REVIEW

CURRENT
OPINION Assessing cardiovascular disease: looking
beyond cholesterol
Malcolm Kendrick

Purpose of review
The low-density lipoprotein (LDL)-cholesterol level is a weak predictor of developing cardiovascular (CV)
disease and can only explain a small proportion of CV risk. It is not used to determine CV risk on either the
atherosclerotic cardiovascular disease (ASCVD) calculator in the United States, or the Qrisk3 in the UK.
A study in JAMA in 2022 suggested that ‘the absolute benefits of statins are modest and may not be
strongly mediated through the degree of LDL reduction’. Perhaps it is time to look beyond cholesterol to a
different causal model -- the ‘thrombogenic’ model of ASCVD.
Recent findings
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) pandemic demonstrated that infectious
agents damage the endothelium and the glycocalyx -- the glycoprotein layer protecting underlying
endothelial cells. There are numerous other conditions leading to this kind of damage, which can trigger
thrombus formation, causing strokes and myocardial infarctions.
Although these are acute events, they highlight a mechanism for the development of ASCVD which centres
on endothelial damage and thrombus formation as both the primary causal mechanism for acute events,
and the driver behind progression towards atherosclerotic plaque development.
Summary
The cholesterol hypothesis, that a raised LDL is directly causal for ASCVD, does not adequately explain
cardiovascular risk in individuals, or populations. An alternative ‘thrombogenic’ hypothesis is proposed as
a more valid causal model.
Keywords
atherosclerotic cardiovascular disease, glycocalyx, low-density lipoprotein-cholesterol, lipoprotein (a),
thrombogenic

INTRODUCTION Whilst it is true that statins reduce the risk of

&&

The ‘low density lipoprotein (LDL)-cholesterol
hypothesis’ is widely accepted as the best model
explaining how atherosclerotic cardiovascular dis-
ease (ASCVD) develops. It states that a raised LDL
level causes thickenings within arterial walls which
gradually develop into larger plaques.
More vulnerable plaques may then ‘rupture’,
triggering the final thrombotic event, fully occlud-
ing an artery, leading to events such as myocardial
infarction (MI) and strokes.
However, the association between a raised LDL
level and the development of ASCVD is weak. Indeed,
many studies have found no association or even an
inverse association, particularly in the older popula-
& Curr Opin Endocrinol Diabetes Obes 2022, 29:427–433
tion, where most deaths from ASCVD occur [1 ].
The inability of LDL to accurately predict risk
highlighted by the fact that the two most widely
used calculators for ASCVD, in the United States and
UK, do not use LDL levels to establish the risk of a
future cardiovascular (CV) event [2,3].
ASVCD, the absolute reduction in risk is small [4 ].
Additionally, several agents that significantly lower
LDL demonstrated no benefit on ASCVD, including
cholesterol ester transfer protein inhibitors such as
torcetrapib and evacetrapib. Evacetrapib reduced
LDL by 37% and increased high-density lipoprotein
(HDL) by 120% but had no effect on CV risk [5].
Mid-Cheshire Hospitals NHS Foundation Trust. Leighton Hospital,
Crewe, Cheshire, UK
Correspondence to Malcolm Kendrick, MbChB, Mid Cheshire Hospitals
NHS Foundation Trust, Macclesfield, Cheshire, CW1 4QJ, UK.
Tel: +44 7714 427642; e-mail: malcolmken@doctors.org.uk
DOI:10.1097/MED.0000000000000761
This is an open access article distributed under the terms of the Creative
Commons Attribution-Non Commercial-No Derivatives License 4.0
(CCBY-NC-ND), where it is permissible to download and share the
work provided it is properly cited. The work cannot be changed in any
way or used commercially without permission from the journal.

1752-296X Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. www.co-endocrinology.com
Obesity and nutrition

KEY POINTS

Low-density lipoprotein (LDL)-cholesterol is a weak
predictor of cardiovascular risk

Factors that drive endothelial damage and thrombus

formation greatly increase atherosclerotic
cardiovascular disease (ASCVD) risk.

The thrombogenic can explain a number of causal risk
factors that do not fit within the LDL-cholesterol
hypothesis, including type II diabetes, smoking and
systemic lupus erythematosus.

