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INTERNATIONAL
JOURNAL
OF BIOMEDICINE
REVIEW ARTICLE
http://dx.doi.org/10.21103/Article11(2)_RA1
International Journal of Biomedicine 11(2) (2021) 111-122
Twindemic of Coronavirus Disease (COVID-19)
and Cardiometabolic Diseases
Gundu H. R. Rao, Emeritus Professor
Laboratory Medicine and Pathology
Director of Thrombosis Research, Lillehei Heart Institute
University of Minnesota, Minneapolis, USA
Abstract
Metabolic diseases, like hypertension, excess weight, obesity, type 2 diabetes, and vascular diseases, have rapidly increased to
epidemic proportions worldwide. Metabolic risks (such as oxidative stress, chronic inammation, insulin resistance, altered glucose
and lipid metabolism, changes in hemodynamics, endothelial dysfunction, and subclinical atherosclerosis) contribute signicantly to
the progress of vascular disease and drive it eventually to acute vascular events like heart attacks and stroke. Although this situation
has been noticed and discussed extensively by the global public health experts, and professional societies, the unprecedented SARS-
CoV-2 pandemic has demonstrated for the rst time the interdependency or syndemic nature of metabolic diseases and a pathogenic
virus that takes advantage of the compromised metabolic function in these diseases. The most common clinical symptoms reported
are fever, cough, fatigue, shortness of breath, dyspnea, chest pain, sore throat, and sputum production. The main mode of transmission
is through respiratory particles containing viral virions. Both asymptomatic and symptomatic patients seem to be infectious. The
spike (S) protein of SARS-CoV-2 seems to have a 10- to 20-fold higher afnity to the human ACE2 receptor than that of SARS-CoV.
Since these receptors are highly expressed on a variety of cells, including vascular endothelial cells and adipose tissue, individuals
with compromised function of these tissues are more vulnerable to greater infection, replication, and severity with COVID-19. In
most cases, the severity of the coronavirus disease is associated with pre-existing comorbidities, which include metabolic diseases
such as hypertension, obesity, diabetes, and vascular diseases. Those with such diseases, or with elevated risk factors for such
diseases, will have a compromised endothelium, favoring endothelial dysfunction. The infection of the endothelium by SARS-CoV-2
and resulting endothelialitis seems to add to this problem by further damaging the endothelium, causing dysfunction, disruption
of vascular integrity, and endothelial cell death. These events lead to the exposure of the thrombogenic basement membrane and
result in the activation of the thrombotic and clotting cascade. Because of these observations, critical care clinicians recommend
aggressive anti-thrombotic and thrombolytic therapies in the management of acute COVID-19 cases. In the absence of a cure for
coronavirus disease, sensible medicine proposes the following: primary prevention by following the best public health practices, such
as social distancing, use of face coverings, and quarantine of COVID-positive individuals; and a gentler, moderate, and humble view
and application of available treatment options and their effectiveness in patients with COVID-19. The FDA has created a special
emergency program for possible coronavirus therapies, the Coronavirus Treatment Acceleration Program (CTAP). Currently, there
are 590 drug development programs in planning stages, 390 trials in review, and ve authorized for emergency use. None are approved
for use in COVID-19 management. Currently, there are at least 51 studies listed in the COVID-19 vaccine tracker of the Regulatory
Affairs Professional Society (RAPS) site. At the time of this writing, vaccines from Pzer-BioNTech, Moderna, Oxford-AstraZeneca,
and Johnson&Johnson have emergency use authorization in the US. (International Journal of Biomedicine. 2021;11(2):111-122.)
Key Words: SARS-CoV-2 • COVID-19 • vaccine • metabolic diseases
For citation: Rao GHR. Twindemic of Coronavirus Disease (COVID-19) and Cardiometabolic Diseases. International Journal of
Biomedicine. 2021;11(2):111-122. doi:10.21103/Article11(2)_RA1
Introduction
A novel coronavirus SARS-CoV-2, which escaped
from Wuhan, China, in early January of 2019, has caused
unprecedented healthcare and economic crisis worldwide.(1-9)
This $16 trillion killer virus has caused havoc in all countries,
and now after almost a year, has mutated into much more
sophisticated ‘new novel’ virus variants, with a very high rate
of transmission.(10,11) The spreading rate of the British and South
African variants seems to be greater than 70%, compared to the
normal SARS-CoV-2 virus. Variations in the UK variant seem
to occur at the level of N501Y of the spike protein and involve
Contact Information: Emeritus Professor Gundu H.R. Rao, Laboratory
Medicine and Pathology, Director, Thrombosis Research, Lillehei Heart
Institute, University of Minnesota. E-mail: gundurao9@gmail.com
112 Gundu H. R. Rao / International Journal of Biomedicine 11(2) (2021) 111-122
23 separate mutations of the spike.(11) Globally, according to
Johns Hopkins University in Baltimore, Maryland, USA, over
112 million (mil) individuals are COVID-19 positive with 2.4
million deaths. The USA (28 mil), India (11.0 mil) Brazil (10.3
mil), Russia (4.16 mil), and the UK (4.15 mil) are competing for
the top ve ranks in terms of the number individuals COVID-
positive. In COVID-related deaths, the USA, Brazil, Mexico,
India, UK, and Italy are the top-ranking countries. In early April
2019, when I published my rst article on this topic, the rankings
were different: there were 2.9 million infected individuals
worldwide with 203,670 deaths. Conrmed cases ranked as
follows: USA (941,628), Spain (223,759), Italy (195,351),
France (161,665), Germany (157, 026), United Kingdom
(149,569), Turkey (107,773), Iran (90,481), China (83,909),
Russia (80, 949), and Brazil (59,479). India with the second
largest population and second-highest number of diabetics,
with relatively poor healthcare infrastructure (1.2% GDP VS
17% in the USA), ranked 16th with 26,917 cases. Malaysia
and Bangladesh were way far below in their rankings. If one
were to rank these countries based on case fatality rates (CFRs),
then the ranking was as follows; Mexico (87%), Italy (3.5%),
Hungary (3.1%), Indonesia (2.9%), South Africa (2.7%). India
with 1.4% CFR, ranked number 19.
COVID medicine and the public health response to this
pandemic is a fast-changing eld, with many controversies.
The authors of CovidReference.com have been making every
effort to provide updates on this topic with the mini-series; the
most recent is the sixth edition of this mini-book.(6) According
to the authors, in December of 2019, several patients from
Wuhan developed pneumonia and respiratory failure. In early
January 2020, a beta-coronavirus, later named SARS-CoV2,
was isolated from the bronchoalveolar lavage of patients.
From the rst identication of COVID-19 in Wuhan, to the
time of the rst publication of this reference book (January 13,
2020), SARS-CoV-2 had spread to every corner of the world.
