertension was present in 4357 patients (34.6%), among whom 2573 (59.1%) had a positive test; 634 of these patients (24.6%) had severe illness. There was no association between any single medication class and an increased likelihood of a positive test. None of the medications examined was associated with a substantial increase in the risk of severe illness among patients who tested positive. Conclusions We found no substantial increase in the likelihood of a positive test for Covid-19 or in the risk of severe Covid-19 among patients who tested positive in association with five common classes of antihypertensive medications.
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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. Results Of the 8910 patients with Covid-19 for whom discharge status was available at the time of the analysis, a total of 515 died in the hospital (5.8%) and 8395 survived to discharge. The factors we found to be independently associated with an increased risk of in-hospital death were an age greater than 65 years (mortality of 10.0%, vs. 4.9% among those ≤65 years of age; odds ratio, 1.93; 95% confidence interval [CI], 1.60 to 2.41), coronary artery disease (10.2%, vs. 5.2% among those without disease; odds ratio, 2.70; 95% CI, 2.08 to 3.51), heart failure (15.3%, vs. 5.6% among those without heart failure; odds ratio, 2.48; 95% CI, 1.62 to 3.79), cardiac arrhythmia (11.5%, vs. 5.6% among those without arrhythmia; odds ratio, 1.95; 95% CI, 1.33 to 2.86), chronic obstructive pulmonary disease (14.2%, vs. 5.6% among those without disease; odds ratio, 2.96; 95% CI, 2.00 to 4.40), and current smoking (9.4%, vs. 5.6% among former smokers or nonsmokers; odds ratio, 1.79; 95% CI, 1.29 to 2.47). No increased risk of in-hospital death was found to be associated with the use of ACE inhibitors (2.1% vs. 6.1%; odds ratio, 0.33; 95% CI, 0.20 to 0.54) or the use of ARBs (6.8% vs. 5.7%; odds ratio, 1.23; 95% CI, 0.87 to 1.74). 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.)
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We have provided clinical and basic evidence showing that SARS-CoV-2 is targeting endothelial cells, triggering the systemic manifestations commonly observed in COVID-19 patients, including thromboembolism, hypertension, vasculitis, and kidney failure (1). The infection of endothelial cells by SARS-CoV-2 is also corroborated by pathologic findings of viral inclusion structures in endothelial cells in COVID-19 patients. Furthermore, we noticed that most of the drugs identified in this paper, have been shown to improve endothelial dysfunction: in addition to ACE inhibitors (2) and metformin (3), we especially want to point the attention to the modulators of Sigma receptors, which can synergistically combine their antiviral action to a favorable profile in terms of endothelial function (4,5), hopefully leading to promising outcomes in the clinical scenario. https://www.nature.com/articles/s41586-020-2286-9
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With the capability of inducing elevated expression of ACE2, the cellular receptor for SARS-CoV-2, angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors (ARBs/ACEIs) treatment may have a controversial role in both facilitating virus infection and reducing pathogenic inflammation. We aimed to evaluate the effects of ARBs/ACEIs on COVID-19 in a retrospective, single-center study. 126 COVID-19 patients with preexisting hypertension at Hubei Provincial Hospital of Traditional Chinese Medicine (HPHTCM) in Wuhan from January 5 to February 22, 2020 were retrospectively allocated to ARBs/ACEIs group (n=43) and non-ARBs/ACEIs group (n=83) according to their antihypertensive medication. 125 age- and sex-matched COVID-19 patients without hypertension were randomly selected as non-hypertension controls. In addition, the medication history of 1942 hypertension patients that were admitted to HPHTCM from November 1 to December 31, 2019 before COVID-19 outbreak were also reviewed for external comparison. Epidemiological, demographic, clinical and laboratory data were collected, analyzed and compared between these groups. The frequency of ARBs/ACEIs usage in hypertension patients with or without COVID-19 were comparable. Among COVID-19 patients with hypertension, those received either ARBs/ACEIs or non-ARBs/ACEIs had comparable blood pressure. However, ARBs/ACEIs group had significantly lower concentrations of CRP (p=0.049) and procalcitonin (PCT, p=0.008). Furthermore, a lower proportion of critical patients (9.3% vs 22.9%; p=0.061), and a lower death rate (4.7% vs 13.3%; p=0.216) were observed in ARBs/ACEIs group than non-ARBs/ACEIs group, although these differences failed to reach statistical significance. Our findings thus support the use of ARBs/ACEIs in COVID-19 patients with preexisting hypertension.