The thrombogenic hypothesis, that endothelial damage
and subsequent clot formation underlies the formation
and growth of plaques, may represent a better model
for ASCVD.

There is a need to research the thrombogenic

hypothesis in more depth.

FIGURE 1. The Three processes that drive ASCVD. This

Examining ASCVD from a process perspective,
plaques have been found to contain lipoprotein
remnants, assumed to originate from LDL. However,
there remains the likelihood that the majority of
these remnants actually originated from lipoprotein
(a) (Lp(a)). This points to a different causal model, as
Lp(a) plays a role in thrombus formation and lysis,
not lipid transport.
The different causal model was first postulated
in 1852 by Karl von Rokitansky, which he called the
encrustation hypothesis. It is possibly better known
as the ‘thrombogenic hypothesis’ [6]. He proposed that
ASCVD develops as a result of a dysfunction in a
normal three-step process.
Step one damage to the endothelium/glycoca-
lyx. This damage leads to step two, the formation of
a thrombus to cover the damaged area. The throm-
bus is, in turn, covered by a new layer of endothe-
lium which effectively draws the thrombus into the
artery wall.
Step three is that the remnant thrombus is
broken down or lysed by various repair mecha-
nisms, such as macrophage action, which can
break down and remove the remnants of damaged
material.
However, if damage is accelerated, plaques are
bigger and/or more difficult to break down, or repair
is hampered, plaques can develop and grow.
Therefore, the thrombogenic hypothesis pro-
poses that factors that can increase the risk of ASCVD
are those that do one of three essential things:
(1) Increase the rate of endothelial/glycocalyx dam-
age beyond that which the repair mechanism
can handle.
figure outlines that ASCVD is driven by three interlinked
processes. Endothelial/glycocalyx damage, accelerated
thrombus formation and impaired repair to the resultant
damage/thrombus. If all three processes are occurring
ASCVD will be greatly accelerated. ASCVD, atherosclerotic
cardiovascular disease.
(2) Drive the formation of larger and/or more diffi-
cult to lyse/remove thrombi.
(3) Interfere with the repair processes (see Fig. 1).
To put this another way, if the process of damage
occurs faster than repair, plaques will form, and
grow larger. If the repair systems are working at a
rate matching the damage, plaque growth will be
slowed, or prevented.
This is a concept supported by the paper ‘Why
atherothrombosis is in principle a hematologic disease’.
The authors present evidence that conditions, and
drugs, which affect thrombosis also affect the devel-
opment of atherosclerotic plaques. They propose
that plaques develop from the organisation of mural
thrombi that have not been fully cleared away by
the repair processes, thus creating a ‘vulnerable’ area
for further thrombi to develop [7].
RECENT EVIDENCE IN SUPPORT OF THE
THROMBOGENIC HYPOTHESIS
This review will look at the three interlinked proc-
esses involved in atherosclerotic plaque formation
(1) Glycocalyx and endothelial damage