According to Nobel laureate Joshua Lederberg, the success of
the “wonder drugs” of the 1950s led to the belief that the “war on
microbes” had been won, but the emergence of new infectious
agents such as HIV and Ebola has shattered that illusion. In a
speech in 1989, Lederberg warned against complacency in the
age-old contest between mankind and microbes—viruses and
bacteria. He laid out why man’s “only real competitors remain
viruses”; he further explained how all terrestrial life “is a dense
web of mutualism and genetic interactions”; there are abundant
sources of genetic variation “for viruses to learn new tricks
(as proved by SARS-CoV-2), not necessarily conned to what
happens routinely or even frequently.” Now we have the proof
of his prophecy, SARS-CoV-2, a novel and intelligent virus,
if one may call it that, which has acquired multiple reading
frames to delete unwanted mutations. One feels as if it has
used articial intelligence, pattern recognition, and machine
learning techniques to become a highly contagious and most
potent killer virus. The novel virus has improved over all the
other members of this family, by acquiring the biochemical and
structural features essential for rapid transmission, transfection,
and replication by avoiding and deleting deleterious mutations
and keeping favorable ones.
A recent comment published in the Lancet says that
COVID-19 is not a pandemic, it is a syndemic.(12) Syndemics
involve the clustering of two or more diseases within a
population; the biological, social, and psychological interaction
of those diseases; and the large-scale social forces that
precipitate disease clustering in the rst place.(13-15) According to
the experts, a syndemic approach reveals biological and social
interactions that are important for prognosis, treatment, and
health policy. Therefore, limiting the harm caused by SARS-
CoV-2 will demand far greater attention to non-communicable
diseases (NCDs), and socioeconomic inequality than has hitherto
been admitted. Disparities that exist in the rate of infection and
severity of this disease in the African American community and
other minority communities substantiate this observation by
the experts. For argument’s sake, COVID-19, for instance, is
a pandemic over another pandemic—cardiometabolic diseases.
(16-18) If we were to stretch our imagination further, we would
have to include all the metabolic disease risk factors also as
coexisting conditions. Addressing COVID-19 management,
therefore, means, addressing all the metabolic risk factors as
well as metabolic diseases such as hypertension, excess weight,
endothelial dysfunction, inammation, obesity, diabetes,
vascular diseases, and chronic respiratory diseases. The SARS-
CoV-2 pandemic is a nightmare for workers in public health and
critical care. The effect of this pandemic will stay with us for a
long time to come. In this overview, we will discuss coronavirus
disease and its syndemic nature on cardiometabolic risks, and
metabolic and vascular diseases.
SARS-CoV-2 Biochemistry
The rst human coronavirus was rst discovered and
characterized by June Almeida a virologist in St Thomas
Hospital in London in 1964. Since that time, ve new human
coronaviruses have been identied, including the severe
acute respiratory syndrome virus, which caused signicant
mortality. Coronaviruses are single-stranded RNA virus
genomes. The virion consists of genomic RNA embedded
in phospholipid double layers and coated with two different
types of nucleocapsid proteins (N). The membrane (M)
protein (a type of transmembrane glycoprotein), the envelope
(E) protein, and the surface (S) protein. Beta coronaviruses
have a shorter spike-like surface protein called hemagglutinin
esterase. The lipid bilayer envelope of the virus protects the
membrane proteins and the nucleocapsid proteins when the
virus survives outside the host.
Coronaviruses have positive-sense RNA genomes,
consisting of six conserved proteins. The conserved proteins
are the polyproteins pp1a and pp1b, which encompass multiple
protein domains involved in various aspects of coronavirus
genome replication. The size of this virus is between 60
nanometers (nm) to a maximum of 140 nm. Respiratory droplets
are typically 5-10 micrometers, and each droplet may contain
250 virions, which means just normal talking can generate more
than 750,000 virions. In the high-case fatality rate (CFR) strain,
the nucleocapsid protein and the spike protein are signicantly
enriched. The N protein is multifunctional, contributes to viral
transcription efciency and pathogenicity. The SARS-CoV-2
spike proteins bind to the ACE2 host receptor with a 10 to 20-
Gundu H. R. Rao / International Journal of Biomedicine 11(2) (2021) 111-122 113
fold afnity compared to SARS-CoV and contain a polybasic
furin cleavage site, resulting in a unique insert to SARS-CoV-2
that enhances infectivity. Cleavage of S protein generates a
polybasic Arg-Arg-Ala-Arg C-terminal sequence on S1 and S2.
Furthermore, their analysis revealed a four-amino acid insertion
in the long connecting region between the fusion peptide of
the spike protein, in all high-CFR viruses, but not in low-CFR
ones. Yet another difference they noticed was increased positive
charge of the amino acids, comprising the nuclear localization
signals (NLSs), a known marker of NLS strength. (19) Recent
ndings suggest the interaction of yet another receptor, called
neuropilin-1(NRP1), and neuropilin 2 (NRP2) that facilitate
the entry of this virus into cells. Key cell entry mechanism
includes higher ACE2 (hACE2) binding afnity of the spike to
the receptor-binding domain, reduced dependence on target cell
proteases for entry, due to pre-activation by convertase furin.(20)
Transmission
The spike protein is a type 1 transmembrane protein,
comprising 1255 amino acids and seems to be the key to the
host cell interactions. The virus has undergone signicant
mutations as it has evolved worldwide. However, the S protein
seems to be the key determinant of evolution, transmission,
and virulence of SARS-CoV-2. Coronavirus entry into host
cells is mediated by the transmembrane spike (S) glycoprotein
that forms homotrimers protruding from the viral surface.(21)
This protein comprises two functional subunits, responsible
for binding to the host cell receptor (S1subunit), and fusion of
the viral and cellular membranes (S2 subunit). For all viruses
of this group, the S unit is cleaved by host proteases at the S2
site of the fusion peptide. Because of this mode of transmission,
coronavirus entry into the host cell is a complex process, that
requires both receptor binding and proteolytic processing of the
S protein, to promote virus-cell fusion. SARS-CoV-2 entry into
a cell involves the interaction of its spike protein with the cell’s
membrane-bound angiotensin-converting enzyme 2 (ACE2),
which is cleaved by the transmembrane protease serine 2
(TMPRSS2), suggesting that co-expression of both genes is
required for infection. (22)
The step between the SARS-CoV-2 spike glycoprotein
and the ACE2 receptor seems to be the most critical point for
the entry of the virus into the host cells. The high afnity of the
S protein to the human ACE2 receptor seems to facilitate the
spread of this virus in human populations. According to experts,
four important enzymes are essential for the pathogenesis: the
S protein that facilitates virus entry through the ACE2 to the
host cell surface receptor, the major protease of CoV3Clpro, the
papain-like protease (PLpro) involved in the assembly of new
viruses, and RNA-dependent polymerase (RdPr) that facilitate
CoV RNA genome replication. The processing and activation of
coronavirus S protein are critical for the infectivity of the virus.
The proprotein convertase family (PC) is composed of nine
serine-secreting proteases and is widely involved in regulating
various biological processes in normal and disease states.
Therefore, the PC family, especially Furin, can be considered
the key player that mediates the maturation of the S protein
processing and recognition of membrane proteins. According
to the experts, Furin can be considered a critical molecule that
makes SARS-COV-2 cause adverse cardiovascular events
through the ACE receptor. (23)
Clinical Manifestations
Researchers from the department of statistics, University
of Dhaka, published a Meta-Analysis on clinical manifestations
and comorbidities of coronavirus infection.(24) Of the total of
33 eligible studies, including 7673 infected patients, the most
prevalent clinical symptoms were fever (84.49%), cough
(56.39%), fatigue (33.65%), dyspnea (22.34%), sputum
production (22.34%), and myalgia (16.26%). Other symptoms
included shortness of breath, diarrhea, headache, chest pain,
vomiting, sore throat, and poor appetite, loss of smell and taste,
and chills. The most prevalent comorbidity was hypertension
(20%), cardiovascular disease (11.9%), and diabetes (9.8%).
Other less know comorbidities include excess weight, obesity,
chronic kidney disease, chronic liver disease, chronic pulmonary
disease, and cerebrovascular disease.(25-29) These viruses enter
the nasal epithelial cells, using the surface spike (S) protein to
bind ACE2, which serves as receptors for SARS-CoV-2, on the
bronchial epithelial cells and type II pneumocytes. Researchers
have analyzed the ACE2 RNA expression prole at single-cell
resolution. High ACE2 (hACE2) expression has been identied
in type II alveolar cells of the lung, esophagus, enterocytes of
the ileum and colon, cholangiocytes, myocardial cells, kidney
proximal tubule cells, bladder urothelial cells, fat cells, and
vascular endothelial cells.(20-22)
Following infection and viral replication, downregulation
of ACE2 enzyme occurs, resulting in dysfunction of the
angiotensin system, resulting in hypokalemia, vasoconstriction,
and development of acute respiratory distress syndrome
(ARDS). Endothelium, comprising a monolayer of endothelial
cells is the largest organ of the body, covering a large surface
area, and reaching out to every tissue and organ. Based on
emerging evidence from patients with COVID-19, experts
postulate that endothelial cells are essential contributors to the
initiation and propagation of severity of COVID-19. Because
of these observations, one can further speculate that the injury
to the endothelium could introduce a cascade of events, leading
to platelet activation, thrombin generation, and promotion of
both thrombotic and thrombolytic events (Figure 1).
To distinguish the term ‘vascular disease’ from the
vascular damage and pathology observed in the severely ill
Fig. 1. Platelet interaction with injured
endothelium. (Courtesy: Prof. James G. White).
114 Gundu H. R. Rao / International Journal of Biomedicine 11(2) (2021) 111-122
Covid-19 patients, we refer to this condition as a disease of the
blood vessels.(29) In most cases, the severity of the coronavirus
disease is associated with pre-existing comorbidities, which
include metabolic diseases such as hypertension, obesity,
diabetes, and vascular diseases. Those with such diseases,
or with elevated risk factors for such diseases, will have a
compromised endothelium, favoring endothelial dysfunction.
The infection of endothelium by SARS-CoV-2 seems to
add to this problem, by further damaging the endothelium,
causing dysfunction, disruption of vascular integrity, and
endothelial cell death. These events lead to the exposure of the
thrombogenic basement membrane and result in the activation
of the thrombotic and clotting cascade. Because of these
observations, critical care clinicians recommend aggressive
anti-thrombotic and thrombolytic therapies in the management
of acute COVID-19 cases.
Twindemic of COVID-19 and Cardio-
metabolic Diseases
The hospitalization rate for COVID-19 is 4.6% per
100,000 population, and almost 90% of the hospitalized patients
have some type of underlying condition, according to the
Centers for Disease Control and Prevention, USA. According
to the Associated Hospitalization Surveillance Network, which
includes laboratory-conrmed cases in 99 counties in 14 states,
the hospitalization rate increased with patient age. Those aged
65 years and older were admitted at a rate of 13.8%, those aged
50 to 64 at 7.4%, and 18 to 49 at 2.5%. Hypertension was the
most common morbidity among the oldest patients, with a
prevalence of 72%, followed by cardiovascular disease (CVD)
at 50.8% and obesity at 41%. Is this the common pattern of
comorbidity in all geographical areas? Not necessarily. The rst
large study conducted in the city of New York concluded that
pre-existing conditions such as hypertension and diabetes were
highly prevalent, and the pattern was similar to the data reported
from China.(30) In January of 2020, Huang and associates reported
clinical features of 41 patients hospitalized with Covid-19 in
Wuhan.(31) The median age was 49 and all were males. According
to the authors, less than half had underlying diseases, including
diabetes (20%), hypertension (15%), and cardiovascular disease
(15%). Chen and associates from Wuhan’s Jinyintan Hospital
reported a study of 99 COVID-19 patients.(32,33) The average
age was 55 years. Half of the patients had chronic diseases,
including cardiovascular and cerebrovascular diseases. Wang
and associates from Zhongnan Hospital, Wuhan, reported
clinical characteristics of 138 hospitalized patients with the
2019 coronavirus.(34) Of the 138 COVID-19 patients, 64 had one
or more coexisting medical conditions; hypertension (31.2%),
diabetes (10.1%), and CVD (14.5%).
A meta-analysis of ve studies by cardiologists of
Shandong University, China, reported the presence of
comorbidities in COVID-19 patients admitted to hospitals.
(34) The leading comorbidities were hypertension (17.1%),
cardiac-cerebrovascular disease (16.4%), and diabetes (9.7%),
in that order.(34) Severity and fatality seem to increase with
comorbidities such as hypertension, obesity, cardiovascular
disease, diabetes, and chronic pulmonary disease.(26-28) In a large
study of 72,314 patients from China, the authors reported that
those who needed hospitalization had underlying conditions,
especially hypertension, diabetes, and cardiovascular disease.
(35,36) Early risk assessment—monitoring risk factors for hypoxia,
neutrophil extracellular traps, blood vessel damage, lung injury,
cardiac injury (cTn1 and proBNP), cytokine storm (IL-6, IL-7,
IL-22, IL-17, etc.), and activation of the coagulation cascade
cascade (brinogen, D-dimer, plasmin)—will help the clinicians
in making a wise decision for appropriate interventions.