428 www.co-endocrinology.com Volume 29
Number 5
October 2022


(2) Formation of larger/more difficult to lyse
thrombi
(3) Interference with repair processes
GLYCOCALYX AND ENDOTHELIAL
DAMAGE
All blood vessels are lined with endothelial cells
which are, in turn, covered by a ‘gel’ layer, the
glycocalyx, which is where nitric oxide (NO) is
synthesised, along with many other anticoagulant
factors (see Fig. 2).
The glycocalyx acts as the protective layer nec-
essary to maintain vascular endothelial cell func-
tion, and homeostasis. It is also important to protect
the underlying endothelial cells from direct physical
damage [8].
It has been increasingly recognised that in many
acute illnesses the glycocalyx is thinned and weak-
ened. This, in turn, increases the risk of acute car-
&&
diovascular events [9 ].
For example, destruction of the glycocalyx/endo-
thelium is critical in sepsis, where it is a major con-
tributor to the underlying pathophysiology. The
destruction of the glycocalyx is primarily due to exo-
toxins released by bacteria in the bloodstream. This, in
turn, is followed by widespread thrombus formation,
known as disseminated intravascular coagulation [10].
In Sars-Cov2 infection the glycocalyx/endothe-
lium is also attacked and weakened, and this is the
trigger for the blood clots that are commonly seen with
&&
coronavirus disease 2019 (COVID-19) infection [9 ].
FIGURE 2. The glycocalyx. This graphic shows the structure of the glycocalyx, which protrudes from endothelial cells in all
blood vessels and creates a protective and anticoagulant ‘gel’ layer. It is constructed from combined molecules of glucose and
various proteins.
1752-296X Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.
Assessing cardiovascular disease Kendrick
Unlike sepsis, where the glycocalyx broken
down by an external agent, with severe acute respi-
ratory syndrome coronavirus 2 (SARS-CoV2), the
damage occurs within endothelial cells. Endothelial
cells in the lungs, and the vasculature, have a high
concentration of Angiotensin Converting Enzyme 2
receptors, and SARS-CoV2 hijacks this receptor to
gain entry before multiplying and ‘bursting out’. So,
the cells are damaged from ‘within’, rather than in
sepsis, from ‘without’. The end result is similar.
It is now also known that there is also consid-
erable overlap between SARS-CoV2 infection and
Kawasaki’s disease. In both conditions there is a
form of widespread vasculitis, with the glycoca-
lyx/endothelium seriously compromised. With
SARS-CoV2 the presence of virions within cells pro-
vides an additional target for ‘attack’ by the immune
system, increasing the damage [11].
It seems that the process Kawasaki’s is very
similar, although an infectious agent has not been
identified. In Kawasaki’s, ASCVD can develop rap-
idly, and in the years following the acute episode the
risk of a CV event can be increased by >50-fold [12].
The acute problems, seen shortly after an initial
triggering event, highlight the role that the healthy
glycocalyx plays in preventing thrombus formation.
However, it is also hypothesised to be critical in
the longer-term progression and development of
&
ASCVD [13 ].
Looking at longer term conditions, one impor-
tant factor known to cause chronic damage to the
glycocalyx is a raised blood glucose level [14].
Interestingly, patients with type II diabetes are at
www.co-endocrinology.com 429
Obesity and nutrition
an increased risk of ASCVD, sepsis, and other infec-
tion diseases. Possibly due to a damaged glycocalyx
allowing infectious agents to enter cells more
easily [15].
Here, we have a possible ‘positive reinforcement
loop’, increasing both infection risk and thrombus
formation, which may also be why patients with
type II diabetes are more susceptible to severe SARS-
CoV2 infections.
Other chronic conditions known to damage the
glycocalyx and increase the risk of CVD include:
(1) Systemic lupus erythematosus (SLE) [16]
(2) Smoking [17]