COVID-19: Hematological Disorders
The most common hematological ndings reported
include lymphocytopenia, neutrophilia, eosinopenia, mild
thrombocytopenia, less frequently thrombocytosis.(37)
According to a meta-analysis, leukocytosis, lymphopenia, and
thrombocytopenia are associated with the severity and even
fatality of COVID-19 cases.(38) During this disease, changes
in hemostasis have also been reported, such as prolonged
prothrombin time and activated partial thromboplastin time
and increased D-dimer levels. In severe cases of this disease,
D-dimer levels seem to get elevated, with the formation of
microthrombi in peripheral blood vessels. Furthermore, IL-6,
IL-10, and serum ferritin were also strong discriminators for
the severity of the disease. Several mediators modulate the
release of chemoattractant and neutrophil activity. It is believed
that higher values of proinammatory markers are related to
extensive lung injury.(39) The neutrophils are known to develop a
sophisticated network of extracellular bers composed of DNA
containing histones, called neutrophil extracellular traps (NETs).
There is some evidence to suggest that NETosis is conditional
on the production of reactive oxygen species (ROS). Whereas
several stimuli trigger NETosis, including pathogen-associated
molecular patterns, damage-associated molecular patterns, and
inammatory mediators.
In an earlier article on this topic, we described that
neutrophilia predicts poor outcome in patients with severe
COVID-19 cases, and neutrophil to lymphocyte ratio may
be an independent risk factor for the severity of this disease.
(27) In a recent article, Shivakumar with associates from India
found that the neutrophil-to-lymphocyte-to monocyte ratio and
the platelet-to-lymphocyte ratio were prognostic signicant in
COVID-19.(40) According to these authors, in inammation,
platelet production increases due to the increased synthesis of
thrombopoietin, which is modulated by cytokines. Acute lung
injury also leads to leaky blood vessels. Activated platelets
enhance lymphocyte adhesion to the endothelium. These events
enhance the inammation, platelet activation, expression
of tissue factor, and promote a prothrombotic condition.
The elevation of D-dimer, observed in some of the studies,
indicates the occurrence of a prothrombotic event, followed by
thrombolysis. In a normal situation, the thrombolytic system
should clear thrombus formed by endogenous thrombolytic
agents. Researchers from the University of North Carolina
by infecting Serpine1-knockout mice with SARS-CoV have
demonstrated the increased expression of tissue factor and
Serpine2 in the absence of Serpine1 and an overall dysfunction
of the urokinase pathway. The results of these studies
Gundu H. R. Rao / International Journal of Biomedicine 11(2) (2021) 111-122 115
demonstrate that a ne balance exists between host coagulation
and brinolysis pathways regulating pathological disease
outcomes, including infection by highly pathogenic viruses
such as SARS-CoV-2.(41-43)
COVID-19: Hypertension
Hypertension is the leading cause of cardiovascular
disease and premature death worldwide.(44) Estimates suggest
that 31% of adults (1.39 billion) worldwide had hypertension
in 2010. These gures just estimate and do not represent reality.
Having said that, we assure readers that hypertension is one of
the leading metabolic diseases, which signicantly contributes
to vascular dysfunction, arterial stiffness, hardening of the
arteries, and progress of subclinical atherosclerosis.
In the editorial of the American Journal of Hypertension
(AJH. 2020;33(5):373), Schiffrin and associates discuss
hypertension as one of the most frequently reported comorbidities
in patients with COVID-19. They state in their review that the
frequency with which COVID-19 patients are hypertensive is
not entirely surprising nor does it necessarily imply a causal
relationship between hypertension and COVID-19 or its severity,
since hypertension is exceedingly frequent in the elderly, and
older people appear to be at particular risk of being infected with
SARS-CoV-2 virus and of experiencing severe forms of and
complications of this disease.
This can be said for all the known metabolic diseases.
Early reports suggesting that SARS-CoV-2 binds to ACE2 in the
lungs to enter the cells has raised questions about the possibilities
that ACE-inhibitors or angiotensin receptor blockers (ARBs)
used in the treatment of hypertension may somehow alter the
severity of the otherwise of coronavirus disease.
The authors of this editorial concluded, that there is
no evidence that hypertension is related to the outcomes of
COVID-19, or that ACE-inhibitors or ARBs use is harmful.
This editorial in AJH discussed the coronavirus disease more
from the treatment of hypertension point of view and did not
discuss the role of hypertension as a pre-existing condition
that enhanced the severity of the coronavirus disease.
A great number of studies have shown that aging and
hypertension are associated with impairments of endothelium-
dependent vascular relaxation in the coronary, forearm, and
renal arteries, and endothelial dysfunction.(45, 46) The normal
hemodynamics is maintained by a ne balance between the
vasoactive compounds generated between the vessel wall
components and the circulating blood components. As an
example, in Figure 2, we have shown a schematic representation
of the role of vasoactive metabolites of arachidonic acid and
L-arginine, generated by the endothelial cells as the mediators
of vasodilation.
We also have shown that the synthesis of these endogenous
vasodilators is inhibited by lipid hydroperoxides and oxidized
lipoproteins formed in the circulating blood. According to Prof.
Mehra of Harvard University, the virus enters the lung, destroys
the lung tissue, breaks open some blood vessels, then starts to
infect endothelial cells, initiates a local immune response, and
inames the endothelium. He further elaborates, “A respiratory
virus infecting blood cell, and circulating through the body, is
virtually never heard of.” The pathophysiology of hypertension
involves the complex interaction of multiple vascular effectors,
including activation of the sympathetic nervous system, of the
renin-angiotensin-aldosterone system, and the inammatory
mediators. Oxidative stress and endothelial dysfunction are
consistently observed in hypertensive subjects. COVID-19
patients with hypertension seem to have severe pneumonia,
excessive inammation, compromised endothelium, organ
and tissue damage, and severity of the disease. Patients with
hypertension should be given additional attention to prevent the
added disease burden posed by the pre-existing comorbidity.
COVID-19: Excess Weight and Obesity
According to the World Health Organization, in 2016 more
than 1.9 billion adults, 18 years or older, were overweight. Of
these over 650 million were obese. Over 340 million children
and adolescents, aged 5-19, were overweight or obese. These
obese individuals are at a higher risk for coronavirus disease. In
the rst meta-analysis of its kind, published on 26 August 2020,
in Obesity Reviews, researchers pooled data from scores of
articles capturing 399,000 patients. They found that people with
obesity who contacted SARS-CoV-2 were 113% more likely
than people of healthy weight to land in the hospital, 74% more
likely to be admitted to an ICU, and 48% more likely to die.(47)
People with obesity are prone to have the metabolic disease, with
unhealthy levels of blood sugar, fat, and elevated blood pressure.