(3) Hypertension [18]
(4) Antiphospholipid syndrome [19]
With antiphospholipid syndrome (APS), the
immune system attacks the endothelial cell
membrane itself, creating widespread vascular
damage. Many patients with SLE have APS, and it is
this subset of patients at greatest risk of ASCVD [20].
It is not within the scope of this article to
describe all conditions, or agents that can damage
the endothelium/glycocalyx. However, an increas-
ing body of evidence suggests that any factor, or
disease, with this effect, increases the risk of ASCVD
&&
[21 ].
FORMATION OF LARGER/MORE
DIFFICULT TO LYSE THROMBI
Once the endothelium has been damaged this trig-
gers thrombus formation. One of the key mecha-
nisms here is that an undamaged and healthy
endothelium expresses tissue factor pathway inhib-
itor (TFPI). TPFI limits the actions of tissue factor
(TF), which is perhaps the single most potent pro-
coagulant factor.
Thus, when TFPI production falls, TF is released
&
to drive thrombus formation [22 ]. In addition to
this mechanism, the glycocalyx is where NO, a
highly potent anticoagulant, is synthesised (indeed,
there are a host of anticoagulant actions which
require a healthy glycocalyx to function). This
means that, when damage occurs, the endothelium
shifts towards a prothrombotic state [23].
It would not be possible to review all the factors
involved in thrombus formation and breakdown, as
this is a highly complex process. So it may be most
useful to look at three important players: von Wil-
lebrand factor (vWF), fibrinogen, and Lp(a) to
review their impact on thrombi.
These three factors operate in very different
stages of coagulation. vWF has a key role in
430 www.co-endocrinology.com
formation of the initial platelet plug, fibrinogen is
the raw material of the final ‘fibrin’ clot, and Lp(a) is
critical in thrombus breakdown or lysis.
Von Willebrand factor
vWF is a glycoprotein required for the formation of
haemostatic ‘plugs’ and arterial thrombi. It binds to
platelets, factor VIII, and collagen in the underlying
artery wall.
A meta-analysis of patients admitted to hospital
with major adverse CV events found that they had
significantly higher vWF levels. The difference in CV
risk versus those with normal levels of vWF was very
nearly 50% [24].
Fibrinogen
Fibrinogen has a key role in the final act of thrombus
formation. After the platelet/erythrocyte plug has
formed, strands of fibrinogen link to form fibrin,
which wraps around the plug, binding it. This is the
final step in the clotting ‘cascade’.
A Scottish study of risk factors for coronary heart
disease showed that high levels of fibrinogen were
associated with a greatly increased CV risk, for both
men and women [25].
In a more recent meta-analysis, the increased
risk was independent of other CVD risk factors
including lipid levels, and antithrombotic and other
medications, such as aspirin. It is of interest that the
risk of ASCVD was much greater in patients with
type II diabetes, who have higher levels of other pro-
&
coagulant factors [26 ]’’.
Lipoprotein(a)
The issue of Lp(a) is complex, but important. Lp(a) is
identical to LDL, apart from the attachment of an
additional protein, known as apolipoprotein(a) (apo
(a)).
This apparently small difference is highly sig-
nificant, because apo(a) is virtually identical in
structure to plasminogen. The key difference is that
apo(a) has different folding structure (kringle) at one
end. It is this ‘folding’ difference that turns apo(a)
into, effectively, ‘antiplasminogen’.
Plasminogen is incorporated into all thrombi as
they form. It is inactive until it is converted to
plasmin by tissue plasminogen activator (TPa),
which is an enzyme synthesised by endothelial cells.
Once TPa has triggered this conversion plasmin
lyses strands of fibrin, essential for the breakdown
of thrombi.
However, if there is a higher concentration of Lp
(a)/apo(a) within thrombi, this blocks the action of
Volume 29
Number 5
October 2022

TPa on plasminogen, resulting in a thrombus that is
highly resilient [27].
Lp(a) also binds to TFPI. Thus, Lp(a) can stim-
ulate clot formation and make it more difficult to
remove the resultant thrombi. A raised Lp(a) is
&&
associated with a tripling of CVD risk [28 ].
Why does Lp(a) have this function? Linus Paul-
ing first hypothesised that, because humans cannot
synthesise vitamin C, which plays a key role in the
production of collagen, a lack of vitamin C will lead
to a breakdown and ‘cracks’ in blood vessel walls.
Lp(a), which is almost exclusively found in ani-
mals that cannot synthesise vitamin C, binds very
strongly to the endothelium. and the underlying arte-
rial wall, creating thrombi that are particularly ‘tough’.
This reduces blood loss, allowing the animal to survive
until sufficient vitamin C can be consumed [29].
However, this protective role is a double-edged
sword. As Lp(a) can also drive the formation of
thrombi which are more difficult to lyse. This, in
turn, results in accelerated plaque formation.
Whist this review has only looked in more detail
at three of the pro-coagulant factors/conditions, all
of which can significantly increase CV risk, there are
many others including type II diabetes, Cushing
disease, APS and raised factor VIII [30].
Haemophilia
To briefly examine this area from a different per-
spective, it is worth looking at people with haemo-
philia. A recent study found that the relative risk of
CV events in haemophilia was around one third of
predicted risk. The authors concluded that ‘haemo-
philia protects against CVD’ [31].
INTERFERENCE WITH REPAIR PROCESSES
Endothelial damage, clot formation and repair, rep-
resents a continual process. This is highlighted in
people who smoke – who have a significantly higher
risk of CVD. Smoking leads directly to glycocalyx
damage, reduced NO production and bioavailability
which, in turn, creates a pro-coagulant and inflam-
&
matory environment [32 ].
This damage can, in turn, be measured by an
increase in microparticles – the breakdown products
of endothelial cells. However, smoking also stimu-
lates the production and release of endothelial pro-
genitor cells (EPCs), which cover over areas of
endothelial damage, driving the healing process [33].
Therefore, with smoking, increased damage and
repair occurs simultaneously. This means that dam-
age to the endothelium/glycocalyx does not neces-
sarily lead to (accelerated) atherosclerotic plaque
formation.
1752-296X Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.
Assessing cardiovascular disease Kendrick
However, if the repair systems are impaired,
or the damage is simply too extensive, plaque for-
mation/growth will occur. This is probably why, as
people become older, and the repair systems become
less robust, a risk factor such as smoking becomes
more significant [34].
The conjecture that reduced repair is as impor-
tant as damage is supported by the fact that low EPC
levels are an initial sign of endothelial dysfunction
&
and represent one of the early signs of ASCVD [35 ].
Of course, EPCs do not represent the only repair
system(s). But it is clear that protection against
ASCVD requires a positive balance between repair
and damage. This can perhaps be most clearly seen
when we look at agents, which have been designed
to block endothelial cell growth and repair, simul-
taneously reducing NO synthesis.
These are vascular endothelial growth factor
(VEGF)-inhibitors. VEGF is a hormone which drives
endothelial cell proliferation, survival, and migra-
tion [36]. It also stimulates the production of EPCs
in the bone marrow.
VEGF-inhibitors are used in cancer treatments to
prevent endothelial growth and thus angiogenesis,
as new blood vessels to deliver the blood supply
required for growth in many tumours.
It is no surprise, therefore, that the adverse effects
of VEGF-inhibitors centre around vascular damage,
including haemorrhage, retinal detachment, venous
thrombosis, strokes, MI and heart failure [37].
At one time, the increased cardiovascular risks
associated with bevacizumab, the first widely used
VEGF-inhibitor, nearly led to its withdrawal from
the market. This highlights the critical importance
of repair in the triad of endothelial damage, clot
formation, impaired repair.
SUMMARY
For the last seventy years the LDL-cholesterol