They also seem to have a lower immune response than healthy
individuals. Patients with metabolic syndrome, as well as those
who are obese have been shown to have reduced response to the
vasodilator acetylcholine after intra-arterial infusion, suggesting
vascular dysfunction.(48-50)
Researchers who reviewed Data from 6916 patient records
from Kaiser Permanente reported that compared to normal body
mass index (BMI) of 18-24 kg/m2, the risk of death more than
doubled for patients with a BMI of 40-44 kg/m2 and nearly
doubled again, for those with a BMI of 45kg/m2 or more.(51) In
an accompanying editorial, David A Kass, a Cardiologist at the
Johns Hopkins University, wrote, “that these ndings are taken
with prior research, should put to rest the contention that obesity
is common in severe COVID-19, because it is common in the
population.” The pathophysiology of hypertension involves the
complex interaction of multiple vascular effectors, including
activation of the sympathetic nervous system, of the renin-
Fig. 2. Contribution of endothelial dysfunction to
altered hemodynamics
116 Gundu H. R. Rao / International Journal of Biomedicine 11(2) (2021) 111-122
angiotensin-aldosterone system, and the inammatory mediators.
(52) Oxidative stress and endothelial dysfunction are consistently
observed in hypertensive subjects.(53)
As the body weight increases,
the blood pressure also rises. Therefore, people with excess
weight or obesity will have the added burden of hypertension and
clinical manifestation associated with this altered blood vessel
function. Each metabolic disease is syndemic in its nature, as it
adds additional disease burden to the pre-existing conditions.
As we have discussed earlier, obesity has reached epidemic
proportions worldwide. In the USA alone, the prevalence of
obesity has increased 50% in the past three decades, with 70% of
all adults being classied as either overweight or obese. Beyond
an impaired response to infections, people with obesity also
suffer from chronic, low-grade inammation. Fat cells secrete
inammation triggering chemical messengers called cytokines,
and more come from immune cells called macrophages, that
clean up dead and dying fat cells. These, in turn, impair vascular
homeostasis and lead to endothelial dysfunction.(54) Data on how
to treat COVID-19 patients with obesity are scant. Dr. Scott
Khan, an obesity medicine physician at the National Center for
Weight and Wellness, suggests giving such patients higher doses
of anticoagulants. Looks like it is left to the attending clinicians
to develop and administer the best treatment protocol, based on
the clinical symptoms presented at the time of admission.
COVID-19: Type-2 Diabetes
According to a recent article in the journal Science, dozens
of studies have reported that many of the sickest COVID-19
patients have been people with obesity.(47) The impact extends
to the 32% of people in the United States who are overweight.
The largest descriptive study of hospitalized COVID-19 patients
by Genentech researchers found that 77% of the nearly 17,000
patients hospitalized with CIVID-19 were overweight (29%)
or obese (48%). These obese individuals also will have other
compounding problems, diabetes being one. It is well known
that the blood of people with diabetes has prothrombotic status,
meaning, ‘increased tendency to clot.’ Coronavirus injures
endothelial cells, which are already compromised in obese and
diabetic individuals, and as such response to this insult by activation
of platelet and coagulation pathways. Furthermore, immunity
also weakens in people with excess weight, obesity, and diabetes.
According to the authors of an article in NEJM, there seems to
be a bidirectional relationship between Covid-19 and diabetes.
(55) The virus binds to the ACE2 receptors, which are expressed in
key metabolic organs and tissues, including pancreatic beta cells,
adipose tissue, the small intestine, kidneys. The authors speculate
that SARS-CoV-2 may cause pleiotropic alterations of glucose
metabolism that could complicate the pathophysiology of pre-
existing diabetes or its clinical manifestations.
Metabolic diseases such as hypertension, excess weight,
and obesity induce vascular remodeling through various
mechanisms. Under normal conditions, vascular structure, vessel
wall physiology, and ow dynamics are maintained by a variety
of endogenous modulators. However, metabolic stress forces
the vessel to adapt and remodel depending upon the nature of
the stress. Metabolic factors such as hyperglycemia, oxidative
stress, and chronic inammation play a role in diabetes. Since
hypertension, excess weight, and obesity contribute signicantly to
the development of diabetes, major drivers of vascular remodeling
are endothelial dysfunction due to altered synthesis of vasodilators
and vasoconstrictors, and changes in the complex signaling
pathways.(56) Irrespective of whether it is hypertension, excess
weight, obesity, or diabetes, the molecular mechanisms involved in
the development of altered blood ow, arterial stiffness, hardening
of the arteries, and vascular dysfunction seem to be the same.
However, in the case of diabetes hyperglycemic state of the blood
adds one more contributor to the vascular damage and remodeling.
No matter how we look at this situation, all the metabolic diseases
have one thing in common, a dysfunctional vascular system, and
a compromised immune system, that contributes to the severity of
coronavirus disease in these patients.
To address such issues, an international group of leading
diabetes researchers participating in the CoviDIAB Project
have established a global registry of patients with Covid-19-
related diabetes. The goal of the registry is to establish the
extent and phenotype of new-onset diabetes that is dened by
hyperglycemia, conrmed Covid-19, negative history of diabetes,
and a history of normal glycated hemoglobin (covidiab.e-
dendrite.com). Since our interest is metabolic diseases, any
infectious disease that is syndemic on metabolic risks becomes
an important topic of interest. In the countries with the largest
number of diabetic individuals, China, India, and the USA, there
are an equal number of prediabetic individuals. If we put together
pre-diabetics and diabetics, the total number of people at risk for
COVID-19 related risk exceeds a billion individuals. Therefore,
in our opinion, individuals with hypertension, excess weight,
obesity, and diabetes are at a greater risk of severe COVID-19.
The question of why China and India with the largest populations
of diabetics have relatively low rates of COVID-related mortality
is quite puzzling. In China, the COVID-19 pandemic’s epicenter,
Wuhan, and its province, Hubei, Chinese Center for Disease
Control-network, formed 1300 epidemic investigation teams,
in addition to the 40,000 doctors and nurses. They used very
cleverly tracing tools with big data support. In the rst week
of January the novel coronavirus infection was detected, and
on 23 January 2020, they locked down the city of 11 million
people and soon the rest of the Hubei-a province of nearly 60
million. The WHO-China Joint Mission on Coronavirus Disease
2019 Task Force concluded, “In the face of an unknown virus,
China has rolled out perhaps the most ambitious, agile, and
aggressive, disease containment effort in history.” The strategy
that underpinned this containment effort was initially a national
approach, that promoted universal temperature monitoring,
masking, and handwashing.(57) As far as India is concerned, the
general population thinks that they have innate immunity, as
they are exposed to a variety of Asian viruses, including several
strains of coronaviruses. The second surge of COVID-19 in India
has demonstrated that those individuals with comorbidities such
as hypertension and type 2 diabetes are at higher risk for severe
coronavirus disease and death. Yet, COVID-related deaths and
case fatality rates reported are relatively low in India.
COVID-19: Cardiac Health
Novel coronavirus disease seems to affect all the vital
organs of the body including the heart. Several studies have
Gundu H. R. Rao / International Journal of Biomedicine 11(2) (2021) 111-122 117
reported that many COVID-19 survivors experience some
type of heart damage, even if they do not have underlying
heart disease. “Very early into the pandemic, it was clear that
many patients who were hospitalized were showing evidence of
cardiac injury,” says Dr. Gregg Fonarow, chief of the division
of cardiology at the University of California, Los Angeles. He
further elaborates on this condition, “This raises concerns that
there may be individuals who get through the initial infection
but are left with cardiovascular damage and complications.”
In JAMA Cardiology, analysis of autopsies on 39 COVID-19
patients identied infections in the hearts of patients who had
not been diagnosed with cardiovascular issues while they were
ill.(58) The novel virus can damage the heart in several ways. For
instance, the virus may directly invade the heart muscle; it may
indirectly harm the heart by disrupting the balance between
oxygen supply and demand. The heart injury may be measured
by elevated levels of the enzyme, cardiac troponin in the blood.
An elevated level of this cardiac enzyme has been reported in
about one-quarter of patients hospitalized with COVID-19.
Invasion of the heart muscle may induce myocarditis, which
results in an enlarged or weakened heart, low blood pressure,
and uid accumulation in the lungs.
Since the virus uses the ACE2 enzyme as the preferred
receptor for entry, the virus may directly invade these receptors
on myocardial tissues and cause direct viral harm. It also can
affect the heart muscle itself through inammation, leading to
signicant heart failure. Dr. Hyung Chun a Yale Cardiologist
and director of Translational Research, says one emerging
belief is that the endothelial cells, which line the blood vessels,
in people with cardiac issues respond differently to the body’s
immune response. They seem to release inammatory cytokines
that further compromise the body’s inammatory process and
lead to the formation of blood clots. The ‘inamed’ endothelium
seems to contribute to worsening outcomes in COVID-19 and
is an important factor contributing to the risk of heart attacks
and stroke. As a rule, those conrmed with COVID-19 infection
should be on the lookout for symptoms that may indicate
damage to the heart or cardiac complications. These symptoms
include shortness of breath, chest pain, or heart palpitations.
These symptoms may indicate myocarditis, which is one of
the potential factors for developing acute coronavirus disease
2019 cardiovascular syndrome (ACovCS). The American Heart
Association Journal, Circulation, has published a ‘White paper’
on this topic.(59) The article reviews the best available data on
acute COVID-19 Cardiovascular syndrome epidemiology,
pathogenesis, diagnostic, and treatment.
COVID-19: Cardiovascular Disease
The pre-existing metabolic risks seem to cause worse
outcomes and increased risk of death in patients with COVID-19,
whereas this virus can also cause vascular damage, myocardial
injury, arrhythmia, acute coronary syndrome, and venous
thromboembolism. Dr. Nishiga and associates of the Stanford
Cardiovascular Institute (CVI), Stanford University School of
Medicine, summarized the current understanding of COVID-19
and the cardiovascular system in the journal Nature.(60) As we
have discussed earlier, the interaction between the viral spike (S)
protein and angiotensin-converting enzyme 2, which facilitates
the entry of the virus into host cells, seems to be involved in
the cardiovascular manifestations of COVID-19. In one of
the earliest reports from Wuhan, involving 41 hospitalized
covid-19 patients, the prevalence of comorbidity was greater
than 30% and the most common underlying metabolic diseases
were diabetes(20%), hypertension (15%), and CVD (15%).(2)
In a report from Italy involving 1,591 patients with COVID-19
who needed ICU care, 49% had hypertension, 22% had CVD,
and 17% had diabetes.(61) Whereas in a report from New York,
USA, of the 393 COVID patients who were on ventilators, up
to 50% had hypertension, 36% had obesity, 25% had diabetes
and 14% had coronary artery disease.(62) Recent observations
suggest that approximately 25% of people hospitalized with
COVID-19 have cardiovascular complications, contributing to
about 40% of all COVID-19-related deaths.
Even though acute hypoxic respiratory failure is the
characteristic clinical feature of SARS-CoV-2, many diverse
clinical cardiovascular (CV) manifestations have been reported,
including heart failure, circulatory shock, cardiomyopathy,
arrhythmia, and vascular thrombosis. Since it has been well
established that CV-related manifestations portend greater
mortality, they pose a great challenge to the clinicians working to
develop an appropriate treatment protocol. It becomes essential
for the clinicians to think through and consider all possible
CV clinical manifestations, appropriate biomarkers for early
diagnosis of these risks, and to develop appropriate therapies
for COVID-19-positive patients.(63) According to a white paper
published by the American Heart Association editors, the two
take-home points are 1) Elevated levels of troponin are frequently
seen in patients with COVID-19 disease and are associated with
increased severity of disease and risk of death; and 2) In the
absence of a specic cause, elevated levels of cardiac troponins
are likely attributable to myocardial injury from inammation
or a direct effect of SARS-CoV-2 infection.(64) The paper also
poses some questions that need to be addressed. 1) The role
of troponin in clinical risk stratication, and as a prognostic
factor of disease severity and mortality. 2) Mechanistic studies
are needed to evaluate the cause of myocardial injury and
determine whether there is a potential for a therapeutic option.
Many studies have reported that infection with COVID-19 may
predispose one to venous and arterial thromboembolism to a
greater degree with worse disease severity.(65) The management
of CVD in patients with COVID-19 includes general supportive
treatment, circulatory support, other symptomatic treatment,
and psychological assistance, as well as online consultation.