hypothesis has been the most widely accepted
causal model for the development of ASCVD. How-
ever, it cannot explain how many different factors
such as smoking, SLE, or chronic kidney disease can
lead to ASCVD.
In addition, a raised LDL level is a relatively weak
predictor of risk. Indeed, LDL is not used to calculate
CV risk using Qrisk3, or the ACC/AHA risk calculator.
An alternative model is one that was first pro-
posed over one hundred and fifty years ago by Karl
von Rokitansky, which is that atherosclerotic pla-
ques represent the build-up/metamorphosis of
thrombi that have been deposited onto, then incor-
porated into the arterial wall.
Other researchers, for example, Elspeth Smith,
promoted the thrombogenic hypothesis widely.
www.co-endocrinology.com 431
Obesity and nutrition
Forty years ago, she wrote: ‘After many years of
neglect, the role of thrombosis in myocardial infarc-
tion is being reassessed. It is increasingly clear that
all aspects of the haemostatic system are involved.
Not only in the acute occlusive event, but also in all
stages of atherosclerotic plaque development, from
the initiation of atherogenesis to the expansion and
growth of large plaques’ [38].
It should be recognised that this was written
before NO and EPCs had been identified, and also
before the protective function of the glycocalyx and
the structure of apo(a) had been established.
CONCLUSION
We now have a greater understanding of the endo-
thelial/glycocalyx function and how endothelial
damage links to thrombus formation and lysis,
and these new findings strongly suggest that Roki-
tansky, Duguid, Ross and Elspeth Smith, and others,
may well have been correct.
Thus, whilst this article is entitled ‘‘Assessing
cardiovascular disease: looking beyond choles-
terol’’, it may have been more accurate to call it,
‘Assessing cardiovascular disease, looking before cho-
lesterol’, because the thrombogenic hypothesis pre-
cedes the cholesterol hypothesis by many years. It is
fascinating that recent research now provides an
increasing evidence base.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
The author has written three books critical of the LDL-
cholesterol hypothesis. The Great Cholesterol Con, A
Statin Nation and The Clot Thickens.
REFERENCES AND RECOMMENDED
READING
Papers of particular interest, published within the annual period of review, have
been highlighted as:
& of special interest
&& of outstanding interest
1. Hee Kim S, Young Son K. Association between lipoprotein cholesterol and
& future cardiovascular disease and mortality in older adults: a Korean nation-
wide longitudinal study. Lipids Health Dis 2021; 20:3.
This paper is important as it found that LDL-C is unrelated to CV mortality in those
aged >65, where the greatest number of CV deaths occur. There was also a
significant negative association with ‘ischaemic brain disease.’ It also included
more than 60,000 individuals, far larger than many other studies looking at LDL-C
– rather than total cholesterol.
2. https://tools.acc.org/ldl/ascvd_risk_estimator/index.html#!/calulate/estima-
tor/.
3. https://qrisk.org/three/.
432 www.co-endocrinology.com
4. Byrne P, Demasi M, Jones M. Evaluating the association between low-density
&& lipoprotein cholesterol reduction and relative and absolute effects of statin
treatment: a systematic review and meta-analysis. JAMA Intern Med 2022;
182:474–481.
This paper is of considerable interest, as it highlights the modest impact of statins
on absolute risk. Many papers have used relative risk reduction (RRR), which can
make the benefits appear greater than they may in be, in reality. In addition is makes
the point an benefits of stating may no be due to the degree of LDL-C lowering, and
thus potentially contradicts the hypothesis that LDL-C is causally related to CV risk.
Also, published in the high impact journal JAMA.
5. Michael Lincoff J, Nicholls S, Riesmeyer J. Evacetrapib and cardiovascular
outcomes in high-risk vascular disease. N Engl J Med 2017; 376:1933–
1942.
6. Minelli S, Minelli P, Montinari MR. Reflections on atherosclerosis: lesson from
the past and future research directions. J Multidiscip Healthc 2020;
13:621–633.
7. Sloop G, Gheorghe Pop G, Weidman J. Why atherothrombosis is in principle
a hematologic disease: the effect of disorders and drugs which affect
thrombosis on the development of atherosclerotic plaques. Int Arch Cardi-
ovasc Dis 2018. doi:10.23937/iacvd-2017/1710012.
8. Yamaoka-Tojo M. Vascular endothelial glycocalyx as a mechanism of vascular
endothelial dysfunction and atherosclerosis. World J Cardiovasc Dis 2020;
10:731–749.
9. Vollenberg R, Tepasse PR, Ochs K. Indications of persistent glycocalyx
&& damage in convalescent COVID-19 patients: a prospective multicenter study
and hypothesis. Viruses 2021; 13:2324.
This paper demonstrates that the way that COVID-19 can cause increased blood
clotting/cardiovascular risk is, in large part, driven by damage to the glycocalyx.
This also links to Kawasaki’s disease, and provides an insight into how damage to
the protective glycocalyx ‘gel’ can link many conditions together, known to increase
the risk of CV Disease. Including a number of infectious diseases, such as
periodontitis, flu COVD-19 and many more. Which are not explained by the
LDL-C hypothesis.
10. Sullivan RC, Matthew D. Endothelial glycocalyx degradation during sepsis:
causes and consequences. Matrix Biol Plus, 2021;12:100094.
11. Yamaoka-Tojo M. Endothelial glycocalyx damage as a systemic inflamma-
tory microvascular endotheliopathy in COVID-19. Biomed J 2020;
43:399–413.
12. Walsh N. CV risks persist long after Kawasaki disease — a quarter of kids
experienced a CV event 20 years after the diagnosis. MedPage Today.
November 8, 2020. Available at: https://www.medpagetoday.com/meeting-
coverage/acr/89549.
13. Kurihara O, Takano M, Miyauchi Y. Vulnerable atherosclerotic plaque features:
& findings from coronary imaging. J Geriatr Cardiol 2021; 18:577–584.
The importance of this paper is that it links earlier stage plaque erosion/endothelial
dysfunction to the creation of fibrin rich plaque thrombosis, related to an imbalance
of thrombotic and fibrinolytic factors, that can both initiate and propagate throm-
bosis. This, for example, links smoking to haemostatic factors such as haemo-
concentration – more commonly found in the summer. It therefore links early stage
endothelial damage, plaque erosion, and the formation of thrombi into an on-going
process.
14. Sampei S, Hideshi Okada H, Tomita H. Endothelial glycocalyx disorders may
be associated with extended a diabetic mouse model. Front Cell Dev Biol.
2021; 9: doi: 10.3389/fcell.2021.623582.
15. Abe T, Ogura H, Shiraishi A. Characteristics, management, and in-hospital
mortality among patients with severe sepsis in intensive care units in Japan:
the FORECAST study. Crit Care 2018; 22:322.
16. Ki-Jo K, Ji-Young K, In-Woon B. Elevated serum levels of syndecan-1 are
associated with renal involvement in patients with systemic lupus erythema-
tosus. J Rheumatol 2015; 42:202–209.
17. Kahn K. Heart health: atherosclerosis and aging — insights into the role of the
endothelial glycocalyx in cardiovascular health. Today’s Geriatric Med. 12;8.
Available at: https://www.todaysgeriatricmedicine.com/archive/JA19p8.
shtml.
18. Triantafyllidi. Benas. Dimitrios. HDL cholesterol levels and endothelial glyco-
calyx integrity in treated hypertensive patients over 40 years old. J Hypertens
2021; 39:e226.
19. Miranda S, Billoir P, Le Besnerais M. New insights into antiphospholipid-
related endothelial dysfunction by assessment of vascular glycocalyx
layer: results from a preliminary cross-sectional study. Lupus 2020; 29
(2):157–164.
20. Ajeganova S, Hafström I, Frostegård J. Patients with SLE have higher risk of
cardiovascular events and mortality in comparison with controls with the same
levels of traditional risk factors and intima-media measures, which is related to
accumulated disease damage and antiphospholipid syndrome: a case–con-
trol study over 10 years. Lupus Sci Med 2021; 8:e000454.
21. Qu J, Cheng Y, Wenchao Wu W. Glycocalyx impairment in vascular disease:
&& focus on inflammation. Front Cell Dev Biol 2021; 9:730621.
This paper makes very clear the role of glycocalyx disruption/damage in ASCVD. It
makes clear that damage to the glycocalyx initiates the process of endothelial
dysfunction, inflammation, attachment of leucocytes to the arterial wall and
thrombosis. In addition, it explains how diabetes and sepsis are both related to
glycocalyx damage, and both lead to increased risk of ASCVD.
Volume 29
Number 5
October 2022