COVID-19: Cerebrovascular Disease
In one of the early studies reported from Wuhan, China,
researchers conducted a retrospective study of 214 patients
admitted with COVID-19 infection. Of these (mean age of
52) 78 patients (36.4%) had neurologic manifestations.(66)
SARS-CoV-2 binds to ACE-2, leading to the downregulation
of this receptor function and contributes to the post-ischemic
inammation cascade resulting in decreased perfusion of the
ischemic areas of cerebral tissue with larger infarct volume
and ischemic stroke.(67) Furthermore, ACE2 dysfunction may
118 Gundu H. R. Rao / International Journal of Biomedicine 11(2) (2021) 111-122
cause hypertensive peaks and impairment of cerebrovascular
endothelium, leading to intracerebral hemorrhage. It has also
been reported that systemic hypotension may induce hypo
ischemic encephalopathy and microbleeds. Researchers from
Saudi Arabia report that neurological complications range
from dizziness, headache, hyposmia, encephalopathy, infarcts,
microhemorrhages, and stroke.(68) They also report decreased
deformability of red blood cells and hypercoagulability,
resulting in hypoxia and inammation in these patients. A
systematic review has analyzed data from 1,210 articles with
226 cases of ischemic stroke.(69,70) According to this report,
large vessel occlusion (LVO) was observed in 105 patients,
acute intracranial bleeding in 35 patients, intracerebral
hemorrhage (ICH) in 24 patients, 4 patients had non-traumatic
subarachnoid hemorrhage (SAH), remaining 7 patients had
simultaneous presence of SAH and ICH. The authors concluded
that cerebrovascular events are relatively common ndings in
COVID-19 infection and could have a multifactorial etiology.
Furthermore, of the total of 226 cases of ischemic stroke,
35 cases of intracranial bleeding, and 14 cases of cerebrovascular
sinus thrombosis (CVST), were reported. According to these
investigators, postmortem brain magnetic resonance imaging
(MRI) showed extensive signs of cerebrovascular involvement,
including microbleeds with subcortical and posterior
predominance. Among these patients, D-dimer levels were at
least four-fold higher than normal values. Inammation is a
common occurrence in Covid-19 patients. It is well known that
both acute and chronic infections and inammatory states serve
as triggers of stroke. By and large, COVID-19 patients with pre-
existing metabolic diseases such as hypertension, excess weight,
obesity, type-2 diabetes, and CVDs have increased severity at
the time of admission to the hospital. These pre-existing risks
make it very difcult to develop an optimal treatment regimen.
COVID-19: Arterial and Venous Diseases
Coronavirus disease severity is associated with venous
thromboembolism as well as arterial thrombosis. Thrombotic
complications, as well as coagulopathy, have been reported
in COVID-19 positive individuals. COVID-19 associated
coagulopathy (CAC), detected by the increase in D-dimer and
brinogen levels with minimal abnormalities in prothrombin
time and platelet count has been reported in COVID-positive
cases. The high mortality associated with thromboembolic
diseases in COVID-19 has prompted clinicians to use D-dimer
as a useful marker for assessing the severity of the disease.(71)
According to a review by Harvard Medical School researchers,
in critically ill patients with COVID-19, elevated levels
of D-dimer were found in 100% of participants, elevated
brinogen in 74% of the participants, and factor V11 in 100%
of participants. Antiphospholipid antibodies were detected
in 53% of the participants, decreased protein C, protein S,
and antithrombin levels were detected in all participants.(72)
Coagulation abnormalities were associated with acute vascular
events such as stroke, peripheral arterial ischemia, and venous
thromboembolism. Guidelines from the American College of
Chest Physicians suggest prophylaxis with Low Molecular
Weight Heparins (40mg) and fondaparinux 2.5 mg, in the absence
of any contraindications, such as active bleeding. However,
this professional society does not recommend post-discharge
thromboprophylaxis. The International Society on Thrombosis
and Hemostasis suggests duration of 14 to 30 days for post-
discharge thromboprophylaxis. Thromboprophylaxis for patients
who do not require hospitalization is not currently recommended.
Prevention
When discussing prevention strategies, we need to
consider the unprecedented pandemic of SARS-CoV-2 as
well as a pre-existing epidemic of metabolic risks, metabolic
diseases, and vascular diseases worldwide, which increase the
severity of COVID-19. Having said that, we need to remember
that no country has reduced, reversed, or prevented the increase
in the incidence of metabolic diseases. Metabolic diseases have
increased rapidly to epidemic proportions worldwide in the last
three decades. COVID-19 is not going to go away any sooner.
Twindemic is going to continue to play havoc for quite some
time to come and will be a public health experts’ nightmare.
In a large study of 72,314 patients from China, the authors
reported that those who needed hospitalization had underlying
conditions, especially hypertension, obesity, diabetes, and
cardiovascular disease.(35,36) Early risk assessment, monitoring
risk factors for hypoxia, neutrophil extracellular traps (NETs),
blood vessel damage, lung injury, platelet activation, the
formation of microthrombi or microbleeds, cardiac injury (cTn1
and proBNP), cytokine storm (IL-6, IL-7, IL-22, IL-17, etc.),
activation of the coagulation cascade (brinogen, D-dimer,
plasmin), will help the clinicians in making a wise decision for
appropriate interventions.(73,74)
In the absence of a cure for coronavirus disease, sensible
medicine proposes a gentler, moderate, and humble view of
available treatment options and their effectiveness in patients
with COVID-19. The approach encourages clinicians, to
elevate usual care, reduce unnecessary interventionism,
focus, and rely on scientic rigor. By and large, treatment
options are based on clinical diagnosis-based treatments for
observed symptoms. For patients with COVID-19, who are not
hospitalized or who are hospitalized with moderate disease, but
do not require supplemental oxygen, the National Institutes of
Health (NIH, USA) panel does not recommend any specic
antiviral or immunomodulatory therapy, for the treatment of
coronavirus disease in these patients. For those hospitalized
with severe conditions, the panel recommends Remedesivir
200 mg intravenously (IV) for 1 day followed by a 100 mg
dose for four days or until hospital discharge. A combination
of Remedesivir and dexamethasone 6 mg IV up to 10 days. As
mentioned earlier, currently, there are no US FDA-approved
therapies, for coronavirus disease treatment. FDA has created a
special emergency program for possible coronavirus therapies,
the Coronavirus Treatment Acceleration Program (CTAP).
Currently, there are 590 drug development programs in planning
stages, 390 trials in review, and ve authorized for emergency
use, none approved for use in COVID-19 management.
As of this writing, there are at least 51 studies listed
in the COVID-19 vaccine tracker of the Regulatory Affairs
Professional Society (RAPS) site. The top ten entries, which are
Gundu H. R. Rao / International Journal of Biomedicine 11(2) (2021) 111-122 119
under phase 3 trial, include Ad5-nCoV, a recombinant vaccine
by CanSino Biologics (China); AZD1222, a replication-
decient adenovirus vector vaccine (The University of Oxford,
the Jenner Institute); CoronaVac by Sinovac; JNJ-78436735, a
non-replicating viral vector by Johnson and Johnson; mRNA-
1273, an mRNA-based vaccine by Moderna; an unnamed
inactivated vaccine by Wuhan Institute of Biological Products;
NVX-CoV2373, a nanoparticle vaccine by Novavax. There
are several new entries in phase 2/3 trials, including the BCG
vaccine by the University of Melbourne and Mass. General
Hospital, Boston; BNT162, an mRNA-based vaccine by Pzer-
BioNTech; and Covaxin, an inactivated virus vaccine by Bharat
Biotech, National Institute of Virology, India. According to
a recent article in the New Engl. J. Med., condence in any
COVID-19 vaccine that is made available under an emergency
use authorization (EUA) will depend on the rigor of the clinical
criteria, including the duration of follow-up, safety, and efcacy
of the vaccine.(75) With phase 3 clinical trials of COVID-19
vaccine underway, safety and efcacy data will be provided
to the FDA soon after they are compiled.(76) Emergency use
authorization will be made by the FDA’s Center for Biologics
Evaluation and Research (CBER). The decision of this branch
of the FDA has been approved by the Vaccines and Related
Biological Products Advisory Committee (VRBPAC).
There are twelve vaccines against SARS-CoV-2 that
have been authorized for use in various locations around the
world. These include mRNA vaccines, viral vector vaccines,
subunit vaccines, and inactivated virus vaccines. mRNA
vaccines do not contain any part of the virus. They carry a
chemically synthesized piece of messenger RNA, containing
the information needed for cells to make the spike proteins of
the virus that is essential for infection. Like the mRNA, vector
vaccines also do not contain the SARS-Cov-2 virus. They use
adenovirus as the delivery system. Subunit vaccines use part
(spike protein) of the SARS-Cov-2 virus. Inactivated vaccines
contain the entire SARS-CoV-2 virus inactivated by beta-
propiolactone. At the time of this writing, globally, the following
vaccines have been given emergency use authorization against
COVID-19: mRNA-1273 (Moderna, US), BNT162b2 (Pzer-
BioNTech, US), Ad26CoV2.S (Viral vector, Johnson &
Johnson, US), ChAdOx1(Viral vector, AstraZeneca/Oxford,
UK), NVX-CoV2373 (Novavax Inc, US), CVnCoV-mRNA
(GSK, Germany), Gam-COVID-Vac (Sputnik V, Viral vector,
Russia), CoronaVac (inactivated virus, China), and BBIBP-
CorV (inactivated virus, China), Covaxin (inactivated virus,
Bharath Biotech, India).(77)
A variety of nanobodies (nAbs) against SARS-CoV-2,
which target the S protein of the virus, are in preclinical
development.(78) Monoclonal antibodies are usually large and must
be produced in mammalian cell expression systems. On the other
hand, nanobodies are single-domain antibodies with small size,
good solubility, stability and could be produced in Escherichia
coli and yeast cell cultures. Therefore, they could be produced
at relatively low cost in large quantities. National Institutes of
Health researchers have isolated tiny antibodies against SARS-
CoV-2. One of the advantages of the nanoantibodies is that they
can be aerosolized to use in inhalers to coat the lungs and airways,
the preferred route of SARS-CoV-2 entry.
Considering the contribution of comorbidities to the
progression and severity of the coronavirus disease, one
would expect that China, India, and the USA, with the largest
populations of diabetic subjects, should have the highest CFR
(Deaths per 100,000 population) for COVID-19. On the other
hand, Mexico (8.5%), Peru (3.6%), Italy (3.5%), and South
Africa have a lot more mortality than the USA (1.0%) and India
(1.7%) (Coronavirus.jhu.edu/data/mortality; February 4, 2021).
Since the three major populations with the highest number of
diabetics have not shown a comparatively high case fatality
rate, it is worthwhile discussing the other two comorbidities
(hypertension and obesity) as the chief contributors for the
Covid-19 progression and severity. Trends in the prevalence of
hypertension in the USA, according to the NHANES survey of
age-standardized prevalence, decreased from 48.4% in 1999-
2000 to 45.4% in 2015-2016. However, the absolute burden of
hypertension consistently increased, from 87.0 million in 1999-
2000 to 108 million in 2015-2016.(79) Hypertension appears to
be more common in Mexico, than among Mexican Immigrants
in the United States. As far as obesity goes, the number of
obese children and adolescents aged ve to 19 years, has risen
tenfold in the past four decades and if current trends continue,
there will be more obese children and adolescents than those
moderately.(80) Among adolescents, obesity prevalence in the
USA was 16.8% in 2007 and 18.5% in 2016. Age-standardized
obesity in adults increased from 33.7% in 2007 to 39.6% in
2015. Whereas 62% of the participants in Mexico reported, at
least, being overweight.(81) When considering obesity data based
on the BMI, we should keep in mind that South Asians have
a different body fat distribution, compared to the European
and Western populations. South Asians in general have central
abdominal obesity.
If we carefully analyze a series of clinical events, that
develop a post-SARS-CoV-2 infection, we can begin to
understand, why metabolic diseases serve as independent risk
factors for the progression and severity of coronavirus disease.
The initial route of entry is via the nasal and oral mucosa, the
preferred receptor that facilitates the transmission seems to be
the ubiquitous ACE2, which is found in multiple types of cells
and tissue including vascular endothelium. Recent ndings, that
following the injury to the lung tissue, the virus gets entry into the
endothelium, opens a whole new avenue for the progress of the
disease and its severity. The endothelium is the largest organ of
the body, covering a large surface area and reaching out to every
tissue and organ. As such, the injury to the endothelium could
introduce a cascade of events, leading to platelet activation,
thrombin generation, and promotion of both thrombotic and
thrombolytic events.(29,41) Furthermore, people with metabolic
diseases such as hypertension, excess weight, obesity, diabetes
(Type 2), and vascular disease, already have a compromised
endothelium, and invasion of the SARS-CoV-2 virus leads to
endothelialitis and causes further injury to the vascular system,
disruption of vascular integrity and endothelial cell death.
(82-85) These events lead to the exposure of the subendothelial
basement membrane and result in the activation of thrombotic
and clotting cascade of events.
This unprecedented pandemic of SARS-CoV-2 has
taught us two lessons: rst, the importance of robust public
120 Gundu H. R. Rao / International Journal of Biomedicine 11(2) (2021) 111-122
health infrastructure, and second, the need for an immediate
call for action to reduce, reverse, or prevent metabolic diseases
worldwide. The recent statement from the Institute for Fiscal
Studies Deaton Review on inequality (IFS Deaton Review, Jan
5, 2021), stressed that the opportunity cost of the pandemic for
young people is potentially huge, but also that it is a “once-in-
a-generation opportunity to tackle the disadvantages faced by
many that this pandemic has so devastatingly exposed.” In a
recent editorial of the Lancet Public Health, the editor concludes
that adopting a broadened, equity-based approach to population
health should be an essential part of building a more resilient
society that is better prepared for future pandemics.(86)
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