22. Neubauer K, Zieger B. Endothelial cells and coagulation. Cell Tissue Res
& 2022; 387:391–398.
This paper presents a very clear explanation of the role of the endothelium/
glycocalyx in modulating coagulation, and how damage can lead to a cascade
of pro-coagulant activity. From platelet activation/aggregation and the role of von
Willebrand Factor in co-ordinating the response of endothelial injury. As the
authors state: ‘Vascular ECs (endothelial cells) form a dynamic lining at the
interface between tissue and blood. They maintain blood fluidity and protect
against injury of the vessel wall through delicate regulation of platelet activity,
blood coagulation, and thrombolysis.’ It provides a very good overview of the
processes.
23. Potje S, Tiano Dal-Cin P, Paulo M. The role of glycocalyx and caveolae in
vascular homeostasis and diseases. Front Physiol 2021; 11:620840.
24. Fan M, Wang X, Peng. Prognostic value of plasma von Willebrand factor
levels in major adverse cardiovascular events: a systematic review and meta-
analysis. BMC Cardiovasc Disord 2020; 20:72.
25. Tunstall-Pedoe H, Woodward M, Tavendale R. Comparison of the prediction
by 27 different factors of coronary heart disease and death in men and women
of the Scottish heart health study: cohort study. BMJ 1997; 315:722–729.
26. Surma S, Banach M. Fibrinogen and atherosclerotic cardiovascular diseases—
& review of the literature and clinical studies. Int J Mol Sci 2022; 23:193.
This is an important meta-analysis of fibrinogen/coagulation factors. ‘The results of
numerous studies indicate that plasma fibrinogen concentration, especially in con-
junction with the assessment of the concentration of D’dimer or albumin, is a valuable
biomarker of the primary and secondary risk of CVD.’ It also links endothelial damage
to the hypercoagulation, and excess thrombosis seen in COVID-19. Furthermore,
it suggests that, because statins can reduce fibrinogen concentration, this may be
why they have shown some benefit in the treatment of COVID-19
27. Riches K, Porter K. Lipoprotein(a): cellular effects and molecular mechanisms.
Hindawi Rev 2012;Article ID 923289.
28. Finneran P, Pampana A, Khetarpal A. Lipoprotein(a) and coronary artery
&& disease risk without a family history of heart disease. J Am Heart Assoc
2021; 10:e017470.
Prior to the launch of statins, a great deal of research was being done on
lipoprotein (a) and its association with ASCVD. There was then a prolonged
hiatus, when very little research was done. This recent paper highlights, once
again, the importance of Lipoprotein (a) (Lp(a)) as a risk factor. It also opens up the
question as to whether it is LDL-C that the lipoprotein that is causal in ASCVD, or
lipoprotein (a). Both are normally included in the overall measurement of LDL-C, in
the LDL-C and Lp(a) are exactly the same molecule, other than the addition of the
apolipoprotein (a) to Lp(a) and it is possible that the primary focus of the research
community has been on the wrong version of LDL-C i.e. the molecule that does not
have the apo (a) protein attached.
29. Shil, RM, Niedzwiecki. Dietary vitamin C and age-induced lipid and hormonal
metabolic changes in a humanized mouse model not synthesizing vitamin c
and producing lipoprotein(a) [Gulo (/); Lp(a)þ]. J Nutr Metab 2021;Article
ID 5591697.
1752-296X Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.
Assessing cardiovascular disease Kendrick
30. Khandelwal D, Mathur V, Vyas A. Elevated factor VIII levels and arterial stroke:
a review of literature with a case report. Egypt J Neurol Psychiatr Neurosurg
2021; 57:20.
31. Van Der Valk P, Makris M, Fischer K. Reduced cardiovascular morbidity in
patients with hemophilia: results of a 5-year multinational prospective study.
Blood Adv 2022; 6:902–908.
32. Hahad O, Arnold N, Jurgen H. Cigarette smoking is related to endothelial
& dysfunction of resistance, but not conduit arteries in the general population—
results from the gutenberg health study. Front Cardiovasc Med 2021;
8:674622.
As this paper states ‘Cigarette smoking is one of the most complex and least
understood cardiovascular risk factors.’ This is the first paper to study smoking
exposure and cessation and assess makers of endothelial function. The key points
in the discussion were that ‘In the setting of smoking–induced endothelial
dysfunction factors conferring smoking–dependent endothelial damage and
therefore acceleration of vascular aging A possible mechanism by which exposure
to cigarette smoke and its constituents mainly toxic species such as free radicals
and reactive aldehydes induces endothelial dysfunction is the reduced NO
bioavailability and further the increased expression of adhesion molecules. Smok-
ing–induced abnormalities in NO production result in increased adherence of
platelets and macrophages to the vessel wall which provokes the progression of a
procoagulant and inflammatory environment.’ In short smoking causes endothelial
damage and a pro–coagulant environment.
33. Mobarrez F, Antoniewicz L, Bosson J. The effects of smoking on levels of
endothelial progenitor cells and microparticles in the blood of healthy volun-
teers. PLoS One 2014; 9:e90314.
34. Rethineswaran VK, Kim DY, Kim YJ. Augmented the function of late endothe-
lial progenitor cells by preventing replicative senescence. Int J Mol Sci 2021;
22:4796.
35. Morrone D, Picoi M, Felice F. Endothelial progenitor cells: an appraisal of
& relevant data from bench to bedside. Int J Mol Sci 2021; 22:12874.
This paper provides an important overview of the key role that endothelial
progenitor cells (EPCs) have in repairing the endothelium and protecting against
future ASCVD. It suggests that the senescence of these cells in ageing may have
an important causal role in increasing the risk of ASCVD in the elderly, and the
slowing the decline in EPCs may have an important therapeutic role. ‘Taken
together, these findings are the proof of concept that EPC senescence may be
counteracted by appropriate treatments aimed at slowing down the decline in EPC
function during aging and that treatments stimulating EPCs in elderly people may
have clinical implications for the aging population.’
36. Wang A, Bove A, Simon G. Molecular bases of VEGFR-2-mediated physio-
logical function and pathological role. Front Cell Dev Biol 2020; 8:.
37. Tsiros D, Sheehy CE, Nugent MA. Heparin–Avastin complexes show en-
hanced VEGF binding and inhibition of VEGF-mediated cell migration. Int J
Transl Med 2021; 10:101–115.
38. Smith E, Douglas Thompson W. Fbrin as a factor in atherogenesis. Thromb
Res 1994; 73:1–19.
www.co-endocrinology.com 433